USOO7655685B2

(12) United States Patent (10) Patent No.: US 7.655,685 B2 McElroy et al. (45) Date of Patent: Feb. 2, 2010

(54) CANNABINOID RECEPTOR (56) References Cited ANTAGONSTS/INVERSEAGONSTS U.S. PATENT DOCUMENTS USEFUL FOR TREATING METABOLC DISORDERS, INCLUDING OBESITY AND 6,476,060 B2 11/2002 Lange et al. DABETES 6,974,810 B2 12/2005 Lange et al. 7,482.470 B2 1/2009 McElroy et al. (75) Inventors: John F. McElroy, Wilmington, DE 7.528, 162 B2 5/2009 Kruse et al. US); Robert J. Chorvat, West Chester 2004/0248944 A1 12/2004 Kruse et al. ( s s s 2007/02133O2 A1 9/2007 McElroy et al. PA (US) 2009/0036511 A1 2/2009 McElroy et al. (73) Assignee: Jenrin Discovery, Inc., West Chester, PA (US) FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this EP 1429761 B2 11/2006 patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. OTHER PUBLICATIONS (21) Appl. No.: 12/262,765 PCT/US08/82173 International Search Report and Written Opinion. (22) Filed: Oct. 31, 2008 Lange, J.H.M. et al.; Synthesis, Biological Properties and Molecular 9 Investigations of Novel 3,4-Diarylpyrazolines as Potent and Selec (65) Prior Publication Data y:Sannabinoid Receptor Antagonists; J. Med. Chem. 2004, US 2009/O1 18345A1 May 7, 2009 Primary Examiner Kamal A Saeed O O Assistant Examiner—Samantha L. Shterengarts Related U.S. Application Data (74) Attorney, Agent, or Firm Vance Intellectual Property, (60) Provisional application No. 60/984,760, filed on Nov. PC 2, 2007. (57) ABSTRACT (51) Int. Cl. A6 IK 3L/45 (2006.01) The present invention provides novel pyrazoles that are useful CO7D 23/06 (2006.01) as cannabinoid receptorantagonists and pharmaceutical com (52) U.S. Cl...... 514/403; 548/379.1: 548/379.4: positions thereof and methods of using the same for treating 548/379.7 obesity, diabetes, hepatic disorders, and/or cardiometabolic (58) Field of Classification Search ...... 514/403; disorders. 548/379.1, 379.4, 379.7 See application file for complete search history. 58 Claims, No Drawings US 7,655,685 B2 1. 2 CANNABINOID RECEPTOR ing body weight secondary to reducing the amount of calories ANTAGONSTS/INVERSEAGONSTS that reach the systemic circulation. Unfortunately, these indi USEFUL FOR TREATING METABOLC rect therapies produce only a modest initial weight loss (ap DISORDERS, INCLUDING OBESITY AND proximately 5% compared to placebo) that is usually not DABETES maintained. After one or two years of treatment, most patients return to or exceed their starting weight. In addition, most CROSS-REFERENCE TO RELATED approved anti-obesity therapeutics produce undesirable and APPLICATIONS often dangerous side effects that can complicate treatment and interfere with a patient’s quality of life. The present application claims priority benefit under 35 10 The lack of therapeutic effectiveness, coupled with the U.S.C. S119(e) of U.S. Provisional Patent Application Ser. spiraling obesity epidemic, positions the treatment of obe No. 60/984,760 filed Nov. 2, 2007. The disclosure this appli sity as one of the largest and most urgent unmet medical cation is incorporated herein by reference. needs. There is, therefore, a real and continuing need for the development of improved medications that treat or prevent FIELD OF THE INVENTION 15 obesity. The endocannabinoid system, comprised of the cannab The present invention provides cannabinoid receptor inoid receptors (CB1 and CB2) and their endogenous ligands antagonists/inverse agonists and pharmaceutical composi (e.g., anandamide, 2-AG), plays a prominent role in the con tions thereof and methods of using the same for treating trol of food intake and energy metabolism. CB1 receptors are obesity, diabetes, hepatic disorders, and/or cardiometabolic widely expressed in the brain, including cortex, hippocam disorders. The present invention also relates to a novel pus, amygdala, pituitary and hypothalamus. CB1 receptors method for treating obesity, diabetes, hepatic disorders, and/ have also been identified in numerous peripheral organs and or cardiometabolic disorders using a pyrazoline. tissues, including thyroid gland, adrenal gland, reproductive organs, adipose tissue, liver, muscle, pancreas, and gas BACKGROUND OF THE INVENTION 25 trointestinal tract. CB2 receptors are localized almost exclu Obesity is associated with an increase in the overall amount sively in immune and blood cells Endocrine Reviews 2006, of adipose tissue (i.e., body fat), especially adipose tissue 27, 73. localized in the abdominal area. Obesity has reached epi The plant-derived cannabinoid agonist A-tetrahydrocan demic proportions in the United States. The prevalence of 30 nabinol (A-THC), the main psychoactive component of obesity has steadily increased over the years among all racial marijuana, binds to both CB1 and CB2 receptors. A-THC is and ethnic groups. The most recent data from the Centers for widely reported to increase appetite and food intake (hyper Disease Control and Prevention, and the National Center for phagia) in humans and in animals. This hyperphagic effect is Health Statistics report 66% of the adult population over largely blocked by pretreatment with selective CB1 receptor weight (BMI, 25.0-29.9), 31% obese (BMI,30-39.9), and 5% 35 blockers (i.e., CB1 blockers)(e.g., rimonabant (SR141716A, extremely obese (BMI, 240.0). Among children aged 6 AcompliaR)), strongly supporting the belief that CB1 recep through 19 years, 32% were overweight and 17% were obese. tor activation mediates the hyperphagic effect of A-THC, This translates to 124 million Americans medically over Endocrine Reviews 2006, 27, 73. weight, and 44 million of these deemed obese. Obesity is In humans, rimonabant produces a clinically meaningful responsible for more than 300,000 deaths annually, and will 40 weight loss in obese patients. Obese patients also experience Soon overtake tobacco usage as the primary cause of prevent improvements in diabetic and cardiometabolic risk factors able death in the United States. Obesity is a chronic disease associated with obesity, including an increase in the level of that contributes directly to numerous dangerous co-morbidi high density lipoprotein cholesterol (HDL), and decreases in ties, including type 2 diabetes, cardiometabolic diseases, triglycerides, glucose, and hemoglobin Alc (HbAlc, a hepatic disorders, cardiovascular disease, inflammatory dis 45 marker of cumulative exposure to glucose) levels. Rimona eases, premature aging, and some forms of cancer. Type 2 bant also produces greater reductions in abdominal fat depos diabetes, a serious and life-threatening disorder with growing its, which are a known risk factor for diabetes and heart prevalence in both adult and childhood populations, is cur disease Science 2006, 311, 323. Taken together, these rently the 7" leading cause of death in the United States. improvements in adiposity and cardiometabolic risk factors Since more than 80% of patients with type 2 diabetes are 50 produce an overall decrease in the prevalence of the metabolic overweight, obesity is the greatest risk factor for developing syndrome Lancet2005, 365, 1389 and NEJM 2005, 353, type 2 diabetes. Increasing clinical evidence indicates that the 2121. best way to control type 2 diabetes is to reduce weight. In patients with type 2 diabetes not currently treated with The most popular over-the counter drugs for the treatment other anti-diabetic medications, rimonabant was shown to of obesity, phenylpropanolamine and ephedrine, and the most 55 significantly improve blood Sugar control and weight, as well popular prescription drug, fenfluramine, were removed from as other risk factors such as HDL and triglycerides, when the marketplace as a result of safety concerns. Drugs cur compared to placebo (International Diabetes Federation rently approved for the long-term treatment of obesity fall World Diabetes Congress, Cape Town, South Africa, 2006). into two categories: (a) CNS appetite Suppressants such as After six months of treatment, HbA1c levels were signifi Sibutramine and rimonabant, and (b) gut lipase inhibitors 60 cantly lowered by 0.8% from a baseline value of 7.9 as com Such as orlistat. CNS appetite Suppressants reduce eating pared to a reduction of 0.3% in the placebo group. These behavior through activation of the satiety center in the brain results are consistent with preclinical studies that demon and/or by inhibition of the hunger center in the brain. Gut strate improved glycemic and lipid control in diabetic and lipase inhibitors reduce the absorption of dietary fat from the dyslipidemic mice, rats, and dogs (Pharmacology Biochem gastrointestinal (GI) tract. Although appetite Suppressants 65 istry & Behavior, 2006, 84, 353; American Journal of Physi and gut lipase inhibitors work through very different mecha ology, 2003, 284, R345; American Diabetes Association nisms, they share in common the same overall goal of reduc Annual Meeting, 2007: Abstract Number 0372-OR). US 7,655,685 B2 3 4 The beneficial effects of rimonabant on diabetic and car the prevention or treatment of obesity, diabetes, dyslipidemia, diometabolic risk factors such as high blood pressure, insulin cardiovascular disorders, and/or hepatic disorders. resistance, and elevated triglycerides cannot be explained by diet-related weight loss alone. For example, in patients SUMMARY OF THE INVENTION receiving 20 mg of rimonabant, only approximately 50% of 5 the beneficial effects on triglycerides, fasting insulin, and Accordingly, in an aspect, the present invention provides insulin resistance can be accounted for by weight loss sec novel pyrazolines or pharmaceutically acceptable salts ondary to reduced food intake. These results suggest a direct thereof that are CB1 receptor antagonists/inverse agonists. pharmacological effect of CB1 antagonists on glucose and In another aspect, the present invention provides novel lipid metabolism, in addition to indirect effects on metabo 10 pharmaceutical compositions, comprising: a pharmaceuti lism secondary to hypophagia-mediated weight loss Science cally acceptable carrier and a therapeutically effective 2006, 311, 323 and JAMA 2006, 311, 323). Taken together, amount of at least one of the compounds of the present inven these results suggest that CB1 antagonists might be effective tion or a pharmaceutically acceptable salt form thereof. in the treatment of diabetes, dyslipidemia, cardiovascular In another aspect, the present invention provides novel disorders (e.g., atherosclerosis, hypertension), and hepatic 15 methods for treating obesity, diabetes (e.g., insulin resistance, disorders (e.g., cirrhosis, fatty liver diseases), even in patients inadequate glucose tolerance, Type I diabetes, and Type II that are not clinically overweight or obese. diabetes), dyslipidemia (e.g., elevated triglycerides and low The CB1 receptor is one of the most abundant and widely HDL), cardiovascular disorders (e.g., atherosclerosis and distributed G protein-coupled receptors in the mammalian hypertension), and/or hepatic disorders (e.g., cirrhosis and brain. It is believed that the appetite-suppressant properties of fatty liver disease), comprising: administering to a mammal CB1 antagonists are mediated through an interaction with in need of such treatment a therapeutically effective amount CB1 receptors in the hypothalamus (regulation of food of at least one of the compounds of the present invention or a intake), and in the mesolimbic region (rewarding properties pharmaceutically acceptable salt form thereof. of food). However, CB1 receptors are far more broadly dis In another aspect, the present invention provides processes tributed in brain (e.g., neocortex, hippocampus, thalamus, 25 for preparing novel compounds. cerebellum, and pituitary), and while interacting with tar In another aspect, the present invention provides novel geted CB1 receptors in hypothalamus and mesolimbic compounds or pharmaceutically acceptable salts for use in regions to Suppress appetite, CB1 antagonists have equal therapy. access to non-targeted CB1 receptors that have little if any In another aspect, the present invention provides the use of role inappetite control. Binding to non-targeted receptors can 30 novel compounds for the manufacture of a medicament for often lead to unwanted side effects of CNS drugs Endocrine the treatment of obesity, diabetes, dyslipidemia, cardiovascu Reviews 2006, 27: 73. The CB1 blockers rimonabant and lar disorders, and/or hepatic disorders. taranabant produce psychiatric and neurological side effects. These and other objects, which will become apparent dur These include depressed mood, anxiety, irritability, insomnia, ing the following detailed description, have been achieved by 35 the inventors discovery that the presently claimed com dizziness, headache, seizures, and Suicidality. pounds or pharmaceutically acceptable salt forms thereofare These side effects are dose-related and appear pronounced expected to be effective CB1 receptor blockers. at the most efficacious weight-reducing doses of rimonabant and taranabant (JAMA 2006, 311, 323; Cell Metabolism DETAILED DESCRIPTION OF THE INVENTION 2008, 7.68). The occurrence of therapeutic efficacy (appetite 40 Suppression) and side effects over the same dose range All references cited herein are hereby incorporated in their strongly suggest that both effects are mediated through con entirety herein by reference. current antagonism of CB1 receptors in both targeted and A CB1 blocker is a neutral CB1 receptor antagonist and/or non-targeted brain regions. Brain-penetrant CB1 blockers a CB1 receptor inverse agonist. do not selectively target CB1 receptors in efficacy brain 45 The present invention is based on the finding that a CB1 regions, while ignoring CB1 receptors in side effect brain receptor blocker has beneficial effects on cardiometabolic regions. disorders including obesity, diabetes, and dyslipidemia that The beneficial effects of the CB1 antagonistrimonabant on cannot be explained by weight loss derived from CNS-medi body weight, adiposity, and diabetic and cardiometabolic risk ated appetite Suppression alone, and that this effect is medi factors such as high blood pressure, insulin resistance and 50 ated, at least in part, through interaction at peripheral CB1 blood lipids cannot be explained by weight loss derived from receptors. To this end, the present invention provides com CNS-mediated appetite suppression alone JAMA 2006, 311, pounds that are designed to preferentially target CB1 recep 323. Approximately 50% of the benefit is likely derived from tors in peripheral tissues (e.g., adipose tissue, liver, muscle, an interaction with CB1 receptors in peripheral tissues known pancreas, and gastrointestinal tract), while sparing CB1 to play an active role in metabolism. These include adipose 55 receptors in brain. With these types of compounds, peripher tissue, liver, muscle, pancreas, and gastrointestinal tract. ally-mediated beneficial effects of CB1 blockers should be In view of the above, it is highly desirable to find effective maintained, whereas CNS side effects should be reduced or and highly selective CB1 receptor blockers with limited or no eliminated. CNS adverse side effects, including mood disorders. Particu The compounds of the present invention have been larly, it is desirable to find compounds that preferentially 60 designed to have reduced CNS exposure by virtue of their target CB1 receptors in peripheral tissues (e.g., adipose tis inability or limited ability to penetrate the blood-brain barrier Sue, liver, muscle, pancreas, and gastrointestinal tract), while (BBB), or by their participation in active transport systems, sparing CB1 receptors in brain. In this way, peripherally thus reducing centrally mediated side-effects, a potential mediated beneficial effects of CB1 blockers should be main problem with many anti-obesity agents. It is expected that the tained, whereas CNS side effects should be reduced or elimi 65 peripherally restricted compounds of the present invention nated. This should provide a novel opportunity to develop will have no or very limited CNS effects, including mood safer alternatives to highly brain penetrant CB1 blockers for disorders, seizures, and Suicidality. Thus, their peripherally US 7,655,685 B2 5 6 mediated CB1 antagonistic properties should provide thera Z is selected from H, COR, and CONR; peutic agents with greater safety. Q is selected from: (CH),CHA(CH),C(O)NR2 (CH), Moreover, if the maximum dosage of a drug used in the CAA"(CH),C(O)NR2 (CH), CHA(CH2)CO.R. (CH), treatment of obesity, diabetes, dyslipidemia, cardiovascular CAA"(CH2)CO.R. (CH2)CHA(CH), SONR, (CH), disorders, and/or hepatic disorders is limited as a result of 5 CHA(CH), SOR, (CH), CHA(CH),C(NH)NH. (CH), CNS side effects (e.g., seizures, depression, anxiety, Suicid CHA(CH),C(NOH)NH2. (CH), CHA(CH), CONH ality, movement disorders, and hyperactivity), incorporation CHA(CH),CO.R., (CH),CAA"(CH), CONHCHA of a peripherally restricting group in Such a drug would lower (CH),CO.R., (CH), CHA(CH), CONHCHA(CH), the brain concentration of the drug relative to the concentra CONHCHA(CH),CO.R., (CH), CHA(CH2)CONH tion in the systemic circulation, thereby affording the oppor 10 CHA(CH2)CONR (CH),CAA"(CH2)CONHCHA tunity to increase the dosage employed to treat the peripheral (CH),CONR' (CH), CHA(CH), CONHCHA(CH), disorder (e.g., obesity, diabetes, dyslipidemia, cardiovascular CONHCHA(CH),CONR, C-C-cyclic amino-(CH), disorders, and/or hepatic disorders). The increased dosage COR, C-C-cyclic amino-(CH2), CONR, C-C-cy may provide greater therapeutic efficacy, as well as a more cloalkylene-(CH2)COR, and C-C-cycloalkylene rapid onset of therapeutic action. 15 (CH), CONR; 1 In another embodiment, the present invention provides provided that when Q is (CH2)CAA"(CH),C(O)NR or novel compound of Formula I or a stereoisomer or pharma (CH),CAA"(CH),COR, then (a) m is other than 0, (b) A ceutically acceptable salt thereof: is other than H, or (c) both (a) and (b): A is selected from H. C. alkyl, (CH2)Cle-cycloalkyl, OH, CHOH, CH(CH)OH, C(CH),OH, (CH),CO.R., (CH),C(O)NR', and (CH)-phenyl, wherein the phenyl is substituted with 0-3 groups selected from H. C. alkyl, halo gen, CFO C. alkyl, and NO; alternatively, Q is CHA(CH),C(O)NR or CHA(CH), 25 CO.R, and (a) A is selected from OH, (CH),CO.R', and (CH),C(O)NR'; (b) R is (CH),(CHR), (CH), OH or CH(CHOH); or (c) both (a) and (b): A" is C alkyl, M is C=O or SO; 30 R is independently selected from H. (CH), (CHR), (CH), OH, CH(CH2OH)2, C1 alkyl, C2-alkenyl, and C2 alkynyl: R" is independently selected from H. (CH)(CHR), 35 (CH2), OH, C alkyl, C2-alkenyl, and C2-alkynyl, R’ is independently selected from H. C. alkyl, C2-alk enyl, and C2-alkynyl: p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12: wherein: m is selected from 0, 1, 2, 3, and 4; and, X,Y,X,Y,X", andY" are independently selected from: H, 40 C. alkyl, halogen, CF. O—C alkyl, NO, NR, O(CH), n is selected from 1, 2, 3, and 4. COR, O(CH),CN, OCH-CH=CHCOR, CHO(CH), In another embodiment, the present invention provides COR, CHOCH-CH=CHCOR, O(CH), PO(OR), CHO novel compounds wherein: (CH),PO(OR), NR(CH),COR, NR(CH), PO(OR), M is SO. NRCH-CH=CHCOR, NRSOR, NRCO(CH),COR, 45 2 In another embodiment, the present invention provides NRCO(CH),CONR, O(CH),CHCOR, O(CH), novel compounds of formula Ia or a stereoisomer or pharma CH(CH2)COR, CHO(CH), CHCOR, O(CH), ceutically acceptable salt thereof, CHCONR's O(CH),CH(CH),CONR, O(CH), CH-tetrazole, CHO(CH),CHCONR, CHO (CH),

