(12) United States Patent (10) Patent No.: US 9.220,715 B2 Demopulos Et Al

US009220715B2

(12) United States Patent (10) Patent No.: US 9.220,715 B2 Demopulos et al. (45) Date of Patent: *Dec. 29, 2015

(54) TREATMENT OF ADDICTION AND A613 L/454 (2006.01) IMPULSE-CONTROL DISORDERS USING A613 L/485 (2006.01) PDE7 INHIBITORS (Continued) (71) Applicant: Omeros Corporation, Seattle, WA (US) (52) U.S. Cl. CPC ...... A6 IK3I/5513 (2013.01); A61 K3I/I35 (72) Inventors: Gregory A. Demopulos, Mercer Island, (2013.01); A61 K3I/I37 (2013.01); A61 K WA (US); George A. Gaitanaris, 31/197 (2013.01); A6IK3I/337 (2013.01); Seattle, WA (US); Roberto A61K 31/35 (2013.01); A61 K3I/357 Ciccocioppo, Camerino (IT) (2013.01); A61 K3I/381 (2013.01); A61 K 3 1/385 (2013.01); A61 K31/4015 (2013.01): (73) Assignee: Omeros Corporation, Seattle, WA (US) A61K 31/4025 (2013.01); A61 K31/4162 (*) Notice: Subject to any disclaimer, the term of this (2013.01); A61 K3I/4178 (2013.01); A61 K patent is extended or adjusted under 35 31/433 (2013.01); A61K 31/435 (2013.01); U.S.C. 154(b) by 0 days. A6 IK3I/44 (2013.01); A61 K3I/4439 (2013.01); A61 K3I/454 (2013.01); A61 K This patent is Subject to a terminal dis- 3 1/46 (2013.01); A61K3I/485 (2013.01); claimer. A6 IK3I/496 (2013.01); A61 K3I/4985 (2013.01); A61 K3I/505 (2013.01); A61 K (21) Appl. No.: 13/835,607 31/517 (2013.01); A6IK3I/519 (2013.01); (22) Filed: Mar 15, 2013 A61 K3I/527 (2013.01); A61K3I/53 (2013.01); A61 K3I/5377 (2013.01); A61 K (65) Prior Publication Data 3 I/55 (2013.01); A61K 45/06 (2013.01) US 2013/02675O2A1 Oct. 10, 2013 (58) Field of Classification Search Cl. TU, CPC ...... A61K31/5513; A61K 31/5377; A61 K 3 1/53: A61K 31/4985; A61K 31/496; A61 K Related U.S. Application Data 31/519; A61 K31/527; A61 K31/46; A61 K 31/435; A61 K31/4439; A61K 31/433; (63) Continuation-in-part of application No. 13/290,868, A61K 31/41.78: A61K 31/4162: A61 K filed on Nov. 7, 2011. 31/4025; A61K 31/35; A61K 45/06 (60) Provisional application No. 61/643,611, filed on May See application file for complete search history. 7, 2012, provisional application No. 61/482,994, filed on May 5, 2011, provisional application No. (56) References Cited 61/411,437, filed on Nov. 8, 2010, provisional U.S. PATENT DOCUMENTS application No. 61/411,431, filed on Nov. 8, 2010. 5,610,288 A 3, 1997 Rubenstein (51) Int. Cl. 5,718,709 A 2f1998 Considine et al. A 6LX3/553 (2006.01) (Continued) A 6LX3/5377 (2006.01) A6 IK3I/53 (2006.01) FOREIGN PATENT DOCUMENTS A6 IK3I/4985 (2006.01) A6 IK3I/496 (2006.01) BR O607402-2 A2 9, 2009 A 6LX3/59 (2006.01) DE 199 SO 647 A1 10, 1999 A 6LX3/527 (2006.01) (Continued) A6 IK3 L/46 (2006.01) A6 IK3I/435 (2006.01) OTHER PUBLICATIONS A6 IK3I/4439 (2006.01) Siuciak, J., et al., “Inhibition of the Striatum-Enriched A6 IK3I/433 (2006.01) Phosphodiesterase PDE10A: A Novel Approach to the Treatment of A6 IK3I/478 (2006.01) Psychosis.” Neuropharmacology 51:386-396 (2006). A6 IK3I/4I62 (2006.01) (Continued) A6 IK3I/4025 (2006.01) A6 IK3I/35 (2006.01) A6 IK 45/06 (2006.01) Primary Examiner — Renee Claytor A6 IK3I/35 (2006.01) (74) Attorney, Agent, or Firm — Marcia S. Kelbon A6 IK3I/37 (2006.01) A 6LX3/97 (2006.01) (57) ABSTRACT A6 IK3I/337 (2006.01) This disclosure is directed to treatment of addictions and A 6LX3L/357 (2006.01) primary impulse-control disorders using phosphodiesterase 7 A6 IK3I/38 (2006.01) (PDE7) inhibitors, alone or in combination with other thera A6 IK3I/385 (2006.01) peutic agents. A6 IK3I/405 (2006.01) A6 IK3I/44 (2006.01) 34 Claims, 47 Drawing Sheets US 9.220,715 B2 Page 2

(51) Int. Cl. EP 1348 701 A1 3f2002 A 6LX3L/505 (2006.01) E. 13. A 3.583 A 6LX3/57 (2006.01) EP 1775 298 A1 7/2005 A6 IK3I/55 (2006.01) ES 2308916 12/1987 RU 2351 371 4/2009 (56) References Cited WO WO 94.21244 9, 1994 WO WO 88,04399 6, 1998 U.S. PATENT DOCUMENTS WO WOOOf 682O3 11, 2000 WO WOOOf 68230 11, 2000 5,739,119 A 4, 1998 Galli et al. WO WOO1,29049 A2 4, 2001 5,759,829 A 6, 1998 Shewmaker et al. WO WOO1/32175 A1 5, 2001 5,789,573 A 8, 1998 Baker et al. WO WOO1/32618 A1 5. 2001 5,801,154 A 9, 1998 Baracchini et al. WO WOO1,34601 A2 5, 2001 6,146,876. A 1 1/2000 Robision et al. WO WOO1,364.25 A2 5, 2001 6,531.498 B1 3/2003 Eggenweiler et al. WO WOO1,62904 A1 8/2001 6,613,778 B1 9/2003 Eggenweiler et al. WO WOO 1/74.786 A1 10, 2001 6,617.357 B2 9/2003 Aubart et al. WO WOO1,982.74 A2 12/2001 6,649,592 B1 1 1/2003 Larson WO WOO2,28847 A1 4, 2002 6,737,436 B1 5/2004 Eggenweiler et al. WO WOO2,40449 A1 5. 2002 6,753,340 B2 6/2004 Vergne et al. WO WO O2/4O450 A1 5, 2002 6,818,651 B2 11/2004 Weinbrenner et al. WO WO O2/O74754 A1 9, 2002 6,838,559 B2 1/2005 Vaccaro et al. WO WO O2/O76953 A1 10, 2002 6,849,638 B2 2/2005 Stolle et al. WO WO O2/O85894 A1 10, 2002 6,852,720 B2 2/2005 Vergne et al. WO WO O2/085906 A2 10, 2002 6,884,800 B1 4/2005 Eggenweiler et al. WO WO O2/O87513 A2 11/2002 6,903,109 B2 6/2005 Heintzelman et al. WO WO O2/O87519 A2 11/2002 6,936,609 B2 8/2005 Ergilden et al. WO WO O2/O88079 A2 11/2002 6,958,328 B2 10/2005 Heintzelman et al. WO WO 02/088080 A2 11/2002 7,022,849 B2 4/2006 Pitts et al. WO WO 02/088138 A1 11, 2002 7,087.614 B2 8, 2006 Guo et al. WO WO 02/102313 A2 12/2002 7,122,565 B2 10/2006 Vergne et al. WO WO 02/102314 A2 12/2002 7,214,676 B2 5/2007 Bernardelli et al. WO WO O2/102315 A2 12/2002 7,268,128 B2 9/2007 Inoue et al. WO WO O2/O53975 A1 3f2003 7.491,742 B2 2/2009 Eggenweiler et al. WO WOO3,053975 A1 T 2003 7,498.334 B2 3/2009 Eggenweiler et al. WO WOO3,055882 A1 T 2003 7,579,455 B2 8/2009 Paolo et al. WO WOO3,057149 A2 7, 2003 7932,250 B2 4/2011 Inoue et al. WO WO 03/064389 A1 8, 2003 2002/0156064 A1 10, 2002 Aubart et al. WO WOO3,082.277 A1 10, 2003 2002fO198198 A1 12/2002 Bernardelli et al. WO WOO3,082839 A1 10, 2003 2003/0045557 A1 3/2003 Vergne et al. WO WO 03/088963 A1 10, 2003 2003/0092721 A1 5, 2003 Pitts et al. WO WO 2004/026818 A1 4, 2004 2003/00929.08 A1 5, 2003 Pitts et al. WO WO 2004/044196 A1 5, 2004 2003/010.0571 A1 5/2003 Vaccaro et al. WO WO 2004/065391 A1 8/2004 2003. O104974 A1 6, 2003 Pitts et al. WO WO 2004/111053 A1 12/2004 2003/01 19829 A1 6, 2003 Stolle et al. WO WO 2004/111054 A1 12/2004 2003/01628O2 A1 8/2003 Guo et al. WO WO 2006/004.04.0 A1 1/2006 2003/019 1167 A1 10/2003 Vergne et al. WO WO 2006/092691 A1 9, 2006 2003/0212089 A1 11/2003 Heintzelman et al. WO WO 2006/092692 A1 9, 2006 2004/0044212 A1 3f2004 Weinbrenner et al. WO WO 2007/038551 A2 4, 2007 2004/0082578 A1 4/2004 Heintzelman et al. WO WO 2007/047978 A2 4, 2007 2004/0106631 A1 6/2004 Bernardelli et al. WO WO 2007/063391 6, 2007 2004/O127707 A1 7, 2004 Sterk WO WO 2008, 113881 A1 9, 2008 2004/0249148 Al 12/2004 Ergüden et al. WO WO 2008, 130619 A2 10, 2008 2005/005968.6 A1 3/2005 Eggenweiler et al. WO WO 2008. 142550 A2 11/2008 2005/0148604 A1 7/2005 Inoue et al. WO WO 2009/140309 A2 11/2009 2005/0222138 A1 10, 2005 Ohhata et al. WO WO 2010/027975 A1 3f2010 2006/0116516 A1 6, 2006 Pitts et al. WO WO 2010/030851 A1 3f2010 2006/0128.707 A1 6/2006 Inoue et al. WO WO 2010.109148 A1 9, 2010 2006/O128728 A1 6/2006 Inoue et al. WO WO 2010/116088 A2 10, 2010 2006/0154949 A1 7/2006 Heintzelman et al. 2006/0229306 A1 10, 2006 Terricabras Belart et al. OTHER PUBLICATIONS 2007.0049558 A1 3, 2007 Bernardelli et al. 2007/OO72899 A1 3/2007 Johnson et al. Miro, X., et al., “Differential Distribution of cAMP-Specific 2007/0129388 A1 6, 2007 Rawson et al. Phosphodiesterase 7A mRNA in Rat Brain and Peripheral Organs.” 2007/0208029 A1 9, 2007 Barlow et al. Synapse, 40:201-214 (2001). 3:29:29: A. 2587 S. et al. 1 Reyes-Irrisari, E., et al., “Neuronal Expression of cAMP-Specific 2008/0260643 A1 10, 2008 iA cal Phosphodiesterase 7B mRNA in the Rat Brain.” Neuroscience 2008/0282364 A1 11/2008 Black et al. 132:1173-1175 (2005). 2009/011 1837 A1 4/2009 Cox et al. Vergne, Fabrice, et al., “Discovery of Thiadiazoles as a Novel Struc 2009,029 1917 A1 11/2009 Akama et al. tural Class of Potent and Selective PDE7 Inhibitors. Part 1: Design, 2010, O152213 A1 6/2010 Ayuso-Gontan et al. Synthesis and Structure-Activity Relationship Studies.” Bioorganic & Medicinal Chemistry Letters 14:4607-4613 (2004). FOREIGN PATENT DOCUMENTS Vergne, Fabrice, et al., “Discovery of Thiadiazoles as a Novel Struc tural Class of potent and Selective PDE7 Inhibitors. Part 2: Metabo EP O 321 201 A2 12, 1988 lism-Directed Optimization Studies Towards Orally Bioavailable EP 1 193261 A1 10, 2000 Derivatives.” Bioorganic & Medicinal Chemistry Letters 14:4615 EP 1348 433 A1 3, 2002 4621 (2004). US 9.220,715 B2 Page 3

(56) References Cited Delva, Jorge, et al., “The Epidemiology of Alcohol, Marijuana, and Cocaine Use Among Mexican American, Puerto Rican, Cuban OTHER PUBLICATIONS American and Other Latin American Eighth-Grade Students in the United States: 1991-2002.” American Journal of Public Health Lorthois, Edwige, et al., “Spiroquinazolinones as Novel, Potent and 95(4):696-702 (2005). Selective PDE7 Inhibitors. Part 1.” Bioorganic & Medicinal Chem Liu, Xiu, et al., “Additive Effect of Stress and Drug Cues on Rein istry Letters 14:4623-4626 (2004). statement of Ethanol Seeking Exacerbation by History of Depen Smith, Susan J., et al., “Discovery of BRL 50481 (3-(N.N- dence and Role of Concurrent Activation of Corticotropin-Releasing dimethylsulfonamido)-4-methyl-nitrobenzene), a Selective Inhibitor Factor and Opioid Mechanisms.” The Journal of Neuroscience of Phosphodiesterase 7: In Vitro Studies in Human Monocytes, Lung 22(18):7856-7861 (2002). Macrophages, and CD8"T-Lymphocytes.” Molecular Pharmacology Ramsey, Nick, et al., “Emotional but not Physical Stress Enhances 66(6): 1679-1689 (2004). Intravenous Cocaine Self-Administration in Drug-Naive Rats.” Sasaki, Takashi, et al., “Novel Alternative Splice Variants of Rat Brain Research 608:216-222 (1993). Phosphodiesterase 7B Showing Unique Tissue-Specific Expression Shaham, Yavin, et al., “Stress Reinstates Heroin-Seeking in Drug and Phosphorylation.” Biochemistry 381:211-220 (2002). Free Animals: an Effect Mimicking Heroin, not Withdrawal.” Kadoshima-Yamaoka, Kumiko, et al., “ASB16165, a Novel Inhibitor Psychopharmacology 119:334-341 (1995). for Phosphodiesterase 7A (PDE7A), Suppresses IL-12-Induced Merlo Pich, Emilio, et al., “Increase of Extracellular Corticotropin IFN-Y Production by Mouse Activated T Lymphocytes.” Immunology Releasing Factor-Like Immunoreactivity Levels in the Amygdala of Letters 122: 193-197 (2009). Awake Rats During Restraint Stress and Ethanol Withdrawal as Mea Kang, N.S., et al., “Docking and 3-D QSAR Studies of Dual PDE4 sured by Microdialysis.” The Journal of Neuroscience 15(8):5439 PDE7 Inhibitors.” Molecular Simulation 33(14): 1109-1117 (2007). 5447 (1995). Pitts, William, et al., “Identification of Purine Inhibitors of Childress, A., et al., “Conditioned Craving and Arousal in Cocaine Phosphodiesterase 7 (PDE7).” Bioorganic & Medicinal Chemistry Addiction: a Preliminary Report.” NIDA Research Monograph Letters 14:2955-2958 (2004). 81:74-80 (1988). Kempson, James, et al., “Fused Pyrimidine Based Inhibitors of Weiss, Friedbert, “Control of Cocaine-Seeking Behavior by Drug Phosphodiesterase 7 (PDE7): Synthesis and Initial Structure-Activ Associated Stimuli in Rats: Effects on Recovery of Extinguished ity Relationships.” Bioorganic & Medicinal Chemistry Letters Operant-Responding and Extracellular Dopamine Levels in 15:1829-1833 (2005). Amygdala and Nucleus Accumbens.” PNAS 97(8):4321-4326 Yamamoto, Satoshi, et al., “Pharmacological Profile of a Novel (2000). Phosphodiesterase 7A and -4 Dual Inhibitor, YM-393059, on Acute Katner, Simon, et al., “Reinstatement of Alcohol-Seeking Behavior and Chronic Inflammation Models.” European Journal of Pharma by Drug-Associated Discriminative Stimuli after Prolonged Extinc cology 550:166-172 (2006). tion in the Rat.” Neuropsychopharmacology 20:471-479 (1999). Castro, Ana, et al., “CODES, a Novel Procedure for Ligand-Based Lee, Buyean, et al., “Pharmacological Blockade of O2-Adrenocep Virtual Screening: PDE7 Inhibitors as an Application Example.” tors Induces Reinstatement of Cocaine-Seeking Behavior in Squirrel European Journal of Medicinal Chemistry. 43:1349-1359 (2008). Monkeys.” Neuropsychopharmacology 29:686-693 (2004). Bloom, Timothy, et al., “Identification and Tissue-Specific Expres Lee A.D., et al., “The Role of Corticotropin-Releasing Factor in sion of PDE7 Phosphodiesterase Splice Variants.” Pharmacology Stress-Induced Relapse to Alcohol-Seeking Behavior in Rats.” 93: 14 188-14192 (1996). Psychopharmacology 150:317-324 (2000). Banks, William, et al., “Delivery Across the Blood-Brain Barrier of Shea, Kenneth J., “Molecular Imprinting of Synthetic Network Poly Antisense Directed Against Amyloid f: Reversal of Learning and mers: The DeNovo Synthesis of Macromolecular Binding and Cata Memory Deficits in Mice Overexpressing Amyloid Precursor Pro lytic Sites.” TRIP2(5):166 (1994). tein.” The Journal of Pharmacology and Experimental Therapeutics Pachori. Alok, et al., “Blood Pressure-Dependent Attenuation of 297(3): 1113-1121 (2001). Cardiac Hypertrophy by AT1R-AS Gene Therapy.” Hypertension Barnes, Matthew J., et al., “Synthesis and Structure—Activity Rela 39:969-975 (2002). tionships of Guanine Analogues as Phosphodiesterase 7 (PDE7) Scherr, Michael, et al., “Rapid Determination and Quantitation of the Inhibitors.” Bioorganic & Medicinal Chemistry Letters 11:1081 Accessibility to Native RNAs by Antisense Oligodeoxynucleotides 1083 (2001). in Murine Cell Extracts.” Nucleic Acids Research 26(22):5079-5085 Bernardelli, Patrick, et al., “Spiroquinazolinones as Novel, Potent (1998). and Selective PDE7 Inhibitors. Part 2: Optimization of 5.8- Lloyd, B.H., et al., “Determination of Optimal Sites of Antisense disubstituted Derivatives.” Bioorganic & Medicinal Chemistry Let Oligonucleotide Cleavage within TNFO. mRNA. Nucleic Acids ters 14:4627-4631 (2004). Research 29(17):3664-3673 (2001). Hetman, J.M., et al., “Cloning and Characterization of PDE7B, a Altschul, Stephen, et al., “Gapped BLAST and PSI-BLAST: a New cAMP-Specific Phosphodiesterase.” PNAS97(1):472-476 (2000). Generation of Protein Database Search Programs.” Nucleic Acids Yang, Guchen, et al., “Phosphodiesterase 7A-Deficient Mice Have Research 25(17):3389-3402 (1997). Functional T Cells.” The Journal of Immunology 171:6414-6420 Fedor, Martha, et al., “Substrate Sequence Effects on “Hammerhead” (2003). RNA Catalytic Efficiency.” PNAS USA 87:1668-1672 (1990). Siuciak, J.A., et al., “Behavioral and Neurochemical Characteriza Yamamoto, Satoshi, et al., “The Effects of a Novel Phosphodiesterase tion of Mice Deficient in the Phosphodiesterase-1B (PDE1B) 7A and -4 Dual Inhibitor, YM-393059, on T-Cell-Related Cytokine Enzyme.” Neuropharmacology 53:113-124 (2007). Production InVitro and InVivo.” European Journal of Pharmacology Cifani, Carlo, et al., “A Preclinical Model of Binge Eating Elicited by 541: 106-114 (2006). Yo-yo Dieting and Stressful Exposureto Food: Effect of Sibutramine, Martinez, Ana, et al., “Benzyl Derivatives of 2,1,3-Benzo- and Fluoxetine, Topiramate, and Midazolam.” Psychopharmacology Benzothieno3.2-athiadiazine 2,2-Dioxides: First 204: 113-125 (2009). Phosphodiesterase 7 Inhibitors,” Journal of Medicinal Chemistry Gearhardt, Ashley, et al., “Binge Eating Disorder and Food Addic 43:683-689 (2000). tion.” Current Drug Abuse Reviews 4:201-207 (2011). Ohman, E.M., et al., “Early Clinical Experience with Integrelin, an Williams, Jennifer, "Omeros announces expansion of potential indi Inhibitor of the Platelet Glycoprotein IIb/IIIa Integrin Receptor.” cations for PDE7 inhibitors.” PR Newswire, May 2011. (Business European Heart Journal 16(Supplement L):50-55 (1995). announcement online). . istry 120:446-451 (1996). Compton, William, et al., “Major Increases in Opioid Analgesic Zhang, Li, et al., “A Discrete Site Modulates Activation of I Abuse in the United States: Concerns and Strategies.” Drug and Domains.” The Journal of Biological Chemistry 271 (47):29953 Alcohol Dependence 81: 103-107 (2006). 29957 (1996). US 9.220,715 B2 Page 4

(56) References Cited Swiergiel, Arthur, et al., “Attenuation of Stress-Induced Behavior by Antagonism of Corticotropin-Releasing Factor Receptors in the Cen OTHER PUBLICATIONS tral Amygdala in the Rat.” Brain Research 623:229-234 (1993). Ehrman, Ronald, et al., “Conditioned Responses to Cocaine-Related Jackson, David, et al., “PotentO4B1 Peptide Antagonists as Potential Stimuli in Cocaine Abuse Patients.” Psychopharmacology 107:523 Anti-Inflammatory Agents,” Journal of Medicinal Chemistry 529 (1992). 40:3359-3368 (1997). Monti, Peter, et al., "Alcohol Cue Reactivity: Effects of Detoxifica Merrifield, R.B., “Solid Phase Peptide Synthesis I. The Synthesis of tion and Extended Exposure.” Journal of Studies on Alcohol and a Peptide.” Journal of the American Chemical Society 85(14):2149 Drugs 54.235-245 (1993). 2154 (1963). Mautino, Mario, et al., “Enhanced Inhibition of Human Pomerleau, Ovide, et al., “Reactivity to Alcohol Cues in Alcoholics Immunodeficiency Virus Type 1 Replication by Novel Lentiviral and Non-Alcoholics: Implications for a Stimulus Control Analysis of Vectors Expressing Human Immunodeficiency Virus Type 1 Enve Drinking.” Addictive Behaviors 8:1-10 (1983). lope Antisense RNA.” Human Gene Therapy 13:1027-1037 (2002). Morten Stormark, Kjell, et al., “Autonomic Cued Reactivity in Alco Jensen, Silke, et al., “Taming of Transposable Elements by Homol holics: the Effect of Olfactory Stimuli.” Addictive Behaviors ogy-Dependent Gene Silencing.” Nature Genetics 21(2):209-12 20(5):571-584 (1995). (1999). Miller, Norman, et al., “Dissociation of “Conscious Desire” (Crav Haseloff, Jim, et al., “Simple RNA Enzymes with New and Highly ing) from and Relapse in Alcohol and Cocaine Dependence.” Annals Specific Endoribonuclease Activities.” Nature 334:585-591 (1998). of Clinical Psychiatry 6(2):99-106 (1994). Cech, Thomas, et al., “Biological Catalysis by RNA.” Annual Review Tiffany, Stephen, et al., “Is Craving the Source of Compulsive Drug of Biochemistry 55:599-629 (1986). Use?” Journal of Psychopharmacology 12(1):23-30 (1998). Compton, Wilson, et al., “Abuse of Prescription Drugs and the Risk of Katner, Simon, et al., “Ethanol-Associated Olfactory Stimuli Rein Addiction.” Drug and Alcohol Dependence 838:S4-S7 (2006). state Ethanol-Seeking Behavior After Extinction and Modify Siegal, H.A., et al., “Probable Relationship Between Opioid Abuse Extracellular Dopamine Levels in the Nucleus Accumbens.” Alco and Heroin Use.” American Family Physician 68(11):2134-2141 holism. Clinical and Experimental Research 23(11): 1751-1760 (2003). (1999). Ciccocioppo, Robert, et al., “Reversal of Stress- and CRF-Induced Gracy, K. Noelle, et al., "Heroin-Specific Stimuli Reinstate Operant Anorexia in Rats by the Synthetic Nociceptin/Orphanin FQ Receptor Heroin-Seeking Behavior in Rats After Prolonged Extinction.” Phar Agonist, Ro 64-6198.” Psychopharmacology 161: 113-119 (2002). macology Biochemistry and Behavior 65(3):489-494 (2000). McKay, James, et al., “An Examination of the Cocaine Relapse Le, A.D., et al., “Reinstatement of Alcohol-Seeking by Priming Process.” Drug and Alcohol Dependence 38:35-43 (1995). Injections of Alcohol and Exposure to Stress in Rats.” Goeders, Nick, et al., “Non-Contingent Electric Footshock Facili Psychopharmacology 1.33:169-174 (1998). tates the Acquisition of Intravenous Cocaine Self-Administration in Volpicelli, Joseph, et al., “Naltrexone in the Treatment of Alcohol Rats.” Psychopharmacology 1 14:63-70 (1994). Dependence.” Archives of General Psychiatry 49:876-880 (1992). Brown, Sandra, et al., “Stress, Vulnerability and Adult Alcohol O'Brien, Charles, "A Range of Research-Based Pharmacotherapies Relapse.” Journal of Studies on Alcohol 56(5):538-545 (1995). for Addiction.” Science 278(5335):66-70 (1997). Haney, Margaret, et al., “Social Stress Increases the Acquisition of Michaeli, Tamar, et al., “Isolation and Characterization of a Previ Cocaine Self-Administration in Male and Female Rats.” Brain ously Undetected Human cAMP Phosphodiesterase by Research 698:46-52 (1995). Complementation of cAMP Phosphodiesterase-Deficient Sac Wallace, Barbara, “Psychological and Environmental Determinants charomyces cerevisiae' The Journal of Biological Chemistry of Relapse in Crack Cocaine Smokers,” Journal of Substance Abuse 268(17): 12925-12932 (1993). Treatment 6:95-106 (1989). Han, Ping, et al., “Alternative Splicing of the High Affinity cAMP Ahmed, Serge, et al., “Cocaine-but not Food-Seeking Behavior is Specific Phosphodiesterase (PDE7A) mRNA in Human Skeletal Reinstated by Stress after Extinction.” Psychopharmacology Muscle and Heart.” The Journal of Biological Chemistry 132:289-295 (1997). 272(26): 16152-16157 (1997). Nash, Frank, et al., “The Role of the Hypothalamic-Pituitary Gardner, Clare, et al., “Cloning and Characterization of the Human Adrenocortical Axis in Post-Stress induced Ethanol Consumption by and Mouse PDE7B, a Novel cAMP-Specific Cyclic Nucleotide Rats.” Progress in Neuro-Psychopharmacology & Biological Psy Phosphodiesterase.” Biochemical and Biophysical Research Com chiatry 12:653-671 (1988). munications 272: 186-192 (2000). Mollenauer, Sandra, et al., “EtOH Self-Administration in Anticipa Sasaki, Takashi, et al., “Identification of Human PDE7B, a cAMP tion of Noise Stress in C57BL/6J Mice.” Pharmacology Biochemis Specific Phosphodiesterase.” Biochemical and Biophysical Research try and Behavior 46:35-38 (1991). Communications 271:575-583 (2000). Blanchard, Robert, et al., “Social Structure and Ethanol Consump Packer, Milton, et al., “Effect of Oral Milrinone on Mortality in tion in the Laboratory Rat.” Pharmacology Biochemistry & Behavior Severe Chronic Heart Failure.” The New England Journal of Medi 28:437-442 (1987). cine 325: 1468-1475 (1991). Higley, J.D., et al., “Nonhuman Primate Model of Alcohol Abuse: Lehnart, Stephan, et al., “Phosphodiesterase 4D Deficiency in the Effects of Early Experience, Personality, and Stress on Alcohol Con Ryanodine-Receptor Complex Promotes Heart Failure and sumption.” PNAS USA 88:7261-7265 (1991). Arrhythmias.” Cell 123(1):25-35 (2005). Shaham, Yavin, “Immobilization Stress-Induced Oral Opioid Self Ma, Zhenkun, et al., “Asymmetric Dipolar Cycloaddition Reactions: Administration and Withdrawal in Rats: Role of Conditioning Fac A Practical, Convergent Synthesis of Chiral Pyrrolidines.” Tetrahe tors and the Effect of Stress on “Relapse” to Opioid Drugs.” dron. Asymmetry 8(6):883-887 (1997). Psychopharmacology 1 11:477-485 (1993). Weiss, Frank, et al., “Environmental Stimuli Potently Reinstate Alco Dunn, Adrian, et al., “Physiological and Behavioral Responses to hol-Seeking Behavior: Effect of Repeated Alcohol Intoxication.” Corticotropin-Releasing Factor Administration: is CRF a Mediator Society for Neuroscience Abstract 25: 1081 (1999). of Anxiety or Stress Responses?” Brain Research Review 15:71-100 Bardelle, Catherine, et al., “Phosphodiesterase 4 Conformers: Prepa (1990). ration of Recombinant Enzymes and Assay for Inhibitors.” Analytical Merali, Zui, et al., “Aversive and Appetitive Events Evoke the Release Biochemistry 275: 148-155 (1999). (Abstract only). of Corticotropin-Releasing Hormone and Bombesin-Like Peptides at Koob, George, et al., “Corticotropin Releasing Factor, Stress and the Central Nucleus of the Amygdala.” The Journal of Neuroscience Behavior.” Seminars in the Neurosciences 6:221-229 (1994). 18(12):4758-4766 (1998). Castro, Ana, et al., “CoMFA of Benzyl Derivatives of 2,1,3-Benzo Heinrichs, Stephen, et al., “Corticotropin-Releasing Factor Antago and Benzothieno 3.2-O.Thiadiazine 2,2-Dioxides: Clues for the nist Reduces Emotionality in Socially Defeated Rats Via Direct Design of Phosphodiesterase 7 Inhibitors.” European Journal of Neurotropic Action.” Brain Research 581:190-197 (1992). Medicinal Chemistry 36:333-338 (2001). US 9.220,715 B2 Page 5

(56) References Cited Polivy, Janet, et al., “Food Restriction and Binge Eating: A Study of Former Prisoners of War.” Journal of Abnormal Psychology OTHER PUBLICATIONS 103(2):409–411 (1994). Gold, Mark S., et al., “Overeating, Binge Eating and Eating Disorders Barnes, Matthew, et al., “Synthesis and Structure-Activity Relation as Addictions.” Psychiatric Annals 33(2): 112-116 (2003). ships of Guanine Analogues as Phosphodiesterase 7 (PDE7) Inhibi Pelchat, Marcia L., et al., “Images of Desire: Food-Craving Activa tors.” Bioorganic & Medicinal Chemistry Letters 11:1081-1083 tion During fMRI,” Neuroimage 23: 1486-1493 (2004). (2001). Ifland, J.R., et al., “Refined Food Addiction: A Classic Substance Yoshida, Masaru, et al., “Study of Biodegradable Copoly(L-Lactic Abuse Disorder.” Medical Hypotheses 72:518-526 (2009). Acid/Glycolic Acid) Formulations with Controlled Release of Z-100 Gearhardt, Ashley N., et al., “Food Addiction: An Examination of the for Application in Radiation Therapy.” International Journal of Diagnostic Criteria for Dependence.” Journal of Addiction Medicine Pharmaceutics 115:61-67 (1995). 3(1):1-7 (2009). Banwell, Martin, et al., “4,5-Diaryl-1H-Pyrrole-2-Carboxylates as Mizes, J. Scott, “Bulimia: A Review of its Symptomatology and Combretastatin A-4/Lamellarin THybrids: Synthesis and Evaluation Treatment.” Adv Behav Res Ther 7:91-142 (1985). as Anti-Mitotic and Cytotoxic Agents.” Bioorganic & Medicinal Crowther, Janis H., et al., “The Role of Daily Hassles in Binge Chemistry 14:4627-4638 (2006). Eating.” International Journal of Eating Disorders 29:449-454 Le, A.D., et al., “Role of Alpha-2 Adrenoceptors in Stress-Induced (2001). Reinstatement of Alcohol Seeking and Alcohol Self-Administration Herman, C. Peter, et al., “Anxiety, Restraint, and Eating Behavior.” in Rats.” Psychopharmacology 179:366-373 (2005). Journal of Abnormal Psychology 84(6):666-672 (1975). Gibson, L.C.D., et al., “The inhibitory profile of Ibudilast against the Cifani, Carlo, et al., “Pre-exposure to Environmental Cues Predictive human phosphodiesterase enzyme family.” European Journal of of Food Availability Elicits Hypothalamic-Pituitary-Adrenal Axis Pharmacology 538:39-42 (2006). Activation and Increases Operant Responding for Food in Female Liu, X, et al., “Reinstatement of Ethanol-Seeking Behavior by Stress Rats.” Addiction Biology 14:397–407 (2009). and Drug-Related Cues in Rats with a History of Ethanol-Depen Volkow, Nora D., et al., “How Can Drug Addiction Help Us Under dence.” Program No. 290.11, 2000 Neuroscience Meeting Planner, stand Obesity?” Nature Neuroscience 8(5):555-560 (2007). New Orleans, LA: Society for Neuroscience, 2000. Online. (Meeting Stunkard, Albert J. "Eating Patterns and Obesity.” Psychiatr. Q. Abstract). 33:284-295 (1959). Ciccocioppo, Roberto, et al., “Cocaine-Predictive Stimulus Induces Javaras, Kristin N., et al., “Co-Occurrence of Binge Eating Disorder Drug-Seeking Behavior and Neural Activation in Limbic Brain with Psychiatric and Medical Disorders,” J Clin Psychiatry 69(2): Regions after Multiple Months of Abstinence: Reversal by D1 266-273 (2008). Antagonists.” PNAS 98(4): 1976-1981 (2001). Foulds Mathes, Wendy, et al., “The Biology of Binge Eating.” Appe Erb, Suzanne, et al., “The Role of Corticotropin-Releasing Factor and tite 52(3):545-553 (2009). Corticosterone in Stress- and Cocaine-Induced Relapse to Cocaine Yanovski, Susan Z., "Binge Eating Disorder and Obesity in 2003: Seeking in Rats.” The Journal of Neuroscience 18(14):5529-5536 Could Treating an Eating Disorder Have a Positive Effect on the (1998). Obesity Epidemic.” International Journal of Eating Disorders Kenny, Paul J., “Common Cellular and Molecular Mechanisms in 34:51.17-5120 (2003). Obesity and Drug Addiction.” Nature Reviews Neuroscience 12:638 Koob, George F., et al., “Neurobiological Mechanisms for Opponent 651 (2011). Motivational Processes in Addiction.” Phil Trans RSoc B363:31 13 Avena, Nicole, et al., “Evidence for Sugar Addiction: Behavioral and 3123 (2008). Neurochemical Effects of Intermittent, Excessive Sugar Intake.” Nestler, Eric J., “Is There a Common Molecular Pathway for Addic Neurosci Biobehav Rey 32(1):20-39 (2008). tion?” Nature Neuroscience 8(11): 1445-1449 (2005). Avena, Nicole, et al., “Dysregulation of Brain Reward Systems in Drevets, Wayne C. et al., “Amphetamine-Induced Dopamine Eating Disorders: Neurochemical Information from Animal Models Release in Human Ventral Striatum Correlates with Euphoria.” Soci of Binge Eating, Bulimia Nervosa, and Anorexia Nervosa.” ety of Biological Psychiatry. 49:81-96 (2001). Neuropharmacology 63(1):87-96 (2012). Brody, Arthur L., et al., “Smoking-Induced Ventral Striatum Corwin, Rebecca L., et al., "Feeding and Reward: Perspectives from Dopamine Release.” American Journal of Psychiatry 161: 1211-1218 Three Rat Models of Binge Eating.” Physiology and Behavior (2004). 104:87–97 (2011). Volkow, Nora D. et al., “Dopamine in Drug Abuse and Addiction.” Ghitza, Udi E. et al., “The Axiogenic Drug Yohimbine Reinstates Arch Neurol 64(11): 1575-1579 (2007). Palatable Food Seeking in a Rat Relapse Model: a Role of CRF Fehr, Christoph, et al., “Association of Low Striatal Dopamine D2 Receptors.” Neuropsychopharmacology 31(10):2188-2196 (2006). Receptor Availability with Nicotine Dependence Similar to That Pickens, Charles L., et al., “Effect of Fenfluramine on Reinstatement Seen with Other Drugs of Abuse.” Am J Psychiatry 165:507-514 of Food Seeking in Male and Female Rats: Implications for the (2008). Predictive Validity of the Reinstatement Model.” Psychopharmacol Lischer, Christian, et al., “The Mechanistic Classification of Addic ogy 221(2):341-353 (2012). tive Drugs.” PLoS Medicine 3(11):e437 (2006). Johnson, Paul M., et al., “Addiction-Like Reward Dysfunction and Johnson, S.W., et al., “Opioids Excite Dopamine Neurons by Compulsive Eating in Obese: Role for Dopamine D2 Receptors.” Nat Hyperpolarization of Local Interneurons.” The Journal of Neurosci 13(5):635-641 (2010). Neuroscience 12(2):483-488 (1992). Hoebel, Bartley G., “Brain Neurotransmitters in Food and Drug Volkow, N.D., et al., “Dopamine in Drug Abuse and Addiction: Reward'” The American Journal of Clinical Nutrition 42: 1133 Results from Imaging Studies and Treatment Implications. Molecu 1150 (1985). lar Psychiatry 9:557-569 (2004). Gearhardt, Ashley N., et al., “Neural Correlates of Food Addiction.” Wardle, Jane, “Stress, Dietary Restraint and Food Intake.” Journal of Arch Gen Psychiatry 68(8):808-816 (2011). Psychosomatic Research 48:195-202 (2000). Wang, Gene-Jack, et al., “Enhanced Striatal Dopamine Release Dur Yacono Freeman, Lisa M., et al., “Daily Stress, Coping, and Dietary ing Food Stimulation in Binge Eating Disorder.” Obesity 19(8): 1601 Restraintin Binge Eating.” International Journal of Eating Disorders 1608 (2011). 36:204-212 (2004). Hudson, James I., “The Prevalence and Correlates of Eating Disor Waters, Anne, et al., “Internal and External Antecedents of Binge ders in the National Comorbidity Survey Replication.” Biol Psychia Eating Episodes in a Group of Women with Bulimia Nervosa.” Inter try 61(3):348-358 (2007). national Journal of Eating Disorders 29:17-22 (2001). Grucza, Richard A. et al., “Prevalence and Correlates of Binge Stice, Eric, et al., "Subtyping Binge Eating-Disordered Women Eating Disorder in a Community Sample.” Compr Psychiatry Along Dieting and Negative Affect Dimensions.” International Jour 48(2): 124-131 (2007). nal of Eating Disorders 30:11-27 (2001). US 9.220,715 B2 Page 6

