US007 153858B2

(12) United States Patent (10) Patent No.: US 7,153,858 B2 Dhanoa et al. (45) Date of Patent: Dec. 26, 2006

(54) ARYLPIPERAZINYL COMPOUNDS 5,506,246 A 4/1996 Junge et al...... 514,373 5,585,392 A 12/1996 Junge et al...... 514,373 (75) Inventors: Dale S. Dhanoa, Wakefield, MA (US); 5,602,124 A 2f1997 Tehim et al...... 514, 220

Dongli Chen, Chestnut Hill, MA (US); 26,- - - 20 S.C.O."OZ (a ii. SISNE As (IL); 6,423,717 B1 7/2002 Bromidge et al...... 514,252.13 s s 6,476,050 B1 11/2002 Aquila et al...... 514,318 Srinivasa Rao Cheruku, Woburn, MA 6,599,904 B1 7/2003 Bromidge et al...... 514,252.13 (US); Yael Marantz, Kadima (IL); 6,635,661 B1 10/2003 Cuny et al...... 514,331 Anurag Sharadendu, Salem, NH (US); 6,645.980 B1 11/2003 Cuny et al...... 514/312 Sharon Shachem, Alfey Menashe (IL); 2001/0056090 Al 12/2001 Aquila et al. .. 514,211.15 Alexander Heifetz, IBeni-Brak (IL); 2002fOO16337 A1 2/2002 Cuny et al...... 514,317 Pradyumna Mohanty, Woburn, MA 2002.0035113 A1 3f2002 MoltZen et al...... 514,254.11

(US); Boaz Inbal, Kfars Shmuel (IL); SSA 658 ...,"SOS "O.------35E, SESARStat). 2002/0177721 A1 11/2002 Aquila et al...... 548,530 s s 2003/0050309 A1 3/2003 Aquila et al...... 514,227.5 Shay Bar-Haim, Netanya (IL) 2003/0069233 A1 4/2003 Bromidge et al...... 514/2275 2003/0069418 A1 4/2003 Aquila et al...... 544/59 (73) Assignee: Epix Delaware, Inc., Cambridge, MA 2003/0073681 A1 4/2003 Hauske et al...... 514,211.01 (US) 2003/0092694 A1 5/2003 Nilsson et al...... 514, 183

2003/0114436 A1 6/2003 Aquila et al...... 514,211.15 (*) Notice: Subject to any disclaimer, the term of this 2005/0171347 A1* 8, 2005 Emelen et al...... 544,238 patent is extended or adjusted under 35 U.S.C. 154(b) by 183 days. FOREIGN PATENT DOCUMENTS EP 089089 * 9/1983 (21) Appl. No.: 10/768,579 EP 661266 * 7/1995 EP O 946 539 B1 10, 1999 (22) Filed: Jan. 30, 2004 WO WOOO,56712 9, 2000 WO WO O3,OO985.0 A1 2, 2003 (65) Prior Publication Data OTHER PUBLICATIONS US 2004/O22O192 A1 Nov. 4, 2004 Uchida et al. Chemical Abstracts vol. 127, No. 220471 (1997) (Abstract for JP 09202764, Aug. 5, 1997).* Related U.S. Application Data Bojarski, et al., Bioorganic Med Chem., 10:3817-3827 (2002). (60) Provisional application No. 60/503,520, filed on Sep. Oh, et al., Curr: Med. Chem., 8:999-1034 (2001). 16, 2003, provisional application No. 60/458,297, Rasmussen, et al., J. Pharmacol. Experimental Therapeutics, filed on Mar. 28, 2003, provisional application No. 294(2):688-700 (2000). Lopez-Rodriguez et al. J. Med. Chem. vol. 44, pp. 198-207 (2001).* 60/443,988, filed on Jan. 31, 2003. Becker et al. J. Med. Chem. vol. 49, pp. 3116-3135 (2006).* (51) Int. Cl. * cited by examiner A6 IK 3/495 (2006.01) A6 IK 3/496 (2006.01) Primary Examiner Emily Bernhardt C07D 295/13 (2006.01) (74) Attorney, Agent, or Firm Nicholas P. Triano, III; CO7D 40/06 (2006.01) Goodwin Procter LLP A61 K 3 1/506 (2006.01) CO7D 403/04 (2006.01) (57) ABSTRACT (52) U.S. Cl...... 514/253.01: 514/255.03; The invention relates to 5-HT receptor agonists or antago 514/252.11:544/360; 544/392:544/393; nists. Novel arylpiperazinyl Sulfonamide compounds repre 544/394:544/357: 544/364; 544/382:544/295 sented by Formulae I: and II, and synthesis and uses of those (58) Field of Classification Search ...... 544/392, compounds for treating diseases including those mediated 544/393, 394,360 directly or indirectly by 5-HT receptors, are disclosed. Such See application file for complete search history. conditions include central nervous system disorders such as (56) References Cited generalized anxiety disorder, ADD/ADHD, neural injury, stroke, and migraine. Methods of preparation and novel U.S. PATENT DOCUMENTS intermediates and pharmaceutical salts thereof are also 5,137,901 A 8/1992 Junge et al...... 514,373 included. 5,300,523 A 4, 1994 Junge et al...... 514,456 5,478,828 A 12, 1995 Mattson et al...... 514,253 57 Claims, 12 Drawing Sheets U.S. Patent Dec. 26, 2006 Sheet 1 of 12 US 7,153,858 B2

Figure 1: Effect of Compound A on Proportion of Open Arm Entries in the Elevated Plus Maze test.

25

f .9) .2 E 3 .15 D 5 C .1 Co C 8 .05

O Water (mg/kg) (10 mg/kg) Compound A (mg/kg) U.S. Patent Dec. 26, 2006 Sheet 2 of 12 US 7,153,858 B2

Figure 2: Effect of Compound A on Open Arm Time in the Elevated Plus Maze test.

2O 17.5

1 . 71 5

Water 3 10 20 CDP 3 10 20 BuSpirone (mg/kg) (10 mg/kg) Compound A (mg/kg) U.S. Patent Dec. 26, 2006 Sheet 3 of 12 US 7,153,858 B2

Figure 3: Effect of Compound A on Closed Arm Entries in the Elevated Plus Maze test.

Water 1 3 10 20 CDP 3 10 20 BuSpirone (mg/kg) (10 mg/kg) Compound A (mg/kg) U.S. Patent Dec. 26, 2006 Sheet 4 of 12 US 7,153,858 B2

Figure 4: Effect of Compound A on Total Number of Entries in the Elevated Plus Maze test.

25

Water 1 3 10 20 CDP 3 10 20 Buspirone (mg/kg) (10 mg/kg) Compound A (mg/kg) U.S. Patent Dec. 26, 2006 Sheet S of 12 US 7,153,858 B2

Figure 5: Effect of Compound A On Basal Rectal Temperature (°C) in the StreSS-Induced Hyperthermia test.

3 7

36

35 Water 3 2O 1 3 2O Buspirone Compound A (mg/kg) (mg/kg) U.S. Patent Dec. 26, 2006 Sheet 6 of 12 US 7,153,858 B2

Figure 6: Effect of Compound A on Delta T (°C) in the StreSS-Induced Hyperthermia test.

Water 3 2O 1 3 2O Buspirone Compound A (mg/kg) (mg/kg) U.S. Patent Dec. 26, 2006 Sheet 7 of 12 US 7,153,858 B2

igure 7: Effect of Compound A on Total Distance Traveled (Horizontal Activity) in the Open Field.

8OO 7OO -O Buspirone (20 mg/kg) 6OO -O- ( 1 mg/kg) 500 -O- Compound A (20 mg/kg)

-100 5 10 15 20 25 30 35 40 Time Bin

1600 1400 1200 1000 800 600 400 2OO

Water Buspirone 1 3 2O (20 mg/kg) Compound A (mg/kg) U.S. Patent Dec. 26, 2006 Sheet 8 of 12 US 7,153,858 B2

Figure 8: Effect of Compound A on rearing activi Vertical Activity) in the Open Field.

Water Buspirone 1 3 20 (20 mg/kg) Compound A (mg/kg) U.S. Patent Dec. 26, 2006 Sheet 9 of 12 US 7,153,858 B2

Figure 9: Effect of Compound A on Percent Distance Traveled in the Center in the Open Field during the period of 40 min.

18 16 14 12 10

Water Buspirone 1 3 20 (20 mg/kg) Compound A (mg/kg) U.S. Patent Dec. 26, 2006 Sheet 10 of 12 US 7,153,858 B2

Figure 10: Effect of Compound A on Percent Time Traveled in the Center in the Open Field during the period of 40 min.

2. 5 51152 Water Buspirone 1 3 20 (20 mg/kg) Compound A (mg/kg) U.S. Patent Dec. 26, 2006 Sheet 11 of 12 US 7,153,858 B2

Figure 11: Effect of Compound A on Frequency of Zone Crosses in the Open Field.

70 60 50 -O- Buspirone (20 mg/kg) 40 -O- ( 1 mg/kg) 30 -O- Compound A (20 mg/kg) 20 -O- (3 mg/kg) -O- Water

5 10 15 20 25 30 35 40 Time Bin 180

160 140 120 100 80 60 40 20

Water Buspirone 1 3 2O (20 mg/kg) Compound A (mg/kg) U.S. Patent Dec. 26, 2006 Sheet 12 of 12 US 7,153,858 B2

Figure 12: Effect of Compound A on Distance Traveled in the Open Field.