CH-tetrazole, O(CH2)CH (CH)-tetrazole, NR(CH), 50 Ia CHCOR, CHNR(CH), CHCOR, NR(CH), CH, (CH2)COR, NR(CH2)CHCONR, CHNR(CH), CHCONR, NR(CH), CH (CH),CONR, NR (CH), CH-tetrazole, CHNR(CH),CH-tetrazole, NR (CH), CH (CH)-tetrazole, CONHOH, C(NH)NR', 55 (CH),C(NH)NR, O(CH),CONR, O(CH),C(NH) NR, O(CH),C(NOH)NR, CHO(CH),CONR, NR (CH),CONR, OCH-CH=CHCONR, CHOCHCH-CHCONR, NRCHCH-CHCONR, (CH2)-tetrazole, O(CH2)-tetrazole, O(CH2CH2O).R. NR 60 (CHCHO),R, and SO-NHCHs: Z is selected from: H, C alkyl, OH, O C alkyl, O(CH-CHO).R., OC(O) C, alkyl, O(CH),CO.R. OCH-CH=CHCOR, O(CH), PO(OR), O(CH), CONR, O(CH),C(NH)NH, O(CH),C(NOH)NR, 65 OCH-CH=CHCONR, O(CH)-phenyl-(CH2)COR, and O(CH2)-phenyl-(CH2)-tetrazole; US 7,655,685 B2 7 8 3. In another embodiment, the present invention provides Q is selected from: (CH),CHA(CH),C(O)NR2 (CH), novel compounds of formula Ib or a stereoisomer or pharma CAA"(CH),C(O)NR (CH),CHA(CH2)CO.R., (CH), ceutically acceptable salt thereof, CAA"(CH2)CO.R. (CH2)CHA(CH), SONR, (CH), Ib CHA(CH2)CONHCHA(CH),COR, (CH),CAA" X 5 (CH),CONHCHA(CH),COR, (CH2)CHA(CH), CONHCHA(CH),CONHCHA(CH),COR, (CH2). CHA(CH),CONHCHA(CH),CONR, (CH),CAA" (CH),CONHCHA(CH),CONR, (CH), CHA(CH), O C) CONHCHA(CH),CONHCHA(CH),CONR, C-C-cy 10 clic amino-(CH2)COR, C-C-cyclic amino-(CH), CONR, C-C-cycloalkylene-(CH2)COR, and C-C- cycloalkylene-(CH2)CONR; provided that when Q is (CH2)CAA"(CH),C(O)NR or 1. N (CH),CAA"(CH),COR, then (a) m is other than 0, (b) A 15 is other than H, or (c) both (a) and (b): M A is selected from H. C. alkyl, (CH), C-cycloalkyl, OH, CHOH, CH(CH)OH, C(CH),OH, (CH),COR, (CH),C(O)NR', and (CH)-phenyl, wherein the phenyl is Yi. substituted with 0-3 groups selected from H. C. alkyl, halo gen, CFO C. alkyl, and NO; 4. In another embodiment, the present invention provides alternatively, Q is CHA(CH),C(O)NR or CHA(CH), novel compounds of formula Ic or a stereoisomer or pharma COR, and A is OH or (CH),CO.R or R is (CH), (CHR), ceutically acceptable salt thereof, (CH), OH or CH(CHOH): Ic R is independently selected from H. C. alkyl, Calk X 25 enyl, and C2-alkynyl: R’ is independently selected from H. C. alkyl, C2-alk enyl, and C2-alkynyl: p is selected from 2, 3, 4, 5, 6, 7, and 8: O m is independently selected from 0, 1, 2, and 3; and, 30 n is independently selected from 1, 2, and 3. 5. In another embodiment, the present invention provides novel compounds of formula Ia or a stereoisomer or pharma ceutically acceptable salt thereof, wherein: Q is selected from: (CH),CHA(CH),C(O)NR2 (CH), 35 CAA"(CH),C(O)NR, (CH), CHA(CH), SONR, (CH), CHA(CH),CONHCHA(CH2)CONR (CH), CAA"(CH),CONHCHA(CH2)CONR (CH), CHA (CH),CONHCHA(CH),CONHCHA(CH),CONR, Yi. C-C-cyclic amino-(CH2)COR, C-C-cyclic amino 40 (CH),CONR, and C-C-cycloalkylene-(CH), 5. In another embodiment, the present invention provides CONR; novel compounds of formula Ia or a stereoisomer or pharma provided that when Q is (CH),CAA"(CH),C(O)NR ceutically acceptable salt thereof, then (a) m is other than 0, (b) A is other than H, or (c) both (a)