(56) References Cited Receptors Containing C4 and O.6 Subunits.” Molecular Pharmacol ogy 81:541-548 (2012). OTHER PUBLICATIONS Thiele, Jonathan W., et al., “GABAergic Transmission Modulates Ethanol Excitation of Ventral Tegmental Area Dopamine Neurons.” Pierce, R. Christopher... et al., “The Mesolimbic Dopamine System: Neuroscience 172:94-103 (2011). The Final Common Pathway for the Reinforcing Effect of Drugs of Jalabert, Marion, et al., “Neuronal Circuits Underlying Acute Mor Abuse?' Neuroscience and Biobehavioral Reviews 30:215-238 phine Action on Dopamine Neurons.” PNAS 108(39): 16446-16450 (2006). (2011). Berridge, Kent C. et al., “What is the Role of Dopamine in Reward: Laviolette, Steven R. et al., “The Neurobiology of Nicotine Addic Hedonic Impact, Reward Learning, or Incentive Salience?” Brain tion: Bridging the Gap from Molecules to Behaviour.” Nature Research Reviews 28:309-369 (1998). Reviews Neuroscience 5(1):55-65 (2004). Bonci, Antonello, et al., “Increased Probability of GABA Release Pidoplichko, Volodymyr I., et al., “Nicotine Activates and Desensi during Withdrawal from Morphine.” The Journal of Neuroscience tizes Midbrain Dopamine Neurons.” Nature 390(6658):401–404 17(2):796-803 (1997). (1997). Brodie, Mark S., et al., "Cocaine Effects in the Ventral Tegmental McWilliams, N., “Understanding Personality Structure in the Clini Area: Evidence for an Indirect Dopaminergic Mechanism of Action.” cal Process.” Psychoanalytic Diagnosis, Guilford Press, 2011, Chap Naunyn-Schmiedeberg's Arch Pharmacol 342:660-665 (1990). ter 13. Accessed from http://www.group-analysis.ru/publications/ Olajide, Olumayokun A., et al., “Anti-neuroinflammatory Properties Nancy McWilliams PSYCHOANALYTIC DIAGNOSIS of Synthetic Cryptolepine in Human Neuroblastoma Cells: Possible Understanding Personally Structure in the Clinical Process. Involvement in NF-kB and p38 MAPK inhibition.” European Jour php#TOC id2925495. Russian Language. nal of Medicinal Chemistry 63:333-339 (2013). McWilliams, N., “Understanding Personality Structure in the Clini Liu, Liwang, et al., “Nicotine Persistently Activates Ventral cal Process.” Psychoanalytic Diagnosis, Guilford Press, 2011, Chap Tegmental Area Dopaminergic Neurons via Nicotinic Acetylcholine ter 13, English Language Translation. U.S. Patent Dec. 29, 2015 Sheet 1 of 47 US 9.220,715 B2

FIGURE 1

Effect of OMS 182056 on Cocaine Self-Administration

5 O

s 4 O

3 O

N s 2 O 1 O

0.0 0.3 1.0 3.0 mg/kg U.S. Patent Dec. 29, 2015 Sheet 2 of 47 US 9.220,715 B2

FIGURE 2

Effect of OMS181869 on Cocaine Self-Administration

5 O

s4. O ana

3 O

-- 2 O

1 O

O.O 0.3 1.0 3.0 mg/kg U.S. Patent Dec. 29, 2015 Sheet 3 of 47 US 9.220,715 B2

FIGURE 3

Effect of OMS182401 on Cocaine Self-Administration

Short Access Long ACCeSS 50 50

40 S 40 s: s 5 5 A.; 30 30 s S. 20 S. 20 s 3. 10 10

O O Vehicle OMS182401 Vehicle OMS 182401 (9.0 mg/kg) (9.0 mg/kg) **P: <0.01 U.S. Patent Dec. 29, 2015 Sheet 4 of 47 US 9.220,715 B2

FIGURE 4

Effect of SKF82958. On Cocaine Self-Administration

a 1 5

area

- sN Ys-s O 5

veh 0.3 1.0 mg/kg U.S. Patent Dec. 29, 2015 Sheet 5 of 47 US 9.220,715 B2

FIGURE 5 Effect of OMS182056 on Non-Reinforced Lever Press Response

4 O

3 O --

2 O

1 O

Ext O.O 3.0 mg/kg U.S. Patent Dec. 29, 2015 Sheet 6 of 47 US 9.220,715 B2

FIGURE 6 Effect of SKF82958 on Non-Reinforced Lever Press Response

4. O

3 O --

Yse ead 2 O

1 O

Ext O.O 10 mg/kg U.S. Patent Dec. 29, 2015 Sheet 7 of 47 US 9.220,715 B2

FIGURE 7

Chronic Effect of OMS182401 on Cocaine Self-Administration long Access {}

- *** -O- 40 s ^- -.-O -- w8 {* *...**{- *.8 ( --ro I - r; - \ s 33 x r O. " / Reinforced v. r; A \, do Bense \, or 7 or . 'pre- b - & ^. d k post treatment regities:

tays

sk:- wice -- (833824; 4.5 gfxg, 8:3} U.S. Patent Dec. 29, 2015 Sheet 8 of 47 US 9.220,715 B2

FIGURE 8 Effect of OMS182056 on First Day of Extinction 100

0.0 1.O 3.0 mg/kg U.S. Patent Dec. 29, 2015 Sheet 9 of 47 US 9.220,715 B2

FIGURE 9

Effect of OMS182056 on Yohimbine-induced Relapse to Cocaine Seeking

150

Ext 0.0 1.O 3.0 mg/kg U.S. Patent Dec. 29, 2015 Sheet 10 of 47 US 9.220,715 B2

FIGURE 10

Effect of OMS182401 On Yohimbine-induced Relapse to Cocaine Seeking

4. O

3 O

s 2 O

1 O

*P: < 0.05 (vs Vehicle) *P: < 0.001 (vs Extinction) U.S. Patent Dec. 29, 2015 Sheet 11 of 47 US 9.220,715 B2

FIGURE 11 Effect of OMS182056. On Cue-induced Relapse to Cocaine Seeking 60

50 # U.S. Patent Dec. 29, 2015 Sheet 12 of 47 US 9.220,715 B2

FIGURE 12 Effect of OMS182401 on Cue-induced Relapse to Cocaine Seeking

Extinction S- Vehicle 0.3 1.0 3.0

S+ OMS182401 (mg/kg)

"P: < 0.05 (vs Vehicle) *P: < 0.001 (vs Vehicle) U.S. Patent Dec. 29, 2015 Sheet 13 of 47 US 9.220,715 B2

FIGURE 13 Effect of OMS182056 on Cocaine Priming-induced Relapse

250

2 O O

1 5 O i 1 O O 5 O

Ext O.O 1.0 3.0 mg/kg U.S. Patent Dec. 29, 2015 Sheet 14 of 47 US 9.220,715 B2

FIGURE 14 Effect of SKF82959 on Cocaine Priming-induced Relapse

150 s

s 10 O

i 5 O

t O.O 1.0 mg/kg U.S. Patent Dec. 29, 2015 Sheet 15 Of 47 US 9.220,715 B2

FIGURE 15 Effect of OS 820 t of Nicotie Self-Administration (Sha 120 min) 5 a; otive ever

inactive ever

s s

, mg/kg PD7

*p-0.01 U.S. Patent Dec. 29, 2015 Sheet 16 of 47 US 9.220,715 B2

FIGURE 16 Effect of OS 182401 on Nicotine Self-Administration (IgA 120 min) f 5 a; Active ever

b inactive lever

U.S. Patent Dec. 29, 2015 Sheet 17 Of 47 US 9.220,715 B2

FIGURE 17 Effect Of OMS182399 On Nicotine Self-Administration (Sha 120 min)

Vehicle 1.0 3.0 9.0

Dose (mg/kg) *P&O.01 U.S. Patent Dec. 29, 2015 Sheet 18 of 47 US 9.220,715 B2

FIGURE 18A

Effects of OMS182399 On food Self-administration

8 O

6 O.

4 O

2 O

Vehicle 3 9 OMS182399 (mg/kg) U.S. Patent Dec. 29, 2015 Sheet 19 Of 47 US 9.220,715 B2

FIGURE 18B

Effects of OMS182401 on food Self-administration

8 O

6 O 24.0.O

0. Vehicle 1 3 9 OMS 182401 (mg/kg) U.S. Patent Dec. 29, 2015 Sheet 20 of 47 US 9.220,715 B2

FIGURE 19A-19C

Rewards Break Roint Total Responses 8. 56; 200,

4 3 2

gi..... -- o:...m. --- ... . : While 3 9 Vehicle 3. 9 Wehicle 3. 9 S82401 fragikg OkiS82401 mgkg OMS18240i mg/kg px0.3 p:{}.85 pki).01

19A 19B 19C U.S. Patent Dec. 29, 2015 Sheet 21 of 47 US 9.220,715 B2

FIGURE 20 Effect of OIS 182401 on 1st day of extinction of Nicotine Self-Administration

ai Active ever

pi inactise jeer ItN: 3, PDE7i (mg/kg) *p < 0.05 U.S. Patent Dec. 29, 2015 Sheet 22 of 47 US 9.220,715 B2

FIGURE 21 Effect of OMS 182401 on yohimbine induced reinstatement of Nicotine seeking a) Active ever 40 i

. I S b) inactive lever

& &

"p: <0.001 (vs vehicle); #p: <0.001 (vs extinction) U.S. Patent Dec. 29, 2015 Sheet 23 of 47 US 9.220,715 B2

FIGURE 22

Effect of OS 824f or Nicolife citie induced reinstatement 60a) Active lever it

40 k.

pinactive ever

*p: <0.001 (vs vehicle); #p: <0.001 (vs extinction) U.S. Patent Dec. 29, 2015 Sheet 24 of 47 US 9.220,715 B2

FIGURE 23A as NRNS ** sie: - 8:32:3:

U.S. Patent Dec. 29, 2015 Sheet 25 Of 47 US 9.220,715 B2

FIGURE 23B

25".B x was ra. * 3:8 g RS * 8:38:8 * {3:838:33 {

i. i.

is 3 80 (20 Time in U.S. Patent Dec. 29, 2015 Sheet 26 of 47 US 9.220,715 B2

FIGURE 23C

so, C.

m . Y. S. W. x i:8 RNS ** 8:8:8; 8

is 30 60 120 Time in U.S. Patent Dec. 29, 2015 Sheet 27 Of 47 US 9.220,715 B2

FIGURE 23D

is 38 80 20

Tire in U.S. Patent Dec. 29, 2015 Sheet 28 of 47 US 9.220,715 B2

FIGURE 24A

irre in U.S. Patent Dec. 29, 2015 Sheet 29 Of 47 US 9.220,715 B2

FIGURE 24B

is so 8: to fire imir U.S. Patent Dec. 29, 2015 Sheet 30 of 47 US 9.220,715 B2

FIGURE 24C

8: U.S. Patent Dec. 29, 2015 Sheet 31 of 47 US 9.220,715 B2

FIGURE 24D

1s --- so r --- * &i s ^: --- s * -: -- W w" 888 . --3. w ^ y - W* - ss too -- Mx & :8:

8:8:

U.S. Patent Dec. 29, 2015 Sheet 32 of 47 US 9.220,715 B2

FIGURE 25A

NRNS : t s -air --X*c- xx 1. * xx xxxic: so EY * k-- is:xx: 888& $3;&gsixk:

ii.

is 30 8: 120 Time fnir U.S. Patent Dec. 29, 2015 Sheet 33 of 47 US 9.220,715 B2

FIGURE 25B

NRS

W -i- oxx i::::: r -k- iogastate { ki,

is is 36 so to ine min U.S. Patent Dec. 29, 2015 Sheet 34 of 47 US 9.220,715 B2

FIGURE 25C

R-Nis s: g . --- & --- so 1 <- vehicle ck op: axe { {ikg

is a 80 inte ir U.S. Patent Dec. 29, 2015 Sheet 35 of 47 US 9.220,715 B2

FIGURE 25D

Ri-S

E. 200 g e --& s we -* * . sts: 150 : - * t s r-ir --- so 8: XX- X::ic: in rix (piastate Kg

line air U.S. Patent Dec. 29, 2015 Sheet 36 of 47 US 9.220,715 B2

FIGURE 26 Effect of OMS182399 on yohimbine induced relapse to food seeking hi: 8 gig was raise rats; group p. x O.S. p. x 3.

time reir -- Yeshirtire regik rt- Yetirixie rig i kg - OxS8239 (0.3rrig fixg -- Yohibite 2 is k + (8383.388 rig i ks -- Yohirrbine 2 is k + oxS8239 3 is ke U.S. Patent Dec. 29, 2015 Sheet 37 Of 47 US 9.220,715 B2

FIGURE 27 175 NAc shell -- Wei Ni wa 3 receive OS No. 8 S 150 c s a 125 s 100- a -3-33 - st

t 88 18 8. Time (min)

175- NAC core -- We N et S ~~ OS N is 4. so s 125 :s to: ors : - \s-s es S$

s 120 180 Time (min) Effect of OMS 182399 (9mg/kg ip) on NAC shell/core extracellular DA levels U.S. Patent Dec. 29, 2015 Sheet 38 of 47 US 9.220,715 B2

FIGURE 28 Effect of nicotine (0.4 mg/kg sc) on NAC shell extracellular DA levels in rats pre-treated with OMS182399 (9 mg/kg ip; 10 min before nicotine)

* NAc shell 78

-O-Vehicle, N=12 -A-OMS182399, N=12

8 18 Time (min) U.S. Patent Dec. 29, 2015 Sheet 39 Of 47 US 9.220,715 B2

FIGURE 29A

Effect Of OMS182401 and SKF82958. On dopanimergic VTA neurons

O.3 3 O U.S. Patent Dec. 29, 2015 Sheet 40 of 47 US 9.220,715 B2

FIGURE 29B Effect of OMS182401 on dopanimergic VTA neurons 50 OMS182401 SKF82958

t OS 8: SK88

s p-0.05

. ,3 + . Compound (ii) U.S. Patent Dec. 29, 2015 Sheet 41 of 47 US 9.220,715 B2

FIGURE 30

Effect of PDE7 inhibition. On WAGABA Release Miniature GABAA inhibitory Postsynaptic Potentials (mlPSPs)

Vehicle OMS182401 Vehicle OMS182401 (1 AM) (1M) U.S. Patent Dec. 29, 2015 Sheet 42 of 47 US 9.220,715 B2

FIGURE 31

3: -

xix:8:38 {883: {{s . : .3 SK33 { :: s: opes: :

*p-0.05; *p-0.01 U.S. Patent Dec. 29, 2015 Sheet 43 of 47 US 9.220,715 B2

FIGURE 32

Effects of Direct Administration of PDE7 inhibitor into Rat WTA

Nicotine Self-Administration

25 -

2O Active Lever 3 Inactive Lever 15 O C. s 10 - e -

O -- *p<0.001 0.1 1 OMS182401 (ug/kg) U.S. Patent Dec. 29, 2015 Sheet 44 of 47 US 9.220,715 B2

FIGURE 33

centre OS388 (O.S.

. U.S. Patent Dec. 29, 2015 Sheet 45 of 47 US 9.220,715 B2

FIGURE 34

centre: O838 (striki costs:980s 200 8 OS388 (3.8 at

o 8.

ettarot it in U.S. Patent Dec. 29, 2015 Sheet 46 of 47 US 9.220,715 B2

FIGURE 35

s {xxxx cks3 is a 8 S388 (O.S. x (S38 a.s.