E. 9. -O- "Water s -O d-Amphetamine (4 mg/kg) 3 -- (1 mg/kg) -O- Compound A (3 mg/kg) 3 -O- (20 mg/kg)

5 10 15 20 25 3O 35 40 Time Bin 25OOO 22500

5, 20000 i 17500 g 15000 12500 3 1OOOO 7500 up 50OO 2500 16 1S G S S. s o E S E ve O w s S. US 7,153,858 B2 1. 2 ARYLPPERAZINYL COMPOUNDS erties, e.g., in vivo. The present invention relates to the discovery of new compounds for treating Subjects method of RELATED APPLICATIONS treating a subject afflicted with a condition requiring treat ment, by administering an effective amount of a compound This application claims the benefit of priority under 35 5 of the invention to treat the condition(s). Various conditions U.S.C. 119(e) to copending U.S. Provisional Application will be responsive to the introduction of these compounds, No. 60/443,988, filed on Jan. 31, 2003; 60/458,297, filed on alone and/or in combination with other drugs; or the com Mar. 28, 2003, and 60/503,520, filed on Sep. 16, 2003, the pounds may be used to alter physiological phenomena entire contents of which are incorporated herein by refer associated with certain conditions to achieve a desired CCC. 10 treatment of said condition(s), alone and/or in combination with other drugs. FIELD OF THE INVENTION For example, the compounds of the invention may be used for vasodilation, Smooth muscle contraction, bronchocon The invention generally relates to the field of striction, brain disorders such as vascular disorders, e.g., (5-hydroxytryptamine, or 5-HT) receptor modulators, e.g., 15 blood flow disorders caused by vasodilation and vasospastic agonists or antagonists, and more particularly to new diseases Such as angina, Vascular headache, migraine and arylpiperazinyl compounds which are also 5-HT modula Reynaud's disease; and neuropathological disorders includ tors, and use of these compounds, e.g., in the treatment, ing Parkinson's disease and Alzheimer's disease; modula modulation and/or prevention of physiological conditions tion of the cardiovascular system; prophylaxis and control of associated with serotonin action. the effects of occurrences of cerebral infarct (Apoplexia cerebri) such as stroke or cerebral ischemia; and for the BACKGROUND OF THE INVENTION control of disorders of the intestinal tract which are charac terized by disturbances of the serotoninergic system and also The serotonergic neural system of the brain has been by disturbances of the carbohydrate . The com shown to influence a variety of physiologic functions which 25 pounds may also be useful in treating stress-related Somatic manifest themselves in a variety of disorders such as eating disorders; reflex sympathetic dystrophy such as shoulder/ disorders, Schizophrenia, neuralgia, and addiction disorders; hand syndrome; disorders of bladder function Such as cys depression, obsessive compulsive disorders, panic disorders, titis, bladder detrusor hyper-reflexia and incontinence; and anxiety, sexual dysfunctions caused by the central nervous pain or nociception attributable to or associated with any of system and disturbances in sleep and the absorption of food, 30 the foregoing conditions, especially pain transmission in alcoholism, pain, memory deficits, unipolar depression, dys migraine. thymia, bipolar depression, treatment-resistant depression, In one advantageous aspect, the compounds of the inven depression in the medically ill, panic disorder, obsessive tion have been found to be 5-HT modulators, e.g., agonists compulsive disorder, eating disorders, Social phobia, and or antagonists, and/or SSRIs, that can be used for treating, premenstrual dysphoric disorder. 35 preventing or curing 5-HT-related conditions. In particular, 5-HT receptor modulators e.g., agonists or antagonists, it has been found that certain arylpiperazinyl Sulfonamide and/or selective serotonin reuptake inhibitors (SSRIs) such compounds are effective 5-HT receptor modulators and/or as , , , , SSRIS lorazepam, , , and , may In an embodiment, compounds of the invention include be used for the treatment of the above conditions, as well as 40 for vasodilation, Smooth muscle contraction, bronchocon those having the formula striction, brain disorders such as vascular disorders such as angina and migraine; and neuropathological disorders including Parkinson's disease and Alzheimer's disease. (I) These compounds are also suitable for the modulation of the 45 cardiovascular system. They also intervene in the regulation N.Sr. - - - - of the cerebral circulation and thus represent effective agents R-i-N-x' N- Na, NS-1NS. p R for controlling migraine. They are also Suitable for the R3 / \, prophylaxis and control of the effects of occurrences of cerebral infarct (Apoplexia cerebri) such as stroke or cere 50 bral ischemia. They are also suitable for the control of wherein disorders of the intestinal tract which are characterized by R is a functional group that imparts substantially no disturbances of the serotoninergic system and also by dis 5-HT/5-HT, adrenergic receptor cross-reactivity to the turbances of the carbohydrate metabolism. compound; R and R independently are hydrogen or a controls 5-HT actions, and fluoxetine and 55 functional group that imparts substantially no HERG chan fluvoxamine facilitate serotoninergic neurotransmission via nel inhibition to the compound; Z is N or C; m may be 0, 1, potent and selective inhibition of serotonin reuptake into 2, 3, 4, 5, or 6; n may be 1, 2, 3, 4, 5, or 6; and p may be presynaptic neurons. 3-chloroimipramine inhibits both 5-HT 0, 1, 2, 3, or 4, more preferably greater than 0; and and reuptake. Other compounds of current pharmaceutically acceptable salts and/or esters thereof, m is interest as include Zimeldine, and 60 advantageously 0, n is advantageously 3 or 4, and p is . advantageously 0 or 1. R may be substituted or unsubstituted aryl, alkyl, SUMMARY OF THE INVENTION cycloalkyl or alkylaryl; and RandR independently may be hydrogen or lower alkyl cycloalkyl; trihalomethyl; halo: It is desired to have selective, high affinity, metabolically 65 —NRRs, where R and Rs are independently H, O, Re, or stable 5-HT receptor modulators that possess good bioavail COR, where R may be lower alkyl (e.g., nitro, NHCO ability, CNS penetration, and good pharmacokinetic prop alkyl, e.g., NHCO-lower alkyl such as NHCO (C-C) US 7,153,858 B2 3 alkyl, including NHCO (CH), NHCO-(CHCH), NHCO-(CHCH-CH), NHCO-(CH(CH)) (i.e., cyclopropyl) and NCO-dialkyl, aminoalkyl, e.g., amino (II) (lower)alkyl Such as aminomethyl, aminoethyl, aminopro pyl, aminocyclopropyl, aminobutyl or dialkylamino); Sul fonamidoalkyl, e.g., Sulfonamido(C-C)alkyl, hydroxyl, N SS1 NR cyano; or a conjugated five- or six-membered cyclic or N-1 /\, R heterocyclic ring, provided that R and R are not both hydrogen. When p=0, R is desirably a group other than 10 wherein Substituted or unsubstituted aryl, and R2 and R indepen R may be substituted or unsubstituted aryl, alkyl, dently are desirably other than phenyl or alkoxyphenyl. cycloalkyl or alkylaryl, e.g., toluyl or cyclohexyl. R is The aryl, pyridinyl, pyrimidinyl or pyrazinyl (i.e., where preferably unconjugated when it is a ring-containing group, Z=N) group may be substituted with a substituent such as and may advantageously be substituted or unsubstituted lower alkyl, e.g., C-C cycloalkyl, e.g., C-C; trihalom 15 alkyl or cycloalkyl, e.g., cyclohexyl. R may be lower alkyl, ethyl, e.g., CF or OCF, halo, e.g., F. Br or Cl; a conjugated e.g., C-C; trihalomethyl, e.g., CF; halo, e.g., F. Br or Cl; five- or six-membered cyclic or heterocyclic ring, e.g., a conjugated five- or six-membered cyclic or heterocyclic 3.4-methylenedioxy; nitro; NHCO-alkyl, e.g., NHCO-lower ring, e.g., 3.4-methylenedioxy; —NRRs, where R and Rs alkyl such as NHCO (C-C)alkyl, including NHCO— are independently H, O or COR, where R may be lower (CH), NHCO (CHCH), NHCO-(CHCH-CH), alkyl, e.g., nitro; NHCO-alkyl, e.g., NHCO-lower alkyl such and NHCO—(CH(CH)) (i.e., cyclopropyl); NCO-dialkyl: as NHCO (C-C)alkyl, including NHCO (CH), Sulfonamidoalkyl, e.g., Sulfonamido(C-C)alkyl, hydroxyl; NHCO-(CHCH), NHCO (CHCH-CH), and or cyano. The aryl group itself may be, e.g., Substituted or NHCO—(CH(CH)) (i.e., cyclopropyl); NCO-dialkyl; sul unsubstituted phenyl, naphthyl, toluyl, or biphenyl. fonamidoalkyl, e.g., Sulfonamido(C-C)alkyl; the atoms 25 denoted by the dotted line bond may, taken together, form a Compounds of the invention are also 5-HT receptor four, five, six or seven membered cyclic or heterocyclic ring; agonists or antagonists, e.g., 5-HT receptor agonists or Z is N or C; m may be 0, 1 or 2; n may be 1, 2, 3, or 4; and antagonists including 5-HT14, , , , , , , receptors, and p may be 0 or 1; and pharmaceutically acceptable salts desirably 5-HT, receptor agonists. Surprisingly, it has been and/or esters thereof, m is advantageously 0, n is advanta found that compounds of the invention are very good 30 geously 3 or 4, and p is advantageously 0 or 1. 5-HT, receptor agonists and have superior activity and In an embodiment, R may be lower alkyl, e.g. n-butyl, selectivity. The compounds of the invention are more selec s-butyl, i-butyl p-toluene, p-halophenyl (e.g., p-fluorophe tive in their action, displaying little or no cross-reactivity nyl, p-chlorophenyl or p-bromophenyl), cycloalkyl, e.g., with other receptors such as C.-adrenergic receptors. Fur cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo thermore, compounds of the invention show little or no 35 hexylmethyl, and cyclohexylphenyl. HERG channel inhibition, which would otherwise be a Advantageously, R may be cycloalkyl, e.g., cyclopropyl. disadvantage for drugs based on compounds of the inven cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, and tion. As such, the utility of the compounds of the invention cyclohexylphenyl. In this embodiment, R may be ami as, e.g., anti-anxiety agents, is greatly enhanced. noalkyl, e.g., amino(lower)alkyl such as aminomethyl, ami 40 noethyl, aminopropyl, aminocyclopropyl, aminobutyl or In an embodiment, R may be lower alkyl, e.g., n-butyl, dialkylamino. Advantageously, R may be NHCO-alkyl, e.g. S-butyl, i-butyl; p-toluene, p-halophenyl (e.g., p-fluorophe NHCO (C-C)alkyl, including NHCO (CH), nyl, p-chlorophenyl or p-bromophenyl), cycloalkyl, e.g., NHCO-(CHCH), NHCO-(CHCH-CH), and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo NHCO-(CH(CH), (i.e., NHCO-cyclopropyl) hexylmethyl, and cyclohexylphenyl. In a version of this 45 In an embodiment, R is in the meta-position. In a version embodiment, R may be aminoalkyl, e.g., amino(lower) of this embodiment, R may be aminoalkyl, e.g., amino alkyl Such as aminomethyl, aminoethyl, aminopropyl, ami (lower)alkyl Such as aminomethyl, aminoethyl, aminopro nocyclopropyl, aminobutyl or dialkylamino. In another ver pyl, aminocyclopropyl, aminobutyl or dialkylamino. In sion, R may be NHCO-alkyl, e.g., NHCO (C-C)alkyl, another version, R may be NHCO-alkyl, e.g., NHCO— including NHCO (CH), NHCO (CHCH), NHCO 50 (C-C)alkyl, including NHCO—(CH), NHCO (CHCH-CH), and NHCO-(CH(CH), (i.e., NHCO (CHCH), NHCO-(CHCH-CH), and NHCO-(CH cyclopropyl.) (CH), (i.e., NHCO-cyclopropyl.) In a version of this In an embodiment, R is H and R is other than H and in embodiment, R may be n-butyl, S-butyl, i-butyl, p-toluene, the meta-position. In a version of this embodiment, R may p-halophenyl (e.g., p-fluorophenyl, p-chlorophenyl or p-bro be aminoalkyl, e.g., amino(lower)alkyl Such as aminom 55 mophenyl), cyclohexylmethyl, cyclohexyl, or cyclohexy lphenyl. The compounds of the invention are advanta ethyl, aminoethyl, aminopropyl, aminocyclopropyl, ami geously pharmaceutically acceptable salts, e.g., HC1. nobutyl or dialkylamino. In another version, R may be In particular embodiments, compounds of the invention NHCO-alkyl, e.g., NHCO (C-C)alkyl, including include 4-Methyl-N-(4-4-(3-nitro-phenyl)-piperazin-1-yl)- NHCO (CH), NHCO (CHCH), NHCO (CHCH 60 butyl-benzenesulfonamide: 4-Methyl-N-(4-4-(3-nitro CH), and NHCO—(CH(CH) (i.e., NHCO-cyclopropyl.) phenyl)-piperazin-1-yl-butyl-benzenesulfonamide HC1 In a version of this embodiment, R may be p-toluene, salt; Cyclopropanecarboxylic acid (3-4-4-(toluene-4-sul p-halophenyl (e.g., p-fluorophenyl, p-chlorophenyl or p-bro fonylamino)-butyl-piperazin-1-yl)-phenyl)-amide: N-(3- mophenyl), cyclohexylmethyl, cyclohexyl, or cyclohexy {4-4-(Toluene-4-sulfonylamino)-butyl-piperazin-1-yl)- lphenyl. 