Ia and (b): 45 alternatively, Q is CHA(CH),C(O)NR2 and A is OH or (CH),CO.R or R is (CH), (CHR), (CH), OH or CH(CHOH): M is SO; R is independently selected from Hand C alkyl; 50 R’ is independently selected from Hand C, alkyl: m is independently selected from 0, 1, and 2; and, n is independently selected from 1 and 2. In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharma 55 ceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a pharma ceutically acceptable salt form thereof. In another embodiment, the present invention provides a novel method of modulating the activity of CB1 receptors 60 (e.g., peripheral CB1 receptors) in a patient, comprising: wherein: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a X, Y, X, Y, X", and Y" are individually selected from the pharmaceutically acceptable salt form thereof. following: H, C alkyl, halogen, CF. O—C alkyl, NO. In another embodiment, the present invention provides a O(CHCHO),R, NR(CHCHO).R., and NR; 65 novel method of treating a disease characterized by an inap Zis selected from: H.C. alkyl, OH, O—C alkyl, acety propriate activation of peripheral CB1 receptors, comprising: loxy, and propionyloxy; administering to a patient in need thereof a therapeutically US 7,655,685 B2 10 effective amount of a compound of the present invention or a describe additional embodiments. It is also to be understood pharmaceutically acceptable salt form thereof. that each individual element of the embodiments is intended In another embodiment, the present invention provides a to be taken individually as its own independent embodiment. novel method for treating a disease mediated by the CB Furthermore, any element of an embodiment is meant to be receptor in a patient, comprising: administering to a patient in 5 combined with any and all other elements from any embodi need thereof a therapeutically effective amount of a com ment to describe an additional embodiment. pound of the present invention or a pharmaceutically accept able salt form thereof. In an example, the disease is mediated DEFINITIONS by peripheral CB receptors. In another example, the CB receptors that are blocked are peripheral CB receptors. 10 The examples provided in the definitions present in this In another embodiment, the present invention provides a application are non-inclusive unless otherwise stated. They novel method for treating a disease, comprising: administer include but are not limited to the recited examples. ing to a patient in need thereof a therapeutically effective The compounds herein described may have asymmetric amount of a compound of the present invention or a pharma centers, geometric centers (e.g., double bond), or both. All ceutically acceptable salt form thereof, wherein the disease is 15 chiral, diastereomeric, racemic forms and all geometric iso selected from obesity, diabetes, dyslipidemia, cardiovascular meric forms of a structure are intended, unless the specific disorders, hepatic disorders, and a combination thereof. Stereochemistry or isomeric form is specifically indicated. In another embodiment, the diabetes disorder is selected Compounds of the present invention containing an asym from Type 1 diabetes, Type 2 diabetes, inadequate glucose metrically substituted atom may be isolated in optically active tolerance, and insulin resistance. or racemic forms. It is well known in the art how to prepare In another embodiment, the dyslipidemia disorder is optically active forms, such as by resolution of racemic selected from undesirable blood lipid levels, including forms, by Synthesis from optically active starting materials, or elevated LDL and triglyceride levels, and lowered HDL lev through use of chiral auxiliaries. Geometric isomers of ole els. fins, C=N double bonds, or other types of double bonds may In another embodiment, the cardiovascular disorder is 25 be present in the compounds described herein, and all Such selected from atherosclerosis, hypertension, stroke and heart stable isomers are included in the present invention. Specifi attack. cally, cis and transgeometric isomers of the compounds of the In another embodiment, the hepatic disorder is selected present invention may also exist and may be isolated as a from cirrhosis and fatty liver diseases. mixture of isomers or as separated isomeric forms. All pro In another embodiment, the present invention provides a 30 cesses used to prepare compounds of the present invention novel method for treating a co-morbidity of obesity, compris and intermediates made therein are considered to be part of ing: administering to a patient in need thereof a therapeuti the present invention. All tautomers of shown or described cally effective amount of a compound of the present invention compounds are also considered to be part of the present or a pharmaceutically acceptable salt form thereof. invention. In another embodiment, the co-morbidity is selected from 35 Alkyl includes both branched and straight-chain satu diabetes, dyslipidemia, Metabolic Syndrome, dementia, car rated aliphatic hydrocarbon groups having the specified num diovascular, and hepatic disease. ber of carbon atoms. Calkyl, for example, includes C. C. In another embodiment, the co-morbidity is selected from C, C, Cs, and C alkyl groups. Examples of alkyl include hypertension; gallbladder disease; gastrointestinal disorders; methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, menstrual irregularities; degenerative arthritis; venous statis 40 n-pentyl, and S-pentyl. ulcers; pulmonary hypoVentilation syndrome; sleep apnea; Alkenyl includes the specified number of hydrocarbon Snoring; coronary artery disease; arterial Sclerotic disease; atoms in either straight or branched configuration with one or pseudotumor cerebri; accident proneness; increased risks more unsaturated carbon-carbon bonds that may occur in any with Surgeries; osteoarthritis; high cholesterol; and, increased stable point along the chain, such as ethenyl and propenyl. incidence of malignancies of the ovaries, cervix, uterus, 45 C2-alkenyl includes C2, Cs, Ca, Cs, and Coalkenyl groups. breasts, prostrate, and gallbladder. Alkynyl includes the specified number of hydrocarbon In another embodiment, the present invention also provides atoms in either straight or branched configuration with one or a method of preventing or reversing the deposition of adipose more triple carbon-carbon bonds that may occur in any stable tissue in a mammal by the administration of a compound of point along the chain, such as ethynyl and propynyl. C the present invention. By preventing or reversing the deposi 50 Alkynyl includes C, C, C, Cs, and C alkynyl groups. tion of adipose tissue, compound of the present invention are “Cycloalkyl includes the specified number of hydrocar expected to reduce the incidence or severity of obesity, bon atoms in a saturated ring. Such as cyclopropyl, cyclobu thereby reducing the incidence or severity of associated co tyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. morbidities. C-8 cycloalkyl includes C. C. Cs. C. C7, and Cs cycloalkyl In another embodiment, the present invention provides a 55 groups. compound of the present invention for use in therapy. “Cyclic amine' is a hydrocarbon ring wherein one carbon In another embodiment, the present invention provides the atom of the ring has been replaced by a nitrogen atom. The use of the present invention for the manufacture of a medica cyclic amine can be unsaturated, partially saturated, or fully ment for the treatment of obesity, diabetes, dyslipidemia, saturated. The cyclic amine can also be bicyclic, tricyclic, and cardiovascular disorders, hepatic disorders, and a combina 60 polycyclic. Examples of cyclic amine include pyrrolidine and tion thereof. piperidine. The present invention may be embodied in other specific "Halo’ or “halogen refers to fluoro, chloro, bromo, and forms without departing from the spirit or essential attributes iodo. thereof. This invention encompasses all combinations of "Counterion' is used to represent a small, negatively aspects of the invention noted herein. It is understood that any 65 charged species, such as chloride, bromide, hydroxide, and all embodiments of the present invention may be taken in acetate, and Sulfate. conjunction with any other embodiment or embodiments to The group "C.H.' represents a phenylene. US 7,655,685 B2 11 12 “Aryl” refers to any stable 6, 7, 8, 9, 10, 11, 12, or 13 ternary ammonium salts of the parent compound formed, for membered monocyclic, bicyclic, or tricyclic ring, wherein at example, from non-toxic inorganic or organic acids. For least one ring, if more than one is present, is aromatic. example, such conventional non-toxic salts include, but are Examples of aryl include fluorenyl, phenyl, naphthyl, inda not limited to, those derived from inorganic and organic acids nyl, adamantyl, and tetrahydronaphthyl. selected from 1.2-ethanedisulfonic, 2-acetoxybenzoic, 2-hy “Heteroaryl” refers to any stable 5, 6,7,8,9, 10, 11, or 12 droxyethanesulfonic, acetic, ascorbic, benzenesulfonic, ben membered monocyclic, bicyclic, ortricyclic heterocyclic ring Zoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, that is aromatic, and which consists of carbon atoms and 1, 2, ethane Sulfonic, fumaric, glucoheptonic, gluconic, glutamic, 3, or 4 heteroatoms independently selected from the group glycolic, glycolyarsanilic, hexylresorcinic, hydrabamic, consisting of N, O, and S. If the heteroaryl group is bicyclic or 10 hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, tricyclic, then at least one of the two or three rings must hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl Sul contain a heteroatom, though both or all three may each fonic, maleic, malic, mandelic, methanesulfonic, napsylic, contain one or more heteroatoms. If the heteroaryl group is nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, bicyclic or tricyclic, then only one of the rings must be aro polygalacturonic, propionic, Salicyclic, Stearic, Subacetic, matic. The Ngroup may be N, NH, or N-substituent, depend 15 Succinic, Sulfamic, Sulfanilic, Sulfuric, tannic, tartaric, and ing on the chosen ring and if Substituents are recited. The toluenesulfonic. nitrogen and Sulfur heteroatoms may optionally be oxidized The pharmaceutically acceptable salts of the present inven (e.g., S. S(O), S(O), and N—O). The heteroaryl ring may be tion can be synthesized from the parent compound that con attached to its pendant group at any heteroatom or carbon tains a basic or acidic moiety by conventional chemical meth atom that results in a stable structure. The heteroaryl rings ods. Generally, such salts can be prepared by reacting the free described herein may be substituted on carbon or on a nitro acid or base forms of these compounds with a stoichiometric gen atom if the resulting compound is stable. amount of the appropriate base or acid in water or in an Examples of heteroaryl includes acridinyl, azocinyl, ben organic solvent, or in a mixture of the two: generally, non Zimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophe aqueous media like ether, ethyl acetate, ethanol, isopropanol, nyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriaz 25 or acetonitrile are useful. Lists of suitable salts are found in olyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, Remington's Pharmaceutical Sciences, 18th ed., Mack Pub benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, lishing Company, Easton, Pa., 1990, p 1445, the disclosure of chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, which is hereby incorporated by reference. 2H,6H-1.5.2-dithiazinyl, dihydrofuro2,3-btetrahydrofu “Therapeutically effective amount” includes an amount of ran, furanyl, furazanyl, imidazolyl, 1H-indazolyl, indolenyl, 30 a compound of the present invention that is effective when indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isoben administered alone or in combination to treat obesity or Zofuranyl, isochromanyl, isolindazolyl, isoindolinyl, isoin another indication listed herein. “Therapeutically effective dolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, amount also includes an amount of the combination of com oxadiazolyl, 1.2.3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxa pounds claimed that is effective to treat the desired indication. diazolyl, 1.3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxin 35 The combination of compounds can be a synergistic combi dolyl pyrimidinyl, phenanthridinyl, phenanthrolinyl, phena nation. Synergy, as described, for example, by Chou and Zinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when the phthalazinyl, pteridinyl, pyranyl, pyrazinyl, pyrazolyl, effect of the compounds when administered in combination is pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, greater than the additive effect of the compounds when pyridinyl, pyridyl, pyrimidinyl, 2H-pyrrolyl pyrrolyl, 40 administered alone as a single agent. In general, a synergistic quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, qui effect is most clearly demonstrated at Sub-optimal concentra nuclidinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiaz tions of the compounds. Synergy can be in terms of lower olyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiaz cytotoxicity, increased effect, or some other beneficial effect olyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, of the combination compared with the individual compo thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1.2, 45 nentS. 3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, Obesity is defined as having a body mass index (BMI) of 30 and Xanthenyl. or above. The index is a measure of an individual’s body “Mammal’ and “patient cover warm blooded mammals weight relative to height. BMI is calculated by dividing body that are typically under medical care (e.g., humans and weight (in kilograms) by height (in meters) Squared. Normal domesticated animals). Examples include feline, canine, 50 and healthy body weight is defined as having a BMI between equine, bovine, and human, as well as just human. 