K. K. K-x:... --> -- a U.S. Patent Dec. 29, 2015 Sheet 4 7 Of 47 US 9.220,715 B2

FIGURE 36

Effect of OMS182401 on dopamine D1-mediated stimulation of open field activity

2. s

88: g 38 s 88: gs: 388 s: * 8.83 * . s * 2,3. 2,& 2,3. 2,3.23. 22 &s: &{& & 8,& 8.. 3.- g. 8 *-g. : t -& 3. & 8, 8 . s e ‘e 8. 8 & & US 9.220,715 B2 1. 2 TREATMENT OF ADDICTION AND have been investigated to help alcoholic patients to not only IMPULSE-CONTROL DISORDERS USING control alcohol drinking but also alcohol cravings and relapse PDE7 INHIBITORS (Monti et al., J Stud Alcohol 54.235-45 (1993); Volpicelli et al., Arch Gen Psychiatry 49:876-880 (1992); and O’Brien CROSS-REFERENCE TO RELATED Science 278: 66-70 (1997)). APPLICATIONS Medications such as naltrexone, acamprosate, ondansetron, disulfuram, gamma hydroxybutyrate (GHB), This application is a continuation in part of and claims and topiramate tested for their potential therapeutic effect on priority from the filing date of Application Ser. No. 13/290, alcohol abuse belong to several classes (Volpicellietal. 1992: 868 filed Nov. 7, 2011 and also claims the benefit of Appli 10 O’Brien et al. 1997). Few of these pharmacotherapeutics, cation Nos. 61/643,611 filed May 7, 2012, 61/411,431, filed Such as naltrexone, acamprosate, and disulfuram, have been Nov. 8, 2010, 61/411,437, filed Nov. 8, 2010 and 61/482,994, proven to be of a certain utility and approved for the treatment filed May 5, 2011, the disclosures of which are incorporated of alcoholism. Among these medications, the non-selective herein by reference in their entirety. opioidantagonist naltrexone is currently considered the phar 15 macological best option. However, despite Some promising STATEMENT REGARDING SEQUENCE results none of these medications, including naltrexone, is of LISTING Sufficient efficacy in alcoholism and prognosis remains poor. Nicotine is one of the most widely used addictive drugs, The sequence listing associated with this application is and nicotine abuse is the most common form of Substance provided in text format in lieu of a paper copy and is hereby abuse. The WHO estimates that there are 1.25 billion Smokers incorporated by reference into the specification. The name of worldwide, representing one third of the global population the text file containing the sequence listing is NE 1 over the age of 15. The WHO further estimates that 5 million 0172 SequenceListingFinal ST25; and is being submitted deaths occur each year as a direct result of tobacco use, via EFS-Web with the filing of the specification. making nicotine abuse the largest single preventable cause of 25 death worldwide. In industrialized countries, 70-90% of lung FIELD OF THE INVENTION cancer, 56-80% of chronic respiratory disease, and 22% of cardiovascular disease instances are attributed to nicotine This disclosure is directed to prevention and treatment of addiction. Cigarette smoking is associated with 430,000 Substance and behavioral addictions using phosphodiesterase deaths per year in the US alone and is estimated to cost the 7 (PDE7) inhibitors, alone or in combination with other thera 30 nation 80 billion dollars yearly in health care costs. Tobacco peutic agents or addictive agents. use accounts for one third of all cancers, including cancer of the lung, mouth, pharynx, larynx, esophagus, cervix, kidney, BACKGROUND OF THE INVENTION ureter, and bladder. The overall rates of death from cancer are twice as high among Smokers as among nonsmokers. Smok The World Health Organization (WHO) defines substance 35 ing also causes lung diseases such as chronic bronchitis and addiction as using a Substance repeatedly, despite knowing emphysema; exacerbates asthma symptoms; and increases and experiencing harmful effects. Substance addiction is a the risk of heart disease, including stroke, heart attack, vas chronic, relapsing disease characterized by a loss of control cular disease, and aneurysm. An estimated 20% of the deaths over drug use, compulsive drug seeking and craving for a from heart disease are attributable to Smoking. Expectant Substance, use that persists despite negative consequences, 40 women who Smoke are at greater risk than nonsmokers for and physical and/or psychological dependence on the Sub premature delivery, spontaneous abortion, and infants with stance. Substance addiction typically follows a course of decreased birth weight. tolerance, withdrawal, compulsive drug taking behavior, drug Nicotine use results in increased levels of the neurotrans seeking behavior, practice of addictive behavior, and relapse. mitter dopamine, which activates the reward pathways to Substance abuse and addiction are public health issues with 45 regulate feelings of pleasure and to mediate the desire to significant Social and economic impact on both the addict and consume nicotine. Symptoms associated with nicotine with Society by playing a major role in violent crime and the spread drawal include craving, irritability, anger, hostility, aggres of infectious diseases. Addictive Substances include alcohol, Sion, fatigue, depression, and cognitive impairment, which caffeine, nicotine, cannabis (marijuana) and cannabis deriva lead the abuser to seek more nicotine. Environmental condi tives, opiates and other morphine-like opioid agonists such as 50 tioning factors and exposure to psychological stress represent heroin, phencyclidine and phencyclidine-like compounds, additional factors motivating nicotine use in Smokers. sedative hypnotics Such as benzodiazepines and barbiturates Repeated nicotine use results in the development of tolerance, and psychoStimulants such as cocaine, amphetamines and requiring higher doses of nicotine to produce the same initial amphetamine-related drugs such as dextroamphetamine and stimulation. methylamphetamine. 55 Most therapies developed for nicotine addiction have Alcohol is one of the most commonly abused substances at shown only moderate Success in preventing relapse, leading a global level. Additionally, alcoholism leads to serious liver to a high failure rate in attempts to quit Smoking. Treatments and cardiovascular disease and generates dependence result include the use of nicotine replacement products, anti-depres ing in severe mental disorders, social problems and adverse sants, anti-hypersensitives, and behavioral therapy. consequences including the division of families, tragic acci 60 The National Institute on Drug Abuse estimates that 72 dents and the reduction of work performance. According to million Americans, about one third of the population, have the WHO, alcohol consumption is responsible for 20-30% of tried marijuana. Acute effects of marijuana use include oesophageal and liver cancer, liver cirrhosis, homicides, epi memory and learning problems, distorted perception, diffi lepsy, and motor vehicle accidents worldwide. Globally, alco culty problem solving, loss of coordination, and increased hol abuse leads to about 1.8 million deaths per year. Compul 65 heart rate. Long term abuse can cause the same respiratory sive behavior towards the consumption of alcohol is a core problems observed in tobacco smokers, such as daily cough, symptom of the disorder. In recent years several approaches phlegm production, increased risk of lung infections, and an US 9.220,715 B2 3 4 increased chance of developing cancer of the head, neck and but it can lead to a dependence on the Substitute opiate. Also, lungs. Depression, anxiety, and job-related problems have many Substitution therapies take 3-6 months, allowing time been associated with marijuana use. Longterm marijuanause for addicts to stop treatment midway. can result in addiction with compulsive use that interferes PsychoStimulants, such as cocaine and amphetamines, with daily activities. Cravings and withdrawal symptoms, temporarily cause euphoria, increased alertness, and Such as irritability, increased aggression, sleeplessness, and increased physical capacity in humans. These substances first anxiety make it difficult for addicts to stop using marijuana. increase dopamine transmission, but long term drug usage There are no pharmaceutical treatments available for treating results in a reduction of dopamine activity, leading to dys marijuana addiction and relapse. regulation of the brain reward system and dysphoria. The According to the WHO, an estimated 13 million people 10 WHO estimates 33 million people around the world abuse abuse opioids worldwide, including 9 million heroin addicts. amphetamines. More than 25% of opioid abusers die from suicide, homicide, Chronic cocaine abuse can result in hyperstimulation, or an infectious disease, Such as HIV and hepatitis, within tachycardia, hypertension, mydriasis, muscle twitching, 10-20 years of becoming addicted. Tolerance and physical sleeplessness, extreme nervousness, hallucinations, paranoia, dependence can develop within two to three days. While 15 aggressive behavior, and depression. Cocaine overdose may abuse and addiction to opioid agents is a known phenomenon, lead to tremors, convulsions, delirium, and death resulting what is new is the worsening of this problem in the recent from heart arrhythmias and cardiovascular failure. years (Compton and Volkow, Drug Alcohol Depend 83 Suppl Desipramine, amantadine and bromocriptine have been 1: S4-7 (2006A) and Compton and Volkow, Drug Alcohol shown to decrease cocaine withdrawal symptoms. Depend 81(2): 103-7 (2006B)). Epidemiological surveys of Amphetamine withdrawal symptoms include EEG youth in the United States in 2003 indicated that opioid anal changes, fatigue, and mental depression. Tolerance develops gesics were among the most frequently abused illicit drugs over time and may be associated with tachycardia, auditory among secondary students (12th graders), second only to and visual hallucinations, delusions, anxiety reactions, para marijuana (Delva et al., Am J Public Health 95(4): 696-702 noid psychosis, exhaustion, confusion, memory loss, and pro (2005)). Furthermore, the past few years have seen a marked 25 longed depression with Suicidal tendencies. Current treat increase in the use of opioid medications in the United States ments for amphetamine addiction include phenothiazines, and an even greater increase in problems associated with Such haloperidol, and chlorpromazine for hallucinations, but use. This upsurge in use and problems is particularly concern potential side effects of these drugs include postural hypoten ing because it seems to represent an expanded pathway to sion and severe extrapyramidal motor disorders. Subjects opioid addiction (Siegal et al., Am Fam Physician 67: 942 30 who are addicted to pyschoStimulants will sometimes go 945 (2003)). through psychological withdrawal as well as physiological According to recent epidemiological data, 4.7% (i.e., 11.0 withdrawal, making relapse potentially more likely. million) United States household residents over the age of In the past, treatment for Substance addictions focused on twelve abused an opioid medication in 2002 and 13.7% of behavioral therapy, but dependence on many of these highly these persons (i.e., 1.5 million) met the criteria of a DSM-IV 35 addictive Substances is hard to break. In particular, addictions opioid use disorder (American Psychiatric Association, to alcohol, cocaine, and heroin are considered chronic, relaps Diagnostic and Statistical Manual of Mental Disorders, ing disorders. Also, concurrent abuse of multiple Substances, Fourth Edition. (1994); Substance Abuse and Mental Health Such as nicotine, heroin, cocaine and alcohol, is common. Services Administration, Mortality Data from the Drug The long-lasting, chronic nature of many addictions and Abuse Warning Network, 2002, (2004)). As recently 40 high rates of recidivism present a considerable challenge for reviewed by Compton and Volkow, the annual incidence of the treatment of drug and alcohol addiction, such that under opioid analgesic abuse increased from 628,000 initiates in standing of the neurobiological basis of relapse has emerged 1990 to 2.4 million initiates in 2001 (Substance Abuse and as a central issue in addiction research. Emotional and envi Mental Health Services Administration, Overview of Find ronmental factors (conditioning stimuli) were listed among ings from the 2002 National Survey on Drug Use and Health, 45 the main causes of relapse. For example, it is known that (2003); Substance Abuse and Mental Health Services Admin specific stress conditions such as loss of work and economic istration, Emergency Department Trends From the Drug difficulties, or stimuli predictive of the presence of alcohol Abuse Warning Network, Final Estimates 1995-2002, previously associated with its use such as a bottle of the (2003)). One of the reasons fostering the expansion of opioid preferred wine and a bar-like environment, may strongly addiction is the increased use of analgesic secondary to medi 50 facilitate relapse in detoxified former alcoholics. cal prescription. Short-term use of opioid medication is rarely The growing incidence of obesity in the United States, associated with addiction. Conversely, protracted treatments Europe and other westernized societies also is indicative of with these agents have been associated with development of the prevalence of food addiction-like behavior. As distin addiction in up to 18% of patients. guished from normal eating behaviors, food addiction is a The goals for treatment of opiate addiction, as with other 55 maladaptive behavior, making people who eat in response to types of substance addictions, are to discontinue the use of the addiction rather than hunger feel worse rather than better. The opioid while minimizing painful withdrawal symptoms and overeating of a food addict is also persistent and habitual, preventing relapse. Current treatments involve replacing the eating an excessive amount of food on a regular basis, and addictive drug with a substitution of an opioid receptor ago often eating excessive quantities of unhealthy foods. Food nist or mixed agonist/antagonist. An alternative approach 60 addiction not only leads to obesity, but paradoxically may consists of the use of an opioid receptor antagonist to block also lead to malnutrition. There are several similarities the effect of the agonist. Antagonists provide no relief from between food addiction and drug Substance addiction, includ pain or other withdrawal symptoms; rather, they can precipi ing effects on mood, external cues causing the addictive tate withdrawal, and their therapeutic use was associated with behavior, expectancies, restraint, ambivalence and attribu increased accidental opioid agonists overdosing and 65 tion. increased lethality. Use of agonists with a lower affinity for Two major theoretical positions exist to explain the persis the receptors results in the least severe withdrawal symptoms, tence of addictive behavior and vulnerability to relapse asso US 9.220,715 B2 5 6 ciated with drug and alcohol addiction, homoeostatic hypoth eating. In another aspect of the invention, the addictive or eses and conditioning hypotheses. compulsive disorder is an obsessive-compulsive disorder. Homeostatic hypotheses relate relapse risk to neuroadap In one aspect of the invention, the PDE7 inhibitory agents tive changes and disruption of neuroendocrine homeostasis for treatment of addiction are selected from the following that are thought to underlie anxiety, mood dysregulation and 5 disclosed herein: formula 1A, formula 1B, formula 29, for Somatic symptoms that accompany acute withdrawal, and mula 30, formula 31, formula 32, formula 33, formula 34, that can persist for considerable periods of time during what formula35, formula 36, formula 37, formula38, formula 39, has been referred to as the “protracted withdrawal' phase. formula 40, formula 41, formula 42, formula 43A, formula This view, therefore, implicates alleviation of discomfort and 43B, formula 44, formula 45, formula 46, formula 47, for negative affect as a motivational basis for relapse. 10 mula 48, formula 49, formula 50, formula 51, formula 52, Conditioning hypotheses are based on observations that formula 53, formula 54, formula 6A, formula 6B, formula 6C, relapse is often associated with exposure to drug-related envi formula 6D, formula 6E, formula 6F, formula 6G, formula ronmental stimuli. This view holds that specific environmen 6H, formula 16A, compound 1, compound 2, compound 3. tal stimuli that have become associated with the rewarding 15 and compound 4. actions of a drug by means of classical conditioning can elicit In one aspect of the invention, the PDE7 inhibitory agent Subjective states that trigger resumption of drug use. The has an ICs for inhibiting PDE7A and/or PDE7B activity of homeostatic and conditioning hypotheses are not mutually less than about 1 uM. In one embodiment, the PDE7 inhibi exclusive. In fact, homeostatic and conditioning factors are tory agent has an ICs for inhibiting PDE7A and/or PDE7B likely to exert additive effects in that exposure to drug-related activity of less than about 100 nM. In another embodiment, environmental stimuli may augment Vulnerability to relapse the PDE7 inhibitory agent has an ICs for inhibiting PDE1B conveyed by homeostatic disturbances. activity of greater than 5 times the lesser of the ICs for Clearly, there is a need in the art for new methods for inhibiting PDE7A activity and the ICs for inhibiting PDE7B treating and preventing addiction and the relapse use of addic activity. In another embodiment, the PDE7 inhibitory agent tive agents. The present invention meets these needs by pro 25 has an ICs for inhibiting PDE10 activity of greater than 5 viding methods and pharmaceutical combinations useful in times the lesser of the ICs for inhibiting PDE7A activity and treating and preventing addiction and recividism. the ICs for inhibiting PDE7B activity. In a further embodi ment, the PDE7 inhibitory agent has an ICs for inhibiting SUMMARY OF THE INVENTION PDE3 activity of greater than 10 times the lesser of the ICso 30 for inhibiting PDE7A activity and/or the ICs for inhibiting The present invention provides a method of treating or PDE7B activity. In another embodiment, the PDE7 inhibitory preventing an addiction by determining that a subject has an agent has an ICs for inhibiting PDE3 and PDE4 activity of addiction or is at risk of developing an addiction and then greater than 10 times the lesser of the ICs for inhibiting administering an inhibitor of a phosphodiesterase 7 (PDE7) PDE7A activity and the ICs for inhibiting PDE7B activity. In effective to the subject for the treatment or prevention of the 35 a further embodiment, the PDE7 inhibitory agent has an 1050 addiction. for inhibiting PDE 4 and PDE 8 activity of greater than 10 In one aspect of the invention, the Subject is addicted to an times the lesser of the ICs for inhibiting PDE7A activity and addictive agent. Examples of addictive agents include alco the ICs for inhibiting PDE7B activity. In another embodi hol, nicotine, marijuana, a marijuana derivatives, opioid ago ment, the PDE7 agent has an ICs for inhibiting PDE1, PDE2. nists, benzodiazepines, barbiturates, and psychoStimulants. 40 PDE3, PDE 4, PDE 8, PDE10, and PDE11 activity of greater In one embodiment, the addictive agent is alcohol. In another than 10 times the lesser of the ICs for inhibiting PDE7A embodiment, the addictive agent is nicotine. In a further activity and the ICs for inhibiting PDE7B activity. In a fur embodiment, the addictive agent is an opioid, e.g., morphine, ther embodiment, the PDE7 inhibitory agent is a selective methadone, fentanyl, Sufentanil, codeine, oxycodeine, and PDE7 inhibitor for which the lesser of the ICs for inhibiting heroin. In a further embodiment, the addictive agent is a 45 PDE7A activity and the ICs for inhibiting PDE7B activity is psychostimulant, e.g., cocaine, amphetamine or an amphet less than one tenth the ICso that the agent has for inhibiting the amine derivative. In another embodiment, the addictive agent activity of any other PDE enzyme from the PDE1-6 and is cocaine. PDE8-11 enzyme families. In another embodiment, the In one aspect of the invention, the Subject is addicted to an PDE7 inhibitory agentis a highly selective PDE7 inhibitor for addictive or compulsive behavior or suffers from an impulse 50 which the lesser of the ICs for inhibiting PDE7A activity and control disorder. In another aspect of the invention, the sub the ICs for inhibiting PDE7B activity is less than one fiftieth ject Suffers from a primary impulse-control disorder, i.e., an the ICso that the agent has for inhibiting the activity of any impulse-control disorder in which the disorder is a primary other PDE enzyme from the PDE1-6 and PDE8-11 enzyme disorder rather than a disorder that is either iatrogenic (sec families. In a further embodiment, the PDE7 inhibitory agent ondary to medical treatment) or that is secondary to another 55 has a molecular weight of less than about 450 g/mole. In primary disease or disorder. Addictive or compulsive behav another embodiment, the PDE7 inhibitory agent is able to iors that are primary impulse-control disorders include the cross the blood/brain barrier. following: binge eating, pathological gambling, pathological The present invention provides a method of treating or use of electronic devices, pathological use of electronic video preventing an addiction by determining that a Subject has an games, pathological use of electronic communication 60 addiction or is at risk of developing an addiction and then devices, pathological use of cellular telephones, addiction to administering a chemical compound that inhibits PDE7 activ pornography, sex addiction, compulsive spending, anorexia, ity. The chemical compound has the following characteris bulimia, intermittent explosive disorder, kleptomania, pyro tics: (i) an ICs for inhibiting PDE7A and/or PDE7B activity mania, trichotillomania, compulsive over-exercising, and of less than about 1 uM; and (ii) an ICs for inhibiting PDE 3 compulsive overworking. In another embodiment, the addic 65 greater than 10 times the lesser of the ICs for inhibiting tive or compulsive behavior is a food addiction. In another PDE7A activity and/or the ICs for inhibiting PDE7B activ embodiment, the addictive or compulsive behavior is binge US 9.220,715 B2 7 8 In one embodiment, the chemical compound has an ICso invention, the subject to be treated in accordance with the for inhibiting PDE7A and/or PDE7B activity of less than present invention has an obsessive-compulsive disorder. about 100 nM. In another embodiment, the PDE7 inhibitory The present invention also provides a method of treating or agent has an ICs for inhibiting PDE1B activity of greater preventing an addiction, comprising providing to a subject than 5 times the lesser of the ICs for inhibiting PDE7A 5 having an addiction, an inhibitor of a phosphodiesterase 7 activity and the ICs for inhibiting PDE7B activity. In another (PDE7) and an additional therapeutic agent, wherein each of embodiment, the PDE7 inhibitory agenthas an ICs for inhib the PDE7 inhibitor and the additional therapeutic agent con iting PDE10 activity of greater than 5 times the lesser of the tribute to the effective treatment or prevention of the addic ICs for inhibiting PDE7A activity and the ICs for inhibiting tion. Additional therapeutic agents include, e.g., opioid PDE7B activity. In another embodiment, the PDE7 inhibitory 10 antagonists, mixed opioid partial agonist/antagonists, antide agent has an ICso for inhibiting PDE4 activity of greater than pressants, antiepileptics, antiemetics, corticotrophin-releas 10 times the lesser of the ICs for inhibiting PDE7A activity ing factor-1 (CRF-1) receptor antagonists, selective seroto and the ICs for inhibiting PDE7B activity. In a further nin-3 (5-HT3) antagonists, 5-HT2A/2C antagonists, embodiment, the PDE7 inhibitory agenthas an ICs for inhib cannabinoid-1 (CB1) receptor antagonists and dopamine iting PDE8 activity of greater than 10 times the lesser of the 15 receptor agonists or other dopaminergic agents. ICs for inhibiting PDE7A activity and the ICs for inhibiting Exemplary opioid antagonists include naltrexone and PDE7B activity. In another embodiment, the PDE7 agent has nalmefene. Exemplary antidepressants include fluoxetine, an ICs for inhibiting PDE1, PDE2, PDE3, PDE 4, PDE 8, mirtazapine, and bupropion. Exemplary antiepileptics PDE10, and PDE11 activity of greater than 10 times the lesser include topiramate, levetiracetam, and gabapentin. Anta of the ICs for inhibiting PDE7A activity and the IC50 for larmin is an exemplary CRF-1 receptor antagonist. inhibiting PDE7B activity. In a further embodiment, the Ondensetrom is an exemplary selective serotonin-3 (5-HT3) PDE7 inhibitory agent is a selective PDE7 inhibitor for which antagonist. Exemplary cannabinoid-1 (CB1) receptorantago the lesser of the IC50 for inhibiting PDE7A activity and the nists are rimonabant and tanarabant. Buprenorphine is an ICs for inhibiting PDE7B activity is less than one tenth the exemplary mixed opioid agonist/antagonist. Exemplary ICso that the agent has for inhibiting the activity of any other 25 opioid agonists include morphine, methadone, fentanyl. PDE enzyme from the PDE1-6 and PDE8-11 enzyme fami Sufentanil and heroin. lies. In another embodiment, the PDE7 inhibitory agent is a Exemplary dopaminergic agents include, for example, highly selective PDE7 inhibitor for which the lesser of the levodopa (also referred to as “L-dopa'), carbidopa, and ICs for inhibiting PDE7A activity and the ICs for inhibiting dopamine receptor agonists and precursors such as bro PDE7B activity is less than one fiftieth the ICs that the agent 30 mocriptine, pergolide, pramipexole, ropinirole, cabergoline, has for inhibiting the activity of any other PDE enzyme from apomorphine, lisuride, rotigotine and quinagolide, as well as the PDE1-6 and PDE8-11 enzyme families. In a further fenoldopam, which is selective for dopamine receptor D1. embodiment, the PDE7 inhibitory agent has a molecular In one aspect, the Subject is addicted to an addictive agent, weight of less than about 450 g/mole. In another embodiment, e.g., alcohol, nicotine, marijuana, a marijuana derivative, an the PDE7 inhibitory agent is able to cross the blood/brain 35 opioidagonist, a benzodiazepine, a barbiturate, and a psycho barrier. stimulant. In one embodiment, the addictive agent is alcohol In one aspect of the invention, the Subject is addicted to an and the additional therapeutic agent is an opioid antagonist, addictive agent. Examples of addictive agents include alco Such as naltrexone, or a mixed opioid antagonist/partial ago hol, nicotine, marijuana, a marijuana derivatives, opioid ago nist, Such as buprenorphine. In another embodiment, the Sub nists, benzodiazepines, barbiturates, and psychoStimulants. 40 ject is addicted to a psychoStimulant Such as cocaine, amphet In one embodiment, the addictive agent is alcohol. In another amine, an amphetamine derivative, or methamphetamine and embodiment, the addictive agent is nicotine. In a further the additional therapeutic agent is an antidepressant, such as embodiment, the addictive agent is an opioid, e.g., morphine, bupropion. In a further embodiment, the subject is addicted methadone, fentanyl, Sufentanil and heroin. In a further nicotine and the additional therapeutic agent is an antidepres embodiment, the addictive agent is a psychostimulant, e.g., 45 sant, such as bupropion. cocaine, amphetamine or an amphetamine derivative. In In another aspect, the Subject is addicted to an addictive or another embodiment, the addictive agent is cocaine. compulsive behavior, Such as a primary impulse-control dis In one aspect of the invention, the subject treated with a order, including, for example, pathological gambling, binge PDE7 inhibitor is addicted to an addictive or compulsive eating, pathological use of electronic devices, pathological behavior or suffers from an impulse-control disorder. In 50 use of electronic video games, pathological use of electronic another aspect of the invention, the subject suffers from a communication devices, pathological use of cellular tele primary impulse-control disorder, i.e., an impulse-control phones, addiction to pornography, sex addiction, compulsive disorder in which the disorder is a primary disorder rather spending, anorexia, bulimia, intermittent explosive disorder, than a disorder that is either iatrogenic (secondary to medical kleptomania, pyromania, trichotillomania, compulsive over treatment) or that is secondary to another primary disease or 55 exercising, and compulsive overworking. In one embodi disorder. Addictive or compulsive behaviors that are primary ment, the addictive or compulsive behavior is binge eating impulse-control disorders include the following: binge eat and the additional therapeutic agent is topiramate. In another ing, pathological gambling, pathological use of electronic aspect of the invention, the Subject to be treated in accordance devices, pathological use of electronic video games, patho with the present invention has an obsessive-compulsive dis logical use of electronic communication devices, pathologi 60 order. cal use of cellular telephones, addiction to pornography, sex The present invention provides a method of preventing addiction, compulsive spending, anorexia, bulimia, intermit relapse use of an addictive agent or practice of an addictive or tent explosive disorder, kleptomania, pyromania, trichotillo compulsive behavior, by treating a subject who has under mania, compulsive over-exercising, and compulsive over gone a period of abstinence from, or limited or reduced use of working. In another embodiment, the subject suffers from 65 the addictive agent or the addictive or compulsive behavior by food addiction. In another embodiment, the addictive or com administering a PDE7 inhibitor to the subject. The present pulsive behavior is binge eating. In another aspect of the invention also provides a method of preventing relapse of an US 9.220,715 B2 10 addictive or compulsive behavior associated with a primary following: binge eating, pathological gambling, pathological impulse-control disorder, by treating a subject who has under use of electronic devices, pathological use of electronic video gone a period of remission from, or limited or reduced prac games, pathological use of electronic communication tice of the addictive or compulsive behavior associated with devices, pathological use of cellular telephones, addiction to the primary impulse-control disorder by administering a pornography, sex addiction, compulsive spending, anorexia, PDE7 inhibitor to the subject. The present invention also bulimia, intermittent explosive disorder, kleptomania, pyro provides a method of preventing relapse of addictive or com mania, trichotillomania, compulsive over-exercising, and pulsive behavior associated with an obsessive-compulsive compulsive over-working. In a preferred embodiment, the disorder, by treating a subject who has undergone a period of addictive or compulsive behavior is binge eating. In another remission from, or limited or reduced practice of the addic 10 aspect of the invention, the Subject to be treated in accordance tive or compulsive behavior associated with the obsessive with the present invention has an obsessive-compulsive dis compulsive disorder by administering a PDE7 inhibitor to the order. Subject. Additional therapeutic agents that contribute to the In one embodiment, the additional therapeutic agent of the effect prevention of relapse can be administered with the pharmaceutical composition is an opioid antagonist, a mixed PDE7 inhibitor. This treatment can be administered to sub 15 opioid partial agonist/antagonist, an antidepressant, an anti jects that have previously been treated with a different anti epileptic, an antiemetic, a corticotrophin-releasing factor-1 addiction treatment that is no longer being used. (CRF-1) receptor antagonist, a selective serotonin-3 (5-HT3) In one aspect, the relapse use of addictive agents such as antagonist, a 5-HT2A/2C antagonist, or a cannabinoid-1 alcohol, nicotine, marijuana, marijuana derivatives, opioid (CB1) receptor antagonist. agonists, benzodiazepines, barbiturates, and psychoStimu Exemplary opioid antagonists include naltrexone or lants is prevented through the administration of PDE7 inhibi nalmefene. Exemplary antidepressants include fluoxetine, tors. In a preferred embodiment, the relapse use of cocaine, mirtazapine, or bupropion. Exemplary antiepileptics include amphetamine, or methamphetamine is prevented. topiramate, levetiracetam, and gabapentin. Antalarmin is an In another aspect, the relapse of an addictive or compulsive exemplary CRF-1 receptor antagonist. Ondensetrom is an behavior, in particular addictive or compulsive behavior asso 25 exemplary selective serotonin-3 (5-HT3) antagonist. Exem ciated with a primary impulse-control disorders, is prevented plary cannabinoid-1 (CB1) receptor antagonists are rimona through the administration of PDE7 inhibitors. In a preferred bant and tanarabant. Buprenorphine is an exemplary mixed embodiment, the relapse of the following behaviors is pre opioid agonist/antagonist. vented: binge eating, pathological gambling, pathological use In one aspect, the Subject is addicted to an addictive agent, of electronic devices, pathological use of electronic video 30 e.g., alcohol, nicotine, marijuana, a marijuana derivative, an games, pathological use of electronic communication opioidagonist, a benzodiazepine, a barbiturate, and a psycho devices, pathological use of cellular telephones, addiction to stimulant. In one embodiment, the addictive agent is alcohol pornography, sex addiction, compulsive spending, anorexia, and the additional therapeutic agent is an opioid antagonist, bulimia, intermittent explosive disorder, kleptomania, pyro Such as naltrexone, or a mixed opioid antagonist/partial ago mania, trichotillomania, compulsive over-exercising, and 35 nist, Such as buprenorphine. In another embodiment, the compulsive overworking. In one embodiment, the addictive addictive agent is nicotine and the additional therapeutic or compulsive behavior is binge eating that has been induced agent is Varenicline. In another embodiment, the Subject is by stress. In another embodiment, the subject is treated to addicted to a psychostimulant such as cocaine, amphetamine, prevent relapse of addictive or compulsive behavior associ an amphetamine derivative, or methamphetamine and the ated with an obsessive-compulsive disorder. 40 additional therapeutic agent is an antidepressant, such as The present invention provides a pharmaceutical compo bupropion. In a further embodiment, the subject is addicted sition that includes a PDE7 inhibitor and an additional thera nicotine and the additional therapeutic agent is an antidepres peutic agent, where both the PDE7 inhibitor and the addi sant, such as bupropion. In another embodiment, the Subject tional therapeutic agent contribute to the effective treatment is addicted to more than one addictive agents and the addi or prevention of an addiction. Unit dosages of the pharma 45 tional therapeutic agent is an opioid antagonist, Such as nal ceutical composition are also provided. trexone, or a mixed opioid antagonist/partial agonist, such as In one aspect of the invention, the Subject is addicted to an buprenorphine. addictive agent. Examples of addictive agents include alco The present invention provides a kit for the treatment or hol, nicotine, marijuana, marijuana derivatives, opioid ago prevention of an addiction. The kit includes a first container nists, benzodiazepines, barbiturates, cocaine and other psy 50 containing a PDE7 inhibitor and a second container contain chostimulants. In one embodiment, the addictive agent is ing an additional therapeutic agent. Both the PDE7 inhibitor alcohol. In another embodiment, the addictive agent is nico and the additional therapeutic agent contribute to the effective tine. In a further embodiment, the addictive agentis an opioid, treatment or prevention of an addiction. e.g., morphine, methadone, fentanyl, Sufentaniland heroin. In In one embodiment, the additional therapeutic agent of the a further embodiment, the addictive agent is a psychoStimu 55 pharmaceutical composition is an opioid antagonist, a mixed lant, e.g., cocaine, amphetamine or an amphetamine deriva opioid partial agonist/antagonist, an antidepressant, an anti tive. In a preferred embodiment, the addictive agent is epileptic, an antiemetic, a corticotrophin-releasing factor-1 cocaine. (CRF-1) receptor antagonist, a selective serotonin-3 (5-HT3) In one aspect of the invention, the Subject is addicted to an antagonist, a 5-HT2A/2C antagonist, or a cannabinoid-1 addictive or compulsive behavior or suffers from an impulse 60 (CB1) receptor antagonist. control disorder. In another aspect of the invention, the sub Exemplary opioid antagonists include naltrexone and ject Suffers from a primary impulse-control disorder, i.e., an nalmefene. Exemplary antidepressants include fluoxetine, impulse-control disorder in which the disorder is a primary mirtazapine, and bupropion. Exemplary antiepileptics disorder rather than a disorder that is either iatrogenic (sec include topiramate, levetiracetam, and gabapentin. Anta ondary to medical treatment) or that is secondary to another 65 larmin is an exemplary CRF-1 receptor antagonist. primary disease or disorder. Addictive or compulsive behav Ondensetrom is an exemplary selective serotonin-3 (5-HT3) iors that are primary impulse-control disorders include the antagonist. Exemplary cannabinoid-1 (CB1) receptorantago US 9.220,715 B2 11 12 nists are rimonabant and tanarabant. Buprenorphine is an FIG. 1 demonstrates the effect of OMS182056, a PDE7 exemplary mixed opioid agonist/antagonist. inhibitor, on cocaine self-administration by rats. In one aspect, the Subject is addicted to an addictive agent, FIG. 2 demonstrates the effect of OMS181869, a PDE7 e.g., alcohol, nicotine, marijuana, a marijuana derivative, an opioidagonist, a benzodiazepine, a barbiturate, and a psycho inhibitor, on cocaine self-administration by rats. stimulant. In one embodiment, the addictive agent is alcohol FIG. 3 demonstrates the effect of OMS182401, a PDE7 and the additional therapeutic agent is an opioid antagonist, inhibitor, on cocaine self-administration by rats. Such as naltrexone, or a mixed opioid antagonist/partial ago FIG. 4 demonstrates the effect of SKF82958, a dopamine nist, Such as buprenorphine. In another embodiment, the Sub D1 agonist, on cocaine self-administration by rats. ject is addicted to a psychoStimulant Such as cocaine, amphet FIG. 5 demonstrates the effect of OMS182056, a PDE7 amine, an amphetamine derivative, or methamphetamine and 10 inhibitor, on non-reinforced lever-press response by rats. the additional therapeutic agent is an antidepressant, Such as FIG. 6 demonstrates the effect of SKF82958, a dopamine bupropion. In a further embodiment, the subject is addicted D1 agonist, on non-reinforced lever-press response by rats. nicotine and the additional therapeutic agent is an antidepres FIG. 7 demonstrates the chronic effect of OMS182401, a sant, such as bupropion. In another embodiment, the Subject PDE7 inhibitor, on cocaine self-administration in rats. is addicted to more than one addictive agents and the addi 15 tional therapeutic agent is an opioid antagonist, Such as nal FIG. 8 demonstrates the effect of OMS182056, a PDE7 trexone, or a mixed opioid antagonist/partial agonist, Such as inhibitor, on lever-press response by rats on the first day of buprenorphine. extinction following cocaine addiction. In another aspect of the invention, a Subject at risk of FIG. 9 demonstrates the effect of OMS182056, a PDE7 addiction to an addictive Substance is administered the addic inhibitor, on yohimbine-induced relapse to cocaine seeking tive substance in combination with a PDE7 inhibitor. For by rats. example, a Subject that will be administered an opioid agonist FIG. 10 demonstrates the effect of OMS182401, a PDE7 for the relief of acute or chronic pain is administered an opioid inhibitor, on yohimbine-induced relapse to cocaine seeking agonist in combination with a PDE7 inhibitor such that non by rats. addictive or less addictive analgesia is provided. Examples of 25 FIG. 11 demonstrates the effect of OMS182056, a PDE7 addictive agents that may be administered in combination inhibitor, on cue-induced relapse to cocaine seeking by rats. with a PDE7 inhibitor, as either a fixed-dose combination or as a kit, include benzodiazepines, barbiturates, and pain FIG. 12 demonstrates the effect of OMS182401, a PDE7 medications including alfentanil, allylprodine, alphaprodine, inhibitor, on cue-induced relapse to cocaine seeking by rats. anileridine benzylmorphine, bezitramide, buprenorphine, FIG. 13 demonstrates the effect of OMS182056, a PDE7 butorphanol, clonitaZene, codeine, cyclazocine, desomor 30 inhibitor, on cocaine priming-induced relapse by rats. phine, dextromoramide, dezocine, diampromide, dihydroco FIG. 14 demonstrates the effect of SKF82958, a dopamine deine, dihydromorphine, dimenoxadol, dimepheptanol, dim D1 agonist, on cocaine priming-induced relapse by rats. ethylthiambutene, dioxaphetyl butyrate, dipipanone, FIG. 15 demonstrates the effect of OMS182401, a PDE7 eptazocine, ethoheptazine, ethylmethylthiambutene, ethyl inhibitor, on nicotine self-administration in rats using a short morphine, etonitaZene fentanyl, heroin, hydrocodone, hydro 35 access model. morphone, hydroxypethidine, isomethadone, ketobemidone, FIG. 16 demonstrates the effect of OMS182401, a PDE7 levallorphan, levorphanol, levophenacylmorphan, lofenita inhibitor, on nicotine self-administration in rats using a long nil, meperidine, meptazinol, metazocine, methadone, meto access model. pon, morphine, myrophine, nalbuphine, narceline, nicomor FIG. 17 demonstrates the effect of OMS182399, a PDE7 phine, norlevorphanol, normethadone, nalorphine, 40 inhibitor, on nicotine self-administration in rats using a short normorphine, norpipanone, opium, oxycodone, OXYCON access model. TINR, oxymorphone, papaveretum, pentazocine, phenadox FIGS. 18A and 18B demonstrate that the PDE7 inhibitors one, phenomorphan, phenazocine, phenoperidine, piminod OMS182399 and OMS182401, respectively, do not have an ine, piritramide, propheptazine, promedol, properidine, effect on food self-administration. propiram, propoxyphene Sufentanil, tramadol, tilidine, salts 45 FIGS. 19 A-19C demonstrate the effect of OMS182401, a thereof, mixtures of any of the foregoing, and mixed L-ago PDE7 inhibitor, on motivation of nicotine-addicted mice to nists/antagonists. acquire nicotine in a self-administration progressive ratio In some embodiments, for any of the methods and compo study. sitions described herein, the following PDE7 inhibitors are used formula 1A, formula 1B, formula 29, formula 30, for FIG. 20 demonstrates the effect of OMS182401, a PDE7 mula 31, formula 32, formula 33, formula 34, formula 35, 50 inhibitor, on the first day of extinction of nicotine self-admin formula 36, formula 37, formula 38, formula 39, formula 40, istration. formula 41, formula 42, formula 43A, formula 43B, formula FIG. 21 demonstrates the effect of OMS182401, a PDE7 44, formula 45, formula 46, formula 47, formula 48, formula inhibitor, on cue-induced reinstatement of nicotine seeking 49, formula 50, formula 51, formula 52, formula 53, formula behavior. 54, formula 6A, formula 6B, formula 6C, formula 6D, for 55 FIG. 22 demonstrates the effect of OMS182401, a PDE7 mula 6E, formula 6F, formula 6G, formula 6H, formula 16A, inhibitor, on yohimbine-induced reinstatement of nicotine compound 1, compound 2, compound 3, and compound 4. seeking behavior. In another embodiment of the invention, a PDE7 inhibitor FIGS. 23A-23D demonstrates the effect of OMS182401, a is provided to a Subject that is addicted or at risk of becoming PDE7 inhibitor, on stress induce binge eating by rats. FIG. addicted to an addictive substance to reduce the motivation of 60 23A shows the results for control animals, which were not the Subject to seek or acquire the addictive Substance. stressed or subjected to dietary restriction. FIG. 23B shows the results for experimental animals that were not stressed and BRIEF DESCRIPTION OF THE DRAWINGS were subjected to dietary restriction. FIG. 23C shows the results for experimental animals that were stressed and were The present invention will now be described in greater 65 not subjected to dietary restriction. FIG. 23D shows the detail, by way of example, with reference to the accompany results for experimental animals that were stressed and were ing drawings in which: subjected to dietary restriction. US 9.220,715 B2 13 14 FIGS. 24A-24D demonstrates the effect of OMS182056, a risk for developing an addiction. In various embodiments, the PDE7 inhibitor, on stress induce binge eating by rats. FIG. Subject is addicted to an addictive agent or behavior, includ 24A shows the results for control animals, which were not ing, but not limited to, any of the addictive agents and behav stressed or subjected to dietary restriction. FIG. 24B shows iors described herein. The subject may be physically or physi the results for experimental animals that were not stressed and 5 ologically dependent on the Substance or behavior; the were subjected to dietary restriction. FIG. 24C shows the Subject may be psychologically dependent; or the Subject results for experimental animals that were stressed and were may be both physically and psychologically dependent. The not subjected to dietary restriction. FIG. 24D shows the Subject may be addicted to one or more than one addictive results for experimental animals that were stressed and were agent or behavior. subjected to dietary restriction. 10 As used herein, unless the context makes clear otherwise, FIGS. 25A-30D demonstrates the effect of topiramate, as a “treat, and similar word such as “treatment,” “treating etc., comparator, on stress induce binge eating by rats. FIG. 25A is an approach for obtaining beneficial or desired results, shows the results for control animals, which were not stressed including and preferably clinical results. Treatment can or subjected to dietary restriction. FIG. 25B shows the results involve optionally either the reducing or amelioration of a for experimental animals that were not stressed and were 15 disease or condition, (e.g., addiction or relapse use or behav subjected to dietary restriction. FIG. 25C shows the results for ior), or the delaying of the progression of the disease or experimental animals that were stressed and were not Sub condition (e.g., addiction, or relapse use or behavior). jected to dietary restriction. FIG. 26D shows the results for As used herein, unless the context makes clear otherwise, experimental animals that were stressed and were subjected “prevent, and similar word such as “prevention.” “prevent to dietary restriction. ing” etc., is an approach for preventing the onset or recurrence FIG. 26 demonstrates the effect of the PDE7 inhibitor of a disease or condition, (e.g., addiction, or relapse use or OMS182399 on yohimbine-induced relapse to food seeking behavior) or preventing the occurrence or recurrence of the in a food addiction model. symptoms of a disease or condition, or optionally an approach FIGS. 27 and 28 demonstrates the effect of OMS182399, a for delaying the onset or recurrence of a disease or condition PDE7 inhibitor, on basal and nicotine-induced, respectively, 25 or delaying the occurrence or recurrence of the symptoms of dopamine release in the nucleus and accumbens of Wistar rats a disease or condition. by an in vivo microdialysis study. As used herein the term “PDE7 is used generically to refer FIGS. 29A-29B demonstrate that OMS182401, a PDE7 to all translation products coded by transcripts of either or inhibitor, inhibits spontaneous activity of dopaminergic ven both of these two genes: PDE7A and/or PDE7B. tral tegmental area (VTA) neurons, and potentiates the inhibi 30 As used herein, the term “PDE7 inhibitory agent” or tory effect of SKF82958, a dopamine D1 agonist. “inhibitor of PDE7' refers to an agent, such as a chemical FIG. 30 demonstrates the effect of the PDE7 inhibitor compound, a peptide, or a nucleic acid molecule, that directly OMS 182401 on VTA GABA release. or indirectly inhibits or blocks the phosphodiesterase activity FIG. 31 demonstrates that the PDE7 inhibitor OMS182401 of PDE7A, PDE7B, or PDE7A and PDE7B. In some cases, inhibits the activation of dopaminergic VTA neurons by nico 35 the agent may bind or interact directly with PDE7 protein. An tine and acts synergistically with the dopamine D1 agonist agent that binds to PDE7 may act to inhibitor block the PDE7 SKF82958. activation by any Suitable means, such as by inhibiting the FIG. 32 demonstrates the effect of direct administration of binding of cAMP or substrate ligand with PDE7. In other the PDE7 inhibitor OMS182401 into rat VTA. cases, the PDE7 inhibitory agent may inhibit PDE7 activity FIG.33 demonstrates that the PDE7 inhibitor OMS182399 40 indirectly, such as by decreasing expression of the PDE7 dose-dependently blocks morphine-induced excitation of protein. In some cases, the PDE7 inhibitory agent may inhibit VTA dopamine cells. PDE7 activity by altering the cellular distribution of PDE7, FIG. 34 demonstrates that acute application of the PDE7 for example, by interfering with the association between inhibitor OMS182399 dose-dependently blocks ethanol-in PDE7 and an intracellular anchoring protein. duced excitation of VTA dopamine cells. 45 As used herein, the term "dopaminergic agent” refers to an FIG. 35 demonstrates that acute application of the PDE7 agent that functions to enhance or replicate the effects medi inhibitor OMS182399 dose-dependently reverts cocaine-in ated by dopamine in the central nervous system, including duced excitation of VTA dopamine cells. dopamine (if a clinically effective method of delivery should FIG. 36 demonstrates that the PDE7 inhibitor OMS182401 be developed), dopamine precursors, such as levodopa potentiates the activity of the dopamine D1 agonist 50 (L-dopa), dopamine cofactors, inhibitors of enzymes that SKF82958 in an open field activity model. metabolize dopamine, other dopamine receptor agonists and precursor compounds that are metabolically converted to a DETAILED DESCRIPTION OF THE PREFERRED dopamine receptor agonist, as well as dopamine reuptake EMBODIMENT inhibitors and facilitators of dopamine release. 55 As used herein, the term "dopamine receptor agonist' The present invention is based upon the Surprising discov refers to any molecule that causes the activation of one or ery by the present inventors that selective inhibitors of the more of the Subtypes of the dopamine receptor protein family. type 7 cyclic nucleotide phosphodiesterase (PDE7) cause a As used herein, the term “mammalian subject' includes all striking decrease in relapse of addiction. Using rat models, mammals, including without limitation humans, non-human the decreases were demonstrated in Subjects addicted to 60 primates, dogs, cats, horses, sheep,goats, cows, rabbits, pigs, addictive agents and in Subjects that exhibited compulsive and rodents. behaviors. Generally, a subject is provided with an effective amount of A. Methods of Treating and Preventing Addictions Using a PDE7 inhibitor. As used herein, an “effective amount’ or a PDE7 Inhibitor(s) “therapeutically effective amount of a Substance, e.g., a Thus, the present invention includes methods of treating or 65 PDE7 inhibitor, is that amount sufficient to affect a desired preventing an addiction, comprising administering one or biological or psychological effect, Such as beneficial results, more PDE7 inhibitors to a subject having an addiction or at including clinical results. For example, in the context of treat US 9.220,715 B2 15 16 ing addiction using the methods of the present invention, an ment or prevention of the addiction. The dosage of the PDE7 effective amount of a PDE7 inhibitor is that amount sufficient inhibitor, or the PDE7 inhibitor and the one additional thera to cause the Subject to reduce or discontinue use of an addic peutic agent, may be specifically determined by the medical tive agent. In the case of an addictive behavior, an effective practitioner for treatment or prevention of the addiction rather amount of a PDE7 inhibitor is that amount sufficient to cause than for any other disorder or disease. the subject to reduce or discontinue the addictive behavior. In particular embodiments, the Subject is Suffering from or In one embodiment, a therapeutically effective dose is an at risk for addiction to any physically addictive agent or amount of PDE7 inhibitory agent sufficient to inhibit PDE7 addictive or compulsive behavior, including, e.g., any of enzyme activity in a neuronal cell. In another embodiment of those described below. In particular embodiments, the subject the methods of the invention, a therapeutically effective dose 10 is addicted to alcohol, cocaine, nicotine, marijuana, an opiate is an amount of PDE7 inhibitory agent sufficient to inhibit or other opioid agonist or methamphetamine or other psycho PDE7 enzyme activity in striatal neurons or nucleus acum stimulant, or phencyclidine and phencyclidine derivatives. In bens. The determination of an effective dose of a PDE7 another embodiment, the subject suffers from a primary inhibitory agent Sufficient to cross a cellular membrane and impulse-control disorder. In still another embodiment, the inhibit PDE7 enzyme activity within a cell may be deter 15 subject suffers from obsessive-compulsive disorder. In still mined using a cellular assay for PDE7 inhibition, such as another embodiment, the subject has a history of repeated described by Smith S. J. et al., Molecular Pharmacology dieting and is at risk of binge eating. 66(6): 1679-1689 (2004), hereby incorporated by reference. In particular embodiments, a Subject is considered at risk of The determination of an effective dose of a PDE7 inhibitory addiction or relapse to use of an addictive agent or practice of agent sufficient to inhibit PDE7 enzyme activity in the stria an addictive behavior when the subject has previously been tum may be determined using an assay for measuring the addicted to the same or a different addictive agent or addictive effect of a PDE inhibitory agent on cAMP levels in the stria or compulsive behavior. In certain embodiment, the subject is tum, as described in Siuciak J. A. et al., Neuropharmacology considered at risk of addiction or relapse to use of an addictive 51: 386-396 (2006), hereby incorporated by reference. agent or practice of an addictive behavior when the Subject is According to certain embodiments of the present inven 25 psychologically addicted to an addictive agent or addictive or tion, a subject is provided with a PDE7 inhibitor alone, while compulsive behavior, even if the Subject is no longer physi in other embodiments, a subject is provided with a PDE7 cally addicted. In one embodiment, the subject suffers from inhibitorin combination with an additional therapeutic agent. food addiction. In other embodiments, the addictive behavior It is understood that the effective amount of either or both of is binge eating. Subjects at risk of binge eating typically have a PDE7 inhibitor and an additional therapeutic agent may be 30 at least one of the following in their history: recurring food different when either is provided alone than when provided in restrictions or yo-yo dieting, eating in response to environ combination. For example, when the PDE7 inhibitor and the mental stress, preference for highly palatable and high caloric additional therapeutic agent act synergistically, then a lower food, eating after reaching fullness, and eating to the point of amount of the PDE7 inhibitor, a lower amount of the addi discomfort. In another embodiment, the subject suffers from tional therapeutic agent, or lower amounts of both the PDE7 35 a primary impulse-control disorder. inhibitor or the additional therapeutic agent may be required In certain embodiments, the subject is addicted to or at risk to achieve the same therapeutic effect that would be provided of becoming addicted to a therapeutic agent provided to the by either the PDE7 inhibitor or the additional therapeutic patient to treat a disease or disorder, e.g., a pain medication. In agent alone. In other embodiments, the same amount of the a related embodiment, the Subject may beat risk of abusing an PDE7 inhibitor and the additional therapeutic agent are used 40 addictive therapeutic agent, such as a pain medication. Abus to provide an enhanced therapeutic effect relative to the thera ing an addictive therapeutic agent, in certain embodiments, is peutic effect provided by either the PDE7 inhibitor or the understood to indicate using the agent for a reason different additional therapeutic agent alone. than or in addition to its prescribed use. In such a situation, a According to certain embodiments of the present inven subject may be provided with both an addictive therapeutic tion, a subject is provided with a PDE7 inhibitor in combina 45 agent and a PDE7 inhibitor, alone or in combination with an tion with an addictive therapeutic agent, with the dosage of additional therapeutic agent. For example, a Subject Suffering the addictive therapeutic agent being determined to achieve from pain, or at risk of pain, may be provided with an opioid the desired therapeutic effect and the dosage of the PDE7 agonist and a PDE7 inhibitor, to both provide analgesia and inhibitor being determined to eliminate or reduce the poten prevent or treat addiction to the opioid agonist. tial for addiction to the addictive therapeutic agent. 50 In various embodiments, the subject is provided with the The Subject may be any animal, including a mammal, and, PDE7 inhibitor at the same time that the subject is using an particularly, a human. addictive agent, after the Subject has discontinued use of an In one aspect of the invention, the subject is first deter addictive agent, or before the Subject begins using an addic mined or diagnosed to have an addiction, or to be at risk of tive agent. developing an addiction, by diagnostic testing, observation or 55 Addictive Agents and Impulse Control Disorders analysis by a medical care provider. An effective amount of a The term “addiction' is used to describe a recurring com PDE7 inhibitor, or an effective amount of a PDE7 inhibitor pulsion by an individual to engage in Some specific activity, and one additional therapeutic agent, are then provided to the despite harmful consequences to the individuals health, subject for treatment or prevention of the addiction. In mental state or social life. The term is often reserved for drug another aspect of the invention, the subject is first determined 60 addictions, but it is applied to other compulsions, such as or diagnosed to have an addiction, or to be at risk of devel problem gambling, and binge eating. Factors that have been oping an addiction, by diagnostic testing, observation or Suggested as causes of addiction include genetic, biological/ analysis by a medical care provider, but the Subject has not pharmacological and social factors. been diagnosed or determined to have diabetes or other insu The medical community now makes a careful theoretical lin disorder. An effective amount of a PDE7 inhibitor, or an 65 distinction between physical or physiological dependence effective amount of a PDE7 inhibitor and one additional (characterized by Symptoms of withdrawal) and psychologi therapeutic agent, are then provided to the Subject for treat cal dependence (sometimes referred to simply as addiction). US 9.220,715 B2 17 18 Addiction is now narrowly defined as “uncontrolled, compul Opiates include alfentanil, allylprodine, alphaprodine, anile sive use.” If there is no harm being suffered by, or damage ridine, apomorphine, benzylmorphine, beta-hydroxy 3-meth done to, the patient or another party, then clinically it may be ylfentanyl, bezitramide, carfentanil, clonitaZene, codeine, considered compulsive, but to the definition of some it is not desomorphine, dextromoramide, diacetylmorphine (heroin), categorized as “addiction'. In practice, the two kinds of 5 diampromide, dihydro codeine, dihydroetorphine, dihydro addiction (physiological dependence and psychological morphine, dimenoxadol, dimepheptanol, dimethylthiam dependence) are not always easy to distinguish. Addictions butene, dioxaphetylbutyrate, dipipanone, eptazocine, etho often have both physical and psychological components. heptazine, ethylmethylthiambutene, ethylmorphine, “Physical dependence” (or "drug dependence') refers to a etonitaZene, etorphine, fentanyl, hydrocodone, hydromor state resulting from habitual use of a drug, where negative 10 phone, hydroxypethidine, isomethadone, ketobemidone, physical withdrawal symptoms result from abrupt discon LMM, levorphanol, levophenacylmorphan, lofentanil, mep tinuation. Examples of addictive agents for which a user may eridine, metapon, metazocine, methadone, methadyl acetate, develop a physical dependence include nicotine, opioids, bar metopon, morphine, myrophine, narceline, nicomorphine, biturates, benzodiazepines, alcohol, i.e., ethyl alcohol, GHB, norlevorphanol, normethadone, normorphine, norpipanone, and methaqualone. 15 opium, oxycodone, oxymorphone, papaverine, phenadox Commonly abused stimulants such as cocaine or amphet one, phenomorphan, phenoperidine, piminodine, piritra amine class drugs are not believed to cause significant physi mide, propheptazine, promedol, properidine, propoxyphene, cal dependence. However, their potential for extreme psycho remifentanil, Sufentanil, thebaine, tildine, and tramadol. logical addiction can compel the user to consume amounts Naturally occurring opiates include codeine, morphine, which become physically damaging, but life-threatening noscapine, papaverine, and thebaine. Semi-synthetic opioids withdrawal effects have not been observed. include diacetylmorphine, hydrocodone, hydromorphone, As used herein, “addictive agent(s) includes any and all levorphanol, metapon, nalorphine, naloxone, naltrexone, agents to which a Subject can become addicted, either physi oxycodone, oxymorphone, and tramadol. Synthetic opioids cally or psychologically, or both. As noted above, addiction include ethoheptazine, fentanyl, levorphanol, meperidine, includes addiction to chemical entities, such as drugs, as well 25 methadone, phenazocine, propoxyphene and Sufentanil. as addiction to behaviors, as in impulse control disorders. Three broad classifications of opiates are phenanthrenes, Addictive agents include addictive recreational drugs, as phenylheptylamines, and phenylpiperidines. Examples of well as addictive medications. Examples of addictive agents phenanthrenes include codeine, etorpine, hydrocodone, include, but are not limited to, alcohol, e.g., ethyl alcohol, hydromorphone, morphine, oxycodone, and oxymorphone. gamma hydroxybutyrate (GHB), caffeine, nicotine, cannabis 30 Examples of phenylheptylamines include dimeheptanol, (marijuana) and cannabis derivatives, opiates and other mor dimenoxadol, dipipanone, isomethadone, methadone, meth phine-like opioid agonists such as heroin, phencyclidine and adyl acetate, and propoxyphene. Examples of phenylpip phencyclidine-like compounds, sedative hypnotics such as eridines include alfentanyl, alphaprodine, beta-promedol, benzodiazepines, methaqualone, mecloqualone, etaqualone carfentanyl, fentanyl, lofentanil, meperidine, properidine, and barbiturates and psychoStimulants such as cocaine, 35 and Sufentanil. amphetamines and amphetamine-related drugs such as dex Specific psychostimulants include, by way of example, troamphetamine and methylamphetamine. Other examples amphetamine, cocaine, dextroamphetamine, methamphet include LSD, psilocybin, ecstasy and other hallucinogens. amine, pemoline, Ritalin, Adderall and methylene Examples of addictive medications include, e.g., benzodiaz dioxymethamphetamine. epines, barbiturates, and pain medications including alfenta 40 As noted above, addiction includes addiction to behaviors, nil, allylprodine, alphaprodine, anilleridine benzylmorphine, e.g., food addiction, binge eating disorder, pathological gam bezitramide, buprenorphine, butorphanol, clonitaZene, bling, pathological use of electronic devices, e.g., Black codeine, cyclazocine, desomorphine, dextromoramide, dezo Berry(R), pathological use of electronic video games, patho cine, diampromide, dihydrocodeine, dihydromorphine, logical use of electronic communication devices, dimenoxadol, dimepheptanol, dimethylthiambutene, diox 45 pathological use of cellular telephones, addiction to pornog aphetylbutyrate, dipipanone, eptazocine, ethoheptazine, eth raphy, sex addiction, obsessive-compulsive disorder, com ylmethylthiambutene, ethylmorphine, etonitaZene fentanyl. pulsive spending, intermittent explosive disorder, kleptoma heroin, hydrocodone, hydromorphone, hydroxypethidine, nia, pyromania, trichotillomania, compulsive over isomethadone, ketobemidone, levallorphan, levorphanol, exercising, and compulsive overworking. levophenacylmorphan, lofenitanil, meperidine, meptazinol, 50 In one aspect of the invention, a Subject treated with a metazocine, methadone, metopon, morphine, myrophine, PDE7 inhibitor suffers from food addiction orbinge eating nalbuphine, narceline, nicomorphine, norlevorphanol, disorder, often with secondary health problems such as obe normethadone, nalorphine, normorphine, norpipanone, sity due to excessive consumption of food and/or malnutrition opium, oxycodone, OXYCONTINR, oxymorphone, papav due to excessive consumption of foods that are high in fat eretum, pentazocine, phenadoxone, phenomorphan, 55 and/or Sugar and low in vitamins and minerals. phenazocine, phenoperidine, piminodine, piritramide, proph As used herein “binge eating disorder” or “binge eating eptazine, promedol, properidine, propiram, propoxyphene includes at least one of the following episodic symptoms: Sufentanil, tramadol, tilidine, salts thereof, mixtures of any of eating large amounts of food, eating even when full, rapid the foregoing, mixed L-agonists/antagonists, and the like. eating, feeling that eating behavior is out of control, eating In certain embodiments, a subject may be addicted to an 60 Substantial amounts of food when not hungry, frequent diet opioid agonist. The terms "opioid agonist,” “opioid’ and ing possibly without weight loss, eating alone, feeling “opiate' are used interchangably herein and are used to des depressed or disgusted about eating habits, eating in response ignate a group of drugs that are, to varying degrees, opium- or to stress. Binge eating disorder is distinguished from other morphine-like in their properties. Their main use is for pain types of eating disorders, including food addiction, bulimia relief. These agents work by binding to opioid receptors, 65 and binge-purge syndromes. Unlike bulimia and binge-purge which are found principally in the central nervous system and syndromes, a subject Suffering from binge eating disorder and the gastrointestinal tract. Opiates are also addictive agents. food addiction-like behavior is that subjects suffering from US 9.220,715 B2 19 20 binge eating disorder and food addiction-like behavior do not excessive drug use, and contribute to the high rate of recidi undertake compensatory behavior to attenuate excessive vism typical of both disorders. Corwin, et al., “Feeling and calorie consumption. reward: perspective from three rat models of binge eating.” A body of scientific literature is building to support the Physiol Behav 104:87–97 (2011); Ghitza, et al., “The anxio characterization of certain types of problematic eating behav genic drug yohimbine reinstates palatable food seeking in a iors as addictions, given that binge eating and chronic excess rat relapse model: a role of CRF1 receptors. Neuropsychop eating share many characteristics with addictive behaviors harmacology 31(10):2188-2196 (2006): Mizes, et al., (e.g., diminished control, continued use despite negative con “Bulimia: A review of its symptomatology and treatment.” sequences). Despite similarities, binge eating disorder and Adv. Behav. Res. Ther. 7:91-142 (1985); Crowther, et al., “The food addiction may represent unique yet overlapping condi 10 role of daily hassles in binge eating.” IntJ Eat Disord 29:449 tions. Gearhardt, A. N., et al., Binge Eating Disorder and 454 (2001); Herman, et al., “Anxiety, restraint, and eating Food Addiction, Curr. Drug Abuse Rev, 4:201-207 (2011). behaviour.”J Abnorm Psychol 84:66-72 (1975). As used herein, the term “food addiction” refers to a regu Exposure to environmental conditioning stimuli has also lar, persistent and habitual pattern of overeating characterized been shown to play a critical role in eliciting drug craving in by craving and seeking high caloric foods, overeating in 15 addicted individuals as well as food craving in obese patients response to stimuli other than hunger, diminished control meeting the criteria for food addiction. Gearhardt, et al., over food consumption, continued consumption despite “Food addiction: an examination of the diagnostic criteria for negative consequences and diminished ability to cut down dependence. J Addict Med 3:1-7 (2011). Consistent with and abstain from consumption of an excess of food. Food studies in humans, in laboratory animals it has been shown addiction is a chronic relapsing disorder that typically follows that exposure to environmental conditioning factors and a course of over-eating, tolerance, withdrawal, high caloric exposure to stress (i.e., yohimbine) are similarly effective in food seeking behavior and relapse (initiation of overeating eliciting reinstatement behaviors for drugs of abuse and for after a period of abstinence). highly palatable food. Cifani, et al., “Preclinical model of A natural preference for highly palatable foods rich in fat binge-eating elicited by yo-yo dieting and stressful exposure and carbohydrate has developed for evolutionary reasons due 25 to food: effect of sibutramine, fluoxetine, topiramate and to the high caloric Support associated with Such foods. midazolam.” Psychopharmacology 204: 113-25 (2009); Although it is indisputable that feeding behavior is regulated Cifani, et al., “Pre-exposure to environmental cues predictive by homeostatic mechanisms, eating and overeating are also of food availability elicits hypothalamic-pituitary-adrenal regulated by emotional, affective and learning processes. axis activation and increases operant responding for food in Polivy, et al., “Food restriction and binge eating: a study of a 30 female rats.” Addict Biol. 14(4):397–407 (September 2009): former prisoner of war.” J Abnorm Psychol 103:409–411 Pickens, et al., “Effect of fenfluramine on reinstatement of (1994). In this respect several commonalities exist between food seeking in female and male rats: implications for the excessive eating and drug abuse (reward, reinforcement, predictive validity of the reinstatement model.” Psychophar effects on mood, external cue-control of appetite, stress-in macology (Berl) 221(2):341-353 (May 2012). Neural sys duced motivation). Evidence is accumulating that excessive 35 tems that motivate and reinforce drug abuse have also been intake of certain foods under specific conditions produces proposed to underlie behaviors associated with compulsive behaviors and changes in the brain that resemble an addic food seeking and excessive food intake. Johnson, et al., tion-like state. Gold, et al., “Overeating, binge eating, and “Dopamine D2 receptors in addiction-like reward dysfunc eating disorders as addictions. Psychiatr Ann 33:112-116 tion and compulsive eating in obese rats.” Nat Neurosci (2003); Kenny, et al., “Common cellular and molecular 40 13:635-641 (2010); Hoebel, et al., “Brain neurotransmitters mechanisms in obesity and drug addiction.” Nat Rev Neurosci in food and drug reward.” Am J Clin Nutr 42(5 Suppl): 1133 12:638-651 (2011); Pelchat, et al., “Images of desire: food 1150 (1985); Volkow, et al., “How can drug addiction help us craving activation during fMRI. Neuroimage 23: 1486-1493 understand obesity?” Nat Neurosci 8:555-560 (2005); Cor (2004): Avena, et al., “Evidence for sugar addiction: behav win, et al., “Feeling and reward: perspective from three rat ioral and neurochemical effects of intermittent, excessive 45 models of binge eating.” Physiol Behav 104:87–97 (2011): sugar intake. Neurosci Biobehav Rev. 32:20-39 (2008); Gearhardt, et al., “Neural correlates of food addiction.” Arch Ifland, et al., “Refined food addiction: a classic substance use Gen Psychiatry 68:808–816 (2011): Wang, et al., “Enhanced disorder.” Med Hypotheses 72:518-526 (2009); Gearhardt, et striatal dopamine release during food stimulation during al., “Food addiction: an examination of the diagnostic criteria binge eating disorder.” Obesity 19(8):1601-1608 (August for dependence.” J. Addict Med 3:1-7 (2011). 