65 phenyl)-butyramide: 2,2-Dimethyl-N-(3-4-4-(toluene-4- In a further embodiment, compounds of the invention sulfonylamino)-butyl-piperazin-1-yl)-phenyl)- include those having the formula propionamide; N-(3-4-4-(Toluene-4-sulfonylamino)- US 7,153,858 B2 5 6 butyl-piperazin-1-yl)-phenyl)-isobutyramide: N-(4-4-(3- disorders, e.g., blood flow disorders caused by vasodilation Ethanesulfonylamino-phenyl)-piperazin-1-yl)-butyl-4- and vasospastic diseases such as angina, Vascular headache, methyl-benzenesulfonamide: 4-Methyl-N-(4-4-3- migraine and Reynaud's disease; and neuropathological (propane-2-sulfonylamino)-phenyl-piperazin-1-yl)-butyl)- disorders including Parkinson's disease and Alzheimer's benzenesulfonamide: 4-Methyl-N-(4-4-(3-nitro-phenyl)- disease; modulation of the cardiovascular system; prophy piperazin-1-yl)-butyl-benzenesulfonamide: 4-Methyl-N- laxis and control of the effects of occurrences of cerebral 4-(4-pyridin-2-yl-piperazin-1-yl)-butyl infarct (Apoplexia cerebri) such as stroke or cerebral benzenesulfonamide: N-(4-4-(2-Methoxy-5-nitro-phenyl)- ischemia; and for the control of disorders of the intestinal piperazin-1-yl)-butyl-4-methyl-benzenesulfonamide; tract which are characterized by disturbances of the sero 4-Methyl-N-4-(4-pyrimidin-2-yl-piperazin-1-yl)-butyl 10 toninergic system and also by disturbances of the carbohy benzenesulfonamide: N-(4-4-(3-Methoxy-phenyl)-piper drate metabolism; stress-related somatic disorders; reflex azin-1-yl)-butyl-4-methyl-benzenesulfonamide: N-(4-4- sympathetic dystrophy Such as shoulder/hand syndrome; (3-Ethanesulfonylamino-phenyl)-piperazin-1-yl-butyl-4- disorders of bladder function such as cystitis, bladder detru methyl-benzenesulfonamide: N-4-4-(3- Sor hyper-reflexia and incontinence; and pain or nociception Methanesulfonylamino-phenyl)-piperazin-1-yl)-butyl-4- 15 attributable to or associated with any of the foregoing methyl-benzenesulfonamide: 4-Methyl-N-(4-4-(3-pyrazin conditions, especially pain transmission in migraine. 2-yl-phenyl)-piperazin-1-yl)-butyl-benzenesulfonamide: The invention is also drawn to methods of treating con N-4-(4-Biphenyl-3-yl-piperazin-1-yl)-butyl-4-methyl ditions associated with serotonergic hypofunction or hyper benzenesulfonamide, 4-Methyl-N-4-(4-phenyl-piperazin function, including administering a compound of the inven 1-yl)-butyl-benzenesulfonamide, C-Cyclohexyl-N-(4-4- tion to a Subject to treat the condition. As explained above, (2-methoxy-phenyl)-piperazin-1-yl)-butyl compounds of the invention can have antagonistic activity at methanesulfonamide, N-(3-4-4-(Toluene-4- 5-HT, receptors, which will counteract the negative feed sulfonylamino)-butyl-piperazin-1-yl)-phenyl)-acetamide, back mechanism induced by the inhibition of serotonin N-(3-4-4-(Toluene-4-sulfonylamino)-butyl-piperazin-1- reuptake; this is thereby expected to improve the effect of the yl-phenyl)-propionamide, (3-4-1-(4-Fluoro-benzene 25 serotonin reuptake inhibiting activity of the compounds of sulfonyl)-piperidin-4-ylmethyl-piperazin-1-yl)-phenyl)- the invention. Other compounds of the invention have dimethyl-amine, 1-1-(4-Fluoro-benzenesulfonyl)- agonistic activity at 5-HT receptors like 5-HT. piperidin-4-ylmethyl-4-pyridin-2-yl-piperazine, Another aspect of the invention is a pharmaceutical C-Cyclohexyl-N-(4-4-(3-dimethylamino-phenyl)-piper composition comprising an amount of a compound accord azin-1-yl)-butyl-methanesulfonamide, C-Cyclohexyl-N- 30 ing to Formula I or II effective to treat anxiety, particularly 4-(4-pyridin-2-yl-piperazin-1-yl)-butyl-methanesulfona generalized anxiety disorder, in a mammal Suffering there mide, N-(3-4-1-(4-Fluoro-benzenesulfonyl)-piperidin-4- from, and a pharmaceutically acceptable carrier. ylmethyl-piperazin-1-yl)-phenyl)-acetamide, N-(3-4-4- Another aspect of the invention is a method for treating (4-Fluoro-benzenesulfonylamino)-butyl-piperazin-1-yl)- anxiety, particularly generalized anxiety disorder, in a mam phenyl)-acetamide, N-3-4-(4- 35 mal Such as a human comprising administering a therapeu Cyclohexylmethanesulfonylamino-butyl)-piperazin-1-yl)- tically effective amount of a compound according to For phenyl)-acetamide, N-3-4-(1- mula I or II. Cyclohexylmethanesulfonyl-piperidin-4-ylmethyl)- Another aspect of the invention is a pharmaceutical piperazin-1-yl)-phenyl)-acetamide, composition comprising an amount of a compound accord Cyclopropanecarboxylic acid {3-4-(4-cyclohexylmethane 40 sulfonylamino-butyl)-piperazin-1-yl-phenyl-amide, N-(3- ing to Formula I or II effective to treat panic disorder in a {4-1-(Propane-2-sulfonyl)-piperidin-4-ylmethyl-piper mammal Suffering therefrom, and a pharmaceutically azin-1-yl)-phenyl)-acetamide, N-(3-4-4-(Propane-2- acceptable carrier. sulfonylamino)-butyl-piperazin-1-yl)-phenyl)-acetamide, Another aspect of the invention is a method for treating N-3-4-(4-Cyclohexanesulfonylamino-butyl)-piperazin-1- 45 panic disorder in a mammal such as a human comprising yl-phenyl)-acetamide, N-(3-4-4-(Cyclohexylmethane administering a therapeutically effective amount of a com sulfonyl-methyl-amino)-butyl-piperazin-1-yl)-phenyl)-ac pound according to Formula I or II. etamide, N-(3-4-4-(2-Methyl-propane-1-sulfonylamino)- Another aspect of the invention is a pharmaceutical butyl-piperazin-1-yl)-phenyl)-acetamide, N-3-(4-4- composition comprising an amount of a compound accord Methyl-(2-methyl-propane-1-sulfonyl)-amino-butyl 50 ing to Formula I or II effective to treat attention deficit piperazin-1-yl)-phenyl-acetamide, N-(3-piperazin-1-yl disorder (ADD), with or without hyperactivity, i.e., ADHD, phenyl)-acetamide, Cyclopropanecarboxylic acid in a mammal Suffering therefrom, and a pharmaceutically (3-piperazin-1-yl-phenyl)-amide, and 1-(2-Methoxy-phe acceptable carrier. nyl)-4-1-(toluene-4-Sulfonyl)-piperidin-3-ylmethyl-pip Another aspect of the invention is a method for treating erazine. 55 attention deficit disorder, with or without hyperactivity, in a Another aspect of the invention, as noted above, includes mammal Such as a human comprising administering a thera methods for treating subjects afflicted with a condition peutically effective amount of a compound according to requiring treatment, by administering an effective amount of Formula I or II. a compound of the invention to treat the condition(s). Another aspect of the invention is a pharmaceutical Subjects suffering from various conditions that will be 60 composition comprising an amount of a compound accord responsive to the introduction of these compounds may be ing to Formula I or II effective to treat substance-related treated; or the compounds may be used to alter physiological disorders in a mammal Suffering therefrom, and a pharma phenomena associated with certain conditions to achieve a ceutically acceptable carrier. desired treatment of said condition(s), alone and/or in com Another aspect of the invention is a method for treating bination with other drugs. Such conditions or physiological 65 Substance-related disorders in a mammal Such as a human phenomena include vasodilation, Smooth muscle contrac comprising administering a therapeutically effective amount tion, bronchoconstriction, brain disorders such as vascular of a compound according to Formula I or II. US 7,153,858 B2 7 8 Another aspect of the invention is a pharmaceutical alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbo composition comprising an amount of a compound accord nyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio ing to Formula I or II effective in treating conditions carbonyl, alkoxyl, phosphate, phosphonato, phosphinato, associated with vascular disorders, e.g., angina and cyano, amino (including alkylamino, dialkylamino, ary migraine. lamino, diarylamino, and alkylarylamino), acylamino (in Another aspect of the invention is a method of treating cluding alkylcarbonylamino, arylcarbonylamino, carbamoyl conditions associated with vascular disorders, e.g., angina and ureido), amidino, imino, Sulfhydryl, alkylthio, arylthio. and migraine. thiocarboxylate, Sulfates, alkylsulfinyl, Sulfonato, Sulfa Processes for preparing the compounds and novel inter moyl, Sulfonamido, nitro, trifluoromethyl, cyano, azido, mediates are also included in the invention. 10 heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyls can be further substituted, e.g., with the BRIEF DESCRIPTION OF THE DRAWING substituents described above. An “alkylaryl' or an “aralkyl moiety is an alkyl Substituted with an aryl (e.g., phenylm FIGS. 1-12 illustrate the effects on animals of a com ethyl (benzyl)). “Alkyl also includes the side chains of pound of the invention in various tests, as detailed further in 15 natural and unnatural amino acids. Examples 40 and 41. "Aryl includes groups with aromaticity, including 5- and 6-membered “unconjugated, or single-ring, aromatic DETAILED DESCRIPTION OF THE groups that may include from Zero to four heteroatoms, as INVENTION well as "conjugated, or multicyclic, systems with at least one aromatic ring. Examples of aryl groups include benzene, The features and other details of the invention will now be phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imi more particularly described with reference to the accompa dazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, nying drawings and pointed out in the claims. It will be pyridine, pyrazine, pyridazine, and pyrimidine, and the like. understood that particular embodiments described herein are Furthermore, the term “aryl' includes multicyclic aryl shown by way of illustration and not as limitations of the 25 groups, e.g., , bicyclic, e.g., naphthalene, benzoX invention. The principal features of this invention can be azole, benzodioxazole, benzothiazole, benzoimidazole, ben employed in various embodiments without departing from Zothiophene, methylenedioxyphenyl, quinoline, isoquino the scope of the invention. All parts and percentages are by line, napthridine, indole, benzofuran, purine, benzofuran, weight unless otherwise specified. deazapurine, or indolizine. Those aryl groups having het 30 eroatoms in the ring structure may also be referred to as Definitions “aryl heterocycles”, “heterocycles,” “heteroaryls' or “het For convenience, certain terms used in the specification, eroaromatics’. The aromatic ring can be substituted at one or examples, and appended claims are collected here. more ring positions with Such substituents as described “5-HT receptor modulator” or “5-HT modulator” includes above, as for example, halogen, hydroxyl, alkoxy, alkylcar compounds having effect at the 5-HT, 5-HT, 5-HT, 35 bonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycar 5-HT, 5-HTs, 5-HT or 5-HT7 receptors, including the bonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, Subtypes of each receptor