20 and 24.9. Overweight is defined as having a BMI225. “Treating or “treatment covers the treatment of a dis Obesity has reached epidemic proportions in the U.S., with 44 ease-state in a mammal, and includes: (a) preventing the million obese Americans, and an additional eighty million disease-state from occurring in a mammal, in particular, when deemed medically overweight. Such mammal is predisposed to the disease-state but has not 55 Obesity is a disease characterized as a condition resulting yet been diagnosed as having it; (b) inhibiting the disease from the excess accumulation of adipose tissue, especially state, i.e., arresting it development; and/or (c) relieving the adipose tissue localized in the abdominal area. It is desirable disease-state, i.e., causing regression of the disease state until to treat overweight or obese patients by reducing their amount a desired endpoint is reached. of adipose tissue, and thereby reducing their overall body “Pharmaceutically acceptable salts' refer to derivatives of 60 weight to within the normal range for their sex and height. In the disclosed compounds wherein the parent compound is this way, their risk for co-morbidities such as diabetes and modified by making acid or base salts thereof. Examples of cardiovascular disease will be reduced. It is also desirable to pharmaceutically acceptable salts include, but are not limited prevent normal weight individuals from accumulating addi to, mineral or organic acid salts of basic residues such as tional, excess adipose tissue, effectively maintaining their amines; alkali or organic salts of acidic residues such as 65 body weights at a BMI<25, and preventing the development carboxylic acids; and the like. The pharmaceutically accept of co-morbidities. It is also desirable to control obesity, effec able salts include the conventional non-toxic salts or the qua tively preventing overweight and obese individuals from US 7,655,685 B2 13 14 accumulating additional, excess adipose tissue, reducing the Dyslipidemia contributes to the development of athero risk of further exacerbating their co-morbidities. Sclerosis. Causes may be primary (genetic) or secondary. Type 2 Diabetes or Diabetes mellitus type 2 or (formerly Diagnosis is by measuring plasma levels of total cholesterol, called non-insulin-dependent diabetes mellitus (NIDDM), or TGs, and individual lipoproteins. Treatment is dietary adult-onset diabetes) is a metabolic disorder that is primarily 5 changes, exercise, and lipid-lowering drugs. A linear relation characterized by insulin resistance, relative insulin defi probably exists between lipid levels and cardiovascular risk, ciency, and hyperglycemia. The World Health Organization so many people with “normal cholesterol levels benefit from definition of diabetes is for a single raised glucose reading achieving still lower levels. Normal and abnormal lipid levels with symptoms otherwise raised values on two occasions, of have been defined in the Third Report of the Expert Panel on either fasting plasma glucosee 7.0 mmol/l (126 mg/dl) or 10 Detection, Evaluation, and Treatment of High Blood Choles with a Glucose tolerance test: two hours after the oral dose a terol in Adults. National Institutes of Health, National Heart, plasma glucosee 11.1 mmol/l (200 mg/dl). Type 2 Diabetes is Lung, and Blood Institute, 2001. rapidly increasing in the developed world and there is some The treatment of choice for dyslipidemias is lifestyle evidence that this pattern will be followed in much of the rest change, including diet and exercise. Drugs are the next step of the world in coming years. CDC has characterized the 15 when lifestyle changes are not effective. Lipid lowering drugs increase as an epidemic (Diabetes, Atlanta: Centres for Dis include statins, nicotinic acid, bile acid sequestrants, fibrates, ease Control, Atlanta, Report no. 2007-05-24). In addition, cholesterol absorption inhibitors, and combination treat whereas this disease used to be seen primarily in adults over ments (e.g., niacin and a statin). These agents are not without age 40 (in contrast to Diabetes mellitus type 1), it is now adverse effects, including flushing and impaired glucose tol increasingly seen in children and adolescents, an increase erance (nicotinic acid), bloating, nausea, cramping, and con thought to be linked to rising rates of obesity in this age group. stipation (bile acid sequestrants). Bile acid sequestrants may Insulin resistance means that body cells do not respond also increase TGs, so their use is contraindicated in patients appropriately when insulin is present. Unlike insulin-depen with hypertriglyceridemia. Fibrates potentiate muscle toxic dent diabetes mellitus (Type 1), the insulin resistance is gen ity when used with statins, and may increase LDL in patients erally “post-receptor, meaning it is a problem with the cells 25 with high TGs. that respond to insulin rather than a problem with insulin Drugs enter the CNS from the systemic circulation by production. Type 2 diabetes is presently of unknown etiology crossing the blood-brain barrier (BBB). The BBB is a highly (i.e., origin). About 90-95% of all North American cases of specialized gate-keeper that protects the brain by preventing diabetes are type 2, and about 20% of the population over the the entry of many potentially harmful substances into the age of 65 has diabetes mellitus Type 2 (Nature, 2001, 414, CNS from the systemic circulation. Much is known about the 6865). Diabetes affects over 150 million people worldwide 30 BBB, and of the physical-chemical properties required for and this number is expected to double by 2025. About 55 compounds transported across it. percent of type 2 diabetics are obese-chronic obesity leads to Drugs that do not cross the BBB into the CNS or that are increased insulin resistance that can develop into diabetes readily eliminated through transport mechanisms (J. Clin. (Morbidity and Mortality Weekly Report 2008, 53, 1066). Invest. 1996, 97, 2517) are known in the literature and have Type 2 diabetes is often associated with obesity, hyperten 35 low CNS activity due to their inability to develop brain levels Sion, elevated cholesterol (combined hyperlipidemia), and necessary for pharmacological action. The BBB has at least with the condition often termed Metabolic syndrome (it is one mechanism to remove drugs prior to their accumulation also known as Syndrome X, Reavan's syndrome, or in the CNS. P-Glycoproteins (P-gp) localized in plasma CHAOS). There are several drugs available for Type 2 dia membrane of the BBB can influence the brain penetration and betics, including metformin, thiazolidinediones, which 40 pharmacological activity of many drugs through transloca increase tissue insulin sensitivity, C-glucosidase inhibitors tion across membranes. The lack of accumulation into the which interfere with absorption of some glucose containing brain by some drugs can be explained by their active removal nutrients, and peptide analogs that must be injected. from the brain by P-gp residing in the BBB. For example, the Dyslipidemia is the presence of abnormal levels of lipids typical opioid drug loperamide, clinically used as an antidi and/or lipoproteins in the blood. Lipids (fatty molecules) are 45 arrheal, is actively removed from the brain by P-gp, thus transported in a protein capsule, and the density of the lipids explaining its lack of opiate-like CNS effects. Another and type of protein determines the fate of the particle and its example is domperidone, a dopamine receptor blocker that influence on metabolism. Lipid and lipoprotein abnormalities participates in the P-gp transport (J. Clin. Invest. 1996, 97. are extremely common in the general population, and are 2517). Whereas dopamine receptor blockers that cross the regarded as a highly modifiable risk factor for cardiovascular 50 BBB can be used to treat schizophrenia, the readily-elimi disease due to the influence of cholesterol, one of the most nated domperidone can be used to prevent emesis, without the clinically relevant lipid Substances, on atherosclerosis. In likelihood of producing adverse CNS effects. addition, some forms may predispose to acute pancreatitis. In addition to the above compounds, agents possessing In western Societies, most dyslipidemias are hyperlipi structural characteristics that retard or prevent BBB penetra demias; that is, an elevation of lipids in the blood, often due to tion or contribute to participation in active elimination pro diet and lifestyle. The prolonged elevation of insulin levels 55 cesses have been identified in various classes of therapeutics. can also lead to dyslipidemia. The most prevalent hyperlipi These include antihistamines (Drug Metab. Dispos. 2003, 31, demias include: hypercholesterolemia, characterized by 312), beta-adrenergic receptor antagonists (Eur: J. Clin. elevated cholesterol (usually LDL), hypertriglyceridemia, Pharmacol. 1985, 28, Suppl: 21; Br. J. Clin. Pharmacol., characterized by elevated triglycerides (TGs); hyperlipopro 1981, 11, 549), non-nucleoside reverse transcriptase inhibi teinemia, characterized by elevated lipoproteins; hyperchy 60 tors (NNRTIs, J. Pharm. Sci., 1999, 88, 950), and opioid lomicronemia, characterized by elevated chylomicrons; and antagonists. This latter group has been tested in relation to combined hyperlipidemia, characterized by elevated LDL their activity in the gastrointestinal tract. These peripherally and triglycerides. Abnormal decreases in the levels of lipids selective opioid antagonists are described in various US pat and/or lipoproteins in the blood also can occur. These include ents as being useful in the treatment of non-CNS pathologies hypocholesterolemia, characterized by lowered cholesterol 65 in mammals, in particular those of the gastrointestinal tract (usually high density lipoprotein, or HDL); and abetalipopro see U.S. Pat. No. 5,260,542; U.S. Pat. No. 5,434,171; U.S. teinemia, characterized by lowered beta lipoproteins. Pat. No. 5,159,081; and U.S. Pat. No. 5,270,238. US 7,655,685 B2 15 16 Other types of non-brain penetrant compounds can be pre that either limits compound AA’s ability to cross the BBB pared through the creation of a charge within the molecule. relative to that of SLV319 or enables it to be actively removed Thus, the addition of a methyl group to the tertiary amine from the brain at a rate greater than that of SLV319. Examples functionality of the drugs scopolamine or atropine, unlike the of the amount of compound AA present in the brain can parent molecules, prevents their passage across the BBB include (a) from 50,55, 60, 65,70, 75,80, 85,90,91, 92,93, through the presence of a positive charge. However, the new 94, 95, 96, 97,98, 99, to 100% lower than SLV319, (b) from molecules (methyl-Scopolamine and methyl-atropine) retain 90, 91, 92,93, 94, 95, 96, 97,98, 99, to 100% lower than their full anticholinergic pharmacological properties. As SLV319, and (c) from 98, 99, to 100% lower than SLV319, Such, these drugs can also be used to treat peripheral diseases, when administered at the same dosage. without the concern of adverse CNS effects. The quaternary 10 The compounds of the present invention are expected to be ammonium compound methylmaltrexone is also used for the cannabinoid receptor antagonists or inverse agonists (e.g., prevention and/or treatment of opioid-induced gastrointesti have activity at s 10 uM). Representative compounds have nal side effects associated with opioid administration (J. been tested and shown to be active (e.g., see Tables A, B, and Pharmacol. Exp. Ther: 2002, 300, 118). C). The discovery that the anti-obesity activity of cannabinoid 15 An inverse agonist is a compound that not only blocks the receptor blockers may in part be mediated by a non-CNS action of the endogenous agonist at the receptor, but also mechanism could make it beneficial for the compounds of the exhibits its own activity which is usually the opposite of that present invention to be peripherally restricted (i.e., have an shown by the agonist. Inverse agonists are also effective inability or limited ability to cross the BBB, or be readily against certain types of receptors (e.g. certain histamine eliminated from the brain through active transport systems). receptors/GABA receptors) that have intrinsic activity with It may be desirable for the compounds of the present inven out the interaction of a ligand upon them (also referred to as tion to be peripherally restricted, which in turn will result in constitutive activity). no or very limited CNS effects. Compounds that provide Most methods of treating obesity are dependent on a sig peripherally mediated anti-obesity, anti-diabetic, or anti-dys nificant reduction in energy intake, either by a decrease in lipidemic properties should result in therapeutic agents with 25 food intake (e.g., sibutramine) or by inhibition offat absorp greater safety. It can be desirable that the compounds of the tion (e.g., orlistat). In the present invention, adipose tissue present invention, when administered in a therapeutically may be reduced in the absence of a significant reduction in effective amount, have no or very limited CNS effects. It can food intake. The weight loss, as a result of the present inven also be desirable that the lack of CNS effects is a result of the tion, comes from the treatment with a compound of the compounds of the present invention having minimal brain 30 present invention, largely independent of though not totally concentrations when administered in therapeutically effec dissociated from, appetite and food intake. It can be desirable tive amounts. In this context, minimal brain concentrations that adipose tissue loss occurs while food intake is main means levels that are too low to be therapeutically effective tained, increased or (a) about 1,2,3,4,5,6,7,8,9, 10, 11, 12, for the treatment of a CNS indication or too low to cause 13, 14, 15, 16, 17, 18, 19, or 20% below the normal range of significant or measurable deleterious or undesired side 35 the subject prior to being treated in accordance with the effects, or both. present invention (i.e., its pre-administration level), (b) about SLV319 (Compound I when X and X" are 4-Cl; X, Y, Y', 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below its Y", Z, and Z are H; Q is CH; and M is SO) is a drug that pre-administration level, (c) about 1, 2, 3, 4, 5, 6, 7, 8, 9, or crosses the BBB and is indicated for the treatment of obesity. 10% below its pre-administration level, or (d) about 1, 2, 3, 4, It is believed that SLV319 works to treat obesity via a CNS 40 or 5% below its pre-administration level. mechanism. Compounds like SLV319 and compound AA In some cases, loss of adipose tissue can be accompanied have been described in various publications including.J. Med. by a concomitant loss of lean muscle mass. This is particu Chem. 2004, 47(3), 627 and U.S. Pat. No. 6,476,060. larly evident in cancer patients who show a generalized wast ing of body tissues, including adipose tissue and lean muscle 45 mass. In the present invention, however, it can be desirable for