50 2011). For example, studies suggest that like in drug addicts, Drug addiction can be characterized by progressive esca an altered regulation of striatal dopamine (DA) may exist in lation in drug use, tolerance development, abstinence follow patients with bulimia nervosa. ing abrupt cessation of their use and recurrent relapse, and Interest in the concept of food addiction has recently similar phenomena have been described for high Sucrose high received greater attention, in large part due to the similarities fat food. For example, rats fed with highly palatable sucrose 55 between the behavioral indicators of addiction and binge Solution experience opiate-like withdrawal symptoms fol eating disorder (BED). Episodes of binge eating in humans lowing Sucrose removal. Cross sensitization between Sucrose are characterized by compulsive, non-homeostatic consump and drugs of abuse has also been described. Avena, et al., tion of an unusually large quantity of highly palatable food in “Evidence for sugar addiction: behavioral and neurochemical a short period of time. Even though they are not hungry, effects of intermittent, excessive Sugar intake. Neurosci 60 Subjects eat more rapidly than normal until feeling uncom Biobehav Rev.32:20-39 (2008): Avena, et al., “Dysregulation fortably full. As described by the DMS-IV-TR (American of brain reward systems in eating disorders: Neurochemical Psychiatric Association, “Diagnostic and statistic manual of information from animal models of binge eating, bulimia mental disorders. Washington, D.C. (2000)), these episodes nervosa, and anorexia nervosa. Neuropharmacology (Epub are accompanied by a subjective sense of loss of control over ahead of print) (Nov. 27, 2011). Moreover, it has been well 65 eating, and are associated with feeling of distress, disgust, documented that psychological stress and dysphoric mood depression, being guilty about overeating, and eating alone states play a major role in facilitating overeating as well as because of embarrassment. US 9.220,715 B2 21 22 BED, described for the first time by Stunkard, "Eating or more PDE7 inhibitor(s) and one or more additional thera patterns and obesity.” Psychiatry O 33:284-295 (1959), is peutic agent(s), in which each of the PDE7 inhibitor(s) and probably the most prevalent eating disorder. Hudson, et al., the additional therapeutic agent(s) contribute to the effective “The prevalence and correlates of eating disorders in the treatment or prevention of the addiction. In one embodiment, National Comorbidity Survey Replication. Biol Psychiatry 5 a subject is provided with or administered one PDE7 inhibitor 61:348-58 (2007). It is characterized by repeated episodes of and one additional therapeutic agent. In another embodiment, binge eating in the absence of compensatory behaviors to a Subject is addicted to two or more addictive agents. avoid weight gain. The diagnostic criteria for BED in the The PDE7 inhibitor and the additional therapeutic agent DSM-IV-TR include that binge eating episodes should occur may be administered at the same time (i.e., concurrently), or at least 2 days per week for six months. BED is associated 10 either may be administered before the other (i.e., sequen with significant medical and psychiatric co-morbidity. Jav tially). In general, both the PDE7 inhibitor and the additional aras, et al., "Co-occurrence of binge eating disorder with therapeutic agent are present in the Subject at the same time psychiatric and medical disorders. J Clin Psychiatry 269: for a duration of time and at levels sufficient to provide a 266-273 (2008); Grucza, et al., “Prevalence and correlates of therapeutic benefit to the subject, i.e., in the treatment or binge eating disorder in a community sample. Compr Psy 15 preventing of an addiction or the prevention of a relapse use chiatry 48:124-131 (2007). It is estimated that binge eating (or reinstatement) of an addictive agent or compulsive or afflicts approximately 5% of the US adult population at some addictive behavior. The PDE7 inhibitor and the additional time during their lives (Foulds, et al., “The biology of binge therapeutic agent may be administered by the same or differ eating. Appetite 52:545-553 (2009)) and that it contributes to ent routes of administration. Typically, the PDE7 inhibitor aggravate obesity and associated pathologies. Hudson, et al., and the additional therapeutic agent are each provided to a “The prevalence and correlates of eating disorders in the Subject according to a standard route of administration of a National Comorbidity Survey Replication. Biol Psychiatry commercially available or other pharmaceutical composition. 61:348-58 (2007); Yanovski. “Binge eating disorder and obe In one embodiment, the PDE7 inhibitor and the additional sity in 2003: could treating an eating disorder have a positive therapeutic agent are co-administered using a composition effect on the obesity epidemic?' Int J Eat Disord 34 Suppl: 25 comprising both agents. S117-S1120 (2003). The additional therapeutic agent provided in combination A large body of evidence Suggests that dieting, stress and with a PDE7 inhibitor may be any therapeutic agent that negative affective states represent important triggers of binge contributes to an aspect of the effective treatment or preven eating in patients suffering from BED or bulimia nervosa. tion of the addiction. For example, the additional therapeutic Wardle, et al., “Stress, dietary restraint and food intake.” J 30 agent may be a drug used to treat an addiction or a drug used Psychosom Res 48:195-202 (2000): Freeman, et al., “Daily to alleviate side-effects associated with physiological with stress, coping, and dietary restraint in binge eating.” IntJ Eat drawal from an addictive agent. In addition, the additional Disord 36: 204-212 (2004). Indeed, dieting periods are com therapeutic agent may be any drug that affects brain serotonin mon in the histories of binge eaters, although hunger itself neurotransmission, such as selective serotonin reuptake does not appear to be enough to induce bing eating in the 35 inhibitors (SSRIs), and tricyclic and tetracyclic serotonin and absence of stress and negative affective state. Polivy, et al., norepinephrine reuptake inhibitors (SNRIs) as described “Food restriction and binge eating: a study of former prisoner below, and serotonin agonists such as Sumatriptan, ergono of war.” J Abnorm Psychol 103:409–411 (1994); Waters, et vine, dihydroergotamine and buspirone. In certain embodi al., “Internal and external antecedents of binge eating epi ments, the additional therapeutic agent is an opioid antago sodes in a group of women with bulimia nervosa. Int J Eat 40 nist, including mixed opioid partial agonist/antagonists, an Disord 29:17-22 (2001). Considerable evidence suggests that antidepressant, an antiepileptic, an antiemetic, a dopaminer binge eating may be caused by a unique interaction between gic agent Such as a dopamine D1 receptor agonist, a corti dieting and stress; thus, environmental stress and a history of cotrophin-releasing factor-1 (CRF-1) receptor antagonist, a cyclic food restrictions may be responsible for its precipita selective serotonin-3 (5-HT3) antagonist, a 5-HT2A/2C tion and maintenance. Stice, et al. "Subtyping binge eating 45 antagonist Such as mianserin, mirtazapine and ketanserin, or disordered women along dieting and negative affect dimen a cannabinoid-1 (CB1) receptor antagonist, including but not sions.” Int J Eat Disord 30:11-27 (2001); Crowther, et al., limited to those therapeutic agents specifically described “The role of daily hassles in binge eating.” Int J Eat Disord herein. 29:449-454 (2001). Accordingly, recurring food restrictions In one embodiment, the addictive agent is alcohol and the are consistently the strongest predictor of overeating in 50 additional therapeutic agent is an opioidantagonist or a mixed response to stress. Wardle, et al., “Stress, dietary restraint and opioidantagonist/partial agonist. In a particular embodiment, food intake.” J Psychosom Res 48:195-202 (2000). the opioid antagonist is naltrexone. In another embodiment, While a subject may be addicted to a single addictive agent the mixed opioid partial agonist/antagonist is buprenorphine. or behavior, frequently subject is addicted to two or more In one embodiment, the addictive agent is alcohol, and the addictive agents or behaviors. Addiction to two or more 55 additional therapeutic agent is topiramate or levetiracetam. addictive agents or addictive behaviors is referred to as poly In one embodiment, the addictive agent is nicotine and the addiction. additional therapeutic agent is an antidepressant. In a particu B. Methods of Treating and Preventing Addiction and lar embodiment, the antidepressant is bupropion. Impulse Control Disorders Using PDE7 Inhibitor(s) in Com In one embodiment, the addictive agent is cocaine, and the bination with Other Therapeutic Agents 60 additional therapeutic agent is buprenorphine. PDE7 inhibitors may be effectively used in combination In one embodiment, the addictive agent is a psychoStimu with one or more additional therapeutic agents to treat or lant and the additional therapeutic agent is an antidepressant. prevent addiction, including addiction to one or more of the In a particular embodiment, the antidepressant is bupropion. addictive agents described herein and compulsive or addic In one embodiment, the addictive behavior is binge eating tive behavior. Accordingly, the present invention includes 65 and the additional therapeutic agent is an antidepressant oran methods of treating or preventing an addiction, comprising antiepileptic. In one particular embodiment, the antidepres administering to a Subject addicted to an addictive agent one sant is sibutramine. In another particular embodiment, the US 9.220,715 B2 23 24 antidepressant is fluoxetine. In one particular embodiment, are generally classified by their effects on the opioid recep the antiepileptic is topiramate. tors. Opioid antagonists may antagonize central receptors, In one embodiment, the addictive agent is nicotine, and the peripheral receptors or both. Naloxone and naltrexone are additional therapeutic agent is an anti-epileptic. In a particu commonly used opioid antagonist drugs that are competitive lar embodiment, the anti-epileptic is levetiracetam. In another 5 in that they bind to the opioid receptors with higher affinity particular embodiment, the anti-epileptic agent is naltrexone. than agonists, but do not activate the receptors. This effec In one embodiment, the subject is addicted to two or more tively blocks the receptor, preventing the body from respond addictive agents and the additional therapeutic agent is an ing to opiates and endorphins. opioid antagonist or a mixed opioid partial agonist/antago Many opioid antagonists are not pure antagonists but also nist. In a particular embodiment, the mixed opioid partial 10 produce Some weak opioid partial agonist effects, and can agonist/antagonist is buprenorphine. produce analgesic effects when administered in high doses to In one embodiment, the subject is addicted to both alcohol opioid-naive individuals. Examples of Such compounds and nicotine, and the additional therapeutic agent is an anti include nalorphine, and levallorphan. However, the analgesic epileptic. In a particular embodiment, the anti-epileptic is effects from these drugs are limited and tend to be accompa maltrexone. 15 nied by dysphoria, most likely due to action at the kappa For treatment of alcohol addiction, combinations to be opioid receptor. Since they induce opioid withdrawal effects administered in accordance with the present invention in people who are taking, or have previously used, opioid full include a PDE7 inhibitor and an opioid agonist or a mixed agonists, these drugs are considered to be antagonists. opioid antagonist/partial antagonist, a PDE7 inhibitor and an Naloxone is one example of an opioid antagonist that has antidepressant, a PDE7 inhibitor and a CB1 receptor antago no partial agonist effects. Instead, it is a weak inverse agonist nist/inverse agonist, a PDE7 inhibitor and Varenicline, a at mu opioid receptors, and is used for treating opioid over PDE7 inhibitor and acamprosate, and a PDE7 inhibitor and dose. disulfuram. Specific examples of opioid antagonists that may be used For treatment of a psychostimulant addiction, combina according to the invention include alvimopan, binaltor tions to be administered in accordance with the present inven 25 phimine, buprenorphine, cyclazocine, cyclorphan, cypri tion include, e.g., a PDE7 inhibitor and an antidepressant or a dime, dinicotinate, beta-funaltrexamine, levallorphan, meth PDE7 inhibitor and a partial opioid agonist/antagonist, e.g., ylnaltrexone, nalbuphine, nalide, nalmefene, nalmexone, buprenorphine. nalorphine, nalorphine dinicotinate, naloxone, naloxonazine, For treatment of nicotine addiction, combinations to be maltrendol, naltrexone, naltrindole, oxilorphan, and pentaZo administered in accordance with the present invention 30 cine. include, e.g., a PDE7 inhibitor and an antidepressant, a PDE7 2. Antidepressents inhibitor and nicotine (as a replacement, in an oral, transcu Antidepressents are drugs used to treat depression. The taneous or other conventional formulation), a PDE7 inhibitor three neurotransmitters believed to be involved in depression and an opioid antagonist, a PDE7 inhibitor and a CB1 recep are serotonin, dopamine, and norepinephrine. Certain types tor antagonist/inverse agonist, and a PDE7 inhibitor and 35 of antidepressants increase the levels of one or more of these Varenicline. In one embodiment, an addictive agent, such as neurotransmitters in the brain by blocking their reabsorption. nicotine, and a PDE7 inhibitor are administered together Several different classes of antidepressants have been iden using a transdermal patch delivery system. In another aspect tified, including selective serotonin reuptake inhibitors (SS of the invention, a kit including multiple transdermal patches, RIs), tricyclic and tetracyclic serotonin and norepinephrine including dosages of nicotine in diminishing levels and dos 40 reuptake inhibitors (SNRIs), norepinephrine reuptake inhibi ages of a PDE7 inhibitor in either constant or diminishing tors (NRIs), norepinephrine and dopamine reuptake inhibi levels, are provided for sequential use by a subject addicted to tors (NDRIs), azaspirones, monoamine oxidase inhibitors nicotine to wean the Subject from nicotine addiction. (MAOIs), and atypical antidepressants. For treatment of poly Substance addiction, combinations to SSRIs include, e.g., cericlamine, citalopram, clomi be administered in accordance with the present invention 45 pramine, cyanodothiepin, dapoxetine, duloxetine, escitalo include, e.g., a PDE7 inhibitor and an opioid agonist or a pram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, imi mixed opioid antagonist/partial antagonist. pramine, indalpine, indeloxazine, litoxetine, lofepramine, For treatment of gambling addiction, combinations to be mianserine, milnacipran, mirtazapine, nefazadone, nortrip administered in accordance with the present invention tyline, paroxetine, Sertraline, Sibutramine, tomoxetine, traZ include, e.g., a PDE7 inhibitor and an antidepressant or a 50 odone, Venlafaxine, and Zimeldine. PDE7 inhibitor and an agent affecting dopamine neurotrans Amitriptyline, amoxapine, butriptyline, clomipramine, mission, e.g., a direct or indirect dopamine antagonist. demexiptiline, desipramine, dibenzepin, dimetacrine, dothi The effective amount of either or both of a PDE7 inhibitor epin, doxepin, imipramine, iprindole, lofepramine, mapro and an additional therapeutic agent may be reduced when tiline, melitracen, metapramine, mianserin, mirtazpine, administered in combination than when either is provided 55 nortriptyline, propizepine, protriptyline, quinupramine, set alone. For example, when the PDE7 inhibitor and the addi iptiline, tianeptine, and trimipramine are all tricyclic and tional therapeutic agent act additively or synergistically, then tetracyclic antidepressants. a lower amount of the PDE7 inhibitor, a lower amount of the SNRIs include, e.g., amoxapine, atomoxetine, bici fadine, additional therapeutic agent, or lower amounts of both the desipramine, desvenlafaxine, dulloxetine, maprotiline, mil PDE7 inhibitor or the additional therapeutic agent may be 60 nacipran, nefazodone, reboxetine, Sibutramine, and Venlafax required to achieve the same therapeutic effect that would be ine. provided by either the PDE7 inhibitor or the additional thera Nisoxetine, nortriptyline, reboxetine, talsupram, and peutic agent alone. tomoxetine are all examples of NRIs. 1. Opioid Antagonists NDRIs include, e.g., bupropion, hydroxybupropion, and An opioidantagonist acts on one or more opioid receptors. 65 tesofensine. At least three types of opioid receptors, mu, kappa, and delta AZaspirones include, e.g., buspirone, gepirone, ipsapirone, opioid receptors, have been reported, and opioid antagonists tandospirone, and tiaspirone. Buspirone is an anxiolytic (par US 9.220,715 B2 25 26 tial agonist at 5-HT1 autoreceptors) that may be provided 5-HT3 receptor antagonists include, e.g., alosetron, aza with an anti-depressant such as an SSRI. setron, bemesetron, cilansetron, dolasetron, granisetron, Specific MAOIs include, e.g., amiflamine, brofaromine, indisetron, itasetron, ondansetron, palonosetron, propisetron, clorgyline, alpha-ethyltryptamine, iproclozide, iproniazid, ramosetron, renZapride, tropisetron, and Zatosetron. isocarboxazid, mebanazine, moclobemide, nialamide, par Coritcosteroid antiemetics include dexamethasone and gyline, phenelzine, pheniprazine, pirlindole, Safrazine, sel methylprednisolone. egiline, toloxatone, and tranlcypromine. Lymbic system inhibitors include alprazolam, lorazepam, Atypical antidepressants include, e.g., ameSergide, and midazolam. amineptine, benactyzine, bupropion, clozapine, fezolamine, Dopamine receptor antagonists include diphenhydramine, levoprotiline, lithium, medifoxamine, mianserin, minaprine, 10 olanzapine, oxafloZane, oxitriptan, rolipram, teniloxazine, dronabinol, haloperidol, metoclopramide, and prochlorpera tofenacin, traZodone, tryptophan, and viloxazine. Zine. 3. Antiepileptics NK-1 receptor antagonists used as an antiemetic include The anticonvulsants, also called anti-epileptic drugs aprepitant and morpholine, and an example of a GABA ago (AEDs) are a diverse group of drugs used in prevention of the 15 nist is propofol. occurrence of epileptic seizures and bipolar disorders. AEDs Thiethylperazine is a type of histamine receptor antago Suppress the rapid and excessive firing of neurons that begins nist. a seizure and/or prevents the spread of the seizure within the Cannabinoid receptor antagonists or agonists used as anti brain and offer protection against possible excitotoxic effects emetics include dronabinol, nabilone, rimonabant, that may result in brain damage. Many anticonvulsants block tanarabout, and tetrahydrocannabinol. Sodium channels, calcium channels, AMPA receptors, or Examples of other antiemetics include acetylleucine, NMDA receptors. monoethanolamine, aliZapride, benzquinamide, bietanau Anti-epileptic agents include, but are not limited to, ben tine, bromopride, buclizine, chlorpromazine, clebopride, Zodiazepines, barbituates, valproates, GABA agents, iminos cyclizine, dimenhydrinate, dipheniodol, domperidone, dran tilibenes, hydantoins, NMDA antagonists, sodium channel 25 isetron, meclizine, methalltal, metopimazine, oxypendyl. blockers and Succinamides. pipamazine, piprinhydrinate, Scopolamine, thioproperZaine, Benzodiazepines include, e.g., alprazolam, chlordiazep and trimethobenzamide. oxide, cholrazepate, clobazam, clonazepam, diazepam, 5. Cannabinoid Receptor Antagonists halazapam, lorazepam, oxazepam, and prazepam. The cannabinoid receptors are a class of the G-protein Barbiturates used as anti-epileptics include, e.g., amobar 30 bital, mepobarbital, methylphenobarbital, pentobarbital, phe coupled receptor Superfamily. Their ligands are known as nobarbital, and primidone. cannabinoids. There are currently two known subtypes, CB1 Valproates used as anti-epileptics include, e.g., sodium which is expressed mainly in the brain, but also in the lungs, Valporate, valproic acid, valproate semisodium, and valpro liver, and kidney, and CB2, which is mainly expressed in the mide. 35 immune system and in hematopoietic cells. It is also believed Anti-epileptic GABA agents include, e.g., gabapentin, that there are novel cannabinoid receptors that is, non-CB1 losigamone, pregabalin, retigabine, rufinamide, and and non-CB2, which are expressed in endothelial cells and in vigabatrin. the CNS. Cannabinoid receptor antagonists may be selective Carbamazepine and oXcarbazepine are examples of imi for either the CB1 or CB2 receptor. The present invention nostilbenes. 40 contemplates the use of either or both CB1 and CB2 receptor Hydantoins include, e.g., fosphenyloin Sodium, mepheny antagonists. loin, and phenyloin Sodium. Addictive agents (e.g., alcohol, opiates, Delta(9)-tetrahy NMDA antagonists such as harkoseramide are used as drocannabinol (Delta(9)-THC) and psychostimulants, anti-epileptics. including nicotine) elicit a variety of chronically relapsing Sodium channel blockers such as lamotrigine are also anti 45 disorders by interacting with endogenous neural pathways in epileptic agents. the brain. In particular, they share the common property of Succinimides include, e.g., ethoSuximide, methSuximide, activating mesolimbic dopamine brain reward systems, and and phensuXimide. virtually all abused drugs elevate dopamine levels in the Other anti-epileptic drugs include acetazolamide, briver nucleus accumbens. Cannabinoid-1 (CB1) receptors are acetam, CBD cannabis derivative, clomthiazole edisilate, 50 expressed in this brain reward circuit and modulate the divalproex sodium, felbamate, isovaleramide, lacosamide, dopamine-releasing effects of Delta(9)-THC and nicotine. lamotrigine, levetiracetam, methaneSulphonamide, talam Rimonabant (SR141716), a CB1 receptor antagonist, panel, tiagabine, topiramate, Safinamide, seletracetam, Sore blocks both the dopamine-releasing and the discriminative tolide, Stiripentol, Sultiam, Valrocemide, and Zonisamide. and rewarding effects of Delta(9)-THC in animals. Although 4. Antiemetics 55 CB1 receptor blockade is generally ineffective in reducing Antiemetics are drugs effective against Vomiting and nau the self-administration of cocaine in rodents and primates, it sea. Antiemetics are typically used to treat motion sickness reduces the reinstatement of extinguished cocaine-seeking and the side effects of opioid analgesics, general anaesthetics, behavior produced by cocaine-associated conditioned stimuli and chemotherapy. and cocaine priming injections. Similarly, CB1 receptor Classifications of antiemetics include, e.g., 5-hydrox 60 blockade is effective in reducing nicotine-seeking behavior ytryptamine 3 (5-HT3) receptorantagonists, histamine recep induced by re-exposure to nicotine-associated Stimuli. In tor antagonists, dopamine receptor antagonists, muscarinic human clinical trials, rimonabant was shown to block the receptorantagonists, acetylcholine receptorantagonists, can subjective effects of Delta(9)-THC in humans and prevents nabinoid receptor antagonists, limbic system inhibitors, relapse to Smoking in ex-Smokers. NK-1 receptor antagonists, corticosteroids, tachykinin 65 Other examples of cannabinoid receptor CB1 antagonists antagonists, GABA agonists, cannabinoids, benzodiaz include SR141716A (rimonabant), rosanabant, taranabant epines, anticholinergics, and Substance P inhibitors. and CP-94.5598. US 9.220,715 B2 27 28 6. Dopaminergic Agents of dopamine neurons and increased dopamine release inter Drug addiction is a chronic, relapsing disease character minal areas such as the NAc and in the PFC. ized by a loss of control over drug use, compulsive drug A prototypical example of this mechanism is offered by seeking and craving for a Substance, use that persists despite opiates that following activation of u opioid receptors located negative consequences, and physical and/or psychological 5 onto presynaptic GABA cells lead to a marked inhibition of dependence on the Substance. A fundamental role in the GABAergic neurotransmission resulting in disinhibition of pathogenesis of addiction has been attributed to dopamine. VTA dopaminergic cells. Johnson, S. W., et al., “Opioids Dopamine, in fact, has permeated the natural history of drug excite dopamine neurons by hyperpolarization of local inter addiction at all levels, from its involvement in shaping indi neurons. J Neurosci 12:483-488 (1992). Cannabis deriva vidual response to Vulnerability factors (i.e., genetics, envi 10 tives appear to increase VIA dopamine firing rate with a ronmental and stress) to its role in the mechanism of action of the drugs of abuse. similar mechanism but through selective activation of can The mesocorticolimbic dopamine system originates in the nabinoid receptor 1 (CB1R) located on presynaptic GABA Ventral tegmental area (VTA), which prominently projects to neurons. Also nicotine, increases dopamine neurotransmis the nucleus accumbens (NAc) and the prefrontal cortex 15 sion but through a complex interplay of actions of nicotinic (PPC). It is a defining commonality of all addictive drugs that receptors on GABA and on glutamatergic inputs to dopamine at least initially they stimulate dopamine transmission in the neurons. Lischer C, et al., The mechanistic classification of terminal areas of the mesolimbic system and in particular in addictive drugs. PLoS Med. 3 (11):e437 (2006). In fact, nico the nucleus NAc shell. Nestler, E. J., “is there a common tine through B2-containing nAChRs decreases presynaptic molecular pathway for addiction?” Nat Neurosci 8:1445 GABA release leading to a prolonged disinhibition of dopam 1449 (2005); Pierce, R. C., et al., “The mesolimbic dopamine ine, at the same time acting on homomeric C7-containing system: The final common pathway for the reinforcing effect nAChRs, which are mainly expressed on synaptic terminals of drugs of abuse?” Neurosci Biobehav Rey 30:215-238 of excitatory glutamatergic afferents on dopamine neurons in (2006). Brain imaging studies have extended these observa the VTA, facilitating glutamate release. This effect may also tions to humans. Drevets, W. C., et al., “Amphetamine-in 25 contribute to nicotine-evoked dopamine release. Further duced dopamine release in human Ventral striatum correlates more, recent evidence Suggests that nicotine directly modu with euphoria.” Biol Psychiatry 49:81-96 (2001); Brody A. lates dopamine release in the NAc. Ethanol and benzodiaz L., et al., "Smoking-induced Ventral striatum dopamine epines also appear to stimulate VTA dopamine release.” Am J Psychiatry 161:1211-1218 (2004). The release neurotransmission through inhibition of presynaptic GABA of dopamine from these projections is thought to play an 30 activity via modulation of specific GABA-A receptors sub important role in mediating drug reward, reinforcement and units. in the induction of compulsive addictive behaviour. Although Psychostimulants like amphetamine derivatives and dopamine is involved in the predisposition and in the initial cocaine, comprise the only class of addictive drugs that act stages of the development of drug addiction, this condition, directly on dopaminergic terminals by inhibiting dopamine once established, is associated with long-lasting changes 35 reuptake mechanisms or by facilitating dopamine release related to the chronic exposure to the drugs themselves. from Synapses. Through these mechanisms they increase These changes are collectively indicated as “neuroadap extracellular dopamine levels in terminal areas (i.e., NAc and tive' and are thought to be the substrate of behavioural sen MPF) of the brain dopamine system. Most notably, however, sitization, a long-lasting increase in the sensitivity to the dopamine terminals are also present in the VTA where D1 behavioural stimulant properties of drugs and of changes in 40 and D2-like receptors are expressed on dopaminergic cell the baseline of hedonic state (hedonic allostasis). Berridge K. bodies (autoreceptors) as well as on glutamatergic and C., et at, “What is the role of dopamine in reward: Hedonic GABAergic presynaptic neurons. Direct application of impact, reward learning, or incentive salience'?” Brain Res cocaine in the VIA results in a reduction or to an increase Rev 28:309-369 (1998); Koob, G. F., et al., “Neurobiological (depending on the dose) of dopamine firing rate, an effect that mechanisms for opponent motivational processes in addic 45 could be potentially mediated by D1 receptors located onto tion. Philos Trans R Soc. Lond B Biol Sci. 363:3113-3123 presynaptic GABA and glutamate cells, respectively. Hence (2008). Neuroadaptations occurs also at the level of the presynaptic modulation of VTA DA activity may play a role dopamine system, where a relative reduction in the basal level also in the regulation of the addictive properties of psycho of activity of dopamine transmission in Ventral striatal areas stimulants. Brodie, M. S., et al., "Cocaine effects in the ven and a reduction in dopamine D2-receptor levels has been 50 tral tegmental area. Evidence for an indirect dopaminergic documented. Volkow, N. D., et al., “Dopamine in drug abuse mechanism of action Naunym Schmiedebergs Arch Pharma and addiction: results from imaging studies and treatment col 342:660-665 (1990); Bonci, A., et al., “Increased prob implications.” Mol Psychiatry 9:557-569 (2004); Volkow, N. ability of GABA release during withdrawal from morphine.” D., et al., “Dopamine in drug abuse and addiction: results J Neurosci 17:796-803 (1997). from imaging studies and treatment implications. Arch Neu 55 Accordingly, in one embodiment of the invention the addi rol 64:1575-1579 (2007): Fehr, C. et al., “Association of low tional therapeutic agent administered in combination, con striatal dopamine d2 receptor availability with nicotine currently or sequentially with a PDE7 inhibitor is a dopam dependence similar to that seen with other drugs of abuse.” inergic agent to treat a patient Suffering from an addiction or Am Psychiatry 165:507-514 (2008). compulsive disorder. In another embodiment of the invention, The most common mechanism through which drugs of 60 the PDE7 inhibitor is administered in combination, concur abuse result in dopamine neurotransmission is through modu rently or sequentially with a dopamine receptor agonist to lation of VTA presynaptic Y-aminobutyric acid (GABA) treat a patient Suffering from an addiction or impulse control activity. Lischer, C., et al., “The mechanistic classification of disorder. In another embodiment of the invention, the PDE7 addictive drugs.” PLoS Med 3:e437 (2006). In the VTA, inhibitor is administered in combination, concurrently or GABA neurons act as local inhibitory interneurons playing a 65 sequentially with a dopamine D1 receptor agonist (i.e., a tonic control on corticomesolimbic dopamine cells. Reduc dopamine Subtype D1 receptor agonist) to treat a patient tion in GABA neurotransmission leads to a net disinhibition Suffering from an addiction or impulse control disorder. US 9.220,715 B2 29 30 Exemplary dopaminergic agents suitable for administra tional stress can facilitate acquisition or increase self-admin tion in conjunction with PDE7 inhibitors include, for istration of cocaine, heroin, and ethanol in rodents and example, levodopa (also referred to as “L-dopa’), carbidopa, nonhuman primates. (Goeders and Guerin, Psychopharma and dopamine receptor agonists and precursors such as bro cology, 114, 63, (1994); Haney, et al., Brain Res., 698, 46. mocriptine, pergolide, pramipexole, ropinirole, cabergoline, (1995); Ramsey and Van Ree, Brain Res., 608, 216, (1993); apomorphine, lisuride, rotigotine and quinagolide, as well as Ahmed and Koob, Psychopharmacology, 132, 289, (1997); fenoldopam, which is selective for dopamine receptor D1. Shaham and Stewart, Psychopharmacology 1 19:334 (1995); Suitable dosages of D1 receptor agonists for administra Nash and Maickel, Prog Neuropsychopharmacol Biol Psy tion in conjunction with a PDE7 inhibitor in accordance with chiatry, 12, 653, (1988); Mollenauer, et al., Pharmacol. Bio the present invention may be determined by medical practi 10 tioners but may be, for example, in the range of 0.1 mg to chem. Behav., 46, 35, (1993); Blanchard, et al., Pharmacol. 1,000 mg per day or biweekly, or 0.25 mg to 100 mg per day Biochem. Behav. 28,437, (1987) and Higley, et al., Proc. Natl. or biweekly. Acad. Sci. USA, 88,7261, (1991)). Stressful stimuli have also C. Methods of Treating and Preventing Relapse been shown to elicit reinstatement of cocaine, heroin, and Relapse use, or reinstatement, refers to the process of 15 ethanol-seeking behavior in drug-free animals following returning to the use of alcohol or another addictive agent or extinction and these findings provide experimental Support the practice of an addictive behavior after a period of absti for a role of stress in relapse. (Ahmed and Koob (1997); nence from, or limited or reduced use of an addictive agent or Shaham, Psychopharmacology, 111, 477, (1993); and Sha practice of an addictive behavior. In certain situations, relapse ham and Stewart (1995)). use of an addictive agent refers to the return to use of an Traditionally, stress-related drug-seeking behavior has addictive agent by a Subject who has undergone physical been thought to be mediated via activation of the hypotha withdrawal from the addictive agent. Typically, the subject lamic-pituitary-adrenal (HPA) axis. However, growing evi will have undergone physical withdrawal from the addictive dence Suggests that the non-neuroendocrine corticotropin agent during a period of non-use or limited or reduced use of releasing factor (CRF) system in the central nucleus of the the addictive agent. In one embodiment, relapse use occurs in 25 amygdala (CeA) may play a significant independent role in a subject who has previously undergone a treatment regime the regulation of addictive behavior associated with stress. with an effective amount of an anti-addiction agent to reduce The CeA is rich in CRF immunoreactive cell bodies, termi or eliminate use of an addictive agent, but who is no longer nals, and receptors, and this neuronal CRF system has been using an effective amount of the anti-addiction agent. Anti implicated in the mediation of behavioral and emotional addictive agents include any and all agents used to treat or 30 responses to stressful stimuli. (Dunn and Berridge, Brain Res prevent addiction or withdrawal symptoms. Brain Res Rev. 15, 71 (1990); and Koob et al., Semin Neuro Alcoholism, like many other addictions, is a chronic sci 6:221 (1994)). For example, immobilization stress relapsing disorder characterized by high recidivism rates. elevates extracellular CRF levels in the CeA while intra-CeA Two major factors triggering relapse behavior are stress and injection of the CRF receptor antagonist, C-helical CRF9-41, environmental conditioning experiences (O'Brien et al. 1997: 35 reduces behavioral signs of anxiety produced by Social and Montietal. 1993: Shaham et al. 1995), which probably facili environmental stressors (Merali et al., J. Neurosci., 18, 4758, tate relapse to alcohol-seeking via distinct brain mechanisms. (1998); Merlo Pich et al., J. Neurosci, 15, 5439, (1995); For example, activation of the mesolimbic dopamine system Heinrichs et al., Brain Res., 581, 190 (1992); Swiergiel et al., via an opioid-dependent mechanism (or via direct alterations Brain Res, 623, 229 (1993)). Anxiety and stress-like symp in dopamine transmission in the basolateral nucleus of 40 toms are central to drug and alcohol withdrawal syndromes. amygdala) seems to mediate the effect of drug-associated Considering the evidence on a role of CRF neurons in the cues (Liu and Wiess 2002: Ciccocioppo et al. 2001), and, CeA in the regulation of emotional and anxiogenic effects of extrahypothalamic CRF within the bed nucleus of the stria stress, it is likely that anxiogenic and stress-like conse terminalis and median raphe nucleus is likely to mediate quences of withdrawal from drugs of abuse may be mediated stress-induced reinstatement of drug-seeking behavior (Erb 45 by the CRF system in the CeA as well. et al 1998: Shaham et al. 1995; Le et al. 2000). Changes in the regulation of the activity of the CRF system Several lines of evidence Suggest that molecular mecha within the CeA may represent a critical neuroadaptive mecha nisms underlying relapse to addiction are common to differ nism responsible for the development of dependence and ent classes of drugs of abuse. Drug craving and loss of control compulsive drug-seeking behavior. over drug taking behavior associated to relapse are under the 50 The data discussed above identify neuroadaptive changes direct influence of stress and environmental conditioning in brain circuitries and perturbations in stress systems as an stimuli; the two major factors affecting resumption to drug important element in compulsive drug-seeking behavior and SC. dependence. Another important factor in the long-lasting Chronic drug abuse produces neuroadaptive changes not addictive potential of drugs of abuse is the conditioning of only within systems implicated in the acute reinforcing 55 their rewarding actions with specific environmental stimuli. effects of ethanol, but also within other motivational systems, Environmental cues repeatedly associated with the subjective notably brain stress-regulatory mechanisms. Stress has an effects of drugs of abuse including alcohol can evoke drug established role in the initiation and maintenance of drug craving or elicit automatic behavioral responses (Miller and abuse, and is a major determinant of relapse in abstinent Gold 1994; Tiffany and Carter 1998) that ultimately may lead individuals. (Brown, et al., J Studies Alcohol 56:538 (1995); 60 to relapse. (Childress et al., Conditioned craving and arousal Marlatt, Relapse prevention: introduction and overview of the in cocaine addiction. A preliminary report, in NIDA Research model, in Relapse Prevention. Maintenance Strategies in the Monograph 81, (1988); Ehrman et al., Psychopharmacology, Treatment of Addictive Behaviours, Guilford, London, 107, 523, (1992); Monti et al., J Stud Alcohol. 54:235-45 (1985); McKay, et al., Drug Alcohol Dep., 38,35, (1995); and (1993); Pomerleau et al., Addict. Behav., 8, 1, (1983); Stor Wallace, J Subst Abuse Treat, 6:95, (1989)). The significance 65 market al., Addict. Behav, 20, 571, (1995); Miller and Gold of stress in drug-seeking behavior has also been amply docu Ann. Clin. Psychiatry, 6,99, (1994); and Tiffany and Carter, J. mented in the animal literature. Physical, Social, and emo Psychopharmacol. 12, 23, (1998)). Learned responses to US 9.220,715 B2 31 32 drug-related stimuli may, therefore, contribute critically to Subject who previously reduced or eliminated use of an addic the high rates of relapse associated with cocaine and other tive agent or practice of an addictive or compulsive behavior drug addiction. in response to exposure to an effective amount of another Data from operant response-reinstatement models devel anti-addiction treatment, wherein the Subject is no longer oped to investigate drug-seeking behavior associated with exposed to an effective amount of the anti-addiction treat exposure to drug-related environmental cues in rats indicate ment. The anti-addiction treatment may be an anti-addiction that discriminative stimuli predictive of cocaine, ethanol, or drug or may be a non-pharmacologic therapy Such as coun heroin availability reliably elicit strong recovery of extin Seling, psychotherapy or hypnosis therapy. The relapse use guished drug-seeking behavior in the absence of further drug may be triggered by stress. availability. (Weiss et al., Proc. Natl. Acad. Sci. USA, 97. 10 In certain embodiments, the Subject is no longer exposed to 4321, (2000); Katner et al., Neuropsychopharmacology, 20, an effective amount of an anti-addiction agent because the 471, (1999); Katner and Weiss, Alcohol Clin Exp Res. subject has become tolerant to the agent, such that the blood 23:1751 (1999); and Gracy et al., Pharmacol. Biochem. plasma concentration of the anti-addiction agent that was Behav., 65, 489, (2000)). The response-reinstating effects of previously effective in treating the addiction is no longer these stimuli show remarkable resistance to extinction with 15 effective. In other embodiments, the subject is no longer repeated exposure and, in the case of cocaine, can still be exposed to an effective amount of an anti-addiction agent observed after several months of forced abstinence. Addition because the Subject is now exposed to a lower blood plasma ally, in the case of ethanol, drug-seeking behavior induced by concentration of the anti-addiction agent, and this lower ethanol-predictive discriminative stimuli was found to be blood plasma concentration is not effective. enhanced in genetically alcohol-preferring Prats compared to In certain embodiments of the methods of the present Alcohol Nonpreferring (NP) and nonselected Wistar rats. invention, the Subject has undergone a period of abstinence (Weiss and Ciccocioppo, Soc. Neurosci. Abstr., 25, 1081, from, or limited or reduced use of the addictive agent or (1999)). This observation demonstrates that genetic predis practice of the addictive or compulsive behavior. This period position toward heightened ethanol intake is reflected also by of abstinence or limited or reduced use may be, e.g., at least a greater Susceptibility to the motivating effects of ethanol 25 24 hours, at least 48 hours, at least 3 days, at least 5 days, at cues (i.e., enhanced drug-seeking under conditions where least one week, at least 2 weeks, at least 1 month, at least 2 behavior is not directly reinforced by ethanol itself). months, at least 4 months, at least 6 months, at least 9 months, Together, these findings strongly support the hypothesis that at least one year, at least 2 years, or at least 5 years. learned responses to drug-related stimuli are a significant In another embodiment, the present invention includes a factor in long-lasting Vulnerability to relapse. 30 method of treating or preventing relapse use of an addictive In humans, relapse risk involves multiple determinants that agent, comprising providing a PDE7 inhibitor and an opioid are likely to interact. For example, exposure to drug cues may antagonist to a subject who has undergone physiological augment Vulnerability to relapse imparted by protracted with withdrawal from the addictive agent. drawal symptoms resulting from neuroadaptive changes in In a further embodiment, the present invention includes a dependent individuals. Interactive effects exacerbating 35 method of treating or preventing relapse use of an addictive relapse risk may also exist between the motivating effects of agent, comprising administering a PDE7 inhibitor and a CB1 stress and drug-related cues. Recent work addressing these antagonist, e.g., disulfuram, topiramate, levetiracetam, issues has confirmed that additive interactions between the SSRIs, or ondansetron, to a Subject who has undergone physi response-reinstating effects of ethanol-associated cues and ological withdrawal from the addictive agent. stress can indeed be demonstrated, and that these effects are 40 In particular embodiments, the relapse use is triggered by enhanced in rats with a history of ethanol dependence. (Liu stress, an environmental conditioning factor, or both. and Weiss, Soc. Neurosci. Abstr. 26,786 (2000)). While the methods of the present invention may be prac In experimental laboratories, reinstatement of drug seek ticed in Subjects addicted to a single addictive agent, they may ing is obtained with administration of the C-2 adrenoreceptor also be used in subjects addicted to two or more addictive antagonistyohimbine, which, increasing brain noradrenaline 45 agents. Similarly, while these methods may be used to prevent cell firing and release, acts as a pharmacological stressor. relapse use of the addictive agent from which the subject has Footshock stress and yohimbine-induced reinstatement of undergone withdrawal, they may also be adapted to prevent drug-seeking behaviors both represent valid experimental relapse use or the commencement of use of an addictive agent models to investigate stress-induced alcohol relapse (Lee et different than the one from which the subject has undergone al., Neuropsychopharmacology 29:686-93 (2004) and Le et 50 physiological withdrawal. al., Psychopharmacology 150:317-24 (2000)). D. Pharmaceutical Compositions, Routes of Administra As shown in the accompanying Examples, PDE7 inhibitors tion, Unit Dosage Forms, Kits significantly reduce stress-induced relapse use of an addictive The present invention has established the efficacy of using agent (Example 1). These data indicate, therefore, that PDE7 combinations of a PDE7 inhibitor, in combination with one or inhibitors have anti-relapse properties. 55 more additional therapeutic agents, such as opioid antago Interestingly, various reports have shown that the nonse nists, antidepressents, antiepileptics, antiemetics, and CB1 lective opiate receptor antagonist naltrexone reduces the urge receptor antagonists. Thus, the present invention further to drink elicited by presentation of alcohol cues in human includes compositions comprising one or more PDE7 inhibi alcoholics (Monti et al. 1993, supra) and decreases the effi tors and one or more additional therapeutic agents, such as cacy of an alcohol cue to reinstate extinguished responding at 60 opioid antagonists, mixed opioid antagonists/partial agonist, a previously drug-paired lever in rats (Katner et al. 1999, antidepressents, antiepileptics, antiemetics, CRF1 receptor supra). However, naltrexone does not reduce relapse behavior antagonists and CB1 receptor antagonists. elicited by stress (Le A. D. Psychopharmacology 1998). In particular embodiments, the composition comprises one In a related embodiment, the invention includes a method PDE7 inhibitor and one additional therapeutic agent. In cer of treating or preventing relapse use of an addictive agent or 65 tain embodiments, the additional therapeutic agent is an practice of an addictive or compulsive behavior, comprising opioid antagonist or a mixed opioid antagonist/partial ago administering an effective amount of a PDE7 inhibitor to a nist. In one embodiment, the opioid antagonist is naltrexone. US 9.220,715 B2 33 34 In another embodiment, the mixed opioid partial agonist/ 1-1000 mg/day, 10-100 mg/day, or 25-50 mg/day. In one antagonist is buprenorphine. In certain embodiments, the embodiment, pioglitaZone is provided to a patient at about 30 additional therapeutic agent is an antidepressant. In a particu mg/day. lar embodiment, the antidepressant is bupropion. In certain Certain combinations of PDE7 inhibitors and other thera embodiments, the additional therapeutic agent is an antiepi- 5 peutic agents may not be readily adaptable to coformulation. leptic, an antiemetic, or an opioid antagonist or a mixed For example, one of the agents may be more amenable to opioid partial agonist/antagonist. intravenous administration, while another of the agents may The compositions of the present invention may be admin be more amenable to oral administration. Or, the serum half istered to a Subject as a pharmaceutical composition or for life of the two agents may be such that one must be adminis mulation. In particular embodiments, pharmaceutical com 10 tered more frequently than the other. Accordingly, the present positions of the present invention may be in any form which invention contemplates kits comprising one or more unit dos allows for the composition to be administered to a subject. For age forms of a PDE7 inhibitor and one or more unit dosage example, the composition may be in the form of a solid, liquid forms of another therapeutic agent, Such that the two unit or gas (aerosol). Typical routes of administration include, 15 dosage forms may be provided to a Subject in a therapeuti without limitation, oral, topical, parenteral, Sublingual, rec cally effective manner. tal, vaginal, and intranasal. The term parenteral as used herein In one embodiment, the present invention includes a kit includes Subcutaneous injections, intravenous, intramuscu comprising unit-dosage forms of a PDE7 inhibitor and unit lar, epidural, intrasternal injection or infusion techniques. dosage forms of nicotine. In one embodiment, the unit dosage Pharmaceutical compositions used according to the 20 forms of nicotine comprise a plurality of different unit-dos present invention comprise a PDE7 inhibitor, another thera age forms of nicotine, wherein the different dosage forms of peutic agent, and a pharmaceutically acceptable diluent, nicotine represent decreasing amount that may be taken one excipient, or carrier. “Pharmaceutically acceptable carriers' after the other over a period of time, so as to overcome for therapeutic use are well known in the pharmaceutical art, addiction and effectuate withdrawal from the nicotine. The and are described, for example, in Remingtons Pharmaceuti- 25 unit-dosage forms of nicotine may be present, e.g., in the form cal Sciences, Mack Publishing Co. (A. R. Gennaro edit. of a transdermal patch, gum, or a lozenge. 1985). For example, sterile saline and phosphate buffered E. PDE7 Proteins and Inhibitory Agents saline at physiological pH may be used. Preservatives, stabi Cyclic nucleotide phosphodiesterase type 7 (PDE7) is lizers, dyes and even flavoring agents may be provided in the identified as a unique family based on its primary amino acid pharmaceutical composition. For example, Sodium benzoate, 30 sequence and distinct enzymatic activity. The PDE genes sorbic acid and esters of phydroxybenzoic acid may be added identified as PDE7 (PDE7A and PDE7B), code for cAMP as preservatives. Id. at 1449. In addition, antioxidants and specific PDEs. The biochemical and pharmacological char Suspending agents may be used. Id. acterization of PDE7 shows a high-affinity cAMP-specific Pharmaceutical compositions of the invention are gener 35 PDE (Km=0.2 LM) that is not affected by c0MP nor by ally formulated so as to allow the active ingredients contained selective inhibitors of other PDEs. The PDE7 enzyme selec therein to be bioavailable upon administration of the compo tively decomposes cAMP and is characterized as an enzyme sition to a subject. Compositions that will be administered to that is not inhibited by rolipram, a selective inhibitor of a Subject may take the form of one or more dosage units, PDE4, which is a distinct, cAMP-specific PDE family. Two where for example, a tablet, capsule or cachet may be a single 40 sub-types have been identified within the PDE7 family, dosage unit, and a container comprising a combination of PDE7A (Michael, T., et al., J. Biol. Chem. 268(17): 12925 agents according to the present invention in aerosol form may 12932, 1993; Han, P., et al., J. Biol. Chem. 272(26):16152 hold a plurality of dosage units. 16157, 1997) and PDE7B (U.S. Pat. No. 6,146,876; Gardner, In particular embodiments, the composition comprising a C., et al., Biochem. Biophys. Res. Commun. 272(1): 186-192, PDE7 inhibitor and another therapeutic agent is administered 45 2000; and Saski, T., et al., Biochem. Biophys. Res. Commun. in one or more doses of a tablet formulation, typically for oral 271 (3):575-583, 2000). The two gene products exhibit 70% administration. The tablet formulation may be, e.g., an imme identity in their C-terminal catalytic domains (Hetman J. M., diate release formulation, a controlled-release formulation, or et al., PNAS97(1):472-476 (2000). an extended-release formulation. In one embodiment, a tablet PDE7A has three splice variants (PDE7A1, PDE7A2 and formulation comprises an effective amount of a composition 50 PDE7A3); these variants are generated via alternative splic comprising a PDE7 inhibitor and another therapeutic agent. ing at both the N- and C-termini (Bloom, T. J., and J. A. In particular embodiments, a tablet comprises about 1, 5, 10. Beavo, Proc. Natl. Acad. Sci. USA. 93:14188-14192, 1996). 20,30,50 100, 150, 200,250, or 300 mg of a PDE7 inhibitor, The nucleotide sequence of PDE7A, transcript variant 1, is and about 1, 5, 10, 20, 30, 50 100, 150, 200, 250, or 300 mg accessible in public databases by the accession number of another therapeutic agent. 55 NM 002603. Human PDE7A1 protein (SEQ ID NO: 2, The present invention further includes unit-dosage forms encoded by SEQID NO:1) has 456 amino acids and migrates of pharmaceutical compositions comprising a PDE7 inhibitor at an apparent molecular weight of 53-55 kDa on reduced and another therapeutic agent. Each unit-dosage form com SDS-PAGE. prises a therapeutically effective amount of a pharmaceutical The nucleotide sequence of PDE7A, transcript variant 2, is composition of the present invention, when used in the rec- 60 accessible in public databases by the accession number ommended amount. For example, a unit-dosage form may NM 002604. Human PDE7A2 protein (SEQ ID NO:4, include a therapeutically effective amount in a single tablet, encoded by SEQID NO:3) has 424 amino acids. or a unit-dosage form may include a therapeutically effective The PDE7A protein has a region of about 270 amino acids amount in two or more tablets, such that the prescribed at the carboxy terminal end that displays significant similarity amount comprises a therapeutically effective amount. 65 (-23% homology) to the analogous regions of other cAMP In particular embodiments, a PDE7 inhibitor is provided to hydrolyzing PDEs. This region serves as the catalytic a Subject in an amount in the range of 0.1-1000 mg/day, domain. The amino-terminal region of this protein is diver US 9.220,715 B2 35 36 gent from that of other PDEs and presumably mediates the potent to inhibit the enzymatic activity of PDE7 (PDE7A, distinctive and regulatory properties unique to this enzyme PDE7B, or PDE7A and PDE7B) at an ICs1 uM, preferably family. less than or about 0.1 uM. In one embodiment, the PDE7 The protein sequence of human PDE7B is accessible in inhibitory agent is sufficiently potent to inhibit the enzymatic public databases by the accession number NM 018945, pro 5 activity of PDE7 (PDE7A, PDE7B, or PDE7A and PDE7B) vided as SEQ ID NO:6, encoded by SEQ ID NO:5. Three at an ICs of from about 0.1 to about 500 nM. In one embodi splice variants of PDE7B have been reported: PDE7B1, ment, the PDE7 inhibitory agent is potent to inhibit the enzy PDE7B2 and PDE7B3. PDE7B is published in WO matic activity of PDE7 (PDE7A, PDE7B, or PDE7A and 01/62904, U.S. Pat. No. 6,146,876. PDE7B) at an ICs of from about 1 to about 100 nM. Both PDE7B2 and PDE7B3 possess unique N-terminal 10 sequences. Human PDE7B gene products have an apparent Representative methods for determining the ICso for a molecular weight of 53-55 kDa on reduced SDS-PAGE PDE7 (PDE7A or PDE7B) inhibitory agent are well known in (Sasaki, T., Kotera, J. Omori, K., Biochemical J. 361:211 the art, such as the Scintillation Proximity Assay (SPA) dis 220, 2002). As in PDE7A, the PDE7B has a significantly closed in Bardelle et al., Anal Biochem 15:275(2): 148-55 conserved region of about 270 amino acids common to all 15 (1999). PDEs at the carboxy terminal, which serves as the catalytic PDE7A or PDE7B Selective Inhibitory Agents domain. Similar to the PDE7A protein, the amino-terminal In one embodiment, the PDE7 inhibitor useful in the region of PDE7B protein is divergent and presumably method of the invention is a PDE7A inhibitory agent. In one accounts for the distinctive and regulatory properties unique embodiment, the PDE7A inhibitory agent is potent to inhibit to the individual PDE families. The PDE7B protein shows the enzymatic activity of PDE7A at an ICs of from about 0.1 homology to other cAMP-dependent PDEs (23%) within the to about 500 nM. In one embodiment, the PDE7A inhibitor catalytic domain. The PDE7B polypeptide is 61% homolo has an ICs of from about 1 to about 100 nM. A suitable assay gous to PDE7A, according to WO 2004/044196. for determining the ICs for a PDE7A inhibitor uses recom PDE7 is also uniquely localized in mammalian subjects binant human PDE7A2 enzymes expressed in a baculoviral relative to other PDE families. PDE7A expression has been 25 system. This assay method is a modification of the SPA assay detected in the majority of tissues analyzed, including the reported by Bardelle et al. supra. brain, heart, kidney, skeletal muscle, spleen and uterus In some embodiments, the PDE7 inhibitory agent exhibits (Bloom, et al., PNAS 93:14188, 1996). Within the brain, isozyme-selective activity against PDE7A. A PDE7A selec PDE7A is widely distributed in both neuronal and non-neu tive inhibitory agent reduces PDE7A activity at least two-fold ronal cell populations (Miro, et al., Synapse 40:201, 2001). 30 more than PDE7B activity, more preferably at least 10-fold, at PDE7As wide expression in the brain, including the basal least 20-fold, at least 50-fold, or at least 100-fold. In some ganglia and substantia nigra, provides a theoretical basis for a embodiments, the PDE7A inhibitory agent is an inhibitory role for PDE7A in brain functions. agent that is at least 10-fold (such as at least 20-fold, or at least In the practice of the methods of the invention, represen 50-fold or at least 100-fold) more selective for inhibiting PDE tative PDE7 inhibitory agents that inhibit the phosphodi 35 7A activity than for the enzyme activity of any other PDE esterase activity of PDE7 include: molecules that bind to (PDE1-6, 7B, and 8-11). PDE7 and inhibit the enzyme activity of PDE7 (such as small In one embodiment, the PDE7B inhibitor has an ICs of molecule inhibitors or blocking peptides that bind to PDE7 from about 0.1 to about 500 nM. In one embodiment, the and reduce enzymatic activity), and molecules that decrease PDE7B inhibitory agent is sufficiently potent to inhibit the the expression of PDE7 at the transcriptional and/or transla 40 enzymatic activity of PDE7B at an ICs of from about 0.1 to tional level (such as PDE7 antisense nucleic acid molecules, about 500 nM. In one embodiment, the PDE7B inhibitor has PDE7 specific RNAi molecules and PDE7 ribozymes), an ICs of from about 1 to about 100 nM. Methods for deter thereby preventing PDE7 from cleaving cAMP. The PDE7 mining the ICs for a PDE7B inhibitor are well known in the inhibitory agents can be used alone as a primary therapy or in art, such as the assays disclosed in Bardelle et al., Supra. combination with other therapeutics (such as dopamine 45 In some embodiments, the PDE7 inhibitor exhibits receptor agonists) as an adjuvant therapy to enhance the isozyme-selective activity against PDE7B. A PDE7B selec therapeutic benefits, as discussed Supra. tive inhibitory agent reduces PDE7B activity at least two-fold The inhibition of PDE7 is characterized by at least one of more than PDE7A activity, more preferably at least 10-fold, the following changes that occur as a result of administration at least 20-fold, at least 50-fold, or at least 100-fold. In some of a PDE7 inhibitory agent in accordance with the methods of 50 embodiments, the PDE7B inhibitory agent is an inhibitory the invention: the inhibition of PDE7-dependent enzymatic agent that is at least 10-fold (such as at least 20-fold, or at least cleavage of the 3'-phosphodiester bond in cAMP to form 50-fold or at least 100-fold) more selective for inhibiting 5'-adenosine monophosphate (5'-AMP), a reduction in the PDE7B activity than for the enzyme activity of any other PDE gene or protein expression level of PDE7, measured, for (PDE1-6, 7A, and 8-11). example, by gene expression analysis (e.g., RT-PCR analysis) 55 PDE7 Selectivity as Compared to Other PDEs or protein analysis (e.g., Western blot). In some embodiments, the PDE7 inhibitory agent has an In some embodiments, a PDE7 inhibitory agent is a mol ICs for inhibiting PDE1B activity of greater than 5 times ecule or composition that inhibits the expression of PDE7A, (such as at least 10-fold, at least 20-fold, or at least 50-fold or PDE7B, or both PDE7A and PDE7B, such as an antisense or at least 100-fold) the lesser of the ICs for inhibiting PDE7A small inhibitory nucleotide (e.g., siRNA) that specifically 60 activity and the ICs for inhibiting PDE7B activity. Stated hybridizes with the cellular mRNA and/or genomic DNA differently, the PDE7 inhibitor is more potent (by 5 times, 10 corresponding to the gene(s) of the target PDE7 so as to times, 20 times, 50 times or 100 times) at inhibiting the inhibit their transcription and/or translation, or a ribozyme activity of PDE7A or PDE7B (whichever PDE7A or PDE7B that specifically cleaves the mRNA of a target PDE7. isozyme upon which the PDE7 inhibitor has the most effect), Potency of PDE7 Inhibitory Agents 65 than it is at inhibiting the activity of PDE 1 B. For purposes of In one embodiment, a PDE7 inhibitory agent useful in the the present specification, by way of example, this property methods of the invention is a compound that is sufficiently may be still more simply stated as the PDE7 inhibitor is more US 9.220,715 B2 37 38 potent (by 5 times, 10 times, 20 times, 50 times or 100 times) In some embodiments, the PDE7 inhibitory agent has an at inhibiting the activity of PDE7 than it is at inhibiting the ICs for inhibiting the activity of PDE1, PDE2, PDE3, PDE4, activity of PDE1B. and PDE8, PDE10, and PDE11 of greater than 10 times the Dual inhibition of both PDE7 and PDE1B may confer lesser of the ICs for inhibiting PDE7A activity and the IC50 additional benefit in the treatment of movement disorders 5 for inhibiting PDE7B activity. In accordance with this based on a report that deletion of the gene for PDE in mice embodiment, it is known that the PDE families that specifi stimulated the metabolism of dopamine and sensitized the cally/preferentially hydrolyze cAMP include PDE4, PDE7, animals to the effects of dopaminergic agonists (Siuciak, et and PDE8 and the PDE1, PDE2, PDE3, PDE10, and PDE11 al., Neuropharmacology 53(1): 113-23 (2007)). families show substantial activity against both cAMP and 10 cGMP In some embodiments, the PDE7 inhibitory agent has an In some embodiments, the PDE inhibitory agent is a selec ICs for inhibiting PDE10 activity of greater than 5 times tive PDE7 inhibitor for which the lesser of the ICs for inhib (such as at least 10-fold, or at least 20-fold, or at least 50-fold iting PDE7A activity and the IC50 for inhibiting PDE7B or at least 100-fold) the lesser of the ICs for inhibiting activity is less than one-tenth (Such as one-twentieth, one PDE7A activity and the ICs for inhibiting PDE7B activity. 15 fiftieth, or one-hundredth) the ICso that the agent has for Dual inhibition of both PDE7 and PDE10 may confer addi inhibiting any other PDE enzyme from the PDE1-6 and tional benefit in the treatment of movement disorders based PDE8-11 enzyme families. on a report that selective inhibitors of PDE10 cause an A selective PDE7 inhibitor can be identified, for example, increase in cAMP levels in the striatum (Siuciak J. A. et al., by comparing the ability of an agent to inhibit PDE7 (PDE7A, Neuropharmacology 51(2): 386-96 (2006)). PDE7B or PDE7A and PDE7B) enzyme activity to its ability In some embodiments, the PDE7 inhibitory agent has an to inhibit PDE enzymes from the other PDE families. For ICs for inhibiting PDE3 activity of greater than 10 times example, an agent may be assayed for its ability to inhibit (such as at least 20-fold, at least 50-fold or at least 100-fold) PDE7 activity as well as PDE1, PDE2, PDE3, PDE4, PDE5, the lesser of the ICs for inhibiting PDE7A activity and the PDE6, PDE8, PDE9, PDE10, and PDE11. The ratio of the ICs for inhibiting PDE7B activity. This is because the 25 ICso inhibition for each of the PDE(1-6 and 8-11) isozymes to administration of selective inhibitors of PDE3 to patients in the ICso inhibition of PDE7 (i.e., the more sensitive of heart failure was shown to increase their rate of mortality PDE7A or PDE7B) may be determined by a standard in vitro, (Packer M. et al., N Engl J. Med. 325(21): 1468-75 (1991)). in Vivo, or ex vivo assay, such as those described herein. In some embodiments, the PDE7 inhibitory agent has an In some embodiments, a PDE7 inhibitor is selective for ICs for inhibiting PDE4 activity of greater than 10 times 30 PDE7 and substantially inactive against other PDEs (e.g., (such as at least 20-fold, at least 50-fold or at least 100-fold) PDE1, PDE2, PDE3, PDE4, and PDE8, PDE10, and PDE11) the lesser of the ICs for inhibiting PDE7A activity and the due to targeting of the PDE7 inhibitor to one or more target IC50 for inhibiting PDE7B activity. This is because deletion tissues, such as the brain and/or skeletal muscle. As described of one of the PDE4 genes in mice has been shown to lead to herein, PDE7 is uniquely localized in mammalian subjects cardiac myopathy (Lehnart S. E. et al., Cell 123(1):25-35 35 relative to other PDE families. Within the brain, PDE7A is (2005)). widely distributed in both neuronal and non-neuronal cell In some embodiments, the PDE7 inhibitory agent has a half populations, including the basal ganglia and Substantia nigra maximally effective dose (“EDs) in an in vivo assay of (Miro et al., Synapse 40:201, 2001). PDE7B is expressed in PDE4 inhibition (for example, sedation or inhibition of TNF the brain in the striatum (Reyes-Irisarri et al., Neuroscience alpha levels after endotoxin treatment) of greater than 10 40 132:1173, 2005). times (such as at least 20-fold, at least 50-fold or at least Types of PDE7 Inhibitory Agents 100-fold) the lesser of the EDs in an in vivo assay of PDE7A The PDE7 inhibitory agent can be any type of agent includ and PDE7B inhibition (for example, prevention of relapse to ing, but not limited to, a chemical compound, a protein or cocaine or other psychoStimulant addiction). In accordance polypeptide, a peptidomimetic, a nucleic acid molecule, or with such embodiments, it has been determined that some 45 ribozyme. In some embodiments, PDE7 inhibitory agents are compounds having dual PDE4/PDE7 inhibitory activity pos Small molecule inhibitors including natural and synthetic sess greater selectivity against PDE7 than PDE4 in vivo, as Substances that have a low molecular weight (i.e., less than compared to the PDE4/PDE7 selectivity of the compound as about 450 g/mole), such as, for example, peptides, peptido determined in an in vitro assay. mimetics and nonpeptide inhibitors such as chemical com In some embodiments, the PDE7 inhibitory agent has an 50 pounds. ICs for inhibiting PDE3 activity and PDE4 activity of greater Chemical Compounds: than 10 times (such as at least 20-fold, at least 50-fold or at The PDE7 inhibitors useful in the methods of the invention least 100-fold) the lesser of the ICs for inhibiting PDE7A include agents that are administered by a conventional route activity and the IC50 for inhibiting PDE7B activity. (e.g., oral, intramuscular, Subcutaneous, transdermal, trans In some embodiments, the PDE7 inhibitory agent has an 55 bucal, intravenous, etc.) into the bloodstream and are ulti ICs for inhibiting PDE8 activity of greater than 10 times mately transported through the vascular system across the (such as at least 20-fold, at least 50-fold or at least 100-fold) blood brain barrier to inhibit PDE7 in the brain. Accordingly, the lesser of the ICs for inhibiting PDE7A activity and the for these methods of administration, the PDE7 inhibitors have ICs for inhibiting PDE7B activity. the ability to cross the blood brain barrier. Those PDE inhibi In some embodiments, the PDE7 inhibitory agent has an 60 tors described below that have the ability to cross the blood ICs for inhibiting PDE4 activity and PDE8 activity of greater brain barrier (e.g., those having a molecular weight less than than 10 times (such as at least 20-fold, at least 50-fold or at about 450 g/mole and that are sufficiently lipophilic) are least 100-fold) the lesser of the ICs for inhibiting PDE7A useful in the methods of the invention when the inhibitors are activity and the ICs for inhibiting PDE7B activity. In accor administered by a route that ultimately transports the inhibi dance with this embodiment, it is known that the PDE fami 65 tors to the brain in the bloodstream. lies that specifically/preferentially hydrolyze cAMP include The following is a description of exemplary PDE7 inhibi PDE4, PDE7, and PDE8. tors useful in the methods of the invention. US 9.220,715 B2 39 40 In one embodiment, PDE7 inhibitors useful in the methods methylamino or dimethylamino; an optionally substituted of the invention are selected from those compounds generally acyl group Such as acetyl or propionyl; a carboxyl group; an or specifically disclosed in EP 1454897, WO 2003/053975, optionally Substituted aryl group Such as phenyl or naphthyl; and US 200501.48604, each expressly incorporated herein by an optionally Substituted heteroaryl group Such as pyridinyl, reference in its entirety. In one embodiment, PDE7 inhibitors thiazolyl, imidazolyl or pyrazyl; an optionally substituted useful in the methods of the invention have the formulas: saturated or unsaturated heterocycloalkyl group Such as pip erazinyl or morphonyl; an optionally substituted carbamoyl group; an optionally Substituted amido group; a halogenatom (1A) Such as chlorine, fluorine or bromine; a nitro group; an B1 10 optionally Substituted Sulfone group; an optionally Substi R3 tuted Sulfonylamido group; an oxo group; a urea group; and an optionally Substituted linear, branched or cyclic alkenyl group Such as ethenyl, propenyl or cyclohexenyl. 15 Examples of the heteroaryl group as R include a 5- to 7-membered monocyclic heteroaryl group having 2 to 8 car bon atoms and containing 1 to 4 hetero atoms consisting of oxygen atoms, nitrogen atoms or Sulfur atoms, and a polycy (1B) clic heteroaryl group comprising two or more such identical B1 or different monocyclic compounds fused together, examples of the monocyclic and polycyclic heteroaryl groups being 21 R3 pyrrole, furyl, thienyl, imidazolyl, thiazolyl pyridyl, pyrazyl. R indolyl, quinolyl, isoquinolyl, and tetrazolyl. N N N M n A. 25 In one embodiment, a PDE7 inhibitor useful in the inven tion has the formula: NN || NH