type, such as 5-HT1 ...... ; aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbo 5-HT2, a c.; and 5-HTs a 5-HT modulators may be nyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxy agonists, partial agonists or antagonists. carbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, “Treating, includes any effect, e.g., lessening, reducing, 40 phosphonato, phosphinato, cyano, amino (including alky modulating, or eliminating, that results in the improvement lamino, dialkylamino, arylamino, diarylamino, and alkylary of the condition, disease, disorder, etc. lamino), acylamino (including alkylcarbonylamino, arylcar “Alkyl includes saturated aliphatic groups, including bonylamino, carbamoyl and ureido), amidino, imino, straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, (e.g., n-butyl, S-butyl, i-butyl), pentyl, hexyl, heptyl, octyl, 45 alkylsulfinyl, Sulfonato, Sulfamoyl, Sulfonamido, nitro, trif nonyl, decyl), branched-chain alkyl groups (e.g., isopropyl. luoromethyl, cyano, azido, heterocyclyl alkylaryl, or an tert-butyl, isobutyl), cycloalkyl (e.g., alicyclic) groups (e.g., aromatic or heteroaromatic moiety. Aryl groups can also be cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooc fused or bridged with alicyclic or heterocyclic rings which tyl), alkyl Substituted cycloalkyl groups, and cycloalkyl are not aromatic So as to form a multicyclic system (e.g., substituted alkyl groups. “Alkyl further includes alkyl 50 tetralin, methylenedioxyphenyl). groups which have oxygen, nitrogen, Sulfur or phosphorous “Alkenyl includes unsaturated aliphatic groups analo atoms replacing one or more hydrocarbon backbone carbon gous in length and possible Substitution to the alkyls atoms. In certain embodiments, a straight chain or branched described above, but that contain at least one double bond. chain alkyl has six or fewer carbon atoms in its backbone For example, the term “alkenyl' includes straight-chain (e.g., C-C for straight chain, C-C for branched chain), 55 alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, and more preferably four or fewer. Likewise, preferred hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched cycloalkyls have from three to eight carbon atoms in their chain alkenyl groups, cycloalkenyl (e.g., alicyclic) groups ring structure, and more preferably have five or six carbons (e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl, cyclo in the ring structure. "C-C includes alkyl groups con heptenyl, cyclooctenyl), alkyl or alkenyl Substituted taining one to six carbon atoms. 60 cycloalkenyl groups, and cycloalkyl or cycloalkenyl Substi The term “alkyl also includes both “unsubstituted alkyls' tuted alkenyl groups. The term “alkenyl further includes and “substituted alkyls', the latter of which refers to alkyl alkenyl groups which include oxygen, nitrogen, Sulfur or moieties having Substituents replacing a hydrogen on one or phosphorous atoms replacing one or more hydrocarbon more carbons of the hydrocarbon backbone. Such substitu backbone carbons. In certain embodiments, a straight chain ents can include, for example, alkyl, alkenyl, alkynyl, halo 65 or branched chain alkenyl group has six or fewer carbon gen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy atoms in its backbone (e.g., C-C for straight chain, C-C, carbonyloxy, aryloxycarbonyloxy, carboxylate, for branched chain.) Likewise, cycloalkenyl groups may US 7,153,858 B2 9 10 have from three to eight carbon atoms in their ring structure, boxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, ami and more preferably have five or six carbons in the ring nocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, structure. The term "C-C includes alkenyl groups con alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phos taining two to six carbon atoms. phinato, cyano, amino (including alkylamino, dialkylamino, The term “alkenyl also includes both “unsubstituted arylamino, diarylamino, and alkylarylamino), acylamino alkenyls' and “substituted alkenyls', the latter of which (including alkylcarbonylamino, arylcarbonylamino, car refers to alkenyl moieties having Substituents replacing a bamoyl and ureido), amidino, imino, Sulfhydryl, alkylthio. hydrogen on one or more hydrocarbon backbone carbon arylthio, thiocarboxylate, Sulfates, alkylsulfinyl, Sulfonato, atoms. Such substituents can include, for example, alkyl Sulfamoyl, Sulfonamido, nitro, trifluoromethyl, cyano, azido, groups, alkynyl groups, halogens, hydroxyl, alkylcarbony 10 heterocyclyl, alkylaryl, or an aromatic or heteroaromatic loxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbony moiety. loxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycar “Acylamino' includes moieties wherein an acyl moiety is bonyl, aminocarbonyl, alkylaminocarbonyl, bonded to an amino group. For example, the term includes dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phos alkylcarbonylamino, arylcarbonylamino, carbamoyl and phate, phosphonato, phosphinato, cyano, amino (including 15 ureido groups. alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, “Aroyl includes compounds and moieties with an aryl or arylcarbonylamino, carbamoyl and ureido), amidino, imino, heteroaromatic moiety bound to a carbonyl group. Examples sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, of aroyl groups include phenylcarboxy, naphthyl carboxy, alkylsulfinyl, Sulfonato, Sulfamoyl, Sulfonamido, nitro, trif etc. luoromethyl, cyano, azido, heterocyclyl alkylaryl, or an “Alkoxyalkyl”, “alkylaminoalkyl and “thioalkoxyalkyl aromatic or heteroaromatic moiety. include alkyl groups, as described above, which further “Alkynyl' includes unsaturated aliphatic groups analo include oxygen, nitrogen or Sulfur atoms replacing one or gous in length and possible Substitution to the alkyls more hydrocarbon backbone carbon atoms, e.g., oxygen, described above, but which contain at least one triple bond. 25 nitrogen or Sulfur atoms. For example, “alkynyl' includes straight-chain alkynyl The term “alkoxy” includes substituted and unsubstituted groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, alkyl, alkenyl, and alkynyl groups covalently linked to an heptynyl, octynyl, nonynyl, decynyl), branched-chain alky oxygen atom. Examples of alkoxy groups include methoxy, nyl groups, and cycloalkyl or cycloalkenyl Substituted alky ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. nyl groups. The term “alkynyl further includes alkynyl 30 Examples of Substituted alkoxy groups include halogenated groups having oxygen, nitrogen, Sulfur or phosphorous alkoxy groups. The alkoxy groups can be substituted with atoms replacing one or more hydrocarbon backbone car groups such as alkenyl, alkynyl, halogen, hydroxyl, alkyl bons. In certain embodiments, a straight chain or branched carbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxy chain alkynyl group has six or fewer carbon atoms in its carbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, backbone (e.g. C-C for straight chain, C-C for branched 35 alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, chain). The term "C-C includes alkynyl groups contain dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phos ing two to six carbon atoms. phate, phosphonato, phosphinato, cyano, amino (including The term “alkynyl also includes both “unsubstituted alkylamino, dialkylamino, arylamino, diarylamino, and alkynyls' and “substituted, alkynyls', the latter of which alkylarylamino), acylamino (including alkylcarbonylamino, refers to alkynyl moieties having Substituents replacing a 40 arylcarbonylamino, carbamoyl and ureido), amidino, imino, hydrogen on one or more hydrocarbon backbone carbon sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, atoms. Such substituents can include, for example, alkyl alkylsulfinyl, Sulfonato, Sulfamoyl, Sulfonamido, nitro, trif groups, alkynyl groups, halogens, hydroxyl, alkylcarbony luoromethyl, cyano, azido, heterocyclyl alkylaryl, or an loxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbony aromatic or heteroaromatic moieties. Examples of halogen loxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycar 45 Substituted alkoxy groups include, but are not limited to, bonyl, aminocarbonyl, alkylaminocarbonyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlo dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phos romethoxy, dichloromethoxy, and trichloromethoxy. phate, phosphonato, phosphinato, cyano, amino (including The terms "heterocyclyl or "heterocyclic group' include alkylamino, dialkylamino, arylamino, diarylamino, and closed ring structures, e.g., 3- to 10-, or 4- to 7-membered alkylarylamino), acylamino (including alkylcarbonylamino, 50 rings, which include one or more heteroatoms. Heterocyclyl arylcarbonylamino, carbamoyl and ureido), amidino, imino, groups can be saturated or unsaturated and include pyrroli sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, dine, oxolane, thiolane, piperidine, piperazine, morpholine, alkylsulfinyl, Sulfonato, Sulfamoyl, Sulfonamido, nitro, trif lactones, lactams such as azetidinones and pyrrolidinones, luoromethyl, cyano, azido, heterocyclyl alkylaryl, or an Sultams, Sultones, and the like. The heterocyclic ring can be aromatic or heteroaromatic moiety. 55 Substituted at one or more positions with Such Substituents as Unless the number of carbons is otherwise specified, described above, as for example, halogen, hydroxyl, alkyl “lower alkyl includes an alkyl group, as defined above, but carbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxy having from one to ten, more preferably from one to six, carbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, carbon atoms in its backbone structure. “Lower alkenyland aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, “lower alkynyl have chain lengths of, for example, 2-5 60 phosphonato, phosphinato, cyano, amino (including alkyl carbon atoms. amino, dialkylamino, arylamino, diarylamino, and alkylary “Acyl' includes compounds and moieties which contain lamino), acylamino (including alkylcarbonylamino, arylcar the acyl radical (CHCO ) or a carbonyl group. "Substi bonylamino, carbamoyl and ureido), amidino, imino, Sulf tuted acyl includes acyl groups where one or more of the hydryl, alkylthio, arylthio, thiocarboxylate, sulfates, hydrogen atoms are replaced by for example, alkyl groups, 65 Sulfonato, Sulfamoyl, Sulfonamido, nitro, trifluoromethyl, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, aryl cyano, azido, heterocyclyl, or an aromatic or heteroaromatic carbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, car moiety. US 7,153,858 B2 11 12 The term “thiocarbonyl or “thiocarboxy' includes com this application also include all tautomers thereof. Alkenes pounds and moieties which contain a carbon connected with can include either the E- or Z-geometry, where appropriate. a double bond to a sulfur atom. Combination therapy” (or “co-therapy') includes the The term “ether includes compounds or moieties which administration of a 5-HT modulator of the invention and at contain an oxygen bonded to two different carbon atoms or least a second agent as part of a specific treatment regimen heteroatoms. For example, the term includes “alkoxyalkyl intended to provide the beneficial effect from the co-action which refers to an alkyl, alkenyl, or alkynyl group of these therapeutic agents. The beneficial effect of the covalently bonded to an oxygen atom which is covalently combination includes, but is not limited to, pharmacokinetic bonded to another alkyl group. or pharmacodynamic co-action