body fat to be significantly reduced in the absence of a sig nificant reduction in lean body mass. Adipose tissue loss comes from treatment with a compound of the present inven tion, independent of a significant change in lean body mass. 50 Thus, adipose tissue loss can occur while lean body mass is maintained, increased, or (a) is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% below the normal range of the subject prior to being treated in accordance with the 55 present invention (i.e., its pre-administration level), (b) is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below pre-administration levels, (c) is no more than about 1,2,3,4,5,6,7,8,9, or 10% below pre-administration levels, or (d) is no more than about 1, 2, 3, 4, or 5% below 60 pre-administration levels. In some cases, loss of adipose tissue can be accompanied by a concomitant loss of water mass. This is particularly evident with diet regimens that promote dehydration. In the In compound AA, one of X, Y, X, Y, X", Y, Z, Z", or Q is a present invention, it can be desirable for body fat to be sig group capable of reducing or limiting the CNS activity of 65 nificantly reduced in the absence of a significant reduction in compound AA. This reduced or limited CNS activity occurs water mass. In other words, adipose tissue loss comes from via at least one of X,Y,X'Y', X".Y. Z.Z. and Q being a group treatment with a compound of the present invention, indepen US 7,655,685 B2 17 18 dent of a significant change in water mass. It can be desirable lipase inhibitors, such as orlistat (Xenical(R): 42) fatty acid that adipose tissue loss occurs while water mass is main transporter inhibitors: 43) dicarboxylate transporter inhibi tained, increased, or (a) is no more than about 1, 2, 3, 4, 5, 6, tors; 44) glucose transporter inhibitors; 45) phosphate trans 7,8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, porter inhibitors; 46) serotonin reuptake inhibitors: 47) Met 25, 26, 27, 28, 29, or 30% below the normal range of the formin (Glucophage(R): 48) Topiramate (Topimax(R): 49) Subject prior to being treated in accordance with the present opiate antagonists such as naltrexone, 50) the non-selective invention (i.e., its pre-administration level), (b) is no more transport inhibitor bupropion, and/or 51) MAO inhibitors. than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% Examples of MAO inhibitors include Moclobemide: Bro below pre-administration levels, (c) is no more than about 1, faromine; BW A616U; Ro 41-1049; RS-2232; SR 95191, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below pre-administration levels, 10 Harmaline: Harman; Amiflamine; BW 1370U87: FLA 688; or (d) is no more than about 1, 2, 3, 4, or 5% below pre FLA 788: Bifemelane; Clorgyline: LY 51641; MDL 72,394; administration levels. 5-(4-Benzyloxyphenyl)-3-(2-cyanoethyl)-(3H)-1,3,4-oxa Sibutramine and orlistat are currently marketed for use in diazol-2-one; 5-(4-Arylmethoxyphenyl)-2-(2-cyanoethyl) the treatment of obesity, albeit weight loss is achieved tetrazoles; Lazabemide; Ro 16-6491; Almoxatone; XB308; through entirely different mechanism of action. Sibutramine 15 RS-1636; RS-1653; NW-1015; SL 340026; L-selegiline; inhibits the neuronal reuptake of serotonin and noradrenaline, Rasagiline: Pargyline; AGN 1135; MDL 72.974; MDL and orlistat inhibits gut lipase enzymes that are responsible 72,145; MDL 72,638; LY 54761; MD 780236; MD 240931; for breaking down ingested fat. Bifemelane; Toloxatone; Cimoxatone; Iproniazid: Cannabinoid receptor blockers can promote weight loss Phenelzine; Nialamide; Phenylhydrazine: 1-Phenylcyclopro through inhibition of peripheral cannabinoid receptors, a pylamine; Isocarboxazid; and, Tranylcypromine. Additional mechanism entirely different from appetite Suppressants, gut examples of MAO inhibitors can be found in USPA 2007/ lipase inhibitors, and other agents with similar indications 0004683: U.S. application Ser. No. 1 1/445,044: USPA 2007/ (e.g., serotoninagonists, leptin, fatty acid synthase inhibitors, 0015734; and U.S. application Ser. No. 1 1/424,274. and monoamine oxidase (MAO) inhibitors). Co-administra tion of a cannabinoid receptor blocker together with one or 25 Examples of diabetes disorders include treating Type 1 more other agents that are useful for treating the indications diabetes, Type 2 diabetes, inadequate glucose tolerance, and described above (e.g., obesity, diabetes, dyslipidemia, cardio insulin resistance. vascular disorders, hepatic disorders, and a combination Examples of second components useful for treating diabe thereof) is expected to be beneficial, by producing, for tes include (a) insulin sensitizers including (i) PPAR-Yago example, either additive or synergistic effects. Examples of 30 nists such as the glitaZones (e.g. troglitaZone, pioglitaZone, additional agents include an appetite Suppressant, a lipase englitaZone, MCC-555, rosiglitaZone), and compounds dis inhibitor, and a MAO inhibitor (e.g., MAO-B and a combi closed in WO97/27857, 97/28115,97/28137, and 97/27847: nation of MAO-A/B). Therefore, the present invention pro and (ii) biguanides Such as metformin and phenformin; (b) vides a method of treating obesity, diabetes, dyslipidemia, insulin or insulin mimetics; (c) sulfonylureas such as tolbuta cardiovascular disorders, and/or hepatic disorders, and a 35 mide and glipizide, or related materials; (d) C-glucosidase combination thereof, comprising administering a therapeuti inhibitors (e.g., acarbose); (e) cholesterol lowering agents cally effective amount of a compound of the present invention such as (i) HMG-CoA reductase inhibitors (lovastatin, simv and a second component effective for treating the desired astatin, pravastatin, fluvastatin, atorvastatin, rivastatin, and indication. other statins), (ii) sequestrants (e.g., cholestyramine, colesti Examples of second components include anti-obesity 40 pol, and dialkylaminoalkyl derivatives of a cross-linked dex agents, which include, but are not limited to: 1) growth hor tran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, mone secretagogues; 2) growth hormone secretagogue recep (iv) PPAR-O. agonists (e.g., fenofibric acid derivatives includ tor agonists/antagonists; 3) melanocortin agonists; 4) Mc4r ing gemfibrozil, clofibrate, fenofibrate, and bezafibrate), (v) (melanocortin 4 receptor) agonists; 5) beta-3 agonists; 7) inhibitors of cholesterol absorption (e.g., B-sitosterol) and 5HT2C (serotonin receptor 2C) agonists; 8) orexin antago 45 acyl CoA:cholesterol acyltransferase inhibitors (e.g., melina nists; 9) melanin concentrating hormone antagonists; 10) mide), and (vi) probucol, (f) PPAR-C/Yagonists; (g) antiobe melanin-concentrating hormone 1 receptor (MCH1R) sity compounds (described previously): (h) ileal bile acid antagonists; 11) melanin-concentrating hormone 2 receptor transporter inhibitors: (i) insulin receptor activators, () (MCH2R) agonist/antagonists; 12) galanin antagonists; 13) dipeptidyl peptidase IV, or DPP-4 inhibitors (sitagliptin, CCKagonists; 14) CCK-A (cholecystokinin-A) agonists; 16) 50 vildagliptin and other DPP-4 inhibitors (k) exenatide, (1) corticotropin-releasing hormone agonists; 17) NPY 5 antago pramLintide. (m) FBPase inhibitors, (n) glucagon receptor nists: 18) NPY 1 antagonists; 19) histamine receptor-3 (H3) antagonists, (o) glucagon-like peptide-1, and (p) the gluca modulators: 20) histamine receptor-3 (H3) blockers: 21) gon-like peptide-1 analogues (liraglutide, and others). B-hydroxy steroid dehydrogenase-1 inhibitors (...beta.-HSD The compounds of the present invention are expected to be 1): 22) PDE (phosphodiesterase) inhibitors; 23) phosphodi 55 CB1 receptor blockers and are expected to be useful for esterase-3B (PDE3B) inhibitors; 24) NE (norepinephrine) treating diseases mediated by the CB receptor. The com transport inhibitors; 25) non-selective serotonin/norepineph pounds of the present are expected to possess an affinity in rine transport inhibitors, such as sibutramine, phentermine, or vitro for the central and/or peripheral cannabinoid receptors fenfluramine: 26) ghrelin antagonists; 28) leptin derivatives; under the experimental conditions described by Devane et al., 29) BRS3 (bombesin receptor subtype 3) agonists: 30) CNTF 60 Molecular Pharmacology, 1988, 34, 605-613. The com (Ciliary neurotrophic factors); 31) CNTF derivatives, such as pounds according to the invention are also expected to pos axokine (Regeneron); 32) monoamine reuptake inhibitors; sess an affinity for the cannabinoid receptors present on 33) UCP-1 (uncoupling protein-1), 2, or 3 activators; 34) preparations of electrically stimulated isolated organs. These thyroid hormone beta. agonists: 35) FAS (fatty acid syn tests can be performed on guinea-pig ileum and on mouse vas thase) inhibitors: 37) DGAT2 (diacylglycerol acyltransferase 65 deferens according to Roselt et al., Acta Physiologica Scan 2) inhibitors; 38) ACC2 (acetyl-CoA carboxylase-2) inhibi dinavia 1975, 94, 142-144, and according to Nicolau et al., tors; 39) glucocorticoid antagonists; 40) acyl-estrogens: 41) Arch. Int. Pharmacodyn, 1978,236, 131-136. US 7,655,685 B2 19 20 CB1 receptor affinities can be determined using membrane during which the compound is administered varies on an preparations of Chinese hamster ovary (CHO) cells in which individual basis, and can continue until the desired results are the human cannabinoid CB1 receptor is stably transfected achieved (i.e., reduction of body fat, or prevention of again in (Biochem J. 1991, 279, 129-134) in conjunction with 3H body fat). Therapy could, therefore, last from 1 day to weeks, CP-55,940 as radioligand. After incubation of a freshly pre 5 months, or even years depending upon the Subject being pared cell membrane preparation with the 3H]-radioligand, treated, the desired results, and how quickly the Subject with or without addition of test compound, separation of responds to treatment in accordance with the present inven bound and free ligand is performed by filtration over glass tion. fiber filters. Radioactivity on the filter is measured by liquid A possible example of a tablet of the present invention is as Scintillation counting. The ICs values can be determined follows. from at least three independent measurements. 10 Formulations and Dosages In the present invention, the compound(s) of the present invention can be administered in any convenient manner (e.g., Ingredient mg/Tablet enterally or parenterally). Examples of methods of adminis 15 Active ingredient 100 tration include orally and transdermally. One skilled in this art Powdered lactose 95 is aware that the routes of administering the compounds of the White corn starch 35 present invention may vary significantly. In addition to other Polyvinylpyrrollidone 8 oral administrations, Sustained release compositions may be Na carboxymethylstarch 10 favored. Other acceptable routes may include injections (e.g., Magnesium stearate 2 intravenous, intramuscular, Subcutaneous, and intraperito Tablet weight 250 neal); Subdermal implants; and, buccal, Sublingual, topical, rectal, vaginal, and intranasal administrations. Bioerodible, non-bioerodible, biodegradable, and non-biodegradable sys A possible example of a capsule of the present invention is tems of administration may also be used. Examples of oral as follows. formulations include tablets, coated tablets, hard and soft 25 gelatin capsules, Solutions, emulsions, and Suspensions. If a solid composition in the form of tablets is prepared, the main active ingredient can be mixed with a pharmaceutical Ingredient mg/Tablet vehicle, examples of which include silica, starch, lactose, Active ingredient 50 magnesium Stearate, and talc. The tablets can be coated with 30 Crystalline lactose 60 Sucrose or another appropriate Substance or they can be Microcrystalline cellulose 34 treated so as to have a sustained or delayed activity and so as Talc 5 to release a predetermined amount of active ingredient con Magnesium stearate 1 tinuously. Gelatin capsules can be obtained by mixing the Capsule fill weight 150 active ingredient with a diluent and incorporating the result ing mixture into soft or hard gelatin capsules. A syrup or elixir 35 can contain the active ingredient in conjunction with a Sweet In the above capsule, the active ingredient has a Suitable ener, which is typically calorie-free, an antiseptic (e.g., meth particle size. The crystalline lactose and the microcrystalline ylparaben and/or propylparaben), a flavoring, and an appro cellulose are homogeneously mixed with one another, sieved, priate color. Water-dispersible powders or granules can and thereafter the talc and magnesium Stearate are admixed. contain the active ingredient mixed with dispersants or wet 40 The final mixture is filled into hard gelatin capsules of suit ting agents or with Suspending agents such as polyvinylpyr able size. rolidone, as well as with Sweeteners or taste correctors. Rectal A possible example of an injection solution of the present administration can be effected using Suppositories, which are invention is as follows. prepared with binders melting at the rectal temperature (e.g., cocoa butter and/or polyethylene glycols). Parenteral admin 45 istration can be effected using aqueous Suspensions, isotonic Ingredient mg/Tablet saline Solutions, or injectable sterile solutions, which contain pharmacologically compatible dispersants and/or wetting Active substance 1.0 mg agents (e.g., propylene glycol and/or polyethylene glycol). 1 NHC 20.0 ul acetic acid 0.5 mg The active ingredient can also be formulated as microcap 50 NaCl 8.0 mg Sules or microspheres, optionally with one or more carriers or Phenol 10.0 mg additives. The active ingredient can also be presented in the 1 NNaOH q.S. ad pH 5 form of a complex with a cyclodextrin, for example Cl-, 3-, or HO q.S. ad 1 mL Y-cyclodextrin, 2-hydroxypropyl-3-cyclodextrin, and/or methyl-3-cyclodextrin. The dose of the compound of the present invention admin 55 Synthesis istered daily will vary on an individual basis and to some The compounds of the present invention can be prepared in extent may be determined by the severity of the disease being a number of ways known to one skilled in the art of organic treated (e.g., obesity, diabetes, and cardiometabolic disor synthesis (e.g., see U.S. Pat. No. 6,476,060 B2, J Med Chem ders). The dose of the compound of the present invention will 2004, 47, 627). The compounds of the present invention can also vary depending on the compound administered. 60 be synthesized using the methods described below, together Examples of dosages of compounds of the present invention with synthetic methods known in the art of synthetic organic include from about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, chemistry, or by variations thereon as appreciated by those 0.08, 0.09, 0.1, 0.2,0.3, 0.4,0.5,0.6,0.7, 0.8, 0.9, 1.0, 2, 3, 4, skilled in the art. Preferred methods include, but are not 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, limited to, those described below. The reactions are per 76,80, 85,90, 95, to 100 mg/kg of mammal body weight. The 65 formed in a solvent appropriate to the reagents and materials compound can be administered in a single dose or in a number employed and suitable for the transformations being effected. of smaller doses over a period of time. The length of time It will be understood by those skilled in the art of organic US 7,655,685 B2 21 22 synthesis that the functionality present on the molecule CH2Cl and alkylation of the resultant phenol with t-butyl should be consistent with the transformations proposed. This bromoacetate in the presence of base, in 37% aqueous form will sometimes require a judgment to modify the order of the aldehyde containing piperidine under reflux to the corre synthetic steps or to select one particular process Scheme over sponding acrylophenones (step a). Treatment of the acry another in order to obtain a desired compound of the inven lophenones with hydrazine hydrate in ethanol can produce tion. It will also be recognized that another major consider ation in the planning of any synthetic route in this field is the the 3,4-diarylpyrazolines (step b). The diarylpyrazolines can judicious choice of the protecting group used for protection of be further treated with arylsulfonyldithioimidocarbonic acid the reactive functional groups present in the compounds methyl esters, prepared from the corresponding aryl Sulfona described in this invention. An authoritative account describ mides, CS, and MeI (see J. Med Chem., 47, 627 (2004); ing the many alternatives to the trained practitioner is Greene 10 Chem. Ber: 1966, 99,2885), in a solvent (e.g., acetonitrile) in and Wuts (Protective Groups. In Organic Synthesis, Wiley and the presence of triethylamine at reflux to yield the pyrazole Sons, 1991). All references cited herein are hereby incorpo 1-carboximidothioic acid methyl ester (step c). Further expo rated in their entirety herein by reference. Sure of these iminothioethers to an aqueous solution of