Compound 1 30 NH2. The substituents for the above compounds are defined as follows: A represents N or CR B represents a hydrogen atom or a halogen atom, R represents optionally substituted C-7 cycloalkyl or tert 35 butyl, R represents hydrogen, methyl, or ethyl, R represents a hydrogen, nitro, cyano or halogen atom, NRR, C(=X)R., SONRR, ORs, NRCONRR, 40 NRSOR, NRCOR, a heteroaryl group, optionally Sub stituted C- alkyl, optionally substituted C. alkenyl, or optionally Substituted Saturated or unsaturated heterocy In others embodiments, PDE7 inhibitors useful in the cloalkyl, methods of the invention have the formulas: R represents hydrogen, or C. alkoxy Substituted, if 45 desired, by one or more fluorine atoms, Rs and R are the same or different, and represent a hydro gen atom, optionally substituted C. alkyl, optionally Substi tuted heterocycloalkyl, or optionally substituted acyl or, together with the nitrogenatom which they are bound to, form 50 aZetidinyl, pyrrolidinyl, piperidinyl, morpholino, thiomor pholino, piperazinyl, or homopiperazinyl, each of these groups being optionally Substituted by optionally Substituted C. alkyl, OH, C alkoxy, COH, NRSR, an oxo group, NRCOR, or C(=O)R. 55 R, represents optionally substituted C alkyl, OH, ORs, or NRR, Rs represents hydrogen, an optionally Substituted C alkyl group, or optionally substituted heterocycloalkyl, Ro represents an optionally Substituted C. alkyl group, 60 and X represents O, S, or NH. In regard to the above compounds, “optionally substituted refers to optionally substitutedlinear, branched or cyclic alkyl group Such as methyl, ethyl, propyl or cyclohexyl, a hydroxyl 65 group; a cyano group: an alkoxy group Such as methoxy or ethoxy; an optionally substituted amino group Such as amino, US 9.220,715 B2 41 42 -continued

2 N ON 5 N h N \ f N NH -N N SO2 O N N f N O N

NYY-N Nu/ 15 \ | NH

2O H N

N N 21 N-NN O- N H I \ | N N SO2 25 NH

30 The preparation of the above compounds is described in EP 1454897, WO 2003/053975, and US 200501.48604. In another embodiment, PDE7 inhibitors useful in the methods of the invention are selected from those compounds 35 generally or specifically disclosed in US 2002/0198198, WO 2002/076953, WO 2002/074754, WO 2006/092691, Bioor F ganic & Medicinal Chemistry Letters 14 (2004) 4623-4626, \ ?\- and Bioorganic & Medicinal Chemistry Letters 14 (2004) -N Nu 40 4627-4631, each expressly incorporated herein by reference in its entirety. In one embodiment, PDE7 inhibitors useful in the methods of the invention have the formulas:

O N 45 (2A)

In another embodiment, a PDE7 inhibitor useful in the methods of the invention has the formula: 50 X3, 2 1. Y Z (2B) Compound 2 NH2.