resulting from the combina The term “ester' includes compounds and moieties which 10 tion of therapeutic agents. Administration of these therapeu contain a carbon or a heteroatom bound to an oxygen atom tic agents in combination typically is carried out over a which is bonded to the carbon of a carbonyl group. The term defined time period (usually minutes, hours, days or weeks 'ester” includes alkoxycarboxy groups such as methoxycar depending upon the combination selected). "Combination bonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, therapy may, but generally is not, intended to encompass pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups 15 the administration of two or more of these therapeutic agents are as defined above. as part of separate monotherapy regimens that incidentally The term “thioether includes compounds and moieties and arbitrarily result in the combinations of the present which contain a sulfur atom bonded to two different carbon invention. “Combination therapy” is intended to embrace or heteroatoms. Examples of thioethers include, but are not administration of these therapeutic agents in a sequential limited to alkthioalkyls, alkthioalkenyls, and alkthioalky manner, that is, wherein each therapeutic agent is adminis nyls. The term “alkthioalkyls' include compounds with an tered at a different time, as well as administration of these alkyl, alkenyl, or alkynyl group bonded to a Sulfur atom therapeutic agents, or at least two of the therapeutic agents, which is bonded to an alkyl group. Similarly, the term in a substantially simultaneous manner. Substantially simul “alkthioalkenyls' and alkthioalkynyls' refer to compounds taneous administration can be accomplished, for example, or moieties wherein an alkyl, alkenyl, or alkynyl group is 25 by administering to the Subject a single capsule having a bonded to a sulfur atom which is covalently bonded to an fixed ratio of each therapeutic agent or in multiple, single alkynyl group. capsules for each of the therapeutic agents. Sequential or The term “hydroxy” or “hydroxyl includes groups with Substantially simultaneous administration of each therapeu an —OH or —O. tic agent can be effected by any appropriate route including, 30 but not limited to, oral routes, intravenous routes, intramus The term “halogen' includes fluorine, bromine, chlorine, cular routes, and direct absorption through mucous mem iodine, etc. The term “perhalogenated” generally refers to a brane tissues. The therapeutic agents can be administered by moiety wherein all hydrogens are replaced by halogen the same route or by different routes. For example, a first atOmS. therapeutic agent of the combination selected may be admin “Polycyclyl or “polycyclic radical refers to two or more 35 istered by intravenous injection while the other therapeutic cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, agents of the combination may be administered orally. aryls and/or heterocyclyls) in which two or more carbons are Alternatively, for example, all therapeutic agents may be common to two adjoining rings. Rings that are joined administered orally or all therapeutic agents may be admin through non-adjacent atoms are termed “bridged rings. istered by intravenous injection. The sequence in which the Each of the rings of the polycycle can be substituted with 40 therapeutic agents are administered is not narrowly critical. Such substituents as described above, as for example, halo “Combination therapy' also can embrace the administration gen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy of the therapeutic agents as described above in further carbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbo combination with other biologically active ingredients and nyl, alkoxycarbonyl, alkylaminocarbonyl, non-drug therapies (e.g., Surgery or radiation treatment.) aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbo 45 Where the combination therapy further comprises a non nyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, ami drug treatment, the non-drug treatment may be conducted at nocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phos any suitable time so long as a beneficial effect from the phonato, phosphinato, cyano, amino (including alkylamino, co-action of the combination of the therapeutic agents and dialkylamino, arylamino, diarylamino, and alkylarylamino), non-drug treatment is achieved. For example, in appropriate acylamino (including alkylcarbonylamino, arylcarbony 50 cases, the beneficial effect is still achieved when the non lamino, carbamoyl and ureido), amidino, imino, Sulfhydryl, drug treatment is temporally removed from the administra alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, tion of the therapeutic agents, perhaps by days or even Sulfonato, Sulfamoyl, Sulfonamido, nitro, trifluoromethyl, weeks. cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or An “anionic group, as used herein, refers to a group that heteroaromatic moiety. 55 is negatively charged at physiological pH. Preferred anionic “Heteroatom' includes atoms of any element other than groups include carboxylate, Sulfate, Sulfonate, Sulfinate, carbon or hydrogen. Examples of heteroatoms include nitro Sulfamate, tetrazolyl, phosphate, phosphonate, phosphinate, gen, oxygen, Sulfur and phosphorus. or phosphorothioate or functional equivalents thereof. It will be noted that the structure of some of the com "Functional equivalents’ of anionic groups are intended to pounds of the invention includes asymmetric carbon atoms. 60 include bioisosteres, e.g., bioisosteres of a carboxylate It is to be understood accordingly that the isomers arising group. Bioisosteres encompass both classical bioisosteric from Such asymmetry (e.g., all enantiomers and diastere equivalents and non-classical bioisosteric equivalents. Clas omers) are included within the scope of the invention, unless sical and non-classical bioisosteres are known in the art (see, indicated otherwise. Such isomers can be obtained in sub e.g., Silverman, R. B. The Organic Chemistry of Drug stantially pure form by classical separation techniques and 65 Design and Drug Action, Academic Press, Inc. San Diego, by stereochemically controlled synthesis. Furthermore, the Calif., 1992, pp. 19–23). A particularly preferred anionic structures and other compounds and moieties discussed in group is a carboxylate. US 7,153,858 B2 13 14 The term "heterocyclic group' is intended to include R may be substituted or unsubstituted aryl, alkyl, closed ring structures in which one or more of the atoms in cycloalkyl or alkylaryl; and RandR independently may be the ring is an element other than carbon, for example, hydrogen or lower alkyl cycloalkyl; trihalomethyl; halo: nitrogen, or oxygen or Sulfur. Heterocyclic groups can be —NRRs, where R and Rs are independently H, O, Re, or saturated or unsaturated and heterocyclic groups such as 5 COR, where R may be lower alkyl (e.g. nitro, NHCO pyrrole and furan can have aromatic character. They include alkyl, e.g., NHCO-lower alkyl such as NHCO (C-C) fused ring structures such as quinoline and isoquinoline. alkyl, including NHCO-(CH), NHCO-(CHCH), Other examples of heterocyclic groups include pyridine and NHCO-(CHCH-CH), NHCO-(CH(CH)) (i.e., purine. Heterocyclic groups can also be substituted at one or cyclopropyl) and NCO-dialkyl, aminoalkyl, e.g., amino more constituent atoms with, for example, a halogen, a 10 (lower)alkyl Such as aminomethyl, aminoethyl, aminopro lower alkyl, a lower alkenyl, a lower alkoxy, a lower pyl, aminocyclopropyl, aminobutyl or dialkylamino); Sul alkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, fonamidoalkyl, e.g. Sulfonamido(C-C)alkyl, hydroxyl, a hydroxyl, —CF, —CN, or the like. cyano; or a conjugated five- or six-membered cyclic or The present invention relates to the discovery of new heterocyclic ring, provided that R and R are not both compounds for treating Subjects Suffering from various 15 hydrogen. conditions that will be responsive to the introduction of The aryl, pyridinyl, pyrimidinyl or pyrazinyl (i.e., where these compounds, alone and/or in combination with other Z=N) group may be substituted with a substituent such as drugs. For example, the compounds of the invention may be lower alkyl, e.g., C-C cycloalkyl, e.g., C-C; trihalom used for vasodilation, Smooth muscle contraction, bronchoc ethyl, e.g., CF or OCF, halo, e.g., F. Br or Cl; a conjugated onstriction, brain disorders such as vascular disorders, e.g., five- or six-membered cyclic or heterocyclic ring, e.g., blood flow disorders caused by vasodilation and vasospastic 3.4-methylenedioxy; nitro; NHCO-alkyl, e.g., NHCO-lower diseases Such as angina, Vascular headache, migraine and alkyl such as NHCO (C-C)alkyl, including NHCO— Reynaud's disease; and neuropathological disorders includ (CH), NHCO-(CHCH), NHCO-(CHCH-CH), ing Parkinson's disease and Alzheimer's disease; modula and NHCO—(CH(CH)) (i.e., cyclopropyl); NCO-dialkyl: tion of the cardiovascular system; prophylaxis and control of 25 Sulfonamidoalkyl, e.g., Sulfonamido(C-C)alkyl, hydroxyl, the effects of occurrences of cerebral infarct (Apoplexia or cyano. The aryl group itself may be, e.g., Substituted or cerebri) such as stroke or cerebral ischemia; and for the unsubstituted phenyl, naphthyl, toluyl, or biphenyl. control of disorders of the intestinal tract which are charac In an embodiment, R may be lower alkyl, e.g., n-butyl, terized by disturbances of the serotoninergic system and also S-butyl, i-butyl, p-toluene, p-halophenyl (e.g., p-fluorophe by disturbances of the carbohydrate metabolism. The com 30 nyl, p-chlorophenyl or p-bromophenyl), cycloalkyl, e.g., pounds may also be useful in treating stress-related somatic cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo disorders; reflex sympathetic dystrophy such as shoulder/ hexylmethyl, and cyclohexylphenyl. In a version of this hand syndrome; disorders of bladder function Such as cys embodiment, R may be aminoalkyl, e.g., amino(lower) titis, bladder detrusor hyper-reflexia and incontinence; and alkyl Such as aminomethyl, aminoethyl, aminopropyl, ami pain or nociception attributable to or associated with any of 35 nocyclopropyl, aminobutyl or dialkylamino. In another ver the foregoing conditions, especially pain transmission in sion, R may be NHCO-alkyl, e.g., NHCO (C-C)alkyl, migraine. including NHCO (CH), NHCO-(CHCH), NHCO In one advantageous aspect, the compounds of the inven (CHCH-CH), and NHCO-(CH(CH), (i.e., NHCO tion have been found to be 5-HT modulators, e.g., agonists cyclopropyl.) or antagonists, and/or SSRIs, that can be used for treating, 40 In an embodiment, R is H and R is other than H and in preventing or curing 5-HT-related conditions. In particular, the meta-position. In a version of this embodiment, R may it has been found that certain arylpiperazinyl Sulfonamide be aminoalkyl, e.g., amino(lower)alkyl Such as aminom compounds are effective 5-HT receptor modulators and/or ethyl, aminoethyl, aminopropyl, aminocyclopropyl, ami SSRIS nobutyl or dialkylamino. In another version, R may be 45 NHCO-alkyl, e.g., NHCO (C-C)alkyl, including In an embodiment, compounds of the invention include NHCO (CH), NHCO (CHCH), NHCO (CHCH those having the formula CH), and NHCO—(CH(CH), (i.e., NHCO-cyclopropyl.) In a version of this embodiment, R may be p-toluene, p-halophenyl (e.g., p-fluorophenyl, p-chlorophenyl or p-bro (I) 50 mophenyl), cyclohexylmethyl, cyclohexyl, or cyclohexy lphenyl. R In a further embodiment, compounds of the invention 2 N- ; N1N include those having the formula