Scheme 1

O

(a) yA4 t-BuOC

N YN - 21 e

C

of2. t-BuO-C-N/ r N h f (e) N YN wns 21 e

C C

Scheme 1 shows how to convert 2-, 3-, or 4'-(carbo-t- methylamine and methylene chloride at room temperature butoxymethoxy)-2-phenylacetophenones, prepared from 65 should afford the pyrazoline-1-carboxamidines (step d). commercially available 2-, 3'- or 4'-methoxy-2-phenylac Hydrolysis of the ester usingTFA/CHCl should produce the etophenones via O-demethylation using HBr/HOAc or BBr/ carboxylic acid (step e). US 7,655,685 B2 23 24

Scheme 2

-- r yA. 21 O yA-4 O t-BuOC t-BuOC o

t-BuO-C-N/O R h - t-BuO-C-N/O r

C

\ -- \ N N N1 N1 wns wns o2 e ca e

C C

Scheme 2 describes how 2-(2-, 3- or 4-carbo-t-bu- " vent like acetonitrile in the presence of triethylamine at reflux toxymethoxyphenyl)acetophenones (prepared similarly to to yield pyrazole-1-carboximidothioic acid methyl esters scheme 1) should provide the corresponding acrylophenones (stepc). Further exposure of these iminothioethers to an aque (step a). Treatment of the acrylophenones with hydrazine ous solution of methylamine and methylene chloride at room hydrate in ethanol can produce the 3,4-diarylpyrazolines 65 temperature should afford the pyrazoline-1-carboxamidines (step b). The diarylpyrazolines can be further treated with (step d). Hydrolysis of the ester using TFA/CHCl should arylsulfonyldithioimidocarbonic acid methyl esters in a sol- produce the carboxylic acid (step e). US 7,655,685 B2 25 26

N H e

C O C) C O C o C ? d N - - YN - - { loss-s-s re-s, 1.N H O H n

N YN A NY HNOC n-n NN ROC 1.1.N NN O O US 7,655,685 B2 27 28

-continued C C O O

N A y A - NN -sh,H 20 H 20 21 sa 2 sa

Scheme 3 shows the conversion of 4'-chloro-2-phenylac taining triethylamine should yield the pyrazoline-esters (step etophenone in 37% aqueous formalin and MeOH containing d). Hydrolysis of the ester using TFA/CHCl should produce piperidine and acetic acid at reflux that should occur affording the carboxylic acid (step e). Treatment of the ester with anhy the acrylophenone (J. Agric. Food Chem. 1979, 27(2), 406) drous ammonia in methanol at about 0° to room temperature (step a). Treatment of the acrylophenone with hydrazine hydrate in ethanol can produce the 3,4-diarylpyrazolines 25 can afford the carboxamido compound (stepf). Alternatively, (step b). The diarylpyrazolines can be further treated with the iminothioethers can be coupled with other amino acid arylsulfonyldithioimidocarbonic acid methyl esters in a sol esters to give adducts (step g) that can be hydrolyzed to the vent like acetonitrile in the presence of triethylamine at reflux carboxylic acids (steph). These acids may be converted to the to yield the pyrazole-1-carboximidothioic acid methyl ester carboxamides using oxalyl chloride in dichloroethane fol (step c). Further exposure of these iminothioethers to beta 30 lowed by anhydrous ammonia, or Boc-O in pyridine/THF alaninet-butyl ester in ethanol and methylene chloride con followed by anhydrous ammonia (step i).

Scheme 4 C O O O C) ---(a) O ---(b) f OH C C N YN H e in C W O O C) (d) { N OH ls-k US 7,655,685 B2 29 30

-continued

C C O C) O C) C ( ). ( ), O YN \ (f) YN \ (g) N H COEt Mes11. SN COEt 1. \ COEt e MeHN1 SN 2 rol o? la" C Ol C (i) h

C C

O O NS N N \ 1. COH wns MeHN1 SN 2 2O 2O

Scheme 4 illustrates how oxidation of 4'-chloro-2-pheny then be reacted with arylsulfonyldithioimidocarbonic acid lacrylophenone in methylene chloride with m-chloroperben methyl esters in a solvent like acetonitrile in the presence of Zoic acid should provide the epoxide (step a), which upon triethylamine at reflux to yield the pyrazole-1-carboximidot treatment with hydrazine hydrate in ethanol solution at about hioic acid methyl ether (step f). Further exposure of these 35-40°C. can give the 3,4-diarylpyrazoline alcohol (step b). The pyrazoline can be protected using di-t-butyl-dicarbonate iminothioethers to an aqueous solution of methylamine and (t-Boc anhydride) in the presence of a base to give the N-t- methylene chloride at room temperature can afford the pyra BOC-pyrazoline (step c). The carbamate alcohol can then be Zoline-1-carboxamidines (step g), and hydrolysis of the ester deprotonated with sodium hydride in a solvent like DMF using LiOH in aqueous THF solution can produce the car followed by alkylation with ethyl 4-bromocrotonate to yield boxylic acid (step h). The carboxamides can be prepared by the ester (step d). Removal of the t-BOC group can be treatment of the ester with anhydrous ammonia in alcohol at achieved via treatment with TFA (step e). The pyrazoline can -20°C. to ambient temperature (step i). US 7,655,685 B2 31 32

Scheme 5 C C O C) .

N YN NYN H 1s HN NH |

C C

---

N N N N - - o? le o? le

C(NH)NH CN

Scheme 5 shows how heating a solution of the 3,4-dia- mide derivative (step b). Conversion of the nitrile to the phe rylpyrazoline and S-methylisothiourea in pyridine can form nylcarboxamidine can be accomplished using HCl (gas) in the pyrazoline-1-carboxamidine (step a). Treatment of this 40 amidine with tA-cyanobenzenesulfonyl chloride in acetoni MeOH at 0°C. to room temperature, followed by ammonium trile in the presence of N,N-dimethyl-4-aminopyridine and carbonate or anhydrous ammonia in MeOH at about 0°C. to triethylamine can give the carboxamidine-coupled Sulfona- room temperature (step c).

Scheme 6 C C

O C C C (b) C, C f N N n H 1. US 7,655,685 B2 33 34

-continued

C C

N N HNOCN-n 1.NN - HOCN-n 1.NN H H

O O

C C

Scheme 6 describes how the reaction of a freshly prepared presence of HgCl2 can produce the benzoyl guanidines (step anhydrous acetonitrile solution of 4-chlorobenzoylisothiocy b). Hydrolysis of the ester using LiOH in aqueous THF solu anate, made from 4-chlorobenzoylchloride and ammonium 25 isocyanate (see J Heterocycl. Chem. 1991, 28, 1645), and a tion can produce the carboxylic acid (step c). Further conver 3,4-diarylpyrazoline stirred in the cold can afford the pyra sion of the acid to the acid chloride followed by treatment Zoline-adduct (step a). Treatment of this thiocarboxamide with anhydrous ammonia should afford the carboxamide with amino compounds Such as ethyl beta-alanine in the (step d).

Scheme 7

O

(a) ON C-C ON

HN ON - O ... O C)

N YN ? - MeS o21la"

C e US 7,655,685 B2 35 36

-continued O O (g) EtOC NH RHNOC NH

? (f) ? n n N N

MeS 1. N R N 1. N 2 le 22 le

C C MeOSHN MeOSHN

(h) N NN N N Mes11. SN Me SN 1.NN le le 22 22

C C

Scheme 7 depicts how condensation of a solution of 4'-ni (step d). Acylation of the aniline with ethyl malonyl chloride tro-2-phenylacetophenone in 37% aqueous formalin and in the presence of base should produce the amide (step e). MeOH containing piperidine and acetic acid should afford " Treatment of the amidoester with amines such as methy after heating at reflux, the corresponding acrylophenone (step lamine or anhydrous ammonia in a solvent Such as methanol a). Treatment of the acrylophenone with hydrazine hydrate in or methylene chloride at Zero degrees to room temperature ethanol can produce the 3,4-diarylpyrazoline (step b). The should afford the pyrazole-1-carboxamidines with the termi pyrazoline can then be reacted with arylsulfonyldithioimi- nal carboxamido group (step f). Alternatively, the aniline docarbonic acid methyl esters in a solvent like acetonitrile in 45 compound can be treated with methanesulfonyl chloride to the presence of triethylamine at reflux to yield the corre- give the Sulfonamide (step g), which upon exposure to an sponding pyrazole-1-carboximidothioic acid methyl ester aqueous solution of methylamine and methylene chloride at (stepc). The nitro group can be reduced using sodium dithion- room temperature should afford the pyrazoline-1-carboxam ite in aqueous basic solution to produce the aniline compound idines (Steph).