55 X n N

(2C) 60 X x1's X X3. 2 2 X N Zl 65 In other embodiments, PDE7 inhibitors useful in the meth ods of the invention have the formulas: US 9.220,715 B2 43 44 The substituents for the above compounds are defined as is hydrogen or lower alkyl, and R' and R" together follows: with the nitrogen atom to which they are linked, can (a) X, X2, X, and X are the same or different and are form a 4- to 8-membered heterocyclic ring, which selected from: may contain one or two heteroatoms selected from O. N, provided that not more than two of the groups X, X S, or N; or, X, and X simultaneously represent a nitrogenatom, or, C R, in which R is selected from: (b) X is O, S, or NR, in which R is selected from hydro Q, or gen, CN, OH, NH, lower alkyl, lower alkenyl, or lower lower alkyl, lower alkenyl, or lower alkynyl, these groups alkynyl, these groups being unsubstituted or Substituted with being unsubstituted or substituted with one or several 10 cycloalkyl optionally interrupted with 1 or 2 heteroatoms groups Q2; chosen from O, S, SGEO), SO, or N. cycloalkenyl optionally the group Xs—Rs in which, interrupted with 1 or 2 heteroatoms chosen from O, S, Xs is selected from: S(=O), SO, or N, aryl, heteroaryl, OR, or NRoR in a single bond, which Ro and R are the same or different and are selected lower alkylene, lower alkenylene, or lower alkynylene: 15 from hydrogen or lower alkyl: optionally interrupted with 1 or 2 heteroatoms chosen (c) Y is selected from O, S, or N R, in which R is from O, S, S(=O), SO, or N, the carbon atoms of selected from hydrogen, CN, OH, NH, lower alkyl, lower these groups being unsubstituted or Substituted with alkenyl, or lower alkynyl, these groups being unsubstituted or one or several groups, identical or different, selected substituted with cycloalkyl optionally interrupted with 1 or 2 from SR, OR, NRR, EO. —S, or—NR in which R and R, are the same or different and are selected heteroatoms chosen from O, S, S(=O), SO, or N. cycloalk from hydrogen or lower alkyl, and, enyl optionally interrupted with 1 or 2 heteroatoms chosen Rs is selected from aryl, heteroaryl, cycloalkyl option from O, S, SGEO), SO, or N, aryl, heteroaryl, OR, or ally interrupted with C(=O) or with 1, 2, or 3 het NRoR in which Ro and R are the same or different and eroatoms chosen from O, S, SGEO), SO, or N. 25 are selected from hydrogen or lower alkyl; cycloalkenyl optionally interrupted with C(=O) or (d)Z is chosen from CH NO, O, S, or NR in which R with 1, 2, or 3 heteroatoms chosen from O, S, SGEO), is selected from hydrogen, CN, OH, NH, aryl, heteroaryl, SO or N, or a bicyclic group, these groups being cycloalkyl optionally interrupted with one or several heteroa unsubstituted or substituted with one or several toms chosen from O, S, S(O), SO, or N. cycloalkenyl groups selected from Q, heteroaryl, or lower alkyl 30 optionally interrupted with one or several heteroatoms chosen optionally substituted with Q.: from O, S, SGEO), SO, or N. C(=O)Ra, C(=O)NRRs. in which Q, Q and Q are the same or different and are OR, or, lower alkyl, unsubstituted or substituted with one or selected from: several groups which are the same or different and which are hydrogen, halogen, CN, NO, SOH, P(=O)(OH), selected OR or NRRs: OR OC(=O)R, C(=O)CR, SR, S(–O)R. 35 NRR, Q-R, Q-NRR, NR-Q-NRR, or NR-Q- Ra and Rs being independently selected from hydrogen R in which Q is selected from C(=NR), C(=O), or lower alkyl, or, Ra and Rs, together with the nitro C(=S), or SO, R is selected from hydrogen, or lower gen atom to which they are linked, can form a 4- to alkyl, and R. R. and Rare the same or different and 8-membered heterocyclic ring which may contain one or are selected from: 40 two heteroatoms chosen from O, S, or N, and which may hydrogen, lower alkyl optionally interrupted with be substituted with a lower alkyl: C(=O), (CH), aryl, (CH)-heteroaryl, (CH)-cy (e) Z is chosen from H, CH, or NRR, in which Re and cloalkyl optionally interrupted with C(=O) or with 1 R7 are the same or different and are selected from hydrogen, or 2 heteroatoms chosen from O, S, SGEO), SO, or CN, aryl, heteroaryl, cycloalkyl optionally interrupted with N, in which n is an integer selected from 0, 1, 2, 3 or 45 4. one or several heteroatoms chosen from O, S, S(=O), SO, or these groups being unsubstituted or Substituted with one N. cycloalkenyl optionally interrupted with one or several or several groups selected from lower alkyl, halogen, heteroatoms chosen from O, S, S(O), SO, or N. C(=O) CN, CH, SOH, SOCH, CF, C(=O)NHSOCH, Ra, C(=O)NRRs, OR, or, lower alkyl unsubstituted or OR, COOR, C(=O)RNRR, C(=O)NRR, or 50 substituted with one or several groups selected from OR or SONRR-7, in which R and R, are the same or dif NRR 5s ferent and are selected from hydrogen or lower alkyl Ra and Rs being chosen from hydrogen or lower alkyl, optionally substituted with one or two groups selected and, Ra and Rs, and/or, R and R7, together with the from OR, COOR or NRRs in which R and Rs are nitrogen atom to which they are linked, can form a 4- to hydrogen or lower alkyl, and, 55 8-membered heterocyclic ring which may contain one or R and R, and/or, R and Ra, together with the nitrogen two heteroatoms chosen from P, S, or N, and which may atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain be substituted with a lower alkyl: one or two heteroatoms selected from O, S, SGEO), (f) A is a cycle selected from: SO, or N, and which may be substituted with, 60 a 4- to 8-membered heterocyclic ring, which may con tain one or two heteroatoms selected from O, S, or N, A. A4 and which may be substituted with a lower alkyl, or, Al Al-A 11'N, r NA5 a lower alkyl optionally substituted with OR', NR'R", C(=O)NR'R' or COOR in which Rand R" are the 65 : : same or different and are selected from H. lower alkyl : : optionally substituted with OR or COOR in which R US 9.220,715 B2 45 46 -continued groups are tetrazole, pyridyl, and thienyl. Representative 4 2e A cycloalkyl contain from 3 to 8 carbon atoms. Examples of An Such groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclo hexyl, cyclohepty1 and cyclooctyl. The term “interrupted means that in a backbone chain, a carbon atom is replaced by an heteroatom or a group as defined herein. For example, in : “cycloalkyl or cycloalkenyl optionally interrupted with C(=O) or with 1 heteroatom chosen from O, S, S(O), SO in which or N”, the term “interrupted' means that C(=O) or a heteroa A. A. A. A. As and A are the same or different and are 10 tom can replace a carbon atom of the ring. Example of Such selected from O, S, C, C(=O), SO, SO, or NRs in which groups are morpholine or piperazine. Cycloalkenyl includes Rs is selected from hydrogen, aryl, heteroaryl, cycloalkyl 3- to 10-membered cycloalkyl containing at least one double optionally interrupted with one or several heteroatoms chosen bond. Heterocyclic rings include heteroaryl as defined above from O, S, S(=O), SO, or N, cycloalkenyl optionally inter 15 and cycloalkyl or cycloalkenyl, as defined above, interrupted rupted with one or several heteroatoms chosen from O, S, with 1, 2 or 3 heteroatoms chosen from O, S, S(EO), SO, or S(=O), SO, or N. lower alkyl unsubstituted or substituted N. Bicyclic substituents refer to two cycles, which are the with aryl, heteroaryl, cycloalkyl optionally interrupted with same or different and which are chosen from aryl, heterocy one or several heteroatoms chosen from O, S, SGEO). SO, or clic ring, cycloalkyl or cycloalkenyl, fused together to form N. cycloalkenyl optionally interrupted with one or several said bicyclic Substituents. An example of a bicyclic Substitu heteroatoms chosen from O, S, S(O), SO, or N, CN, ent is indolyl. NRoRo C(=O)NRR, OR, C(=O)R or C(=O) In one embodiment, a PDE7 inhibitoruseful in the methods OR in which Ro and Ro are identical or different and are of the invention has the formula: selected from hydrogen or lower alkyl; * represents the carbon atom which is shared between the 25 cycle A and the backbone cycle containing X and/or Y: Compound 3 each carbon atom of the cycle A is unsubstituted or substi HO tuted with 1 or 2 groups, identical or different, selected from N-1No lower alkyl optionally substituted with OR, NRR, COOR, or CONRR, lower haloalkyl, CN, F, =O, 30 NH SONRR, OR, SR, C(=O)CR, C(=O)NRoRo or NRoRo in which RandR are identical or different and 1s, are selected from hydrogen or lower alkyl optionally substi H tuted with OR, NRR, COOR, or CONRR, in C which R and R are identical or different and are selected 35 from hydrogen or lower alkyl, and, Ro and Ro, and/or, R. In other embodiments, PDE7 inhibitors useful in the meth and R2, together with the nitrogen atom to which they are ods of the invention have the formulas: linked, can form a 4- to 8-membered heterocyclic ring; two atoms of the cycle A, which are not adjacent, may be linked by a 2, 3 or 4 carbon atom chain which may be inter 40 rupted with 1 heteroatom chosen from O, S or N: provided HO that not more than two of the groups A, A, A, A, As, and r-r C A simultaneously represent a heteroatom; and O their tautomeric forms, their racemic forms, their isomers, NH NH and their pharmaceutically acceptable derivatives. 45 In regard to the above compounds, halogen includes fluoro, 1s. 1s. chloro, bromo, and iodo. Preferred halogens are F and Cl. H H Lower alkyl includes straight and branched carbon chains C C having from 1 to 6 carbon atoms. Examples of Such alkyl groups include methyl, ethyl, isopropyl, and tert-butyl. Lower 50 alkenyl includes straight and branched hydrocarbon radicals having from 2 to 6 carbonatoms and at least one double bond. Examples of Such alkenyl groups are ethenyl, 3-buten-1-yl, 2-ethenylbutyl, and 3-hexen-1-yl. Lower alkynyl includes O NH straight and branched hydrocarbon radicals having from 2 to 55 H 1s, 6 carbonatoms and at least one triple bond. Examples of Such H alkynyl groups are ethynyl, 3-butyn-1-yl, propynyl, 2-butyn C 1-yl, and 3-pentyn-1-yl. Lower haloalkyl includes a lower alkyl as defined above, substituted with one or several halo The preparation of the above compounds is described in gens. An example of haloalkyl is trifluoromethyl. Aryl is 60 US 2002/0198198, WO 2002/076953, WO 2002/074754, understood to refer to an aromatic carbocycle containing WO 2006/092691, Bioorganic & Medicinal Chemistry Let between 6 and 10 carbon atoms. An example of an aryl group ters 14 (2004) 4623-4626, and Bioorganic & Medicinal is phenyl. Heteroaryl includes aromatic cycles which have Chemistry Letters 14 (2004) 4627-4631. from 5 to 10 ring atoms, from 1 to 4 of which are indepen In another embodiment, PDE7 inhibitors useful in the dently selected from the group consisting of O, S, and N. 65 methods of the invention are selected from those compounds Representative heteroaryl groups have 1, 2, 3 or 4 heteroat generally or specifically disclosed in EP 1 193261, WO oms in a 5- or 6-membered aromatic ring. Examples of Such 2002/28847, US 20030045557, U.S. Pat. No. 7,122,565, US 9.220,715 B2 47 48 Bioorganic & Medicinal Chemistry Letters 14 (2004) 4607 C-C alkenylene, C-C alkynylene, cycloalkylene, arylene, 4613, and Bioorganic & Medicinal Chemistry Letters 14 divalent heterocycle or a divalent polycyclic group, and, R, (2004) 4615-4621, each expressly incorporated herein by is: reference in its entirety. In one embodiment, PDE7 inhibitors (1)H, =O, NO, CN, lower haloalkyl, halogen, carboxylic useful in the methods of the invention have the formula: acid bioisostere, cycloalkyl, (2) COORs, C(=O)Rs, C(=S)Rs, SORs, SORs, SORs, SRs, ORs: (3) (3) C(=O)NRR, C(=S)NRR, C(=N-CN) NRSR, C(=N SONH)NRR, C(=CH 10 NO)NR's R SONRR, C(=NRs)NHR, C(=NRs)R C(=NR)NHR, C(=NR)R, or NRSR wherein Rs and R are the same or different and are selected from OH. R. R. C(=O)NRR, 15 C(=O)Rs, SORs, C(=S)NRR, C(=CH-NO) NRR, C(=N CN)NRR, C(=N SONH) The substituents for the above compounds are defined as NRoRo C(=NR)NHR or C(=NR)Ro, follows: (4) heterocycle optionally substituted with one or several Y is S or O; groups Rs. R is C1-Cio alkyl, C2-Cio alkenyl, C2-Cio alkynyl, wherein RandR are the same or different and are selected cycloalkyl, cycloalkenyl, heterocycle, aryl, or a polycyclic from H. lower alkyl, C-C alkenyl, C-C alkynyl, X-cy group; each optionally Substituted with one or several groups cloalkyl, Xa-cycloalkenyl, Xa-aryl, Xa-heterocycle or X-Ra, identical or different, in which X is a single bond, X-polycyclic group, wherein X is a single bond, lower lower alkylene, C-C alkenylene, cycloalkylene, arylene, or alkylene, or C-C alkenylene; each optionally Substituted divalent heterocycle, and R is: 25 with one or several groups that are the same or different and selected from halogen, —O, COOR, CN, OR, O-lower (1) H. =O, NO, CN, halogen, lower haloalkyl, lower alkyl optionally substituted with OR, C(=O)-lower alkyl, alkyl, carboxylic acid bioisostere: lower haloalkyl, (2) COORs, C(=O)Rs, C(=S)Rs, SORs, SORs, SORs, 30

NRRs, C(=NR)NHRs, C(=NR)Rs, C(=NR) NHRs, C(=NR)Rs, SONR,Rs, or NR7Rs, wherein R, and Rs are the same or different and are selected from 35 in which X is a single bond or lower alkylene and Rs. Ro, and Ro, are the same or different and are selected from Hor lower alkyl: NRR, or C(=S)NRRo: X-heterocycle, X-aryl, Xe-cycloalkyl, Xe-cycloalkenyl, R is lower alkyl, C-Co alkenyl, C-Co alkynyl, 40 or X-polycyclic group, wherein X is a single bond or lower cycloalkyl, cycloalkenyl, heterocycle, aryl; each optionally alkylene, these groups being optionally Substituted with one Substituted with one or several groups which are the same or or several groups, identical or different, selected from halo different and which are selected from: gens, COOR, OR, or (CH2)NRR- in whichnis 0, 1, or (1) H. carboxylic acid bioisostere, lower haloalkyl, halo 2 and R and R are the same or different and are selected gen, 45 from H or lower alkyl: (2) COORs, ORs, SORs, R is selected from H. CN, OH, lower alkyl, O-lower alkyl, (3) SONR, R2, C(=O)NRR, NRR, wherein R aryl, heterocycle, SONH, or and R are the same or different and are selected from OH, Rs. R. C(=O)NRR, C(=O)Rs, SORs, C(=S) NRR, C(=CH-NO)NRR, C(=N-CN) 50 NRR, C(=N-SONH)NR'Rio, C(=NRs) NHR, or C(=NR)Ro: R is X-R's, wherein X is a single bond or, a group selected from C-C alkylene, C-C alkenylene, C-C alky 55 in which X is a single bond or lower alkylene and Rs and nylene, each optionally substituted with one or several groups Rs are the same or different and are selected from Horlower which are the same or different and which are selected from: alkyl: (1) H. C-C alkyl, C-C cycloalkyl, aryl, heterocycle, Ro is selected from hydrogen, lower alkyl, cyclopropyl, or –O, CN, heterocycle; (2) ORs, =NRs; or 60 or their pharmaceutically acceptable derivatives. (3)NRR, wherein R and Rare the same or different In regard to the above compounds, aryl refers to an unsat and are selected from Rs. RC(=O)NRs RC(=O)Rs. urated carbocycle, exclusively comprising carbon atoms in SORs, C(=S)NRR, C(=CH NO)NRR, the cyclic structure, the number of which is between 5 and 10, C(=NR)NHR, or C(=NR)Ro: including phenyl, naphthyl, or tetrahydronaphthyl. Hetero R's is cycloalkyl, cycloalkenyl, aryl, heterocycle, or a poly 65 cycle refers to a nonsaturated or Saturated monocycle con cyclic group; each optionally Substituted with one or several taining between 1 and 7 carbon atoms in the cyclic structure groups X-R, wherein X is a single bond, lower alkylene, and at least one heteroatom in the cyclic structure, such as US 9.220,715 B2 49 50 nitrogen, oxygen, or sulfur, preferably from 1 to 4 heteroat oms, identical or different, selected from nitrogen, sulfur and oxygen atoms. Suitable heterocycles include morpholinyl, n piperazinyl, pyrrolidinyl, piperidinyl, pyrimidinyl, 2- and O 3-furanyl, 2- and 3-thienyl, 2-pyridyl, 2- and 3-pyranyl. 5 hydroxypyridyl, pyrazolyl, isoxazolyl, tetrazole, imidazole, N triazole, and the like. Polycyclic groups include at least two - O-2- cycles, identical or different, selected from aryl, heterocycle. cycloalkyl, cycloalkenyl groups fused together to form said OH polycyclic group such as 2- and 3-benzothienyl, 2- and 3-ben 10 zofuranyl, 2-indolyl, 2- and 3-quinolinyl, acridinyl, x-y quinazolinyl, indolyl benzo. 1.3dioxolyl, and 9-thioxanta f nyl. Bicyclic groups refer to two cycles, which are the same or different and which are chosen from aryl, heterocycle. cycloalkyl or cycloalkenyl, fused together to form said bicy 15 NsO2 O-2- clic groups. Halogen refers to fluorine, chlorine, bromine, or OH. iodine. Lower alkyl refers to an alkyl is linear or branched and contains 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, The preparation of the above compounds is described in EP isobutyl, n-butyl, pentyl, hexyl and the like. Alkenyl refers to 1 193261, WO 02/28847, US 20030045557, U.S. Pat. No. a linear or branched unsaturated carbonatom chain, compris 7,122,565, Bioorganic & Medicinal Chemistry Letters 14 ing one or several double bonds, preferably one or two double (2004) 4607-4613, and Bioorganic & Medicinal Chemistry bonds. Alkynyl refers to a linear or branched unsaturated Letters 14 (2004) 4615-4621. carbon atom chain, comprising one or several triple bonds, 25 In another embodiment, PDE7 inhibitors useful in the preferably one or two triple bonds. Lower haloalkyl refers to methods of the invention are selected from those compounds a lower alkyl substituted with one or several halogens; pre generally or specifically disclosed in WO 2004/111054, US ferred lower haloalkyl groups include perhaloalkyl groups 2006.0128728, and US 20070270419, each expressly incor such as CF. Cycloalkyl refers to saturated monocarbocyle porated herein by reference in its entirety. In one embodi containing from 3 to 10 carbonatoms; including cyclopropyl. ment, PDE7 inhibitors useful in the methods of the invention cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. have the formulas: Cycloalkenyl refers to unsaturated monocarbocyle contain ing from 3 to 10 carbonatoms. Examples of suitable cycloalk enyl are 3-cyclohexene, and 3-cycloheptene. Carboxylic acid (4A) bioisostere has the classical meaning; common carboxylic 35 R3 and acid bioisostere are tetrazole-5-yl, C(=O)N(H)OH, isox azol-3-yl, hydroxythiadiazolyl, sulfonamido, sulfonylcar boxamido, phosphonic acid, phosphonamido, phosphinic acid, sulfonic acids, acyl sulfonamido, mercaptoazole, acyl 40 cyanamides. In one embodiment, a PDE7 inhibitor useful in the methods of the invention has the formula: R (4B) 21 3. 45 R N N N N (SSN NH R4 50 Compound 4 R O CH / N-N The substituents for the above compounds are defined as O f 55 follows: NN R is a substituted or unsubstituted C-scycloalkyl group or S tert-butyl group; CH3 N R is a hydrogen atom or C- alkyl group; R is a group: NRs R. C(=O)R-7, or S(O)o-Rs: 60 Ra is a hydrogen atom or C- alkoxyl group which is unsubstituted or substituted by one or more fluorine atom(s): Rs and Rare, same or different from each other, a hydro gen atom, substituted or unsubstituted C. alkyl group. Sub stituted or unsubstituted acyl group, substituted or unsubsti 65 tuted heterocycloalkyl group, and substituted or In other embodiments, PDE7 inhibitors useful in the meth unsubstituted heterocycloalkyl ring formed with a nitrogen ods of the invention have the formulas: atom which is binding Rs and Re: US 9.220,715 B2 51 52 R is a group: OR or NRSR; -continued Rs is a hydrogen atom, a halogen atom, a group: NRSR Substituted or unsubstituted Calkyl group, or Substituted or unsubstituted aryl group; R is a hydrogen atom or substituted or unsubstituted C alkyl group; or pharmaceutically acceptable salts or Solvates thereof.

In regard to the above compounds, the term "C-C alkyl 10 group' includes a straight or branched-chained alkyl group having 1 to 3 carbon atoms. The term "C-Cs cycloalkyl group' includes a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclo hexyl and cyclooctyl. The term "heterocycloalkyl group' is 3 15 to 7 membered heterocyclic group containing the same or different 1 to 4 hetero atom(s) Such as oxygen, nitrogen or Sulfur atom(s), and examples may include pyrrolidinyl, pip eridinyl, piperazinyl, homopiperazinyl, tetrahydrofuryl, tet rahydrophyranyl, morpholinyl and azetidinyl. The term "C- Calkoxy group” means alkoxy group having 1 to 3 carbon atoms. The term “acyl group” means acyl group having 1 to 8 carbon atoms. The term “aryl group' is phenyl, naphthyl, biphenyl group, having 6 to 12 carbon atoms, and the term 25 N "heteroaryl group' is 5 to 7 membered monocyclic or poly 2 N O cyclic group thereof containing 2 to 8 carbon atoms and the Y-Sud same or different 1 to 4 hetero atom(s) Such as oxygen, nitro gen, Sulfur atom(s). The examples include pyrrole, furyl, 30 NH 4 thienyl, imidazolyl, thiazolyl pyrazinyl, indolyl, quinolinyl, O N isoquinolinyl, tetrazolyl pyridinyl, pyrazolyl pyridazinyl and pyrimidinyl. Examples of suitable substituent of “substituted or unsubstituted C-C alkyl group' include hydroxyl group 35 and halogen atom, and examples of Suitable Substituent of “substituted or unsubstituted acyl group” include halogen / atom and nitro group. Further, examples of Suitable Substitu N ent of “substituted or unsubstituted aryl group” include C-C, % N r O alkyl, halogen atom, amino group, acyl group, amide group. 40 hydroxyl group, acylamino group, carboxyl group and Sulfo \, f Y-\l. nyl group. Examples of suitable substituent of “substituted or NH 4 unsubstituted C-C cycloalkyl group' is C-C alkyl, O N hydroxyl group and oxo group, and examples of Suitable 45 substituent of “substituted or unsubstituted heterocycloalkyl group' may include carboxy group, acyl group, alkoxy group, amino group, alkylamino group, acylamino group, hydroxyl group, oxo group, ethylenedioxy group, methyl group, ethyl 50 group and hydroxyethyl group. 2 N e NO In other embodiments, PDE7 inhibitors useful in the meth ods of the invention have the formulas: VY-Sud

The preparation of the above compounds is described in 60 WO 2004/111054, US 20060128728, and US 20070270419. In another embodiment, PDE7 inhibitors useful in the methods of the invention are selected from those compounds generally or specifically disclosed in U.S. Pat. No. 6,903,109, US 20040082578, WO 2003/088963, and US 20060154949, 65 each expressly incorporated herein by reference in its entirety. In one embodiment, PDE7 inhibitors useful in the methods of the invention have the formula: US 9.220,715 B2 53 54 (i) hydrogen, halo, Cs straight or branched chain alkyl, arylalkyl, C-7 cycloalkyl, Cs alkoxy, cyano, C. car X (5) boalkoxy, trifluoromethyl, Cs alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, Cs carboxylate, aryl, heteroaryl, and heterocyclyl; ry / (ii) NRoR wherein Ro and R are independently y- / \ R. selected from H. C.s straight or branched chain alkyl, arylalkyl, C-7 cycloalkyl, carboxyalkyl, aryl, het NS eroaryl, or heterocyclyl, or Ro and R taken together R4 10 with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group; (iii) NRCOR wherein R is selected from hydrogen or The substituents for the above compounds are defined as alkyl and R is selected from hydrogen, alkyl, Substi follows: tuted alkyl, C. alkoxyl, carboxyalkyl, RoRN (a) R is selected from the group consisting of 15 (CH), RORNCO(CH), aryl, arylalkyl, heteroaryl, (i) CORs, wherein Rs is selected from H., optionally sub or heterocyclyl, or R and R taken together with the stituted Cs straight or branched chain alkyl, optionally carbonyl group form a carbonyl containing heterocyclyl substituted aryl and optionally substituted arylalkyl: group, wherein Ro and R are independently selected wherein the substituents on the alkyl, aryland arylalkyl from H, OH, alkyl, and alkoxy, and p is an integer from group are selected from Cs alkoxy, phenylacetyloxy, 1-6, wherein the alkyl group may be substituted with hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboxyl, alkyl, aryl, Substituted aryl, heterocyclyl. Sub carboalkoxy, or NROR wherein Ro and R are inde stituted heterocyclyl, heteroaryl, substituted heteroaryl, pendently selected from the group consisting of hydro hydroxamic acid, Sulfonamide, Sulfonyl, hydroxy, thiol, gen, Cs straight or branched chain alkyl, C-7 alkoxy, or arylalkyl; cycloalkyl, benzyl, or aryl; 25 (d) R is selected from the group consisting of (i) hydrogen, (ii) COOR, wherein R is selected from H., optionally (ii) C. Straight or branched chain alkyl, (iii) benzyl, and (iv) Substituted Cs straight or branched chain alkyl, option NRR, wherein R and Ra are independently selected ally substituted aryland optionally substituted arylalkyl; from hydrogen and C alkyl, wherein the C- alkyl and wherein the substituents on the alkyl, aryland arylalkyl benzyl groups are optionally substituted with one or more 30 groups selected from C, cycloalkyl, Cs alkoxy, cyano, group are selected from C1-8 alkoxy, phenylacetyloxy, C. carboalkoxy, trifluoromethyl, Cs alkylsulfonyl, halo hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, gen, nitro, hydroxy, trifluoromethoxy, Cls carboxylate, carboalkoxy, or NROR wherein Ro and R are inde amino, NRR aryl, and heteroaryl; and pendently selected from the group consisting of hydro (e) X is selected from Sand O: gen, Cs straight or branched chain alkyl, C-7 35 and the pharmaceutically acceptable salts, esters and pro cycloalkyl, benzyl, or aryl; drug forms thereof. (iii) cyano; In an alternative embodiment, R. R. and Ra are as above (iv) a lactone or lactam formed with R: and R is NRSR, where Rs and R are independently (v) CONR,Rs wherein R, and Rs are independently selected from hydrogen, Cs straight or branched chain alkyl, Selected from H. C.s straight or branched chain alkyl, 40 arylalkyl, C-7 cycloalkyl, aryl, heteroaryl, and heterocyclyl, C-7 cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, or Rs and R taken together with the nitrogen to which they alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl, and are attached form a heterocyclyl or heteroaryl group. heterocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl, In regard to the above compounds, “alkyl refers to alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl, and straight, cyclic and branched-chain alkyl. The alkyl group heterocyclyl groups may be substituted with carboxyl, 45 may be optionally Substituted with one or more groups such alkyl, aryl, substituted aryl, heterocyclyl, substituted as halogen, OH, CN, mercapto, nitro, amino, C-C-alkyl, heterocyclyl, heteroaryl, substituted heteroaryl, hydrox C-C-alkoxyl, C-C-alkylthio, C-C-alkyl-amino, di(C- amic acid, Sulfonamide, Sulfonyl, hydroxy, thiol, alkoxy, Cs-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, or arylalkyl: formyl, carboxy, alkoxycarbonyl, C-C-alkyl-CO-O-, or R, and Rs taken together with the nitrogen to which they 50 C-Cs-alkyl-CO—NH-, carboxamide, hydroxamic acid, are attached form a heterocyclyl or heteroaryl group; Sulfonamide, Sulfonyl, thiol, aryl, aryl(C-Cs)alkyl, hetero (vi) a carboxylic ester or carboxylic acid bioisostere cyclyl, and heteroaryl. The term “bioisostere' is defined as including optionally Substituted heteroaryl groups; 'groups or molecules which have chemical and physical (b) R is selected from the group consisting of optionally properties producing broadly similar biological properties.” substituted alkyl, optionally substituted aryl, optionally sub 55 (Burger's Medicinal Chemistry and Drug Discovery, M. E. stituted heteroaryl, optionally substituted C-7 cycloalkyl, Wolff, ed. Fifth Edition, Vol. 1, 1995, Pg. 785). The term optionally substituted heterocyclyl, wherein the heterocyclyl “acyl as used herein, whether used alone or as part of a is 1,3-dioxolane or furan, or R is Substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an 60 organic acid by removal of the hydroxyl group. Aryl or 'Ar' whether used alone or as part of a Substituent group, is a carbocyclic aromatic radical including, but not limited to, phenyl, 1- or 2-naphthyl and the like. The carbocyclic aro CC) matic radical may be substituted by independent replacement 65 of 1 to 5 of the hydrogen atoms thereon with halogen, OH, (c) R is from one to four groups independently selected CN, mercapto, nitro, amino, C-Cs-alkyl, C-Cs-alkoxyl, from the group consisting of C-Cs-alkylthio, C-C-alkyl-amino, di(C-Cs-alkyl)amino, US 9.220,715 B2 55 56

(mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, -continued alkoxycarbonyl, C-C-alkyl-CO-O-, C-C-alkyl-CO— NH , or carboxamide. Illustrative aryl radicals include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluo rophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphe nyl, carboxyphenyl, trifluoromethylphenyl, methoxyeth ylphenyl, acetamidophenyl, tolyl, Xylyl, dimethylcarbam ylphenyl and the like. The term "heteroaryl” refers to a cyclic, fully unsaturated radical having from five to ten ring atoms of 10 which one ring atom is selected from S. O. and N: 0-2 ring atoms are additional heteroatoms independently selected from S. O. and N; and the remaining ring atoms are carbon. The radical may be joined to the rest of the molecule via any of the ring atoms. The terms "heterocycle.” “heterocyclic.” 15 and "heterocycle” refer to an optionally substituted, fully or partially saturated cyclic group which is, for example, a 4- to 7-membered monocyclic, I-5 to 11-membered bicyclic, or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, or 3 heteroatoms selected from nitrogenatoms, oxygen atoms, and Sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. The 25 The preparation of the above compounds is described in nitrogenatoms may optionally be quaternized. The heterocy U.S. Pat. No. 6,903,109, US 20040082578, WO 2003/ clic group may be attached at any heteroatom or carbonatom. 088963, and US 20060154949. In another embodiment, PDE7 inhibitors useful in the In other embodiments, PDE7 inhibitors useful in the meth methods of the invention are selected from those compounds ods of the invention have the formulas: 30 generally or specifically disclosed in U.S. Pat. No. 6,958.328, WO 2002/085894, and US 20030212089, each expressly incorporated herein by reference in its entirety. These PDE7 inhibitors have the same formula as those described above (e.g., U.S. Pat. No. 6,903,109), except that R is not a car 35 boxylic ester or carboxylic acid bioisostere. The preparation of these compounds is described in U.S. Pat. No. 6,958.328, US 20030212089, and WO 2002/085894. In another embodiment, PDE7 inhibitors useful in the methods of the invention are selected from those compounds 40 generally or specifically disclosed in WO 2006/004040 and EP 1 775 298, each expressly incorporated herein by refer ence in its entirety. In one embodiment, PDE7 inhibitors useful in the methods of the invention have the formula:

45 (6) R2 R3 / 50 X)-. N S R

55 The substituents for the above compounds are defined as follows: R is substituted or unsubstituted Cls alkyl group, Substi tuted or unsubstituted cycloalkyl group, or Substituted or unsubstituted heterocycloalkyl group (e.g., cyclohexyl, 60 cycloheptyl, or tetrahydropyranyl); R is a hydrogen atom or substituted or unsubstituted C alkyl group (e.g., methyl); R is a hydrogen atom, Substituted or unsubstituted C alkyl group, or a halogen atom; and 65 R is Substituted or unsubstituted aryl group, Substituted or unsubstituted heteroaryl group, or a group CONRR, or COR7. US 9.220,715 B2 57 58 wherein Rs and Rare, same or different from each other, a unsubstituted Sulfonylamide group; oxo group; Substituted or hydrogenatom; Calkyl group which may be substituted by unsubstituted urea group; Straight, branched-chained or a halogen atom, Substituted or unsubstituted aryl group, Sub cyclic alkenyl group Such as ethenyl, propenyl, cyclohexenyl stituted or unsubstituted heteroaryl group, substituted or and the like. unsubstituted heterocycloalkyl group, Substituted or unsub 5 stituted cycloalkyl group, a group NRCORs, CORs, In other embodiments, PDE7 inhibitors useful in the meth NRoRo; Substituted or unsubstituted cycloalkyl group; Sub ods of the invention have the formulas: stituted or unsubstituted heterocycloalkyl group; substituted or unsubstituted aryl group; substituted or unsubstituted het eroaryl group; or Substituted or unsubstituted heterocy 10 (6A) cloalkyl group in which the ring is formed together with the nitrogen atom binding Rs and Re; wherein R, is a hydrogen atom or Substituted or unsubsti tuted C- alkyl group: wherein Rs is substituted or unsubstituted heterocycloalkyl 15 group, or a group OH, OR, or NRRo: wherein Ro and Ro are, same or different from each other, a hydrogen atom; Substituted or unsubstituted C- alkyl group, Substituted or unsubstituted heterocycloalkyl group; Substituted or unsubstituted acyl: a group SOR7, or Substi tuted or unsubstituted heterocycloalkyl group in which the (6B) ring is formed together with the nitrogenatom binding Rs and Re; \ or pharmaceutically acceptable salts or Solvates thereof. NH In regard to the above compounds, the term "cycloalkyl 25 group” means cycloalkyl group having 3 to 8 carbon atoms. The term "heterocycloalkyl group' may be 3 to 7 membered O monocyclic or polycyclic heterocyclic group containing the same or different 1 to 4 hetero atom(s) Such as oxygen, nitro gen or Sulfur atom(s), and examples may include piperidinyl, 30 pyrrolidinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl. morpholinyl, azetidinyl, imidazolidinyl, oxazolidinyl, (6C) hexahydropyrrolidinyl, octahydroindolidinyl, octahydro quinolidinyl, octahydroindolyl, and oxo-derivatives thereof. The term “aryl group' may be aromatic hydrocarbon group, 35 which consists of mono-benzene ring, or binding or con \ densed benzene ring, such as phenyl, naphthyl, biphenyl and NN the like; and dicyclic or tricyclic group, which consists of benzene ring condensed with cycloalkyl or heterocyclic ring, O Such as 1,2,3,4-tetrahydronaphthalene, 2,3-dihydroindene, 40 indoline, coumarone and the like. The term "heteroaryl group' may be 5 to 7 membered monocyclic heteroaryl group or polycyclic heteroaryl group, and having 2 to 8 carbon atoms with 1 to 4 hetero atom(s) such as oxygen, nitrogen, (6D)

Sulfur atom(s), in which the polycyclic heteroaryl group has 45 condensed ring system by the same or different mono cyclic heteroaryl or benzene ring each other; or polycyclic group which is consisted of heteroaryl group condensed with H O cycloalkyl or heterocycloalkyl ring. Examples of Suitable N X Substituent of the present invention may include straight, 50 / branched-chained or cyclic C-C alkyl group, which may be H Substituted by one or more methyl, ethyl, propyl, isopropyl. n-butyl, t-butyl, cyclohexyl, cycloheptyl, methoxymethyl, hydroxymethyl, trifluoromethyl, C-C alkoxy group, halo gen atom, and hydroxyl group; hydroxyl group; cyano group; 55 Substituted or unsubstituted alkoxy group Such as methoxy, ethoxy group; amino group which may be substituted by (6E) C-C alkyl group or acyl group Such as amino, methylamino, ethylamino, dimethylamino, acylamino and the like; car boxylic group; Substituted or unsubstituted ester group; phos 60 phate group; Sulfonic group; Substituted or unsubstituted aryl group; Substituted or unsubstituted heteroaryl group; Satu rated or unsaturated heterocycloalkyl group which may be Substituted; Substituted or unsubstituted carbamoyl group; Substituted or unsubstituted amide group; Substituted or 65 unsubstituted thioamide group; halogen atom; nitro group; substituted or unsubstituted sulfone group; substituted or US 9.220,715 B2 59 60 -continued R is a hydrogen atom or C. alkyl group; (6F) R is a hydrogenatom; nitro group; cyano group; a halogen atom; heteroaryl group; Substituted or unsubstituted C alkyl group; Substituted or unsubstituted Calkenyl group: % saturated or unsaturated heterocycloalkyl group which is Sub \, ( \ IN stituted or unsubstituted; a group: NRR, C(O)R 7, SOR, S ^\ ORs, NRCOR, NRSOR: R is a hydrogenatom or C alkoxy group which is unsub O \Us ( stituted or substituted by one or more fluorine atom(s): O O Rs and Rare, same or different from each other, a hydro (6G) O gen atom; Substituted or unsubstituted C. alkyl group; Sub stituted or unsubstituted acyl group; or Substituted or unsub N^n stituted heterocycloalkyl group; 15 % y-, R, is a hydrogen atom; substituted or unsubstituted C \ f \ HN O alkyl group; substituted or unsubstituted heterocycloalkyl S group; OH: ORs or NRSR; O Rs is a hydrogen atom, Substituted or unsubstituted C. alkyl group; or substituted or unsubstituted heterocycloalkyl group; (6H) or pharmaceutically acceptable salts or Solvates thereof. In regard to the above compounds, the term "C-C alkyl 25 group' refers to a straight or branched-chained alkyl group having 1 to 6 carbon atoms, and the term "C-C alkenyl group' refers to a straight or branched-chained alkenyl group having 2 to 6 carbon atoms. The term “cycloalkyl group' refers to a cycloalkyl group having 3 to 8 carbon atoms Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo heptyl, and cyclooctyl. The term "heterocycloalkyl group” is The preparation of the above compounds is described in EP 3 to 7 membered heterocyclic group containing the same or 1775298 and WO 2006/OO4040. different 1 to 4 hetero atom(s) Such as oxygen, nitrogen or In another embodiment, PDE7 inhibitors useful in the 35 Sulfur atom(s), and examples may include piperidinyl, pyrro methods of the invention are selected from those compounds lidinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl, mor generally or specifically disclosed in WO 2004/111053 and pholinyl, azetidinyl, and homopiperazinyl. The term “het US 2006.0128.707, each expressly incorporated herein by ref eroaryl group' is 5 to 7 membered monocyclic or polycyclic erence in its entirety. In one embodiment, PDE7 inhibitors group thereof containing 2 to 8 carbon atoms and the same or useful in the methods of the invention have the formulas: 40 different 1 to 4 hetero atom(s) Such as oxygen, nitrogen or Sulfur atom(s). The examples include pyrrole, furyl, thienyl, imidazolyl, thiazolyl pyrazinyl, indolyl, quinolinyl, iso

(7A) quinolinyl, tetrazolyl pyridinyl, pyrazolyl pyridaZinyl, and pyrimidinyl. The “halogen atom' includes fluorine, chlorine, 45 bromine and iodine. Examples of the suitable substituent of “substituted or unsubstituted C-C alkyl group”, “substi tuted or unsubstituted C-C cycloalkyl group”, “substituted or unsubstituted alkenyl group”, “substituted or unsubstituted heterocycloalkyl group' and “substituted or unsubstituted 50 acyl group' include a straight or branched-chained, or Sub stituted or unsubstituted alkyl group such as methyl, ethyl, (7B) propyl, isopropyl. n-butyl, tert-butyl, Substituted or unsubsti tuted cycloalkyl group Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; hydroxyl group; 55 cyano group; alkoxy group Such as methoxy and ethoxy; Substituted or unsubstituted amino group Such as amino, methylamino, ethylamino, and dimethylamino; Substituted or unsubstituted acyl group Such as acetyl, and propionyl; Sub stituted or unsubstituted aryl group; Substituted or unsubsti 60 tuted heteroaryl group; Saturated or unsaturated heterocy cloalkyl group which is substituted or unsubstituted; The substituents for the above compounds are defined as substituted or unsubstituted carbamoyl group; substituted or follows: unsubstituted amide group; halogen atom; nitro group; Sub A is N or CR; stituted or unsubstituted Sulfone group, oxo group; urea B is N or CH: 65 group; a straight or branched-chained, or cyclic alkenyl group R is Substituted or unsubstituted Css cycloalkyl group or which is substituted or unsubstituted such as ethenyl, prope tert-butyl group; nyl, and cyclohexenyl. US 9.220,715 B2 61 62 In other embodiments, PDE7 inhibitors useful in the meth Rs is hydrogen or Ce alkyl, ods of the invention have the formulas: or a pharmaceutically acceptable salt or Solvate thereof. In one embodiment, a PDE7 inhibitoruseful in the methods of the invention has the formula:

CH3 SON(CH3)2. - C 10 N N." ON NO O 15 The preparation of the above compounds is described in U.S. Pat. No. 6,617,357, US 2002.0156064, and Molecular NH2. Pharmacology, 66:1679-1689, 2004. In another embodiment, PDE7 inhibitors useful in the methods of the invention are selected from those compounds S N generally or specifically disclosed in U.S. Pat. No. 6,852,720, x - C EP 1 348 433, and WO 2003/082277, each expressly incor porated herein by reference in its entirety. In one embodi N N." On ment, PDE7 inhibitors useful in the methods of the invention O 25 have the formula:

(9)