55 (II) wherein R is a functional group that imparts Substantially no 5-HT/5-HT, adrenergic receptor cross-reactivity to the compound; R2 and R independently are hydrogen or a 60 functional group that imparts substantially no HERG chan nel inhibition to the compound; Z is N or C; m may be 0, 1, 2, 3, 4, 5, or 6; n may be 1, 2, 3, 4, 5, or 6; and p may be wherein 0, 1, 2, 3, or 4, more preferably greater than 0; and R may be substituted or unsubstituted aryl, alkyl, pharmaceutically acceptable salts and/or esters thereof, m is 65 cycloalkyl or alkylaryl, e.g., toluyl or cyclohexyl. R is advantageously 0, n is advantageously 3 or 4, and p is preferably unconjugated when it is a ring-containing group, advantageously 0 or 1. and may advantageously be substituted or unsubstituted US 7,153,858 B2 15 16 alkyl or cycloalkyl, e.g., cyclohexyl. R may be lower alkyl, Methanesulfonylamino-phenyl)-piperazin-1-yl)-butyl-4- e.g., C-C trihalomethyl, e.g., CF; halo, e.g., F. Br or Cl; methyl-benzenesulfonamide: 4-Methyl-N-(4-4-(3-pyrazin a conjugated five- or six-membered cyclic or heterocyclic 2-yl-phenyl)-piperazin-1-yl)-butyl-benzenesulfonamide: ring, e.g., 3.4-methylenedioxy; —NRRs, where R and Rs N-4-(4-Biphenyl-3-yl-piperazin-1-yl)-butyl-4-methyl are independently H, O or COR, where R may be lower 5 benzenesulfonamide, 4-Methyl-N-4-(4-phenyl-piperazin alkyl, e.g., nitro; NHCO-alkyl, e.g., NHCO-lower alkyl such 1-yl)-butyl-benzenesulfonamide, C-Cyclohexyl-N-(4-4- as NHCO (C-C)alkyl, including NHCO—(CH), (2-methoxy-phenyl)-piperazin-1-yl)- NHCO-(CHCH), NHCO-(CHCH-CH), and butylmethanesulfonamide, N-(3-4-4-(Toluene-4- NHCO—(CH(CH)) (i.e., cyclopropyl); NCO-dialkyl; sul sulfonylamino)-butyl-piperazin-1-yl)-phenyl)-acetamide, fonamidoalkyl, e.g., Sulfonamido(C-C)alkyl; the atoms 10 N-(3-4-4-(Toluene-4-sulfonylamino)-butyl-piperazin-1- denoted by the dotted line bond may, taken together, form a yl-phenyl)-propionamide, (3-4-1-(4-Fluoro-benzene four, five, six or seven membered cyclic or heterocyclic ring; sulfonyl)-piperidin-4-ylmethyl-piperazin-1-yl)-phenyl)- Z is N or C; m may be 0, 1 or 2; n may be 1, 2, 3, or 4; and dimethyl-amine, 1-1-(4-Fluoro-benzenesulfonyl)- p may be 0 or 1; and pharmaceutically acceptable salts piperidin-4-ylmethyl-4-pyridin-2-yl-piperazine, and/or esters thereof, m is advantageously 0, n is advanta 15 C-Cyclohexyl-N-(4-4-(3-dimethylamino-phenyl)-piper geously 3 or 4, and p is advantageously 0 or 1. azin-1-yl)-butyl-methanesulfonamide, C-Cyclohexyl-N- In an embodiment, R may be lower alkyl, e.g., n-butyl, 4-(4-pyridin-2-yl-piperazin-1-yl)-butyl-methanesulfona S-butyl, i-butyl; p-toluene, p-halophenyl (e.g., p-fluorophe mide, N-(3-4-1-(4-Fluoro-benzenesulfonyl)-piperidin-4- nyl, p-chlorophenyl or p-bromophenyl), cycloalkyl, e.g., ylmethyl-piperazin-1-yl)-phenyl)-acetamide, N-(3-4-4- cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo (4-Fluoro-benzenesulfonylamino)-butyl-piperazin-1-yl)- hexylmethyl, and cyclohexylphenyl. Advantageously, R phenyl)-acetamide, N-3-4-(4- may be cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopen Cyclohexylmethanesulfonylamino-butyl)-piperazin-1-yl)- tyl, cyclohexyl, cyclohexylmethyl, and cyclohexylphenyl. In phenyl)-acetamide, N-3-4-(1- this embodiment, R may be aminoalkyl, e.g., amino(lower) Cyclohexylmethanesulfonyl-piperidin-4-ylmethyl)- alkyl Such as aminomethyl, aminoethyl, aminopropyl, ami 25 piperazin-1-yl-phenyl)-acetamide, nocyclopropyl, aminobutyl or dialkylamino. Advanta Cyclopropanecarboxylic acid {3-4-(4-cyclohexylmethane geously, R may be NHCO-alkyl, e.g., NHCO—(C-C) sulfonylamino-butyl)-piperazin-1-yl)-phenyl-amide, N-(3- alkyl, including NHCO-(CH), NHCO-(CHCH), {4-1-(Propane-2-sulfonyl)-piperidin-4-ylmethyl-piper NHCO-(CHCH-CH), and NHCO-(CH(CH), (i.e., azin-1-yl)-phenyl)-acetamide, N-(3-4-4-(Propane-2- NHCO-cyclopropyl.) 30 sulfonylamino)-butyl-piperazin-1-yl)-phenyl)-acetamide, In an embodiment, R is in the meta-position. In a version N-3-4-(4-Cyclohexanesulfonylamino-butyl)-piperazin-1- of this embodiment, R may be aminoalkyl, e.g., amino yl-phenyl-acetamide, N-(3-4-4-(Cyclohexylmethane (lower)alkyl Such as aminomethyl, aminoethyl, aminopro sulfonyl-methyl-amino)-butyl-piperazin-1-yl)-phenyl)-ac pyl, aminocyclopropyl, aminobutyl or dialkylamino. In etamide, N-(3-4-4-(2-Methyl-propane-1-sulfonylamino)- another version, R may be NHCO-alkyl, e.g., NHCO— 35 butyl-piperazin-1-yl)-phenyl)-acetamide, N-3-(4-4- (C-C)alkyl, including NHCO—(CH), NHCO— Methyl-(2-methyl-propane-1-sulfonyl)-amino-butyl (CHCH), NHCO-(CHCH-CH), and NHCO-(CH piperazin-1-yl)-phenyl-acetamide, N-(3-piperazin-1-yl (CH), (i.e., NHCO-cyclopropyl.) In a version of this phenyl)-acetamide, Cyclopropanecarboxylic acid embodiment, R may be n-butyl, S-butyl, i-butyl, p-toluene, (3-piperazin-1-yl-phenyl)-amide, and 1-(2-Methoxy-phe p-halophenyl (e.g., p-fluorophenyl, p-chlorophenyl or p-bro 40 nyl)-4-1-(toluene-4-Sulfonyl)-piperidin-3-ylmethyl-pip mophenyl), cyclohexylmethyl, cyclohexyl, or cyclohexy erazine. lphenyl. The compounds of the invention are advanta Compounds of the invention are also 5-HT receptor geously pharmaceutically acceptable salts, e.g. HC1. agonists or antagonists, e.g., 5-HT receptor agonists or In particular embodiments, compounds of the invention antagonists including 5-HTL, , C, , , , , receptors, and include 4-Methyl-N-(4-4-(3-nitro-phenyl)-piperazin-1-yl)- 45 desirably 5-HT, receptoragonists. Surprisingly, it has been butyl-benzenesulfonamide: 4-Methyl-N-(4-4-(3-nitro found that compounds of the invention are very good phenyl)-piperazin-1-yl-butyl-benzenesulfonamide HC1 5-HT, receptor agonists and have superior activity and salt; Cyclopropanecarboxylic acid (3-4-4-(toluene-4-sul selectivity compared to certain agonists on the market, e.g., fonylamino)-butyl-piperazin-1-yl)-phenyl)-amide: N-(3- BuSpar R (buspirone, Bristol-Myers Squibb.) {4-4-(Toluene-4-sulfonylamino)-butyl-piperazin-1-yl)- 50 The compounds of the invention are more selective in phenyl)-butyramide: 2,2-Dimethyl-N-(3-4-4-(toluene-4- their action, displaying no cross-reactivity with other recep sulfonylamino)-butyl-piperazin-1-yl)-phenyl)- tors such as C.-adrenergic receptors. Furthermore, these propionamide; N-(3-4-4-(Toluene-4-sulfonylamino)- compounds are not only selective, but bind well to 5-HT1 butyl-piperazin-1-yl)-phenyl)-isobutyramide: N-(4-4-(3- receptors, e.g., 5-HT, receptors, and are not rapidly Ethanesulfonylamino-phenyl)-piperazin-1-yl)-butyl-4- 55 metabolized to what are usually toxic metabolites. The methyl-benzenesulfonamide: 4-Methyl-N-(4-4-3- compounds of the invention thus will have a longer half-life (propane-2-sulfonylamino)-phenyl-piperazin-1-yl)-butyl)- in Vivo, e.g., wherein the compound is not metabolized or is benzenesulfonamide: 4-Methyl-N-(4-4-(3-nitro-phenyl)- only partially metabolized (HLM T'>20–90 min. up to piperazin-1-yl)-butyl-benzenesulfonamide: 4-Methyl-N- 100% of the compound remaining unchanged.) Applicants 4-(4-pyridin-2-yl-piperazin-1-yl)-butyl 60 do not wish or intend to be limited to a particular theory of benzenesulfonamide: N-(4-4-(2-Methoxy-5-nitro-phenyl)- operation; however, compounds of Formula I where R is piperazin-1-yl)-butyl-4-methyl-benzenesulfonamide; cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, 4-Methyl-N-4-(4-pyrimidin-2-yl-piperazin-1-yl)-butyl cyclohexyl, cyclohexylmethyl, and cyclohexylphenyl; and benzenesulfonamide: N-(4-4-(3-Methoxy-phenyl)-piper R, is NRRs, where R and Rs are independently H, O or azin-1-yl)-butyl-4-methyl-benzenesulfonamide: N-(4-4- 65 COR, where R may be lower alkyl, e.g. nitro; NHCO (3-Ethanesulfonylamino-phenyl)-piperazin-1-yl-butyl-4- alkyl, e.g., NHCO-lower alkyl such as NHCO (C-C) methyl-benzenesulfonamide: N-4-4-(3- alkyl, including NHCO (CH), NHCO-(CHCH), US 7,153,858 B2 17 18 NHCO-(CHCH-CH), and NHCO-(CH(CH)) (i.e., The invention is also drawn to methods of treating con cyclopropyl): NCO-dialkyl, are particularly good in this ditions associated with serotonergic hypofunction or hyper regard. As such, the utility of the compounds of the inven function, including administering a compound of the inven tion as, e.g., anti-anxiety agents, is greatly enhanced. tion to a Subject to treat the condition. As explained above, R may be substituted or unsubstituted aryl, alkyl, compounds of the invention can have antagonistic activity at cycloalkyl or alkylaryl, e.g. toluyl or cyclohexyl; R may be 5-HT, receptors, which will counteract the negative feed lower alkyl, e.g., C-C; trihalomethyl, e.g., CF; halo, e.g., back mechanism induced by the inhibition of serotonin F. Br or Cl; a conjugated five- or six-membered cyclic or reuptake; this is thereby expected to improve the effect of the heterocyclic ring, e.g. 3,4-methylenedioxy; —NRRs. serotonin reuptake inhibiting activity of the compounds of where R and Rs are independently H, O or COR, where R. 10 the invention. Other compounds of the invention have may be lower alkyl, e.g., nitro; NHCO-alkyl, e.g., NHCO agonistic activity at 5-HT receptors like 5-HT. lower alkyl such as NHCO (C-C)alkyl, including Another aspect of the invention is a pharmaceutical NHCO (CH), NHCO (CHCH), NHCO (CHCH composition comprising an amount of a compound accord CH), and NHCO—(CH(CH)) (i.e., cyclopropyl); NCO ing to Formula I or II effective to treat anxiety, particularly dialkyl; Sulfonamidoalkyl, e.g., Sulfonamido(C-C)alkyl; 15 generalized anxiety disorder, in a mammal Suffering there the atoms denoted by the dotted line bond may, taken from, and a pharmaceutically acceptable carrier. together, form a four, five, six or seven membered cyclic or Another aspect of the invention is a method for treating heterocyclic ring; Z is N or C; m may be 0, 1 or 2; n may anxiety, particularly generalized anxiety disorder, in a mam be 1, 2, 3, or 4; and p may be 0 or 1; and pharmaceutically mal Such as a human comprising administering a therapeu acceptable salts and/or esters thereof, m is advantageously 0. tically effective amount of a compound according to For n is advantageously 3 or 4, and p is advantageously 0 or 1. mula I or II. In an embodiment, R may be lower alkyl, e.g., n-butyl, Another aspect of the invention is a pharmaceutical S-butyl, i-butyl; p-toluene, p-halophenyl (e.g., p-fluorophe composition comprising an amount of a compound accord nyl, p-chlorophenyl or p-bromophenyl), cycloalkyl, e.g., ing to Formula I or II effective to treat panic disorder in a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo 25 mammal Suffering therefrom, and a pharmaceutically hexylmethyl, and cyclohexylphenyl. Advantageously, R acceptable carrier. may be cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopen Another aspect of the invention is a method for treating tyl, cyclohexyl, cyclohexylmethyl, and cyclohexylphenyl. In panic disorder in a mammal such as a human comprising this embodiment, R may be aminoalkyl, e.g., amino(lower) administering a therapeutically effective amount of a com alkyl Such as aminomethyl, aminoethyl, aminopropyl, ami 30 pound according to Formula I or II. nocyclopropyl, aminobutyl or dialkylamino. Advanta Another aspect of the invention is a pharmaceutical geously, R may be NHCO-alkyl, e.g. NHCO (C-C) composition comprising an amount of a compound accord alkyl, including NHCO-(CH), NHCO-(CHCH), ing to Formula I or II effective to treat attention deficit NHCO-(CHCH-CH), and NHCO-(CH(CH), (i.e., disorder (ADD), with or without hyperactivity, i.e., ADHD, NHCO-cyclopropyl.) 35 in a mammal Suffering therefrom, and a pharmaceutically The present invention relates to the discovery of new acceptable carrier. compounds for treating Subjects method of treating a subject Another aspect of the invention is a method for treating afflicted with a condition requiring treatment, by adminis attention deficit disorder, with or without hyperactivity, in a tering an effective amount of a compound of the invention mammal Such as a human comprising administering a thera to treat the condition(s). Various conditions will be respon 40 peutically effective amount of a compound according to sive to the introduction of these compounds, alone and/or in Formula I or II. combination with other drugs. Another aspect of the invention is a pharmaceutical Another aspect of the invention includes methods for composition comprising an amount of a compound accord treating Subjects Suffering from various conditions that will ing to Formula I or II effective to treat substance-related be responsive to the introduction of these compounds; or 45 disorders in a mammal Suffering therefrom, and a pharma altering physiological phenomena associated with certain ceutically acceptable carrier. conditions to achieve a desired treatment of said Another aspect of the invention is a method for treating condition(s), alone and/or in combination with other drugs. Substance-related disorders in a mammal Such as a human Such conditions or physiological phenomena include comprising administering a therapeutically effective amount vasodilation, Smooth muscle contraction, bronchoconstric 50 of a compound according to Formula I or II. tion, brain disorders such as vascular disorders, e.g., blood Another aspect of the invention is a pharmaceutical flow disorders caused by vasodilation and vasospastic dis composition comprising an amount of a compound accord eases such as angina, Vascular headache, migraine and ing to Formula I or II effective in treating conditions Reynaud's disease; and neuropathological disorders includ associated with vascular disorders, e.g., angina and ing Parkinson's disease and Alzheimer's disease; modula 55 migraine. tion of the cardiovascular system; prophylaxis and control of Another aspect of the invention is a method of treating the effects of occurrences of cerebral infarct (Apoplexia conditions associated with vascular disorders, e.g., angina cerebri) such as stroke or cerebral ischemia; and for the and migraine. control of disorders of the intestinal tract which are charac Processes for preparing the compounds and novel inter terized by disturbances of the serotoninergic system and also 60 mediates are also included in the invention. by disturbances of the carbohydrate metabolism; stress The invention is also drawn to methods of treating con related Somatic disorders; reflex sympathetic dystrophy Such ditions associated with serotonergic hypofunction or hyper as shoulder/hand syndrome; disorders of bladder function function, including administering a compound of the inven Such as cystitis, bladder detrusor hyper-reflexia and incon tion to a Subject to treat the condition. As explained above, tinence; and pain or nociception attributable to or associated 65 compounds of the invention can have antagonistic activity at with any of the foregoing conditions, especially pain trans 5-HT, receptors, which will counteract the negative feed mission in migraine. back mechanism induced by the inhibition of serotonin US 7,153,858 B2 19 20 reuptake; this is thereby expected to