Scheme 8

O NC (a) O O NC f N YN H US 7,655,685 B2 37 38

-continued N N N PhCN SN PhCN SN (n-Busin SN N NF NF O O (d) O O (c) O O -e- re f f f N N N YN N a. 1. H H MeS1 SN lao

rol C e PhCN1SNN HN1SNN \-N \-N O O (f) O O NS NS wnsN wnN 2 le 2 le

C C

40 Scheme 8 illustrates how treatment of 4-cyano-2-pheny tion and one equivalent of trityl chloride at room temperature lacrylophenone with hydrazine hydrate in ethanol will pro (step c). Reaction of this adduct with arylsulfonyldithioimi duce the 3,4-diarylpyrazoline (step a). The pyrazoline can docarbonic acid methyl esters in a solvent like acetonitrile in then be reacted with tri-n-butyltin azide, conveniently pre the presence of triethylamine at reflux should yield the pyra pared in situ by the reaction of one equivalent of sodium azide 45 Zole-1-carboximidothioic acid methyl ester (step d). Treat and one equivalent of tri-n-butyltin chloride (see J. Med. ment of the iminothioether with aqueous methylamine and Chem. 1991, 56,2395), in reluxingtoluene or xylene to afford methylene chloride at room temperature should afford the the tri-n-butyltin-tetrazole adduct (stepb). The tri-n-butyltin- pyrazole-1-carboxamidines (step e). Removal of the trityl adduct can be converted to the trityl-tetrazole adduct by treat- group with aqueous TFA in THF at room temperature should ment with one equivalent of aqueous sodium hydroxide solu- yield the unprotected tetrazole (step f).

Scheme 9

O O 1N N O- (a) O 21 rt /- 2 | US 7,655,685 B2 40

-continued

-- O / C YN YN Mes11. NN H 21 e

C

-(e/ , O O -- i / “O O

N N N n 1. R = TBDMS 1. MeHN1 SN MeHN1 SN 2 le ca le

C C R = Et, TBDMS

Scheme 9 shows how to convert 2-, 3-, or 4-polyethoxy Wilen, S. H. Tables of Resolving Agents and Optical Resolu lated analogs of 2-phenylacetophenones, prepared from com tions 1972, 308 or using enantiomerically pure acids and mercially available 2-, 3- or 4'-methoxy-2-phenylacetophe 40 bases. A chiral compound of the present invention may also nones via O-demethylation using HBr/HOAc or BBr/ be directly synthesized using a chiral catalyst or a chiral CHCl and alkylation of the resultant phenols with alkyl capped or TBDMS-capped halides prepared as described in ligand, e.g., Jacobsen, E. Acc. Chem. Res. 2000, 33, 421-431 Nuclear Medicine and Biology, 32,799 (2005). Treatment of or using other enantio- and diastereo-Selective reactions and these polyether ketones in 37% aqueous formaldehyde con 45 reagents known to one skilled in the art of asymmetric Syn taining piperidine under reflux should give the corresponding thesis. Examples of stereoisomers include compounds shown acrylophenones (step a). Treatment of the acrylophenones below. with hydrazine hydrate in ethanol can produce the 3,4-dia rylpyrazolines (step b). The diarylpyrazolines can be further

treated with arylsulfonyldithioimidocarbonic acid methyl 50 esters, prepared from the corresponding aryl Sulfonamides, CS, and Mel (see J. Med Chem., 47,627 (2004); Chem. Ber: 1966, 99, 2885), in a solvent (e.g., acetonitrile) in the pres ence of triethylamine at reflux to yield the pyrazole-1-carbox imidothioic acid methyl ester (step c). Further exposure of 55 these iminothioethers to an aqueous solution of methylamine and methylene chloride at room temperature should afford the pyrazoline-1-carboxamidines (step d). Removal of the TBDMS-capping group using anhydrous tetrabutylammo nium fluoride in THF should produce the hydroxyl-PEG ana 60 log (step e). One stereoisomer of a compound of the present invention may be a more potent cannabinoid receptorantagonist than its counterpart(s). Thus, stereoisomers are included in the present invention. When required, separation of the racemic 65 material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent Such as described in US 7,655,685 B2 41 42

-continued -continued

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodi 25 ments that are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

30 Tables A, B, and C show a variety of examples of com pounds of the present invention synthesized using the route described below. The following examples are representative of the proce 35 dures used to prepare the preferred compounds in this appli cation.

ABBREVIATIONS 40 MeOH methanol DCM dichloromethane EtOAc—ethyl acetate 45 HCl hydrochloric acid PE petroleum ether NMM N-methylmorpholine IBCF iso-butylchloroformate 50 TEA triethylamine The preparation of the diphenyl pyrazolines with optional Substituents on the 3-phenyl group were prepared according to the procedures previously described J. Med Chem., 47. 55 627(2004); J. Agric. Food Chem., 27, 406 (1979). The pyra Zolines were condensed with sulfonylated carbamic acid methyl esters obtained from the appropriately substituted Sulfonamide and methyl chloroformate as previously described. Chlorination of the product acylsulfonamides with 60 phosphorus pentachloride in heated cholorbenzene produced the imidoylchlorides which were readily converted to the various amino ester adducts as previously described J. Med Chem., 47, 627(2004). Conversion of these esters to acids, 65 carboxamides, Substituted carboxamides, or di-amino acid variants were carried via conventional methodology, and pro cedures representative of this chemistry are described below. US 7,655,685 B2 43 44

SCHEME 3a Z Z

N ---(a) NW YN A YN 1s,le -sh,le 21 -Y 21 Sy X 4\ |

Z Z

Nf e-(c) Nf as-s-sA YN -sh,A YN H 2O H 2O 2 sa Ny 2 sa N | 1 HY 2 X 21 X

Example 1 then extracted with EtOAc. The combined extracts were washed with brine and dried over anhydrous NaSO. The To 10 mmoles of imidoyl chloride suspended in 20 mL of carboxylic acid products (70-95% yields) were obtained by DCM was added dropwise to a cooled solution of 12 mmols evaporation of the solvent in vacuo. of glycine methyl ester hydrochloride salt and 25 mmoles of TEA in 50 mL DCM, after the addition, the reaction mixture 50 Example 3 was allowed to warm to ambient temperature. After stirring for about one hour, the solvent was removed in vacuo and water (50 mL) was added and the mixture was extracted with The carboxylic acids (1 mmol), obtained from the ester by EtOAc. The combined extracts were washed with brine, and the procedure described in Example 2, in 40 mL of dry DCM then dried over anhydrous NaSO. After solvent removal in 55 containing NMM (3 mmol) was cooled to about -15°C. with vacuo the residue was purified by silica gel column chromato a salt ice bath. A solution of IBCF (1.1 mmol) in dry DCM (20 gram (PE/EtOAc: 2/1) to afford the carboxamidine (50-80% mL) was added dropwise overa 5 min period and after stirring yields). for 20 mins in an ice-brine bath, dry ammonia/THF solution was added in one portion, and the reaction mixture was then Example 2 60 allowed to slowly warm to rt where it was stirred for 20 mins. The solvent was removed by evaporation, and the residue was Lithium hydroxide monohydrate (10 mmoles) and 5 diluted with 20 mL of water and extracted with EtOAc. The mmoles of carboxamidine ester in THF (50 mL) and water combined extracts were washed with 15 mL of 1N HCl solu (16 mL) was stirred at room temperature for 5-7 hrs. The pH tion and 30 mL of brine, and then dried over anhydrous of the solution was then adjusted to ~1-2 by the addition of 1N 65 NaSO. After filtration of the solution and removal of the HCl solution, and the solvent was removed under reduced Solvent in vacuo, the residue was purified by silica gel chro pressure. Water (15 mL) was added to the residue which was matography to give the carboxamide adduct (60-80% yields).

US 7,655,685 B2 63 64 therefore to be understood that within the scope of the (CH),CAA"(CH2)COR, (CH2)CHA(CH), appended claims, the invention may be practiced otherwise SONR, (CH), CHA(CH), SOR, (CH), CHA that as specifically described herein. (CH),C(NH)NH. (CH), CHA(CH),C(NOH)NH, What is claimed is: (CH), CHA(CH),CONHCHA(CH),CO.R., (CH), 1. A compound of Formula I or a stereoisomer or pharma CAA"(CH),CONHCHA(CH2)COR, (CH), CHA ceutically acceptable salt thereof: (CH),CONHCHA(CH),CONHCHA(CH),COR, (CH), CHA(CH),CONHCHA(CH),CONR, (CH),CAA"(CH2)CONHCHA(CH),CONR, 10 (CH), CHA(CH),CONHCHA(CH2)CONHCHA (CH),CONR, C-C-cyclic amino-(CH2)COR, C-C-cyclic amino-(CH2)CONR, C-C-cy cloalkylene-(CH2)COR, and C-C-cycloalkylene (CH),CONR; 15 provided that when Q is (CH),CAA"(CH),C(O)NR or (CH),CAA"(CH),COR, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b): A is selected from H. C. alkyl, (CH2)Cle-cycloalkyl, OH, CHOH, CH(CH)OH, C(CH),OH, (CH), CO.R. (CH),C(O)NR', and (CH)-phenyl, wherein the phenyl is substituted with 0-3 groups selected from H. C. alkyl, halogen, CF. O—C alkyl, and NO; alternatively, Q is CHA(CH),C(O)NR or CHA(CH), 25 CO.R, and (a) A is selected from OH, (CH),CO.R. and (CH),C(O)NR'; (b) R is (CH),(CHR), (CH), OH or CH(CHOH); or (c) both (a) and (b): wherein: A" is C alkyl, X,Y,X,Y,X", andY" are independently selected from: H, C. alkyl, halogen, CF. O—C alkyl, NO, NR, 30 M is C=O or SO; O(CH2)COR, O(CH),CN, OCH-CH=CHCOR, R is independently selected from H. (CH), (CHR), CHO(CH),COR, CHOCH-CH=CHCOR, (CH), OH, CH(CHOH), C alkyl, Calkenyl, and O(CH), PO(OR), CHO(CH), PO(OR), NR(CH), C2-alkynyl, COR, NR(CH), PO(OR), NRCHCH=CHCOR, 35 R" is independently selected from H. (CH)(CHR), NRSOR, NRCO(CH),COR, NRCO(CH), (CH2), OH, C alkyl, C2-alkenyl, and C2-alkynyl: CONR, O(CH), CHCOR, O(CH2)CH (CH), R’ is independently selected from H. C. alkyl, C2-alk COR, CHO(CH), CHCOR, O(CH), enyl, and C-alkynyl: CHCONR, O(CH), CH (CH),CONR', p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12: O(CH2)CH-tetrazole, CHO(CH2)CHCONR, 40 m is selected from 0, 1, 2, 3, and 4; and, CHO(CH2)CH-tetrazole, O(CH2)CH (CH)-tet n is selected from 1, 2, 3, and 4. razole, NR(CH), CHCOR, CHNR(CH), 2. A compound of claim 1, wherein: M is SO. CHCOR, NR(CH), CH (CH),COR, NR 3. A compound of claim 1, wherein the compound is of (CH),CHCONR, CHNR(CH2)CHCONR, 45 formula Ia or a stereoisomer or pharmaceutically acceptable NR(CH2)CH (CH),CONR, NR(CH2)CH salt thereof: tetrazole, CHNR(CH),CH-tetrazole, NR(CH), CH(CH)-tetrazole, CONHOH, C(NH)NR',