The preparation of the above compounds is described in 30 US 2006O128.707 and WO 2004/111053. In another embodiment, PDE7 inhibitors useful in the methods of the invention are selected from those compounds generally or specifically disclosed in U.S. Pat. No. 6,617.357, US 20020156064, and Molecular Pharmacology, 66:1679 35 1689, 2004, each expressly incorporated herein by reference The substituents for the above compounds are defined as in its entirety. In one embodiment, PDE7 inhibitors useful in follows: the methods of the invention have the formula: R is a group selected from cycloalkyl, heterocycloalkyl, aryland heteroaryl, those groups being optionally Substituted 40 by one or more groups, identical or different, selected inde (8) pendently of each other from halogen, trifluoromethyl, nitro, cyano, oxo, NRRs. COR CONRRs, OR S(O).R. S(O), NRRs, tetrazolyl and (C-C) alkyl which is option ally substituted by 1 to 3 groups, identical or different, 45 selected independently of each other from OR, NRRs, and COR; wherein n is an integer from 0 to 2 inclusive, R and SOR1. Rs are identical or different and independently of each other are a hydrogen atom or a group of formula X-R, wherein X is a single bond or a (C-C) alkylene group, and R is a 50 group selected from (C-C) alkyl, cycloalkyl, heterocy The substituents for the above compounds are defined as cloalkyl, aryl, and heteroaryl, follows: R is a group selected from (C-C) alkyl, (C-C) alkenyl, R is NRR, where RandR, are independently H or C. (C-C) alkynyl, aryl, and cycloalkyl, alkyl, or represents a 5 to 7 member ring comprised of carbon R is a group selected from cycloalkyl, heterocycloalkyl, or carbon and one or more additional heteroatoms selected 55 aryland heteroaryl, these groups being optionally Substituted from O, N, or S; by one or more groups, identical or different, selected inde R2 is H. Cls alkyl, C- alkyl-Ar, C- alkyl-Cs. pendently of each other from halogen, nitro, cyano, trifluo cycloalkyl, C2-salkenyl, C2-alkenyl-Ar, or C2-alkenyl-Cs. romethyl, oxo, (C-C) alkyl, OR, NRR, COR COR cycloalkyl, wherein Aris substituted or unsubstituted phenyl: CONHOH, CONRR, S(O).R. S(O)NRR, NRCOR, R is NO, halo, CN, C(O)OR, COR, or NRR, where R. 60 NRSOR, N(SOR), NRCONRRs, C(=NCN)NRR, and R, are independently H or C. alkyl: NRC(=NCN)NRR, and tetrazolyl optionally substituted R is H, OC alkyl, halo, C(O)NRR, C(O)OR7 Cs with a (C-C) alkyl, wherein m is an integer from 0 to 2 alkyl, OCHF, CHORs, OC alkyl-Ar, or CH-NHC(O) inclusive, R and R, are identical or different and indepen CH: dently of each other are a hydrogen atom or a group of Rs is H, halo, or alkyl: 65 formula X-R, wherein X is a single bond or a (C-C) R is Cls alkyl, OC alkyl, or halo; alkylene group, R, is a group selected from (C-C) alkyl, R is hydrogen or an ester or amide-forming group; cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these US 9.220,715 B2 63 64 groups being optionally Substituted by 1 to 3 groups, identical alkylamino, di(C-C) alkylamino (each alkyl amino being or different, selected independently of each other from identical or different, independently of each other), carboxy, hydroxy, (C-C) alkoxy, (C-C) alkyl, amino, mono (C-C) (C-C) alkoxycarbonyl, and benzyl, and Rs is a hydrogen alkylamino, di(C-C) alkylamino (each alkyl amino being atom or a (C-C) alkyl group, or identical or different, independently of each other), carboxy, a racemic form thereof, an isomer thereof, an N-oxide (C-C) alkoxycarbonyl, and benzyl, and Rs represents a thereof or a pharmaceutically acceptable acid or base salt hydrogen atom or a (C-C) alkyl group: thereof. a racemic form thereof, an isomer thereof, an N-oxide The preparation of these compounds is described in U.S. thereof, or a pharmaceutically acceptable acid or base salt Pat. No. 6,753,340, US 20030191167, EP 1348 701, and WO thereof. 10 The preparation of the above compounds is described in 2003/082839. U.S. Pat. No. 6,852,720, EP 1 348 433, and WO 2003/ In another embodiment, PDE7 inhibitors useful in the O822.77. methods of the invention are selected from those compounds In another embodiment, PDE7 inhibitors useful in the generally or specifically disclosed in U.S. Pat. No. 6,849,638, methods of the invention are selected from those compounds 15 US 200301 19829, and WO 2002/088138, each expressly generally or specifically disclosed in U.S. Pat. No. 6,753,340, incorporated herein by reference in its entirety. In one US 20030191167, EP 1348 701, and WO 2003/082839, each embodiment, PDE7 inhibitors useful in the methods of the expressly incorporated herein by reference in its entirety. In invention have the formula: one embodiment, PDE7 inhibitors useful in the methods of the invention have the formula: (11)

(10)

The substituents for the above compounds are defined as 30 follows: The substituents for the above compounds are defined as RandR are independently selected from the group con follows: sisting of hydrogen, alkyl of 1-8 carbonatoms, alkenyl of 2-8 R is a group selected from hydrogen, (C-C) alkyl and carbonatoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-7 aryl(C-C) alkyl, carbonatoms, fully saturated heterocycle of 2-6 carbonatoms R, is a group selected from cycloalkyl, heterocycloalkyl, 35 and 1-2 heteroatoms selected from NH, S and O, aryl of 6-12 aryland heteroaryl, those groups being optionally Substituted carbon atoms, that may be substituted with alkyl of 1-6 car by one or more groups, identical or different, selected inde bonatoms, alkenyl of 2-6 carbonatoms, alkynyl of 2-6 carbon pendently of each other from halogen, trifluoromethyl, nitro, atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 cyano, oxo, NRRs, COR CONRRs, OR, S(O).R. carbon atoms and a number of halogen atoms up to the per S(O)NRRs, tetrazolyl, and (C-C) alkyl which is option 40 halo level, haloalkoxy of 1-6 carbon atoms and a number of ally substituted by 1 to 3 groups, identical or different, halogen atoms up to the perhalo level, aryl of 6-12 carbon selected independently of each other from OR, NRRs, and atoms or heteroaryl of 4-11 carbon atoms and 1, 2 heteroat COR, wherein n is an integer from 0 to 2 inclusive, R and oms selected from N. S. and O. heteroaryl of 4-11 carbon Rs are identical or different and independently of each other atoms and 1-2 heteroatoms selected from N, S and O, which are a hydrogen atom or a group of formula X-R, wherein 45 may be substituted with alkyl of 1-6 carbon atoms, alkenyl of X is a single bond or a (C-C) alkylene group, and R is a 2-6 carbon atoms, alkynyl of 2-6 carbonatoms, alkoxy of 1-6 group selected from (C-C) alkyl, cycloalkyl, heterocy carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and a cloalkyl, aryland heteroaryl, number of halogen atoms up to the perhalo level, haloalkoxy R is a group selected from (C-C) alkyl, (C-C) alkenyl, of 1-6 carbon atoms and a number of halogenatoms up to the (C-C) alkynyl, aryland cycloalkyl, 50 perhalo level, aryl of 6-12 carbonatoms or heteroaryl of 4-11 R is a group selected from cycloalkyl, heterocycloalkyl, carbonatoms and 1-2 heteroatoms selected from N, S and O, aryland heteroaryl, these groups being optionally Substituted and Ra-Rs, or R and R combine to form, together with the by one or more groups, identical or different, selected inde nitrogen atom to which they are attached, a 5-7 membered pendently of each other from halogen, nitro, cyano, trifluo saturated ring which may contain 1-2 additional heteroatoms romethyl, oxo, (C-C) alkyl, OR, NRR, COR COR 55 selected from the group consisting of NH, NRs, S and O, or CONHOH, CONRR, S(O).R. S(O)NRR, NRCOR, combine to form, together with the nitrogen atom to which NRSOR, N(SOR), NRCONRRs, C(=N-CN) they are attached, a 5-7 membered unsaturated ring that may NRR-7, NRC(=N CN)NRR-7, and tetrazolyl optionally contain 1-2 additional heteroatoms selected from the group Substituted with a (C-C) alkyl, wherein m is an integer from consisting of N, S and O. 0 to 2 inclusive, R and R, are identical or different and 60 wherein said Saturated or unsaturated ring may be substi independently of each other area hydrogenatom or a group of tuted with 1-2 substituents selected from the group consisting formula X R, wherein X is a single bond or a (C-C) of OH, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon alkylene group, R, is a group selected from (C-C) alkyl, atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-7 carbon cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these atoms, fully saturated heterocycle of 2-6 carbon atoms and groups being optionally Substituted by 1 to 3 groups, identical 65 1-2 heteroatoms selected from NH, S, and O. halogen, or different, selected independently of each other from haloalkyl of 1-2 carbonatoms and a number of halogenatoms hydroxy, (C-C) alkoxy, (C-C) alkyl, amino, mono (C-C) up to the perhalo level, alkoxy of 1-6 carbon atoms, US 9.220,715 B2 65 66 haloalkoxy of 1-6 carbon atoms and a number of halogen number of halogen atoms up to the perhalo level, haloalkoxy atoms up to the perhalo level, and Re-Roi; or of 1-6 carbon atoms and a number of halogenatoms up to the R and R combine to form, together with the nitrogen perhalo level, aryl of 6-12 carbonatoms or heteroaryl of 4-11 atom to which they are attached, an 8-10 membered bicyclic carbonatoms and 1-2 heteroatoms selected from N. S., and O, saturated ring; 5 and heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms R is selected from the group consisting of NH, S, SGEO). selected from N. S., and O, which may be substituted with and O; alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alky R is selected from alkyl of 1-8 carbon atoms, alkenyl of nyl of 2-6 carbonatoms, alkoxy of 1-6 carbonatoms, halogen, 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, C(=C), haloalkyl of 1-6 carbonatoms and a number of halogenatoms S(=O), and C(=O)C); 10 Rs is selected from hydrogen, OH, alkyl of 1-8 carbon up to the perhalo level, haloalkoxy of 1-6 carbon atoms and a atoms, alkenyl of 2-8 carbon atom, alkynyl of 2-8 carbon number of halogenatoms up to the perhalo level, aryl of 6-12 atoms, alkoxy of 1-8 carbonatoms, aryl of 6-12 carbonatoms, carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 which may be substituted with alkyl of 1-6 carbon atoms, heteroatoms selected from N. S., and O. alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, 15 R is selected from alkyl of 1-8 carbon atoms, alkenyl of alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon 2-8 carbon atoms, and alkynyl of 2-8 carbon atoms; and atoms and a number of halogenatoms up to the perhalo level. R is selected from cycloalkyl of 3-7 carbon atoms, fully haloalkyl of 1-6 carbonatoms and a number of halogenatoms saturated heterocycle of 2-6 carbon atoms and 1-2 heteroat up to the perhalo level, aryl of 6-12 carbon atoms and het oms selected from NH, S, and O, aryl of 6-12 carbon atoms, eroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected which may be substituted with alkyl of 1-6 carbon atoms, from N. S., and O. heteroaryl of 4-11 carbon atoms and 1-2 alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, heteroatoms selected from N. S., and O, which may be sub alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon stituted with alkyl of 1-6 carbonatoms, alkenyl of 2-6 carbon atoms and a number of halogenatoms up to the perhalo level. atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon haloalkoxy of 1-6 carbon atoms and a number of halogen atoms, halogen, haloalkyl of 1-6 carbon atoms and a number 25 atoms up to the perhalo level, aryl of 6-12 carbon atoms or of halogen atoms up to the perhalo level, haloalkoxy of 1-6 heteroaryl of 4-11 carbonatoms and 1-2 heteroatoms selected carbon atoms and a number of halogen atoms up to the per from N. S., and O, and heteroaryl of 4-11 carbonatoms and 1-2 halo level, aryl of 6-12 carbon atoms and heteroaryl of 4-11 heteroatoms selected from N, S and O, which may be substi carbonatoms and 1-2 heteroatoms selected from N. S., and O, tuted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon cycloalkyl of 3-7 carbonatoms, fully saturated heterocycle of 30 atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S atoms, halogen, haloalkyl of 1-6 carbon atoms and a number and O, and NR.R., of halogen atoms up to the perhalo level, haloalkoxy of 1-6 RandR, are independently selected from hydrogen, alkyl carbon atoms and a number of halogen atoms up to the per of 1-8 carbonatoms, alkenyl of 2-8 carbonatoms, and alkynyl halo level, aryl of 6-12 carbon atoms or heteroaryl of 4-11 of 2-8 carbon atoms, or R and R, combine together with the 35 carbonatoms and 1-2 heteroatoms selected from N, S and O. nitrogen atom to which they are attached to form a 5-7 mem and pharmaceutically acceptable salts thereof. bered, unsaturated ring which may contain 1-2 additional The preparation of these compounds is described in U.S. heteroatoms selected from N, S and O or to form a 5-7 Pat. No. 6,849,638, US 200301 19829, and WO 2002/088138. membered, saturated ring which may contain 1-2 additional In another embodiment, PDE7 inhibitors useful in the heteroatoms selected from NH, S, and O: 40 methods of the invention are selected from those compounds Rs is selected from alkyl of 1-8 carbon atoms, alkenyl of generally or specifically disclosed in US 2005222 138 and 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, R-R- WO 2003/064389, each expressly incorporated herein by cycloalkyl of 3-7 carbonatoms, fully saturated heterocycle of reference in its entirety. In one embodiment, PDE7 inhibitors 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S, useful in the methods of the invention have the formula: and O, aryl of 6-12 carbon atoms, which may be substituted 45 with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, (12) halogen, haloalkyl of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-6 carbon atoms and a number of halogen atoms up to the per- 50 halo level, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbonatoms and 1-2 heteroatoms selected from N. S., and O, heteroaryl of 4-11 carbonatoms and 1-2 heteroatoms selected from N. S., and O, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 55 carbonatoms, alkoxy of 1-6 carbonatoms, halogen, haloalkyl of 1-6 carbon atoms and a number of halogenatoms up to the perhalo level, haloalkoxy of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroat- 60 The substituents for the above compounds are defined as oms selected from N. S., and O: follows: R is selected from alkyl of 1-8 carbon atoms, alkenyl of R and R2 are each independently, (1) hydrogen atom, or 2-8 carbon atoms, and alkynyl of 2-8 carbon atoms, (2) Cls alkyl, or Ro is selected from OH, aryl of 6-12 carbon atoms, which R and R may be taken together with the carbon atom to may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 65 which they are attached to form Cyc1. 2-6 carbon atoms, alkynyl of 2-6 carbonatoms, alkoxy of 1-6 wherein R and R. do not represent hydrogen atom at the carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and a same time; US 9.220,715 B2 67 68 Z is (1) CRR, (2) O, (3) S, or (4) a bond; alkoxy or Cs alkylthio, which may be substituted with 1-5 of R and R are each independently, (1) hydrogen atom, (2) R. (16) OCOR (17) CONR.R. (18) SONRR (19) Cs alkyl, (3) Cls alkoxy, or (4) hydroxy, or COOR, (20) COCOORs (21) COR, (22) COCOR, R and R may be taken together with the carbon atom to (23) NRCOR, (24) SO2R, (25) NRSORs, or (26) which they are attached to form Cyc1 or C(O); SOR: Rs and R are each independently, (1) hydrogen atom, or Rs and Rio, Rs 1 and Rs are each independently, hydrogen (2) Cls alkyl, or atom, or Cs alkyl, Rs and R may be taken together with the carbon atom to Rao and R2 are Cls alkyl, Cs alkoxy, hydroxy, halogen which they are attached to form Cyc1; atom, nitro, or COOR: Cyc1, which is represented by RandR, R and R. Rs and 10 R and Rea are each independently Cs alkyl; R is, each independently, (1) Co cycloalkyl, or (2) 3-10 R2s, R2, R2s and R2 are each independently hydrogen membered monocyclic hetero-ring comprising 1-2 of het atom, Cs alkyl, or phenyl: eroatom selected from oxygen, nitrogen and Sulfur, and Cyc1 R27, R2s, R29. Rao, R32, Ras and Ras are (1) Cls alkyl, (2) may be substituted with Ro: Cs alkenyl, (3) Cls alkyl substituted with 1-5 of R-7, (4) Ro is (1) Cls alkyl, (2) Cls alkoxy, (3) hydroxy, (4) 15 diphenylmethyl, (5) triphenylmethyl, (6) Cyc3, (7) Cls alkyl COOR, (5) oxo, (6)SOR, or (7) COR; or Cs alkenyl substituted with Cyc3, (8) Cls alkyl substi R is hydrogen atom, or Cs alkyl; tuted with O-Cyc3, S-Cyc3 or SO-Cyc3; R and R are (1) Cls alkyl, or (2) phenyl which may be Rae is hydrogen atom, or Cs alkyl, substituted with Cs alkyl: Rs7 is Cls alkoxy, Cs alkylthio, benzyloxy, halogen R7 and Rs are each independently, (1) hydrogenatom, (2) atom, nitro or COORs: Cs alkyl, (3)Cs alkoxy, (4) hydroxy, (5) cyano, (6) halogen Rs is hydrogen atom, Cs alkyl or Cs alkenyl: atom, (7) COOR (8) CONRSR (9) Cyc2, (10) Cls Cyc3 is (1) C-1s mono-, bi- or tri-cyclic (fused or spiro) alkenyl, (11) Cls alkynyl, (12) NRs Rs (13) nitro, (14) carboring, or (2) 3-15 membered mono-, bi- or tri-cyclic formyl, (15) Cls acyl, (16) Cls alkyl Substituted with (fused or spiro)heteroring comprising 1-4 of heteroatom hydroxy, Cs alkoxy, Cyc2, NRs Rs, or NRs-Cyc2, (17) 25 selected from oxygen, nitrogen and Sulfur, NRCORss (18)NRSORs, (19) SONRssRs (20) Cls Cyc3 may be substituted with 1-5 of R: alkenyl substituted with COOR (21) CH=N-OH, (22) Rao is (1) Cls alkyl, (2) C2s alkenyl, (3) C2-s alkynyl, (4) Cs alkylene-NRao (Cs alkylene)-R, (23) Cls alky Cs alkoxy, (5) Cls alkylthio. (6) hydroxy, (7) halogenatom, lthio, (24) Cls alkyl substituted with 1-3 of halogen atom, (8) nitro, (9) oxo, (10) cyano, (11) benzyl, (12) benzyloxy, (25) Cls alkoxy substituted with 1-3 of halogen atom, (26) 30 (13)C is alkyl, Cs alkoxy or Cs alkylthio Substituted with Cs alkoxy substituted with Cyc2, (27) O—Cyc2, (28) 1-5 of Rao (14) phenyl, phenoxy, phenylthio, phenylsulfonyl OSORs, or (29) CH=N OR; or benzoyl which may be substituted with 1-5 of R., (15) Ra is hydrogen atom, or Cs alkyl, OCOR (16) SO.R. (17)NRCORs, (18) SONRR, Rs and Rare each independently hydrogenatom or Cs (19) COORs, or (20) NRRs: alkyl: 35 Rao is halogen atom; Rs and Rs.2, Rss and Rso are each independently, hydrogen Ra is C1s alkyl, Cs alkoxy, halogen atom, or nitro: atom, or Cs alkyl, R42, R4s and R4s are C-8 alkyl: Rss. Rs. Rs, and Roo are each independently, hydrogen Ra and Ras are hydrogen atom or Cs alkyl, atom, or Cs alkyl, Rae and R47, Rao and Rso are each independently, hydrogen Rss is hydrogenatom, Cisalkyl, or Cisalkoxy. Rs7 is C1s 40 atom or Cs alkyl: alkyl: R7 is (1) SH, (2) NRCHO, (3) Cyc5, (4) Cls alkyl, Cas R is NRR or hydroxy: alkenyl or Cs alkynyl substituted with Cyc5, (5) CO (NH Re and Res are each independently, hydrogen atom, or amino acid residue-CO), OH, (6) NR, CONRR., (7) Cs alkyl, CONRNR, R (8) CONROR (9) CONRCOR 45 (10) C(S)NR7Rs (11) CONRC(S)COORs (12) Ros is Cls alkyl, NRCOCOORs, (13) NRCOORs (14) CONRC(S) Rs7 is Cls alkyl: Rs (15) OCORs, (16) SORs, (17) CONR.R. (18) SONR.R. (19) COOR (20) COCOOR (21) CORs, (22) COCOR (23) NRCORs (24) SO.R. (25) 50 NRooSO-Roi, or (26) NRoRo; n is an integer of 1 or 2; R66, R73. R7s, R77, R79, Rs. Rss. Rss. Roz, Roo and Rio2 are hydrogen atom, or Cs alkyl; R7 and Ros, Rzo and R-7 are each independently, hydrogen (hereinafter it is abbreviated as ring) is Cyc2 wherein the 55 atom, or Cs alkyl, group which attaches to carbonyl is carbon; Rs and R are (1) hydrogen atom, (2) Cls alkyl, (3) R7, Rs, and Cyc2 represented by ring are each indepen phenyl, or (4) Cls alkyl Substituted with cyano or Cs dently, (1) C-5 mono-, bi- or tri-cyclic (fused or spiro)car alkoxy; boring, or (2) 3-15 membered mono-, bi- or tri-cyclic (fused Rios is Cyc6, or spiro)heteroring comprising 1-4 of heteroatom selected 60 Roo. R72, R74, R76, R78. Riso, Rs.2. R84. Rs6. R87, R8s, Roo from oxygen, nitrogen and Sulfur, and Rare (1) hydrogenatom, (2) Cls alkyl, (3)C is alkenyl, Cyc2 may be substituted with 1-5 of R, or R7; (4) Cls alkynyl, (5) Cls alkyl Substituted with 1-5 of Ro, R, is (1) Cls alkyl, (2) Cls alkenyl, (3) Cls alkynyl, (4) (6) diphenylmethyl, (7) triphenylmethyl, (8) Cyc6, (9) Cls Cs alkoxy, (5) Cls alkylthio. (6) hydroxy, (7) halogenatom, alkyl or Cs alkenyl substituted with Cyc6, or (10) Cls alkyl (8) nitro, (9) oxo, (10) carboxy, (11) formyl, (12) cyano, (13) 65 substituted with O-Cyc6, S-Cyc6 or SO-Cyc6; NRRo (14) phenyl, phenoxy or phenylthio, which may be Ro is (1) Cisalkoxy, (2) Cls alkylthio. (3)benzyloxy, (4) Substituted with 1-5 of Ro (15) Cls alkyl, Cs alkenyl, Cs halogen atom, (5) nitro, (6) COORos, (7) cyano, (8) US 9.220,715 B2 69 70 NRoRoz, (9) NosCORoo, (10) hydroxy, (11) SH, (12) (3) 2-(3,3-dimethyl-3,4-dihydro-(2H)-isoquinolin-1- SOH, (13) S(O)OH, (14) OSOH, (15) Calkenyloxy, (16) ylidene)-1-phenylethan-1-one is excluded, or a pharmaco Cs alkynyloxy, (17) COR (18) SOR, or (19) Cls logically acceptable salt thereof. alkoxy or Cs alkylthio substituted with hydroxy: The preparation of these compounds is described in US Ros is hydrogen atom, Cs alkyl, or Cs alkenyl: 2005.2221.38 and WO 2003/064389. Roe and Rio, are each independently, hydrogen atom, or In another embodiment, PDE7 inhibitors useful in the Cs alkyl, methods of the invention are selected from those compounds Ros is hydrogen atom, or Cs alkyl, generally or specifically disclosed in WO 2003/057149, Roo and R11 are C-8 alkyl, expressly incorporated herein by reference in its entirety. In Ro is Cls alkyl, or halogen atom; 10 one embodiment, PDE7 inhibitors useful in the methods of Ros, Ro4. Ros. Roo, Ros. Roo and Rio are (1) C2-s alkynyl. the invention have the formula: (2) Cls alkyl Substituted with Rs which may be substituted with 1-4 of Ro, (3) Cyc8, (4) Cls alkyl or Cs alkenyl substituted with Cyc8, or (5) Cls alkyl substituted with (13) O-Cyc8, S-Cyc8 or SO-Cyc8; Rs is (1) cyano, (2) 15 NRoRoz, (3) NRosCORoo, (4) hydroxy, (5) SH, (6) SOH, (7) S(O)OH, (8) OSOH, (9) Cls alkenyloxy, (10) Cs alkynyloxy, (11) COR (12) SOR, or (13)C is alkoxy or Cs alkylthio substituted with hydroxy: Rao has the same meaning as Ro: Cyc5 and Cyc6 may be substituted with 1-5 of R: The substituents for the above compounds are defined as R2 is (1) Cisalkyl, (2) C2s alkenyl, (3) C2-s alkynyl, (4) follows: Cs alkoxy, (5) Cls alkylthio. (6) hydroxy, (7) halogenatom, (1) X is selected from halogen and NRR, (8) nitro, (9) oxo, (10) cyano, (11) benzyl, (12) benzyloxy, 25 (2)Y is selected from NR, S, and O, with the proviso that (13)C is alkyl, Cs alkoxy or Cs alkylthio Substituted with Y is not S when X is Cl, 1-5 of Rs (14) phenyl, phenoxy, phenylthio or benzoyl, (3) R and R2 are independently selected from hydrogen, which may be substituted with 1-5 of Ra (15) CORs, (16) alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alky SO.R. (17) NR, CORs, (18) SONR.R. (19) nyl of 2-8 carbon atoms, cycloalkyl of 3-7 carbon atoms, 30 polycycloalkyl of 5-9 carbon atoms, heterocycloalkyl of 2-6 COOR, (20) NRR, (21) COR, (22) carbon atoms and 1-2 heteroatoms selected from NH, S, and CONRR, (23) SH. (24) Cls alkyl substituted with O, aryl of 6-12 carbonatoms, which may be substituted with hydroxy or NR-benzoyl, or (25) Cyc7: alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alky R1 is halogen atom; nyl of 2-6 carbonatoms, alkoxy of 1-6 carbonatoms, halogen, Ra is Cls alkyl, Cs alkoxy, halogen atom, or nitro: 35 haloalkyl of 1-6 carbonatoms and a number of halogenatoms R11s, Rio and R1s are Cls alkyl: up to the perhalo level, haloalkoxy of 1-6 carbon atoms and a R 17, R2, R12 and R27 are hydrogenatom, or Cs alkyl, number of halogenatoms up to the perhalo level, aryl of 6-12 R119 and R120 R22 and R12s, R12s and R126 are each inde carbon atoms, or heteroaryl of 4-11 carbon atoms and 1-2 pendently, hydrogen atom or Cs alkyl; heteroatoms selected from N. S., and O. heteroaryl of 4-11 Cyc7 may be substituted with 1-5 group selected from (1) 40 carbonatoms and 1-2 heteroatoms selected from N, S and O, Cs alkyl, (2) Cls alkoxy, (3) halogen atom, or (4) nitro: which may be substituted with alkyl of 1-6 carbon atoms, Cyc8 may be substituted with Ro, and it further may be alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, substituted with 1-4 of R: alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon Ro is (1) COR, (2) CONRR, (3) SH. (4) Cs atoms and a number of halogenatoms up to the perhalo level. alkyl substituted with hydroxy or NR7-benzoyl, or (5) 45 haloalkoxy of 1-6 carbon atoms and a number of halogen Cyc7; atoms up to the perhalo level, aryl of 6-12 carbon atoms, or R has the same meaning as R. heteroaryl of 4-11 carbonatoms and 1-2 heteroatoms selected Cyc5, Cyc6, Cyc7 and Cyc8 are (1) Cls mono-, bi- or from N. S., and O, and RRs, or R and R combine to form, tri-cyclic (fused or spiro)carboring, or (2) 3-15 membered together with the nitrogen atom to which they are attached, a mono-, bi- or tri-cyclic (fused or spiro)heteroring comprising 50 5-7 membered monocyclic Saturated ring, which optionally 1-4 of heteroatom selected from 1-4 of oxygen, nitrogen or contains 1-2 additional heteroatoms selected from the group sulfur, consisting of NH, NR, S, and O, or combine to form, wherein when Rz, is Cyc5, Cyc5 is not phenyl which may together with the nitrogen atom to which they are attached, a be substituted with 1-5 selected from Cs alkyl, Cs alkoxy, 6-10 membered fused polycyclic saturated ring, which hydroxy, halogen atom, nitro, COOH, or COO(Cs alkyl); 55 optionally contains 1-2 additional heteroatoms selected from wherein Cyc7 is not phenyl: the group consisting of NH, NR, S, and O, or combine to Cyc4 is (1) Cs, monocyclic carboring, or (2) 5-7 mem form, together with the nitrogen atom to which they are bered monocyclic heteroring comprising 1-2 of heteroatom attached, a 5-7 membered unsaturated ring, which optionally selected from oxygen, nitrogen and Sulfur, (abbreviated as contains 1-2 additional heteroatoms selected from the group dashed line a hereafter) and (abbreviated as dashed line b 60 consisting of N. S., and O, wherein said monocyclic Saturated hereafter) are (1) a bond, or (2) a double bond; ring, polycyclic Saturated ring or unsaturated ring may be Ro (1) absent or (2) is hydrogen atom; substituted with 1-2 substituents selected from the group wherein consisting of OH, alkyl of 1-6 carbon atoms, alkenyl of 2-6 (1) when dashed linea is a bond, dashed line b is a double carbonatoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-7 bond, and Ro is absent, 65 carbon atoms, heterocycloalkyl of 2-6 carbon atoms and 1-2 (2) when dashed linea is a double bond, dashed line b is a heteroatoms selected from NH, S, and O, halogen, haloalkyl bond, and Ro is hydrogen atom and R is absent, and of 1-2 carbon atoms and a number of halogenatoms up to the US 9.220,715 B2 71 72 perhalo level, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 (10) R is selected from alkyl of 1-8 carbon atoms, alkenyl carbon atoms and a number of halogen atoms up to the per of 2-8 carbon atoms, and alkynyl of 2-8 carbon atoms, and halo level, and R7Rs. pharmaceutically acceptable salts thereof. (4) R is selected from hydrogen, alkyl of 1-8 carbon The preparation of these compounds is described in WO atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon 2003/057149. atoms, cycloalkyl of 3-7 carbonatoms, and heteroaryl of 4-11 In another embodiment, PDE7 inhibitors useful in the carbonatoms and 1-2 heteroatoms selected from N. S., and O, methods of the invention are selected from those compounds which may be substituted with alkyl of 1-6 carbon atoms, generally or specifically disclosed in US 20030092721, U.S. alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, Pat. No. 7,022,849, WO 2002/102315, and US 2006116516, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon 10 atoms and a number of halogenatom Sup to the perhalo level. each expressly incorporated herein by reference in its haloalkoxy of 1-6 carbon atoms and a number of halogen entirety. In one embodiment, PDE7 inhibitors useful in the atoms up to the perhalo level, aryl of 6-12 carbon atoms, or methods of the invention have the formula: heteroaryl of 4-11 carbonatoms and 1-2 heteroatoms selected from N. S., and O, 15 (5)R is selected from alkyl of 1-8 carbonatoms, alkenyl of (14) 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, C(=O), S(=O), and C(=O)C), (6) Rs is selected from hydrogen, OH, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, alkoxy of 1-8 carbon atoms, thioxy of 1-8 carbon atoms, aryl of 6-12 carbon atoms, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and a number of 25 The substituents for the above compounds are defined as halogen atoms up to the perhalo level, haloalkoxy of 1-6 follows: R is H or alkyl; carbon atoms and a number of halogen atoms up to the per R is (a) heteroaryl or heterocyclo, either of which may be halo level, aryl of 6-12 carbon atoms, or heteroaryl of 4-11 optionally substituted with one to three groups T1, T2, T3; or carbonatoms and 1-2 heteroatoms selected from N. S., and O, (b) aryl fused to a heteroaryl or heterocycloring wherein the heteroaryl of 4-11 carbonatoms and 1-2 heteroatoms selected 30 combined ring system may be optionally substituted with one from N. S., and O, which may be substituted with alkyl of 1-6 to three groups T1, T2, T3: carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 L is (a) OR, C(O)R C(O)CR, SR, NRR, C(O) carbonatoms, alkoxy of 1-6 carbonatoms, halogen, haloalkyl NRR, NRSOR, halogen, nitro, or haloalkyl; or (b) of 1-6 carbon atoms and a number of halogenatoms up to the alkyl, aryl, heteroaryl, heterocyclo, or cycloalkyl any of perhalo level, haloalkoxy of 1-6 carbon atoms and a number 35 of halogen atoms up to the perhalo level, aryl of 6-12 carbon which may be optionally substituted with one to three groups atoms, or heteroaryl of 4-11 carbon atoms and 1-2 heteroat T1a, T2a and/or T3a; oms selected from N. S., and O, cycloalkyl of 3-7 carbon Y, Y- and Y are independently (a) hydrogen, halo, or atoms, heterocycloalkyl of 2-6 carbon atoms and 1-2 heteroa —OR, or (b) alkyl, alkenyl, oralkynyl, any of which may be toms selected from NH, S, and O, and NRR, 40 optionally substituted with one to three groups T1b, T2b (7) RandR, are independently selected from alkyl of 1-8 and/or T3b; carbonatoms, alkenyl of 2-8 carbonatoms, and alkynyl of 2-8 R and R are independently H, alkyl, alkenyl, aryl, (aryl) carbon atoms, alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) (8) Rs is selected from OH, aryl of 6-12 carbon atoms, alkyl, heterocyclo, or (heterocyclo) alkyl, any of which may which may be substituted with alkyl of 1-6 carbon atoms, 45 be optionally substituted with one to three groups T1a, T2a alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, and/or T3a; or alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon RandR together with the nitrogenatom to which they are atoms and a number of halogenatoms up to the perhalo level. attached may combine to form a 4- to 8-membered heterocy haloalkoxy of 1-6 carbon atoms and a number of halogen clo ring optionally Substituted with one to three groups Tla, atoms up to the perhalo level, aryl of 6-12 carbon atoms or 50 T2a and/or T3a; heteroaryl of 4-11 carbonatoms and 1-2 heteroatoms selected Ra is hydrogen, alkyl, alkenyl, aryl, heteroaryl, (aryl) from N. S., and O, and heteroaryl of 4-11 carbonatoms and 1-2 alkyl, (heteroaryl) alkyl, heterocyclo, (heterocyclo) alkyl, heteroatoms selected from N. S., and O, which may be sub cycloalkyl, or (cycloalkyl)alkyl, any of which may be option stituted with alkyl of 1-6 carbonatoms, alkenyl of 2-6 carbon ally substituted with one to three groups T1b, T2b and/orT3b; atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon 55 Ra, is alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (het atoms, halogen, haloalkyl of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6-12 carbon eroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocyclo, or atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroat (heterocyclo) alkyl, any of which may be optionally substi oms selected from N. S., and O: tuted with one to three groups T1a, T2a and/or T3a; (9) Ro and Ro are independently selected from hydrogen, 60 Z is N or CH: alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, and T1-1b, T2-2b, and T3-3b are each independently: alkynyl of 2-8 carbonatoms, or Ro and Rio combine together (1) hydrogen or T6, where T6 is (i) alkyl, (hydroxy)alkyl, with the nitrogen atom to which they are attached to form a (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) 5-7 membered, unsaturated ring which may contain 1-2 addi alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, tional heteroatoms selected from N. S., and O, or to form a 5-7 65 heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl) membered, saturated ring which may contain 1-2 additional alkyl; (ii) a group (i) which is itself substituted by one or more heteroatoms selected from NH, NR, S, and O; of the same or different groups (i); or (iii) a group (i) or (ii) US 9.220,715 B2 73 74 which is independently substituted by one or more of the -continued following groups (2) to (13) of the definition of T1-1b, T2-2b (15B) and T3-3b; Z (2) -OH or - OT6: N N (3) -SH or -ST6: 5 (4) - C(O)H, C(O),T6, or - O C(O)T6, where t is 1 )-. or 2: *-n 4NNV Y R (6) halo: 10 (7) cyano; The substituents for the above compounds are defined as (8) nitro: follows: R is H or alkyl: 15 R is (a) heteroaryl, or heterocyclo, either of which may be optionally substituted with one to three groups T1, T2, T3; (b) aryl substituted with one to three groups T1, T2, T3 provided that at least one of T1, T2, T3 is other than H: or (c) aryl fused to a heteroaryl or heterocyclo ring wherein the combined ring (13) oxo; system may be optionally Substituted with one to three groups T4 and T5 are each independently a single bond, T11 S(O) T1, T2, T3; T12-, T11C(O)T12-, T11C(S)T12, T11OT12, T11ST12, Y is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclo, heteroaryl, (aryl)alkyl or (heteroaryl) alkyl any of which may be optionally substituted with one to three groups T1a, T2a, T7, T8. T9, T9a and T10 are: 25 T3a; (1) eachindependently hydrogen or a group provided in the J is (a) hydrogen, halo, or OR, or (b) alkyl, alkenyl, alky definition of T6, or nyl, aryl, heteroaryl, heterocyclo, or, cycloalkyl any of which may be optionally substituted with one to three groups T1b. (2) T7 and T8 may together be alkylene or alkenylene, T2b, T3b; completing a 3- to 8-membered saturated or unsaturated ring 30 Z is (a) OR SR, NRR, NRSOR, halogen, nitro, together with the atoms to which they are attached, which ring haloalkyl; or (b) alkyl, aryl, heteroaryl, heterocyclo, or is unsubstituted or substituted with one or more groups listed cycloalkyl any of which may be optionally substituted with in the description of T1-1b, T2-2b and T3-3b, or one to three groups T1c, T2c, T3c. (3) T7 or T8, together with T9, may be alkylene or alk R is H. alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (het enylene completing a 3- to 8-membered saturated or unsatur 35 eroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo or ated ring together with the nitrogen atoms to which they are (heterocyclo)alkyl any of which may be optionally indepen attached, which ring is unsubstituted or substituted with one dently substituted where valance allows with one to three or more groups listed in the description of T1-1b, T2-2b and groups T1c, T2c, T3c. T3-3b, or R is alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (het (4) T7 and T8 or T9 and T10 together with the nitrogen 40 eroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo or atom to which they are attached may combine to form a group (heterocyclo)alkyl any of which may be optionally indepen N=CT13T14 where T13 and T14 are each independently H dently substituted where valance allows with one to three or a group provided in the definition of T6; and T11 and T12 groups T1d, T2d, or T3d; or are each independently a single bond, alkylene, alkenylene, RandR together with the nitrogenatom to which they are or alkynylene. 45 attached may combine to form a 4 to 8 membered heterocyclo ring optionally Substituted with one to three groups T1c, T2c, The preparation of these compounds is described in US or T3c. 20030092721, U.S. Pat. No. 7,022,849, WO 2002/102315, Ra is hydrogen, alkyl, alkenyl, aryl, heteroaryl, (aryl)a- and US 2006116516. lkyl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, In another embodiment, PDE7 inhibitors useful in the 50 cycloalkyl or (cycloalkyl)alkyl any of which may be option methods of the invention are selected from those compounds ally substituted with one to three groups T1d, T2d or T3d; generally or specifically disclosed in U.S. Pat. No. 6,838.559, T1, T1a, T1b, T1c, T1d, T2, T2a, T2b, T2c, T2d, T3, T3a, U.S. 20030100571, and WO 2002/102314, each expressly T3b, T3c, and T3d (hereinafter abbreviated as T1-1d, T2-2d, incorporated herein by reference in its entirety. In one and T3-3d) are independently embodiment, PDE7 inhibitors useful in the methods of the 55 (1) hydrogen or T6, where T6 is invention have the formulas: (a) alkyl, (hydroxy) alkyl, (alkoxy) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalk enyl) alkyl, aryl, (aryl) alkyl, heterocyclo, (heterocyclo) (15A) alkyl, heteroaryl, or (heteroaryl) alkyl: Z Y 60 (b) a group (a) which is itself substituted by one or more of M the same or different groups (a); or (c) a group (a) or (b) which is independently Substituted by J and one or more (preferably 1 to 3) of the following groups ) (2) to (13) of the definition of T1-1d, T2-2d and T3-3d, sle / 65 (2) OH or OT6, R (3) SH or ST6, (4) C(O)t H, C(O)t T6, or OC(O)T6, where t is 1 or 2: US 9.220,715 B2 75 76 (5) SO3H, S(O)tT6, or S(O)t N(T9)T6, (16a) (6) halo, Z: (7) cyano, (8) nitro, 5 (9) T4NT7 T8, se NR5aR6a