improve the effect of the caused by vasodilation and vasospastic diseases such as serotonin reuptake inhibiting activity of the compounds of angina, Vascular headache, migraine and Reynaud's disease; the invention. Other compounds of the invention have and neuropathological disorders including Parkinson's dis agonistic activity at 5-HT receptors like 5-HT. ease and Alzheimer's disease; modulation of the cardiovas The compounds of the invention are valuable, alone cular system; prophylaxis and control of the effects of and/or in combination with other drugs, for treating a wide occurrences of cerebral infarct (Apoplexia cerebri) Such as variety of clinical conditions which are characterized by stroke or cerebral ischemia; and for the control of disorders serotonin excess or absence, e.g., serotonergic hypofunction of the intestinal tract which are characterized by distur or hyperfunction. Such conditions include eating disorders, bances of the serotoninergic system and also by disturbances Schizophrenia, neuralgia, and addiction disorders; obsessive 10 of the carbohydrate metabolism. compulsive disorders, panic disorders, sexual dysfunctions The compounds may also be useful in treating a variety of caused by the central nervous system and disturbances in other conditions including stress-related Somatic disorders; sleep and the absorption of food, alcoholism, pain, memory reflex sympathetic dystrophy Such as shoulder/hand Syn deficits, unipolar depression, dysthymia, bipolar depression, drome; disorders of bladder function such as cystitis, blad treatment-resistant depression, depression in the medically 15 der detrusor hyper-reflexia and incontinence; and pain or ill, panic disorder, obsessive-compulsive disorder, eating nociception attributable to or associated with any of the disorders, social phobia, premenstrual dysphoric disorder, foregoing conditions, especially pain transmission in mood disorders, such as depression or more particularly migraine. depressive disorders, for example, single episodic or recur For treating certain conditions it may be desirable to rent major depressive disorders and dysthymic disorders, or employ the compounds of the invention in conjunction with bipolar disorders, for example, bipolar I disorder, bipolar II another pharmacologically active agent. The compounds of disorder and cyclothymic disorder; anxiety disorders, such the invention may be presented together with another thera as panic disorder with or without agoraphobia, agoraphobia peutic agent as a combined preparation for simultaneous, without history of panic disorder, specific phobias, e.g., separate or sequential use. Such combined preparations may specific animal phobias, social phobias, stress disorders 25 be, for example, in the form of a twin pack. including post-traumatic stress disorder and acute stress A further aspect of the invention comprises compounds of disorder, and generalized anxiety disorders; Schizophrenia the invention in combination with a or another 5-HTantago and other psychotic disorders, for example, Schizophreni nist and/or SSRI, e.g., a 5-HT antagonist such as form disorders, schizoaffective disorders, delusional disor ondansetron, granisetron, tropisetron or Zatisetron. Addi ders, brief psychotic disorders, shared psychotic disorders 30 tionally, the compounds of the invention may be adminis and psychotic disorders with delusions or hallucinations; tered in combination with an anti-inflammatory corticoster delirium, dementia, and amnestic and other cognitive or oid, such as dexamethasone. Furthermore, the compounds of neurodegenerative disorders, such as Alzheimer's disease, the invention may be administered in combination with a senile dementia, dementia of the Alzheimer's type, vascular chemotherapeutic agent Such as an alkylating agent, anti dementia, and other dementias, for example, due to HIV 35 metabolite, mitotic inhibitor or cytotoxic antibiotic, as disease, head trauma, Parkinson's disease, Huntington's described above. In general, the currently available dosage disease, Pick's disease, Creutzfeldt-Jakob disease, or due to forms of the known therapeutic agents for use in Such multiple etiologies; Parkinson's disease and other extra combinations will be suitable. pyramidal movement disorders such as -induced According to a further or alternative aspect, the invention movement disorders, for example, neuroleptic-induced par 40 provides compounds of the invention for use in the manu kinsonism, neuroleptic malignant syndrome, neuroleptic facture of a medicament for the treatment or prevention of induced acute dystonia, neuroleptic-induced acute akathisia, conditions that will be responsive to the introduction of neuroleptic-induced tardive dyskinesia and medication-in these compounds; or altering physiological phenomena duced postural tremor; Substance-related disorders arising associated with certain conditions to achieve a desired from the use of alcohol, amphetamines (or amphetamine 45 treatment of said condition(s), alone and/or in combination like Substances) caffeine, cannabis, cocaine, hallucinogens, with other drugs. Such conditions or physiological phenom inhalants and aerosol propellants, , opioids, phe ena include vasodilation, Smooth muscle contraction, bron nylglycidine derivatives, sedatives, hypnotics, and anxiolyt choconstriction, brain disorders such as vascular disorders, ics, which substance-related disorders include dependence e.g., blood flow disorders caused by vasodilation and vasos and abuse, intoxication, withdrawal, intoxication delirium, 50 pastic diseases Such as angina, Vascular headache, migraine withdrawal delirium, persisting dementia, psychotic disor and Reynaud's disease; and neuropathological disorders ders, mood disorders, anxiety disorders, sexual dysfunction including Parkinson's disease and Alzheimer's disease; and sleep disorders; epilepsy; Down's syndrome; demyeli modulation of the cardiovascular system; prophylaxis and nating diseases such as MS and ALS and other neuropatho control of the effects of occurrences of cerebral infarct logical disorders such as peripheral neuropathy, for example 55 (Apoplexia cerebri) Such as stroke or cerebral ischemia; and diabetic and chemotherapy-induced neuropathy, and post for the control of disorders of the intestinal tract which are therapeutic neuralgia, trigeminal neuralgia, segmental or characterized by disturbances of the serotoninergic system intercostal neuralgia and other neuralgias; and cerebral and also by disturbances of the carbohydrate metabolism; vascular disorders due to acute or chronic cerebrovascular stress-related somatic disorders; reflex sympathetic dystro damage such as cerebral infarction, Subarachnoid hemor 60 phy such as shoulder/hand syndrome; disorders of bladder rhage or cerebral edema. In an embodiment, conditions function Such as cystitis, bladder detrusor hyper-reflexia and characterized by serotonin excess or absence, (serotonergic incontinence; and pain or nociception attributable to or hypofunction or hyperfunction) do not include depression. associated with any of the foregoing conditions, especially Compounds of the invention may be used for the treat pain transmission in migraine. ment of the above conditions, as well as for vasodilation, 65 According to a further or alternative aspect, the invention Smooth muscle contraction, bronchoconstriction, brain dis provides compounds of the invention for use in the manu orders such as vascular disorders, e.g., blood flow disorders facture of a medicament for the treatment or prevention of US 7,153,858 B2 21 22 physiological disorders associated with serotonin excess or , tomoxetine, Veralipride, Vicqualine, , absence, e.g., serotonergic hypofunction or hyperfunction. and Zometapine, and pharmaceutically acceptable salts The invention also provides methods for treating or thereof, and St. John’s wortherb, or Hypericum perforatum, preventing physiological disorders associated with serotonin or extracts thereof. Preferred agents include excess or absence, e.g., serotonergic hypofunction or hyper 5 selective serotonin reuptake inhibitors, in particular, fluox function, which method comprises administration to a etine, fluvoxamine, paroxetine, and Sertraline and pharma patient in need thereof of an effective amount of a compound ceutically acceptable salts thereof. of the invention or a composition comprising a compound of Suitable classes of anti-anxiety agents of use in the the invention. invention include benzodiazepines and 5-HT agonists or For treating or preventing migraine, the compounds of the 10 antagonists, especially 5-HT, partial agonists, and corti invention may be used in conjunction with other anti cotropin releasing factor (CRF) antagonists. In addition to migraine agents, such as ergotamines or 5-HT agonists, benzodiazepines, other suitable classes of anti-anxiety especially Sumatriptan or rizatriptan. Likewise, for treating agents are nonbenzodiazepine sedative-hypnotic drugs such behavioral hyperalgesia, the compounds of the invention as Zolpidem; mood-stabilizing drugs such as clobazam, may be used in conjunction with an antagonist of N-methyl 15 gabapentin, lamotrigine, loreclezole, oXcarbamazepine, stir D-aspartate (NMDA), such as dizocilpine. ipentol and vigabatrin; and barbiturates. Suitable benzodi It will be further appreciated that for treating or prevent azepines of use in the invention include alprazolam, chlo ing anxiety and/or depression, the compounds of the inven rdizepoxide, clonazepam, chloraZepate, diazepam, tion may be used in combination with an antidepressant halazepam, lorezepam, oxazepam and prazepam, and phar agent or anti-anxiety agent. Suitable classes of antidepres maceutically acceptable salts thereof. Suitable examples of sant agents of use in the invention include: norepinephrine 5-HT agonists or antagonists of use in the invention reuptake inhibitors, selective serotonin reuptake inhibitors, include, in particular, the 5-HT, partial agonists buspirone, inhibitors, reversible monoamine oxi flesinoxan, gepirone, ipsapirone and pindolol, and pharma dase inhibitors, serotonin and noradrenaline reuptake inhibi ceutically acceptable salts thereof. Another class of anti tors, corticotropin releasing factor (CRF) antagonists, 25 anxiety agent of use in the invention are compounds having B-adrenoreceptor antagonists and atypical antidepressants. muscarinic cholinergic activity. Suitable compounds in this Another class of antidepressant agent of use in the invention class include ml muscarinic cholinergic receptor antagonists is noradrenergic and specific serotonergic antidepressants, Such as those compounds described in European Patent Such as . Suitable examples of norepinephrine Specification Nos. 0709 093, O 709 094 and 0 773 021 and reuptake inhibitors include amitripdyline, , 30 International Patent Specification No. WO 96/12711. doxepine, imipramine, , , Another class of anti-anxiety agent of use in the invention , , nortriptyline, and pro are compounds acting on ion channels. Suitable compounds triptyline and pharmaceutically acceptable salts thereof. in this class include carbamazepine, lamotrigine and val Suitable examples of selective serotonin reuptake inhibitors proate, and pharmaceutically acceptable salts thereof. include fluoxetine, fluvoxamine, paroxetine, and Sertraline 35 Therefore, in a further aspect of the invention, a pharma and pharmaceutically acceptable salts thereof. Suitable ceutical composition is provided comprising a compound of examples of monoamine oxidase inhibitors include isocar the invention and an antidepressant or an anti-anxiety agent, boxazid, , tranylcypromain and , and together with at least one pharmaceutically acceptable car pharmaceutically acceptable salts thereof. Suitable rier or excipient. examples of reversible monoamine oxidase inhibitors 40 Suitable antipsychotic agents of use in combination with include , and pharmaceutically acceptable salts the compounds of the invention include phenothiazines, e.g., thereof. Suitable examples of serotonin and noradrenaline chlorpromazine, mesoridazine, thioridazine, acetophena reuptake inhibitors include , and pharmaceuti Zine, fluiphenazine, perphenazine and trifluoperazine; thiox cally acceptable salts thereof. Suitable examples of corti anthenes, e.g., chlorprothixene or thiothixene; heterocyclic cotropin releasing factor (CRF) antagonists include those 45 dibenzazepines, e.g. clozapine or ; butyrophe compounds described in International Patent Specification nones, e.g., haloperidol; diphenylbutylpiperidines, e.g., Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO pimozide, and indolones, e.g., molindolene. Other antipsy 94/13676 and WO94/13677. Suitable examples of atypical chotic agents include loxapine, Sulpiride and . It antidepressants include bupropion, , nefaZoedone, will be appreciated that the antipsychotic agents when used Sibutramine, traZodone and , and pharmaceuti 50 in combination with the compounds of the invention may be cally acceptable salts thereof. Other antidepressants of use in in the form of a pharmaceutically acceptable salt, for the invention include adinozolam, alaproclate, , example, chlorpromazine hydrochloride, mesoridazine amitryptyline/chlordiazepoxide combination, atipamezole, besylate, thioridazine hydrochloride, acetophenazine male aZamianserin, , fefuraline, , binoda ate, fluiphenazine hydrochloride, flurphenazine enathate, line, bipenamol, , bupropion, , cer 55 fluphenazine decanoate, trifluoperazine hydrochloride, thio iclamine, cianopramine, cimoxatone, citalopram, clemeprol, thixene hydrochloride, haloperidol decanoate, loxapine Suc clovoxamine, dasepinil, deanol, , , cinate and molindone hydrochloride. Perphenazine, chlor dothiepin, droxidopa, enefexine, Setazolam, , prothixene, clozapine, olanzapine, haloperidol, pimozide femoxetine, fengabine, fezolamine, fluotracen, idazoxan, and risperidone are commonly used in a non-salt form. , , , levoprotiline, litoxetine, 60 Other classes of antipsychotic agent of use in combination , , , , with the compounds of the invention include , , , mirtazapine, montirelin, receptor antagonists, especially D2, D3 and D4 dopamine nebracetam, nefopam, , nomifensine, norfluoxet receptor antagonists, and muscarinic ml receptor agonists. ine, orotirelin, , pinazepam, pirindole, pizotyline, An example of a D3 dopamine receptor antagonist is the ritaserin, rolipram, Sercloremine, , Sibutramine, 65 compound PNU-99.194A. An example of a D4 dopamine Sulbutiamine, Sulpride, , thoZalinone, thy receptor antagonist is PNU-101387. An example of a mus moliberin, , tiflucarbine, , tofisopam, carinic ml receptor agonist is Xanomeline. US 7,153,858 B2 23 24 Another class of antipsychotic agent of use in combina does not treat one of the three main clinical features of tion with the compounds of the invention is the 5-HT, ADHD, namely inattentiveness, and in addition does not receptor antagonists, examples of which