(CH),C(NH)NR's O(CH2)CONR's O(CH),C Ia (NH)NR, O(CH),C(NOH)NR, CHO(CH), 50 CONR, NR(CH),CONR, OCHCH-CHCONR, CHOCHCH-CHCONR, NRCHCH-CHCONR, (CH2)-tetrazole, 55 O(CH.)-tetrazole, O(CH-CHO).R. NR(CH, CHO),R, and SO-NHCH, Z is selected from: H, C alkyl, OH, O C alkyl, O(CHCHO).R., OC(O) C, alkyl, O(CH),CO.R. OCH-CH=CHCOR, O(CH), PO(OR), O(CH), 60 CONR, O(CH),C(NH)NHO(CH),C(NOH)NR, OCHCH-CHCONR, O(CH2)-phenyl-(CH), COR, and O(CH)-phenyl-(CH2)-tetrazole; Z is selected from H. COR, and CONR; 65 Q is selected from: (CH), CHA(CH),C(O)NR2 (CH), CAA"(CH),C(O)NR (CH),CHA(CH),COR, US 7,655,685 B2 65 66 4. A compound of claim 1, wherein the compound is of wherein: formula Ib or a stereoisomer or pharmaceutically acceptable X, Y, X, Y, X", and Y" are individually selected from the salt thereof: following: H. C. alkyl, halogen, CF. O—C alkyl, Ib NO, O(CH-CHO).R. NR(CHCHO),R, and NR; Zis selected from: H. C. alkyl, OH, O Calkyl, acety loxy, and propionyloxy; Q is selected from: (CH),CHA(CH),C(O)NR2 (CH), CAA"(CH),C(O)NR (CH),CHA(CH),COR, o, O 10 (CH),CAA"(CH2)COR, (CH2)CHA(CH), n SONR, (CH), CHA(CH),CONHCHA(CH), N COR, (CH),CAA"(CH2)CONHCHA(CH), COR, (CH2)CHA(CH2)CONHCHA(CH), CON 1. N 15 HCHA(CH),CO.R., (CH), CHA(CH), CONHCHA M X" (CH),CONR, (CH),CAA"(CH), CONHCHA (CH),CONR, (CH), CHA(CH), CONHCHA (CH),CONHCHA(CH),CONR, C-C-cyclic Yi. amino-(CH2)COR, C-C-cyclic amino-(CH2), CONR, C-C-cycloalkylene-(CH2)COR, and 5. A compound of claim 1, wherein the compound is of C-C-cycloalkylene-(CH2)CONR; formula Ic or a stereoisomer or pharmaceutically acceptable provided that when Q is (CH2)CAA"(CH),C(O)NR or salt thereof: 25 (CH),CAA"(CH2)COR, then (a) m is other than 0. Ic (b) A is other than H, or (c) both (a) and (b): A is selected from H. C. alkyl, (CH2)Cle-cycloalkyl, OH, CHOH, CH(CH)OH, C(CH),OH, (CH), 30 CO.R., (CH),C(O)NR', and (CH)-phenyl, wherein O C) the phenyl is substituted with 0-3 groups selected from H. C. alkyl, halogen, CFO C. alkyl, and NO; alternatively, Q is CHA(CH),C(O)NR or CHA(CH), { CO.R, and A is OH or (CH),COR or R is (CH), (CHR), (CH), OH or CH(CHOH): R is independently selected from H. C. alkyl, Calk 1s enyl, and C2-alkynyl: OS X" R’ is independently selected from H. C. alkyl, C2-alk 40 enyl, and C2-alkynyl: Yi. p is selected from 2, 3, 4, 5, 6, 7, and 8: m is independently selected from 0, 1, 2, and 3; and, 6. A compound of claim 1, wherein the compound is a n is independently selected from 1, 2, and 3. compound of formula Ia or a stereoisomer or pharmaceuti 45 7. A compound of claim 6, wherein: cally acceptable salt thereof, Q is selected from: (CH),CHA(CH),C(O)NR2 (CH), CAA"(CH),C(O)NR (CH), CHA(CH), SONR, (CH), CHA(CH),CONHCHA(CH2)CONR,

Ia 50 (CH),CAA"(CH2)CONHCHA(CH),CONR, (CH), CHA(CH),CONHCHA(CH),CONHCHA (CH2)CONR, C-C-cyclic amino-(CH2)COR, C-C-cyclic amino-(CH2)CONR, and C-C-cy cloalkylene-(CH2)CONR; 55 provided that when Q is (CH),CAA"(CH),C(O)NR then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b): alternatively, Q is CHA(CH),C(O)NR2 and A is OH or 60 (CH),COR or R is (CH)(CHR)(CH), OH or CH(CHOH): M is SO; R is independently selected from H and C alkyl:

65 R’ is independently selected from Hand C, alkyl: m is independently selected from 0, 1, and 2; and, n is independently selected from 1 and 2.

US 7,655,685 B2 69 70 11. A compound selected from the compounds of Table A and C or a stereoisomer or a pharmaceutically acceptable salt TABLE C thereof: X TABLE A 5

X

10 f N YN O t W Q ls S 2 X N NN N1 sas s YN 15 H -HY" 21

Qa N 1s, Number Q y X" X

2O 1 Me 4-OCH-CO-Et H H 2 Me 4-CONHOH C C Number Q y 12. A pharmaceutical composition, comprising: a com 1 CH(CH)CHCOEt 25 pound according to claim 1 and a pharmaceutically accept 2 CH(CH)CH-CO2H able carrier. 3 CH-CO-Me 13. A compound of the formula 4 CH-CO2H 5 CH(CH)COMe 6 CH(CHOHCH)CO-Me 4-C 30 C 7 CH(C(CH))CO-Me 4-C 8 CH-CO-Me 4-OMe 3-OMe 0 CHCOMe 4-OMe 3-CI 1 CH(CHOH)COMe 4-C 2 CH-CONHCH2CO-Me 4-C 35 f 3 CH(CH)CONH 4-C N CHCO-Me YN O 4 CH(CH(CH))CONH 2 40 HN N ls N1 S CHCOMe H 5 CH-CONHCH2CO-Me O 6 CH-CONH2, CX C 6 CH(CH)CONH2, 7 CH-CHCONH2, 45 or a stereoisomer or a pharmaceutically acceptable salt 8 CH(CH)CHCONH, thereof. 9 CH(C(CH))CONH2, 14. A compound of the formula 20 CH(CH(CH))CONH2, 21 CHCH(CH)2)— CONHCH 50 C 22 CH(CHOHCH)CONH, 23 CHCONH, 4-OMe 24 CH(CH)CONH2, 4-OMe 25 CH(CH)CONH, 4-OCH2— 55 CN 26 C(CH),CONH2, 4-CI N 27 CHCH(CH)CONH, 4-CI 4-OMe 4-OMe O 28 CH(CH)CONH2, 60 HN YNn -S 2 29 CH(CH)CONH2, 4-OMe 3-CI 1N1 H 4-CI Me 30 CH-CONH2, O 31 CH(CH(CH))CONH2, 3-OMe 32 CHCHCONH, 4-CI 65 or a stereoisomer or a pharmaceutically acceptable salt thereof. US 7,655,685 B2 71 72 15. A compound of the formula 18. A compound of the formula

C 5 C

10

N N O YN YN O O

HN --> N lsN sa 15 HN N lsN la H H O C C

2O or a stereoisomer or a pharmaceutically acceptable salt or a stereoisomer or a pharmaceutically acceptable salt thereof. thereof. 16. A compound of the formula 19. A compound of the formula

25

C C

NN HO NN O N 35 N 2 O 2 O HN lul N lsN 1. ga HN N lsN 1 ga H H O C 40 C or a stereoisomer or a pharmaceutically acceptable salt or a stereoisomer or a pharmaceutically acceptable salt thereof. thereof. 17. A compound of the formula 45 20. A compound of the formula

C C 50

55 f

{ N NN N O 2 O HN N lsN Sá HN N lsN $3 H 60 H O O C C

65 or a stereoisomer or a pharmaceutically acceptable salt or a stereoisomer or a pharmaceutically acceptable salt thereof. thereof. US 7,655,685 B2 73 74 21. A compound of the formula 24. A compound of the formula

C C

10

N N YN O YN HN ls sa O 15 NH ls sa O S^^ H N HN sH N O OH O C HO C

2O or a stereoisomer or a pharmaceutically acceptable salt or a stereoisomer or a pharmaceutically acceptable salt thereof. thereof. 22. A compound of the formula 25. A compound of the formula

25

C C

N N OH YN 35 O YN 2 O H O HN N lsN S3 HN lus N ls N la H H O O C 40 C or a stereoisomer or a pharmaceutically acceptable salt or a stereoisomer or a pharmaceutically acceptable salt thereof. thereof. 23. A compound of the formula 45 26. A compound of the formula

C 50

f 55 f N N n O N O YN O H 2O H O HN lus N lsN S3 HN N N ls N1 le 2 H 60 2 H O O C C

65 or a stereoisomer or a pharmaceutically acceptable salt or a stereoisomer or a pharmaceutically acceptable salt thereof. thereof. US 7,655,685 B2 75 76 27. A compound of the formula 30. A compound of the formula

C

C

10 f N YN O Nf leo S - 1sN S 15 HN1 n-n N1 HN lsN N C

HO C or a stereoisomer or a pharmaceutically acceptable salt thereof. or a stereoisomer or a pharmaceutically acceptable salt 31. A pharmaceutical composition, comprising: a com thereof. pound according to claim 2 and a pharmaceutically accept 28. A compound of the formula able carrier. 32. A pharmaceutical composition, comprising: a com 25 pound according to claim 3 and a pharmaceutically accept able carrier. C 33. A pharmaceutical composition, comprising: a com pound according to claim 4 and a pharmaceutically accept able carrier. 30 34. A pharmaceutical composition, comprising: a com pound according to claim 5 and a pharmaceutically accept able carrier. 35. A pharmaceutical composition, comprising: a com 35 pound according to claim 6 and a pharmaceutically accept able carrier. 36. A pharmaceutical composition, comprising: a com HN N J.N pound according to claim 7 and a pharmaceutically accept H able carrier. 40 37. A pharmaceutical composition, comprising: a com C pound according to claim 8 and a pharmaceutically accept able carrier. or a stereoisomer or a pharmaceutically acceptable salt 38. A pharmaceutical composition, comprising: a com thereof. pound according to claim 9 and a pharmaceutically accept 29. A compound of the formula 45 able carrier. 39. A pharmaceutical composition, comprising: a com pound according to claim 10 and a pharmaceutically accept able carrier. C 40. A pharmaceutical composition, comprising: a com 50 pound according to claim 11 and a pharmaceutically accept able carrier. 41. A pharmaceutical composition, comprising: a com pound according to claim 13 and a pharmaceutically accept able carrier. 55 42. A pharmaceutical composition, comprising: a com pound according to claim 14 and a pharmaceutically accept able carrier. HN 43. A pharmaceutical composition, comprising: a com 60 pound according to claim 15 and a pharmaceutically accept able carrier. C 44. A pharmaceutical composition, comprising: a com pound according to claim 16 and a pharmaceutically accept able carrier. 65 45. A pharmaceutical composition, comprising: a com or a stereoisomer or a pharmaceutically acceptable salt pound according to claim 17 and a pharmaceutically accept thereof. able carrier. US 7,655,685 B2 77 78 46. A pharmaceutical composition, comprising: a com 53. A pharmaceutical composition, comprising: a com pound according to claim 18 and a pharmaceutically accept pound according to claim 25 and a pharmaceutically accept able carrier. able carrier. 47. A pharmaceutical composition, comprising: a com 54. A pharmaceutical composition, comprising: a com pound according to claim 19 and a pharmaceutically accept pound according to claim 26 and a pharmaceutically accept able carrier. able carrier. 48. A pharmaceutical composition, comprising: a com 55. A pharmaceutical composition, comprising: a com pound according to claim 20 and a pharmaceutically accept pound according to claim 27 and a pharmaceutically accept able carrier. able carrier. 49. A pharmaceutical composition, comprising: a com 10 pound according to claim 21 and a pharmaceutically accept 56. A pharmaceutical composition, comprising: a com able carrier. pound according to claim 28 and a pharmaceutically accept 50. A pharmaceutical composition, comprising: a com able carrier. pound according to claim 22 and a pharmaceutically accept 57. A pharmaceutical composition, comprising: a com able carrier. 15 pound according to claim 29 and a pharmaceutically accept 51. A pharmaceutical composition, comprising: a com able carrier. pound according to claim 23 and a pharmaceutically accept 58. A pharmaceutical composition, comprising: a com able carrier. pound according to claim 30 and a pharmaceutically accept 52. A pharmaceutical composition, comprising: a com able carrier. pound according to claim 24 and a pharmaceutically accept able carrier.