10 The substituents for the above compounds are defined as T4 and T5 are each independently a single bond, T11 follows: S(O)-T12, T11-C(O)-T12, T11-C(S)-T12, T11-O-T12, R is hydrogen or alkyl; R is -T11S-T12, -T11OC(O)-T12, -T11-C(O)O-T12, -T11C 15 (—NT9a)-T12, or T11-C(O) C(O)-T12: T7, T8. T9, T9a and T10 are (1) eachindependently hydrogen or a group provided in the definition of T6, or (2) T7 and T8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T1-1d, T2-2d and T3-3d, or 25 (3) T7 or T8, together with T9, may be alkylene or alk enylene completing a 3- to 8-membered saturated or unsatur ated ring together with the nitrogen atoms to which they are W is S: X is alkoxy; and X is alkyl; attached, which ring is unsubstituted or substituted with one 30 Z* is halogen, haloalkyl, oxazolyl. NRR, C(O)—N or more groups listed in the description of T1-1d, T2-2d and (H)-alkylene-COOH, or phenyl which is unsubstituted or T3-3d, or substituted with heteroaryl, COH, or COT: (4) T7 and T8 or T9 and T10 together with the nitrogen R is hydrogen or alkyl; atom to which they are attached may combine to form a group 35 R is alkyl, alkoxy, unsubstituted or substituted (het N–CT13 T 14 where eroaryl) alkyl, unsubstituted or substituted heterocyclo, T13 and T 14 are each independently Hora group provided unsubstituted or substituted (heterocyclo) alkyl, or (aryl) in the definition of T6; and alkyl wherein the aryl group is substituted with one or two T11 and T12 are each independently a single bond, alky groups T1 and/or T2 and/or further substituted with a group lene, alkenylene, or alkynylene. 40 T3; or R, and R together with the nitrogen atom to which The preparation of these compounds is described in U.S. they are attached combine to form an unsubstituted or substi Pat. No. 6,838,559, U.S. 20030100571, and WO 2002/ tuted heterocycloring; 102314. Rs, is an unsubstituted or Substituted (heteroaryl) alkyl, or In another embodiment, PDE7 inhibitors useful in the 45 (aryl) alkyl wherein the aryl group is substituted with one or methods of the invention are selected from those compounds two groups T1 and/or T2 and/or further substituted with a generally or specifically disclosed in U.S. Pat. No. 7,087.614, group T3; or Rs, and R, together with the nitrogen atom to U.S. 20030162802, and WO 2002/102313, each expressly which they are attached combine to form an unsubstituted or incorporated herein by reference in its entirety. In one Substituted heterocyclo ring; R is hydrogen or alkyl, J is embodiment, PDE7 inhibitors useful in the methods of the 50 hydrogen or alkyl; T1 and T2 are independently alkoxy, invention have the formula: alkoxycarbonyl, heteroaryl, SOH, or SORs, where Rs, is alkyl, amino, alkylamino or dialkylamino; or T1 and T2 together with the aryl ring to which they are attached combine (16) Z to form a bicyclic ring; T3 is H, alkyl, halo, haloalkyl, or 55 cyano; t is 1 or 2; and T6 is alkyl, haloalkyl, cycloalkyl, J alkoxy, or heteroaryl. The preparation of these compounds is described in U.S. R l 2 Pat. No. 7,087,614, U.S. 20030162802, and WO 2002/ s N L. 60 102313. R In another embodiment, PDE7 inhibitors useful in the methods of the invention are selected from those compounds generally or specifically disclosed in US 20030104974, WO The substituents for the above compounds are described 2002/088080, and WO 2002/088079, each expressly incor below. 65 porated herein by reference in its entirety. In one embodi In a related embodiment, PDE7 inhibitors useful in the ment, PDE7 inhibitors useful in the methods of the invention methods of the invention have the formula: have the formulas: US 9.220,715 B2 77 78

NR3aR3b (17A) NRR4 Rs A N1N J* Sl-N R2. l CN- R55 M R6 and n N 4. fNJ *-n 4N Xs

l, 10 (17B) wherein R, is H or alkyl; R is optionally substituted NR3R4 heteroaryl; R is H or alkyl, Ra, is optionally substituted (aryl)alkyl; Rs, is H, alkyl, or C(O)(CH)OYR, where Y is N1 N N a bond or C(O), R is hydrogen or alkyl, and V is an integer 15 from 0 to 2: J and J are independently optionally substituted R 2 X-R, C. alkylene, provided that J and J are not both greater than Calkylene; X and Xs are optional substituents bonded R Rs to any available carbon atom in one or both of J and J. independently selected from hydrogen, OR-7, NRR, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, sub The substituents for the above compounds are defined as stituted alkynyl, cycloalkyl, Substituted cycloalkyl, aryl, Sub follows: stituted aryl, heterocycloalkyl, or heteroaryl; R7 is hydrogen, R is Horalkyl; R is optionally substituted heteroaryl, or alkyl, Substituted alkyl, alkenyl, alkynyl, cycloalkyl, Substi 4-substituted aryl; R is hydrogen oralkyl; R is alkyl, option tuted cycloalkyl, C(O)alkyl, C(O)Substituted alkyl, C(O)cy ally substituted (aryl)alkyl, optionally substituted (heteroary 25 cloalkyl, C(O) substituted cycloalkyl, C(O)aryl, C(O)Substi l)alkyl, optionally substituted heterocyclo, or optionally sub tuted aryl, C(O)O-alkyl, C(O)C)-substituted alkyl, C(O) stituted (heterocyclo)alkyl; or R and R together with the heterocycloalkyl, C(O)heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl; and Rs and Ro are indepen nitrogen atom to which they are attached may combine to dently selected from the group consisting of hydrogen, alkyl, form an optionally Substituted heterocyclo ring; Rs is alkyl, 30 Substituted alkyl, cycloalkyl, Substituted cycloalkyl, alkenyl, optionally substituted (aryl)alkyl, or optionally substituted alkynyl, C(O) alkyl, C(O) substituted alkyl, C(O) cycloalkyl, (heteroaryl)alkyl; and R is hydrogen or alkyl. C(O)Substituted cycloalkyl, C(O)aryl, C(O)Substituted aryl, In a related embodiment, PDE7 inhibitors useful in the C(O)O alkyl, C(O)O substituted alkyl, C(O) heterocy methods of the invention have the formula: cloalkyl, C(O) heteroaryl, S(O)alkyl, S(O), substituted 35 alkyl, S(O) cycloalkyl, S(O) substituted cycloalkyl, S(O) aryl, S(O)Substituted aryl, S(O), heterocycloalkyl, S(O), heteroaryl, aryl, Substituted aryl, heterocycloalkyl, and het eroaryl, or Rs and Ro taken together with the nitrogenatom to which they are attached complete an optionally substituted 40 heterocycloalkyl or heteroaryl ring. In a further related embodiment, PDE7 inhibitors useful in the methods of the invention have the formula:

45 NR3CRC wherein R is H or alkyl; R is optionally substituted X4 heteroaryl; Z is halogen, alkyl, Substituted alkyl, haloalkyl, or N1S/S NRR, R is hydrogen or alkyl; R is alkyl, optionally substituted (heteroaryl) alkyl, optionally substituted hetero 50 R2 l cyclo, optionally Substituted (heterocyclo) alkyl, or (aryl) s an-e alkyl wherein the aryl group is substituted with one or two Rlic groups T1 and T2 and optionally further substituted with a group T3; or R and R, together with the nitrogen atom to wherein R is H or alkyl; R is optionally substituted which they are attached may combine to form an optionally 55 heteroaryl; R is H or alkyl; R is optionally substituted Substituted heterocyclo ring; Rs is (aryl) alkyl wherein the (aryl)alkyl; and X and Xsare optional Substituents bonded to aryl group is substituted with one or two groups T1 and T2 any available carbon atom in one or both of J and J, inde and optionally further substituted with a group T3; R is pendently selected from hydrogen, OR-7, NRRo, alkyl, Sub hydrogen or alkyl; R is hydrogen or alkyl, T1 and T2 are stituted alkyl, alkenyl, Substituted alkenyl, alkynyl, Substi independently alkoxy, alkoxycarbonyl, heteroaryl or SORs, 60 tuted alkynyl, cycloalkyl, Substituted cycloalkyl, aryl, where Rs, is alkyl, amino, alkylamino or dialkylamino; or T1 substituted aryl, heterocycloalkyl, or heteroaryl. and T2 together with the atoms to which they are attached The preparation of these compounds is described in US may combine to form a ring (e.g., benzodioxole); T3 is H. 20030104974, WO 2002/088080, and WO 2002/088079. alkyl, halo, haloalkyl or cyano. In another embodiment, PDE7 inhibitors useful in the 65 methods of the invention are selected from those compounds In another related embodiment, PDE7 inhibitors useful in generally or specifically disclosed in US 20030092908 and the methods of the invention have the formula: WO 2002/087513, each expressly incorporated herein by US 9.220,715 B2 79 80 reference in its entirety. In one embodiment, PDE7 inhibitors heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl) useful in the methods of the invention have the formula: alkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is independently substituted by one or more (prefer (18) ably 1 to 3) of the following groups (2) to (13) of the definition Z of T1-1b, T2-2b, and T3-3b, J (2) OH or OT6, N1 N w (3) SH or ST6, R2 2 (4) C(O)th, C(O),T6, or OC(O)T6, where t is 1 or 2, NN l N J2 N-R 10 (6) halo, (7) cyano, (8) nitro, The substituents for the above compounds are defined as follows: 15 R is hydrogen or alkyl: R is (a) heteroaryl, or heterocyclo, either of which may be optionally substituted with one to three groups T1, T2, T3; (b) (13) oxo, aryl substituted with one to three groups T1, T2, T3 provided T4 and T5 are each independently (1) a single bond, (2) that at least one of T1, T2, T3 is other than H: or (c) aryl fused T1'-S(O)-T12, (3) T11-C(O)-T12, (4) T11-C(S)-T12, (5)- to a heteroaryl or heterocyclo ring wherein the combined ring T11-O-T12, (6) T11-S-T12, (7) T11-O C(O)-T12, (8) T11 system may be optionally Substituted with one to three groups C(O) O-T12, (9) T11-C(—NT9a)-T12, or (10) T11-C T1, T2, T3; (O) C(O)-T12, Zis NRR, NRSOR OR SR, haloalkyl, or halogen; 25 T7, T8. T9, T9a and T10, R and R are independently H, alkyl, alkenyl, aryl, (aryl) (1) are each independently hydrogen or a group provided in alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl) the definition of T6, or alkyl, heterocyclo or (heterocyclo)alkyl any of which may be (2) T7 and T8 may together be alkylene or alkenylene, optionally independently substituted where valance allows completing a 3- to 8-membered Saturated or unsaturated ring with one to three groups T1a, T2a, or T3a; or 30 R and R may be taken together with the nitrogen atom to together with the atoms to which they are attached, which ring which they are attached to form a heterocyclo or heteroaryl is unsubstituted or substituted with one or more groups listed ring optionally independently Substituted where valance in the description of T1-1b, T2-2b, and T3-3b, or allows with one to three groups T1a, T2a, or T3a; (3) T7 or T8, together with T9, may be alkylene or alk R is alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (het 35 enylene completing a 3- to 8-membered saturated or unsatur eroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo or ated ring together with the nitrogen atoms to which they are (heterocyclo)alkyl any of which may be optionally indepen attached, which ring is unsubstituted or substituted with one dently substituted where valance allows with one to three or more groups listed in the description of T1-1b, T2-2b, and groups T1a, T2a, or T3a; T3-3b, or R, and Ra, are independently H, alkyl, alkenyl, aryl, (aryl) 40 (4) T7 and T8 or T9 and T10 together with the nitrogen alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl) atom to which they are attached may combine to form a group alkyl, heterocyclo or (heterocyclo)alkyl: N—CT13T14 where T13 and T14 are each independently H Rs is or a group provided in the definition of T6; and (1) hydrogen, or cyano; T11 and T12 are each independently a single bond, alky (2) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, 45 lene, alkenylene, or alkynylene. aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl The preparation of these compounds is described in US or (heteroaryl)alkyl, any of which may be optionally indepen 2003OO92908 and WO 20O2/O87513. dently substituted where valance allows with one to three In another embodiment, PDE7 inhibitors useful in the groups T1b, T2b, or T3b; or methods of the invention are selected from those compounds (3) C(O)RC(O)OR, C(O) C(O)OR, or SOR: 50 generally or specifically disclosed in US 20040127707 and R is H. alkyl, alkenyl, NRR, heterocyclo, (heterocy WO 2002/085906, each expressly incorporated herein by clo)alkyl, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, reference in its entirety. In one embodiment, PDE7 inhibitors (NR.R.)alkyl, heteroaryl, aryl or (aryl)alkyl, any of which useful in the methods of the invention have the formula: may be optionally independently substituted where valance 55 allows with one to three groups T1b, T2b, or T3b; (19) R is alkyl, alkenyl, NRR, heterocyclo, (heterocyclo) Rs alkyl, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, M (NR.R.)alkyl, heteroaryl, aryl or (aryl)alkyl, any of which N-N may be optionally independently substituted where valance R / O allows with one to three groups T1b, T2b, or T3b; 60 J and J are independently optionally substituted C alkylene, provided that J and J are not both greater than C. R alkylene; and T1-1b, T2-2b, and T3-3b are each independently R3 R4 (1) hydrogen or T6, where T6 is (i) alkyl, (hydroxy)alkyl, 65 (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl) alkyl,

US 9.220,715 B2 83 84 wherein R-7 is C(O)Rs (CH), C(O)Ro, (CH), Ro, -continued Aryl Hetaryl, phenylprop-1-en-3-yl or 1-methylpiperidin : 4-yl, Ras hydrogen, 1-4C-alkyl, OR, furanyl, indolyl phe nyl, pyridyl, phenyl Substituted by R and/or Rs or pyridyl Substituted by R and/or R, R is N(R)R. Rao is N(R)Rs, tetrahydrofuranyl or pyridinyl, R is 1-4C-alkyl, R is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cy cloalkylmethyl, R is hydrogen, 1-4C-alkyl, 3-7C-cy cloalkyl or 3-7C-cycloalkylmethyl, or 10 R and R together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl-, 1-pyr wherein R. denotes hydrogen, hydroxyl, nitro, amino, car rolidinyl-, 1-piperidinyl- or 1-hexahydroazepinyl-ring, boxyl, aminocarbonyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C Aryl is phenyl, pyridyl, pyrimidinyl, phenyl Substituted by alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl, Ra and/or Rs, pyridyl substituted by R and/or R-7, R is 15 R represents 1-4C-alkyl, naphthalenyl, 5-dimethylami halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy, nonaphthalen-1-yl, phenylethen-2-yl, 3.5-dimethylisoxazol Rs is halogen or 1-4C-alkyl, R is halogen, nitro. 1-4C 4-yl, 5-chloro-3-methylbenzobthiophen-2-yl, 6-chloro alkyl, trifluoromethyl or 1-4C-alkoxy, R-7 is halogen or 1-4C imidazo[2.1b-thiazol-5-yl, or represents a phenyl or alkyl, thiophene radical which is unsubstituted or is substituted by Hetaryl is indol-4-yl, 2-methyl-quinolin-4-yl, 5-chloro-6- one or more identical or different radicals selected from the oXo-1-phenyl-1,6-dihydro-pyridazin-4-y-1,3-phenyl-1,2,4- group halogen, cyano. 1-4C-alkyl, trifluoromethyl, 1-4C thiadiazol-5-yl or 3-o-tolyl-1,2,4-thiadiazol-5-yl, alkoxy which is substituted entirely or mainly by fluorine, t is an integer from 1 to 4, u is an integer from 1 to 4, V is an 1-4C-alkoxy, 1-4C-alkylcarbonylamino. 1-4C-alkoxycarbo integer from 1 to 2, X is —C(O)—or—S(O) , and the salts 25 nyl, phenylsulfonyl or isoxazolyl, or of these compounds. a hydrate, Solvate, salt, hydrate of a salt, or Solvate of a salt thereof. The preparation of these compounds is described in US The preparation of these compounds is described in U.S. 2004O1277O7 and WO 2002/085906. Pat. No. 6,818,651, US 20040044212, and WO 2002/040450. In another embodiment, PDE7 inhibitors useful in the 30 In another embodiment, PDE7 inhibitors useful in the methods of the invention are selected from those compounds methods of the invention are selected from those compounds generally or specifically disclosed in U.S. Pat. No. 6,818,651, generally or specifically disclosed in WO 2002/040449, US 20040044212, and WO 2002/04.0450, each expressly expressly incorporated herein by reference in its entirety. In incorporated herein by reference in its entirety. In one one embodiment, PDE7 inhibitors useful in the methods of embodiment, PDE7 inhibitors useful in the methods of the the invention have the formula: invention have the formula: 35

(21) (20) R R 40 R R" R R".

N R 2 R2 rts21N2 N 45 ArH

The substituents for the above compounds are defined as R3. follows: R4 either R. denotes hydrogen, and R. denotes fluorine, chlo 50 rine, bromine, cyano, trifluoromethyl or phenoxy, or R denotes hydrogen, fluorine, chlorine, bromine, trifluorom The substituents for the above compounds are defined as ethyl or cyano, and R. denotes hydrogen, R' and R" both follows: denote hydrogen or together represent a bond, and Ar repre either R denotes hydrogen and R. denotes fluorine, chlo 55 rine, bromine, cyano, trifluoromethyl or phenoxy, or sents a phenyl radical of the formulae IIa, IIb, or IIc R denotes hydrogen, fluorine, chlorine, bromine, trifluo romethyl or cyano and R. denotes hydrogen, R" and R" both denote hydrogen or together represent a bond, 60 R. denotes hydrogen, hydroxyl. nitro, amino, carboxyl, aminocarbonyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl and Radenotes C(O) X-Rs, N(H)—C(O)—R or N(H)— C(O)—N(H)—R, wherein 65 X denotes 0 or N(H), Rs denotes hydrogen, 1-4C-alkyl, 3-7C-cycloalkylmethyl, 6,6-dimethylbicyclo[3.3.Ihept-2-yl, 3-7C-alkynyl, 1-4C US 9.220,715 B2 85 86 alkylcarbonyl-1-4C-alkyl, aminocarbonyl-1-4C-alkyl, furan (Rs)(Ro) where R is a hydrogen atom or an optionally Sub 2-ylmethyl 2-pyridin-2-yleth-1-yl, 2-pyridin-3-ylmethyl, stituted alkyl group, N(R)CSN(Rs)(R), N(R)SON(Rs.) N-methylpiperidin-3-yl, 1-benzylpiperidin-4-yl, morpholin (R), C(R-7)—NO(Rs), cycloaliphatic, heterocycloaliphatic, 4-yl-eth-2-yl, morpholin-4-yl-eth-1-yl, 2-benzo. 1.3dioxol aryl or heteroaryl group; provided that one or more of R. R. 4-yl-eth-1-yl, chroman-4-yl, 1-methoxycarbonyl-2-indol-3- or R is a substituent other than a hydrogen atom; yl-eth-1-yl, 1,3-bis-methoxycarbonylprop-1-yl, 1-methoxycarbonyl-3-methylsulfanyl-eth-1-yl, 1-methoxy R represents an optionally Substituted phenyl, 1- or carbonyl-2-thiazol-2-yl-eth-1-yl, or 4-methylthiazol-5-yl 2-naphthyl, pyridyl, pyrimidinyl, pyridaZinyl, or pyrazinyl eth-2-yl, or represents a benzyl-, phenyl-eth-1-yl or 1-meth group; and oxycarbonyl-2-phenyl-eth-2-yl radical which is 10 the salts, solvates, hydrates and N-oxides thereof. unsubstituted or substituted by one or more radicals selected The preparation of these compounds is described in WO from the group halogen, trifluoromethyl and phenyl, 2001/098.274. R. denotes 2,4-dichlorophenoxymethyl, 2-tert-butoxycar bonylamino-eth-1-yl, 1-acetylpiperidin-4-yl, Arl or Ar2 In another embodiment, PDE7 inhibitors useful in the CH-CH , 15 methods of the invention are selected from those compounds where Ar1 represents 3-chlorophenyl, 4-trifluoromethox generally or specifically disclosed in WO 2001/074786, yphenyl, 3-phenoxyphenyl, indols-yl, 2-methylpyridin-5-yl, expressly incorporated herein by reference in its entirety. In quinolin-6-yl or 2-benzothiazol-6-yl, Ar2 represents furan-2- one embodiment, PDE7 inhibitors useful in the methods of yl, furan-3-yl, thiophen-2-yl, indol-3-yl, 3-trifluorometh the invention have the formula: ylphenyl, 3-methoxyphenyl or pyridin-3-yl, R, represents 1-4C-alkyl, 3-7C-alkenyl, 3-7C-cycloalkyl, 1-ethoxycarbonyl-2-phenyl-eth-1-yl, thiophen-2-yleth-1-yl (23) or a phenyl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, cyano, X- B 1-4C-alkyl, trifluoromethyl, 1-4C-alkylthio. 1-4C-alkoxy, 25 S s X \ / 1-4C-alkoxy which is entirely or predominantly substituted by fluorine, 1-4C-alkylcarbonyl and phenoxy, or a salt thereof. The preparation of these compounds is described in WO The substituents for the above compounds are defined as 2002/040449. 30 follows: In another embodiment, PDE7 inhibitors useful in the methods of the invention are selected from those compounds R represents an aryl or heteroaryl group; generally or specifically disclosed in WO 2001/098274, A, B, P, and E, which may be the same or different, each expressly incorporated herein by reference in its entirety. In represents a nitrogen atom or a C(R) group wherein R is a one embodiment, PDE7 inhibitors useful in the methods of 35 hydrogen or halogen atom or an alkyl, haloalkyl, alkoxy, the invention have the formula: haloalkoxy, hydroxy, NO or —CN group provided that two or more of A, B, D, and E are C(R) groups: X represents an oxygen or Sulphur atom or a N(R) group wherein R is a R (22) hydrogen atom or an alkyl group; R2 40 Q, R, S, and T, which may be the same or different each represents a nitrogenatom or a group C(R) wherein R is an s atom or group -L (Alk), L2(R)s wherein L and L, which may be the same or different, is each a covalent bond or a 4 2 "N's SONHR4. linker atom or group, r is Zero or the integer 1, Alkyl is an 45 aliphatic or heteroaliphatic chain, S is an integer 1, 2 or 3 and Z Ya Y2 X Rs is a hydrogen or halogen atom or a group selected from alkyl, OR where R is a hydrogen atom or an optionally Substituted alkyl group, SR NRR, where R, is as just The substituents for the above compounds are defined as defined for R and may be the same or different, NO, CN, follows: 50 CO.R., SOH, S(O)R., SOR OCOR CONRR, W, X, Y and Z., which may be the same or different, each OCONRR, CSNR,R, OCROCOR, N(R)COR, N(R) represents a nitrogen atom or a C(R) group wherein Rs is a CSR, S(O)NRR, SONRR, N(R)SOR: N(R)CON hydrogen or halogen atom or an alkyl, haloalkyl, alkoxy, (R)(Rs) where Rs is a hydrogen atom or an optionally sub haloalkoxy, hydroxy, NO or —CN group provided that stituted alkyl group, N(R)CSN (R-7) (Rs), N(R)SON(R-7) two or more of W, X, Y, and Z are C(Rs) groups; 55 (Rs), C(R)—NO(R) cycloaliphatic, heterocycloaliphatic, R. R. and R, which may be the same or different, each is aryl or heteroaryl group provided that two or more of Q, R, S, anatom or group -L (Alk), L2(R), wherein Land L, which and T are C(R) groups; and the salts, Solvates, hydrates and may be the same or different, is each a covalent bond or a N-oxides thereof. linker atom or group, r is Zero or the integer 1, Alki is an aliphatic or heteroaliphatic chain, S is an integer 1, 2 or 3 and 60 The preparation of these compounds is described in WO R is a hydrogen or halogen atom or a group selected from 2001 FO74.786. alkyl, —OR, where R, is a hydrogen atom or an optionally In another embodiment, PDE7 inhibitors useful in the Substituted alkyl group. —SR-7, NR7Rs where Rs is as just methods of the invention are selected from those compounds defined for R, and may be the same or different. —NO, CN, generally or specifically disclosed in WO 2000/068230, CO.R., SOH, S(O)R., SOR, OCOR, CONRRs, 65 expressly incorporated herein by reference in its entirety. In OCONRRs, CSNRRs, OCR, OCOR, N(R)CORs, N(R) one embodiment, PDE7 inhibitors useful in the methods of CSRs, S(O)NRRs, SONRRs, N(R)SORs, N(R)CON the invention have the formula: US 9.220,715 B2 87 88 Ro represents Rs or alkylcarbonyl, alkoxycarbonyl, alkyl Sulphonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, (24) cycloalkylsulphonyl, cycloalkylalkylcarbonyl, cycloalkyla lkoxycarbonyl, cycloalkylalkylsulphonyl, arylcarbonyl, aryl Sulphonyl, heteroarylcarbonyl, heteroarylsulphonyl, hetero cyclocarbonyl, heterocycloSulphonyl, arylalkylcarbonyl, arylalkoxycarbonyl, arylalkylsulphonyl, heteroarylalkylcar bonyl, heteroarylalkoxycarbonyl, heteroarylsulphonyl, het erocycloalkylcarbonyl, heterocycloalkoxycarbonyl or het erocycloalkylsulphonyl; or The substituents for the above compounds are defined as 10 NRR represents a heterocyclic ring such as morpholine; follows: Ro represents H, alkyl, cycloalkyl, cycloalkylalkyl, aryla X-Y Z represents NR C=N or N=C NR; lkyl, heteroarylalkyl or heterocycloalkyl; R represents H, alkyl, cycloalkyl, cycloalkylalkyl, aryla R and R2 are the same or different and are each Rs or lkyl, heteroarylalkyl or heterocycloalkyl: NRR represents a heterocyclic ring such as morpholine; R represents ORs, NRR, SR, alkyl or CF; 15 R represents alkyl, cycloalkyl, cycloalkylalkyl, aryl, ary R represents halogen, alkyl, CF or ORs, lalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocy Ra, which can be attached to either X or Z, is a residue cloalkyl: selected from the RS are the same or different and are each selected from H alkyl, cycloalkyl, ORs, NRR, COR CONRR, CONHOH, SONRR, SONR, COR, SO.R., SORSR, CF, NO, and CN, provided that when Xn-, X^2, both m and n represent 0, if one R is ORs, NRR or SR the other is not ORs, NRR, or SR; and Rs represents H, alkyl or F: or CC.A T C.i? V W 25 a pharmaceutically acceptable salt thereof. The preparation of these compounds is described in WO x s x s 2000/068230, incorporated herein by reference in its entirety. In another embodiment, PDE7 inhibitors useful in the CC, CC methods of the invention are selected from those compounds A ls- 9. ls 30 generally or specifically disclosed in US 20040106631, EP 1 400 244, and WO 2004/026818, each expressly incorporated Xn herein by reference in its entirety. In one embodiment, PDE7 y C I) inhibitors useful in the methods of the invention have the 35 formula: Q -V. Q (25) R2 No (CH2) O) . y 40 NH wherein attachment is through any position on the Satu rated ring, provided the attachment is not at a position adja 1s, H cent to V, and the saturated ring may be substituted at any 45 position with one or more Re; R A, B, D, and E are the same or different and each represents C1R, N or N-O; The substituents for the above compounds are defined as V represents O, S, NR, or C(LR)(L.R.); follows: Q and W are the same or different and each represents 50 m is 1, 2 or 3: R is methyl, chloro, bromo or fluoro; R is CLRs or N: -Q'-Q’-Q-Q'or (C-C) alkyl, said (C-C) alkyl is substi T represents O.S or NR7; tuted with one to three OR COOR NRRs, NRC(=O)R. L' and L are the same or different and each represents C(=O)NRRs or SONRRs: C(Rs): R is (C-C) alkyl substituted with one to three F, CN, m and n are the same or different and each represents 0, 1, 55 S(=O)R., SOH, SOR, SR, C(=O) NH SO CH, 2, 3, 4 or 5: C(=O)RNR'C(=O)RNR'SORC(=O)NRR O C the Rss are the same or different and each represents H, (=O)NRRs or SONRRs: halogen, alkyl, cycloalkyl, ORs, NRR, CO-Ro, Rs is H or (C-C) alkyl optionally substituted with one to CONRR, CONHOH, SONRR, SONR, COR, three F, CN, S(-O)R., SOH, SOR, SR, C(=O) NH SOR, SOR, SR, CF, NO or CN: 60 SO, CH, C(=O)R, NRC(=O)R, NR'SOR, C(=O) R represents H. alkyl, cycloalkyl, ORs, NRR, COR NRRs, O C(=O)NRRs or SONRRs; or CONRR, SONRR, SONR, COR. SOR, said (C-C) alkyl is SOR, SR, CF, CN or =O; (1) substituted with one to three OC(=O)R. SR, R, represents H or alkyl: S(=O)R. C(=NR)R. C(=NR)—NRRs. NR—C Rs represents H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, 65 (—NR)—NRRs, NRCOOR NR—C(=O)NRRs. arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or hetero NR—SO NRRs. NR—C(=NR)—R O cycloalkyl; NR—SO, R.; and US 9.220,715 B2 89 90 (2) optionally substituted with one or two OR, COOR, R represents a saturated or partially unsaturated hydrocar C(=O)—R NRRs, NRC(=O)R C(=O)NRRs or bon radical having 1 to 10 carbon atoms, SONRRs: R represents methyl or ethyl, R is H, CN, OH, OCH, SOCH, SONH, or (C-C) A represents O, S, or NRs, wherein R, denotes hydrogen or alkyl; and R is (C-C) alkyl optionally substituted with one 5 (C-C)-alkyl optionally substituted by (C-C)-alkoxy, to three F, CN, S(-O)R., SOH, SOR, C(=O) NH E represents a bond or (C-C)-alkanediyl. SO, CH, OR, SR, COORs, C(=O)R O C(=O) R represents (C-C)-aryl or 5- to 10-membered het NRRs. NRRs, NR'C(=O)R, NR'SOR, C(=O)NRRs eroaryl, where aryl and heteroaryl are optionally identically or SONRRs: or differently substituted by radicals selected from the group R, and Rs are the same or different and are H or (C-C) 10 consisting of halogen, formyl, carboxyl, carbamoyl, alkyl optionally substituted with one to three F, CN, SGEO) —SOH, aminosulphonyl, cyano, hydroxyl, trifluoromethyl, R., SOH, SOR, C(=O) NH SO CH, OR7, SRs. trifluoromethoxy, nitro, (C-C)-alkyl, (C-C)-alkoxy, 1.3- COOR, C(=O)R, O C(=O)NRRs, NRRs, NR'C(=O) dioxa-propane-1,3-diyl, (C-C)-alkylthio, (C-C)-alkylsul R7, NR'SO.R. C(=O)NR,R or SONRRs: phinyl and (C-C)-alkylsulphonyl, —NRRs end optionally Q' is a single bondor (C-C) alkylene; Q is a saturated 4 15 methyl-substituted, 5- to 6-membered heteroaryl or phenyl, to 6-membered heterocyclyl comprising one or two O or N: wherein Rs and Ro independently of one another denote Q is (C-C) alkylene; Q is a 4 to 8-membered, aromatic or hydrogen, (C-C)-alkyl or (C-C)-acyl, or salt thereof. non aromatic, heterocyclyl comprising 1 to 4O, S, S(–O), The preparation of these compounds is described in U.S. SO, or N, said heterocyclyl being optionally substituted with one to three OR, NRR', CN or (C-C) alkyl: Pat. No. 6,936,609 and US 20040249.148. R is H or (C-C) alkyl: In another embodiment, PDE7 inhibitors useful in the R is (C-C) alkyl optionally substituted with one or two methods of the invention are selected from those compounds OR'; generally or specifically disclosed in WO 2006/092692, R, and Rs are the same or different and are H or (C-C) expressly incorporated herein by reference in its entirety. In alkyl optionally substituted with one or two OR'; 25 one embodiment, PDE7 inhibitors useful in the methods of R is H, CN, OH, OCH, SOCH, SONH, or (C-C) the invention have the formulas: alkyl: R" is H or (C-C) alkyl; and R" is H or (C-C) alkyl: provided that (1) the atom of Q’ bound to Q' is a carbon (27A) atom; and (2) the atom of Q" bound to Q is a carbon atom; 30 NH CO2H or a racemic form, isomer, pharmaceutically acceptable derivative thereof. The preparation of these compounds is described in US 20040106631, EP 1 400 244, and WO 2004/026818. 35 In another embodiment, PDE7 inhibitors useful in the (CH2) methods of the invention are selected from those compounds (27B) generally or specifically disclosed in U.S. Pat. No. 6,936,609 NH CO2H and US 20040249148, each expressly incorporated herein by reference in its entirety. In one embodiment, PDE7 inhibitors useful in the methods of the invention have the formula: 40 i. (26) (27C) NH CO2H 45 E NA R3 N21 e 3. and N 50 (27D) R ls N1 NN>{ / NH CO2H R2.

The substituents for the above compounds are defined as 55 follows: R represents (C-Co)-aryl, which is optionally identically or differently substituted by radicals selected from the group consisting of halogen, formyl, carbamoyl, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, nitro, (C-C)-alkyl or 60 wherein n is an integer of from 1 to 4, and where there are (C-C)-alkoxy, and optionally by a radical of the formula stereocenters, each center may be independently R or S. SONRR, wherein Rs and R independently of one another The preparation of these compounds is described in WO denote hydrogen or (C-C)-alkyl, or NRSR denotes 4- to 2006/092692. 8-membered heterocyclyl bonded via a nitrogen atom, In another embodiment, PDE7 inhibitors useful in the optionally identically or differently substituted by radicals 65 methods of the invention are selected from those compounds selected from the group consisting of oxo, halogen, (C-C)- generally or specifically disclosed in US 2006229306 and alkyl and (C-C)-acyl, WO 2004/065391, each expressly incorporated herein by US 9.220,715 B2 91 92 reference in its entirety. In one embodiment, PDE7 inhibitors expressly incorporated herein by reference in its entirety. In useful in the methods of the invention have the formula: one embodiment, PDE7 inhibitors useful in the methods of the invention have the formula:

(28) (29) R N21 10 X N-1\s lsN R

The substituents for the above compounds are defined as R follows: 15 R and Reither (1) independently represent: The substituents for the above compounds are defined as (a) a hydrogen atom; follows: (b) a group selected from alkyl, alkenyland alkynyl groups, wherein each alkyl, alkenyl and alkynyl group is inde X is SO, or SO, pendently optionally substituted by one or more sub R1 is H, or alkyl, stituents selected from halogen atoms, hydroxy, alkoxy, aryloxy, alkylthio, hydroxycarbonyl, alcoxycarbonyl, R2 is alkyl, or halogen. mono- and di-alkylaminoacyl, Oxo, amino, and mono In specific embodiments, R1 is Me. In other specific and di-alkylamino groups; or 25 embodiments R1 is F. In certain embodiments R2 is t-Bu. In (c) a group of formula (CH), Re, wherein n is an integer specific embodiments, R1 is methyl. In more specific from 0 to 4 and R represents a cycloalkyl or cycloalk embodiments, the compounds are selected from: enyl group; (2) R and R form, together with the nitrogen atom to which they are attached, a 3- to 8-membered ring comprising 30 O from 1 to 4 heteroatoms selected from nitrogen, oxygen and 1nus s sulphur, which ring is saturated or unsaturated and optionally substituted by one or more substituents selected from halogen O N 21 atoms, alkyl, hydroxy, alkoxy, acyl, hydroxycarbonyl, alkoxycarbonyl, alkylenedioxy, amino, mono- and di-alky 35 lamino, mono- and di-alkylaminoacyl, nitro, cyano and trif C c luoromethyl groups; R is a group of formula (CH), wherein n is an integer from 0 to 4 and G represents a monocyclic or bicyclic aryl or heteroaryl 40 r group comprising from Zero to four heteroatoms which group is optionally substituted by one or more substituents selected C SN-1-1s from: (1) halogen atoms; (2) alkyl and alkylene groups, wherein each alkyl and 45 alkylenegroup is independently optionally Substituted by one or more Substituents selected from halogen atoms; and (3) phenyl, hydroxy, hydroxyalkyl, alkoxy, alkylenedioxy, aryloxy, alkylthio, amino, mono- and di-alkylamino, acy r lamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, cyano, 50 difluoromethoxy and trifluoromethoxy groups; C SN-1-1s R represents a hydrogen atom, an alkyl or an aryl group. The preparation of these compounds is described in US 2OO6229.306 and WO 2004/065391. Other compounds useful in the methods of the invention 55 include imidazopyridine derivatives (WO 2001/34601), dihy dropurine derivatives (WO 2000/68203), pyrrole derivatives (WO 2001/32618), benzothiopyranoimidazolone derivatives N (DE 19950647), heterocyclic compounds (WO 2002/87519), guanine derivatives (Bioorg. Med. Chem. Lett. 11:1081-1083, 60 F 2001), and benzothienothiadiazine derivatives (Eur: J. Med. Chem. 36:333, 2001). The disclosure of each published patent application and journal article listed above is expressly incor 2 S porated herein by reference in its entirety. ClN s1)n-1 O In another embodiment, PDE7 inhibitors useful in the 65 methods of the invention are selected from those compounds generally or specifically disclosed in WO 2008/130619, US 9.220,715 B2 93 94 In a related embodiment, PDE7 inhibitors useful in the -continued methods of the invention have the formula:

(30) 5 O R2 RO / W 10 Me N O k

wherein 15 R1 is alkyl, R2 is aryl or heteroaryl, R3 is alkyl, aryl, cycloakyl, or alkylaryl. In specific embodiments, R1 is methyl. In certain embodi 2O ments R2 is furanyl or thiophenyl. In other specific embodi ments, R2 is substituted phenyl or benzyl. In preferred embodiments, R3 is iso-butyl. In more specific embodiments, the compounds are selected from: 25

O H3CYo O W Z \ f 30

H3C N O is 35 CH3

O HC N S O W YV 45 HC N O H3C 50 CH3