include normalize ADHD children. MDL100907 and fananserin. Also of use in combination The compounds of the invention may be administered to with the compound of the invention are the serotonin 5 patients (animals and humans) in need of Such treatment in dopamine antagonists (SDAS) which are believed to com dosages that will provide optimal pharmaceutical efficacy. It bine 5-HT, and dopamine receptor antagonist activity, will be appreciated that the dose required for use in any examples of which include olanzapine and Ziperasidone. particular application will vary from patient to patient, not Therefore, in a further aspect of the invention, a pharma only with the particular compound or composition selected, ceutical composition is provided comprising a compound of 10 but also with the route of administration, the nature of the the invention and an antipsychotic agent, together with at condition being treated, the age and condition of the patient, least one pharmaceutically acceptable carrier or excipient. concurrent medication or special diets then being followed The compounds of the invention and the other pharma by the patient, and other factors which those skilled in the art cologically active agent may be administered to a patient will recognize, with the appropriate dosage ultimately being simultaneously, sequentially or in combination. It will be 15 at the discretion of the attendant physician. appreciated that when using a combination of the invention, In the treatment of a condition associated with a serotonin the compound of the invention and the other pharmacologi excess or absence, e.g., serotonergic hypofunction or hyper cally active agent may be in the same pharmaceutically function, an appropriate dosage level will generally be about acceptable carrier and therefore administered simulta 0.001 to 50 mg/kg patient body weight per day, which may neously. They may be in separate pharmaceutical carriers be administered in single or multiple doses. If given orally, Such as conventional oral dosage forms which are taken the dosage level may be about 0.01 to about 30 mg/kg per simultaneously. The term “combination’ further refers to the day, e.g., 0.01 to about 1, 3, 5, 7, 10, 15, 20, 25 or 30 mg/kg case where the compounds are provided in separate dosage per day. If given intravenously, the dosage levels may be forms and are administered sequentially. somewhat lower, e.g., 0.01 to about 0.3, 1, 3, 5, 7 or 10 The invention also relates to the use of Such compounds 25 mg/kg per day. For example, in the treatment or prevention in the treatment of Attention Deficit Hyperactivity Disorder of a disorder of the central nervous system, a suitable oral (ADHD). ADHD, with or without hyperactivity (also dosage level may be about 0.01 to about 30 mg/kg per day, referred to in the literature as Attention Deficit Disorder/ e.g., 0.01 to about 1, 3, 5, 7, 10, 15, 20, 25 or 30 mg/kg per Hyperactivity Syndrome (ADD/HS)), is a condition (or day. The compounds may be administered on a regimen of group of conditions) characterized by impulsiveness, dis 30 1 to 4 times per day, preferably once or twice per day. tractibility, inappropriate behavior in social situations and It will be appreciated that the amount of the compound of hyperactivity. ADD/HS is reported to have a prevalence of the invention required for use in any treatment will vary not 3–5% (using DSM-IV criteria) in children. It is believed that only with the particular compounds or composition selected some 30–60% of such cases persist into adulthood. This but also with the route of administration, the nature of the disorder can impair social function, learning and/or devel 35 condition being treated, and the age and condition of the opment and is therefore now recognized as a serious prob patient, and will ultimately be at the discretion of the lem. It is further recognized that many children with ADHD attendant physician. go on to develop other co-morbid conditions or Social The compositions and combination therapies of the inven problems in adulthood. tion may be administered in combination with a variety of 40 pharmaceutical excipients, including Stabilizing agents, car In clinical terms, ADHD is diagnosed if any one of the riers and/or encapsulation formulations as described herein. three main clinical features—inattention, over-activity and Aqueous compositions of the present invention comprise impulsiveness persists in two or more situations, e.g., in an effective amount of the peptides of the invention, dis both a home and school environment (American Psychiatric Solved or dispersed in a pharmaceutically acceptable carrier Association. Diagnostic and Statistical Manual of Mental 45 or aqueous medium. Disorders, Fourth Edition (DSM-IV) Washington D.C.: "Pharmaceutically or pharmacologically acceptable' American Psychiatric Association, 1994). include molecular entities and compositions that do not A particularly severe form of ADHD is termed Hyperki produce an adverse, allergic or other untoward reaction netic Disorder. This diagnosis may be made if all three of the when administered to an animal, or a human, as appropriate. main clinical features (inattention, over-activity and impul 50 "Pharmaceutically acceptable carrier includes any and all siveness) have been present from an early age, persist in Solvents, dispersion media, coatings, antibacterial and anti more than one situation (e.g., home and School) and impair fungal agents, isotonic and absorption delaying agents and function (The ICD-10 Classification of Mental and Behav the like. The use of Such media and agents for pharmaceu ioural Disorders: Diagnostic Criteria for Research. Geneva: tical active substances is well known in the art. Except World Health Organization, 1993: 155–7). Reports indicate 55 insofar as any conventional media or agent is incompatible that 1 in 200 children suffer from hyperkinetic disorder. with the active ingredient, its use in the therapeutic compo There are currently only a few therapeutic agents which sitions is contemplated. Supplementary active ingredients are recognized as having efficacy in the treatment of child can also be incorporated into the compositions. hood ADHD; at present the drugs of choice include dextro For human administration, preparations should meet Ste amphetamine, pemoline, and in particular methylphenidate 60 rility, pyrogenicity, general safety and purity standards as (Ritalin). Antidepressants and antipsychotic required by FDA Office of Biologics standards. Such as risperidone may also be effective in Some cases, but The compositions and combination therapies of the inven these are not standard treatments. Although methylphenidate tion will then generally be formulated for parenteral admin is probably the most widely used drug in the treatment of istration, e.g., formulated for injection via the intravenous, ADHD, it suffers from a number of disadvantages: it is a 65 intramuscular, Subcutaneous, intralesional, or even intrap controlled drug: is extensively metabolized and may cause eritoneal routes. The preparation of an aqueous composition confusion and hallucinations. Moreover, methylphenidate that contains a composition of the invention or an active US 7,153,858 B2 25 26 component or ingredient will be known to those of skill in The use of sterile formulations, such as saline-based the art in light of the present disclosure. Typically, Such washes, by Surgeons, physicians or health care workers to compositions can be prepared as injectables, either as liquid cleanse a particular area in the operating field may also be Solutions or Suspensions; Solid forms Suitable for using to particularly useful. Therapeutic formulations in accordance prepare solutions or Suspensions upon the addition of a with the present invention may also be reconstituted in the liquid prior to injection can also be prepared; and the form of mouthwashes, or in conjunction with antifungal preparations can also be emulsified. reagents. Inhalant forms are also envisioned. The therapeutic The pharmaceutical forms suitable for injectable use formulations of the invention may also be prepared in forms include sterile aqueous solutions or dispersions; formula Suitable for topical administration, such as in cremes and tions including sesame oil, peanut oil or aqueous propylene 10 lotions. glycol, and sterile powders for the extemporaneous prepa Suitable preservatives for use in such a solution include ration of sterile injectable solutions or dispersions. In all benzalkonium chloride, benzethonium chloride, chlorobu cases the form must be sterile and must be fluid to the extent tanol, thimerosal and the like. Suitable buffers include boric that easy syringability exists. It must be stable under the acid, Sodium and potassium bicarbonate, sodium and potas conditions of manufacture and storage and must be pre 15 sium borates, sodium and potassium carbonate, Sodium served against the contaminating action of microorganisms, acetate, sodium biphosphate and the like, in amounts Sufi Such as bacteria and fungi. cient to maintain the pH at between about pH 6 and pH 8, Solutions of active compounds as free base or pharma and preferably, between about pH 7 and pH 7.5. Suitable cologically acceptable salts can be prepared in water Suit tonicity agents are dextran 40, dextran 70, dextrose, glyc ably mixed with a surfactant, such as hydroxypropylcellu erin, potassium chloride, propylene glycol, Sodium chloride, lose. Dispersions can also be prepared in glycerol, liquid and the like, such that the sodium chloride equivalent of the polyethylene glycols, and mixtures thereof and in oils. ophthalmic solution is in the range 0.9 plus or minus 0.2%. Under ordinary conditions of storage and use, these prepa Suitable antioxidants and stabilizers include sodium rations contain a preservative to prevent the growth of bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea microorganisms. 25 and the like. Suitable wetting and clarifying agents include Therapeutic or pharmacological compositions of the polysorbate 80, polysorbate 20, poloxamer 282 and tylox present invention will generally comprise an effective apol. Suitable viscosity-increasing agents include dextran amount of the component(s) of the combination therapy, 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, dissolved or dispersed in a pharmaceutically acceptable hydroximethylpropylcellulose, lanolin, methylcellulose, pet medium. Pharmaceutically acceptable media or carriers 30 rolatum, polyethylene glycol, polyvinyl alcohol, polyvi include any and all solvents, dispersion media, coatings, nylpyrrolidone, carboxymethylcellulose and the like. antibacterial and antifungal agents, isotonic and absorption Upon formulation, therapeutics will be administered in a delaying agents and the like. The use of Such media and manner compatible with the dosage formulation, and in Such agents for pharmaceutical active Substances is well known in amount as is pharmacologically effective. The formulations the art. Supplementary active ingredients can also be incor 35 are easily administered in a variety of dosage forms, such as porated into the therapeutic compositions of the present the type of injectable solutions described above, but drug release capsules and the like can also be employed. invention. In this context, the quantity of active ingredient and The preparation of pharmaceutical or pharmacological Volume of composition to be administered depends on the compositions will be known to those of skill in the art in 40 host animal to be treated. Precise amounts of active com light of the present disclosure. Typically, such compositions pound required for administration depend on the judgment may be prepared as injectables, either as liquid solutions or of the practitioner and are peculiar to each individual. Suspensions; Solid forms suitable for Solution in, or Suspen A minimal volume of a composition required to disperse sion in, liquid prior to injection; as tablets or other solids for the active compounds is typically utilized. Suitable regimes oral administration; as time release capsules; or in any other 45 for administration are also variable, but would be typified by form currently used, including cremes, lotions, mouth initially administering the compound and monitoring the washes, inhalants and the like. results and then giving further controlled doses at further Sterile injectable solutions are prepared by incorporating intervals. For example, for parenteral administration, a Suit the active compounds in the required amount in the appro ably buffered, and if necessary, isotonic aqueous solution priate solvent with various of the other ingredients enumer 50 would be prepared and used for intravenous, intramuscular, ated above, as required, followed by filtered sterilization. Subcutaneous or even intraperitoneal administration. One Generally, dispersions are prepared by incorporating the dosage could be dissolved in 1 ml of isotonic NaCl solution various sterilized active ingredients into a sterile vehicle and either added to 1000 ml of hypodermolysis fluid or which contains the basic dispersion medium and the injected at the proposed site of infusion, (see for example, required other ingredients from those enumerated above. In 55 Remington's Pharmaceutical Sciences 15th Edition, pages the case of sterile powders for the preparation of sterile 1035 1038 and 1570–1580). injectable solutions, the preferred methods of preparation In certain embodiments, active compounds may be are vacuum-drying and freeze-drying techniques which administered orally. This is contemplated for agents which yield a powder of the active ingredient plus any additional are generally resistant, or have been rendered resistant, to desired ingredient from a previously sterile-filtered solution 60 proteolysis by digestive enzymes. Such compounds are thereof. contemplated to include chemically designed or modified The preparation of more, or highly, concentrated Solutions agents; dextrorotatory peptides; and peptide and liposomal for intramuscular injection is also contemplated. In this formulations in time release capsules to avoid peptidase and regard, the use of DMSO as solvent is preferred as this will lipase degradation. result in extremely rapid penetration, delivering high con 65 Pharmaceutically acceptable salts include acid addition centrations of the active compound(s) or agent(s) to a small salts and which are formed with inorganic acids such as, for aca. example, hydrochloric or phosphoric acids, or Such organic US 7,153,858 B2 27 28 acids as acetic, oxalic, tartaric, mandelic, and the like. Salts Oral formulations include such normally employed formed with the free carboxyl groups can also be derived excipients as, for example, pharmaceutical grades of man from inorganic bases such as, for example, sodium, potas nitol, lactose, starch, magnesium Stearate, Sodium saccha sium, ammonium, calcium, or ferric hydroxides, and Such rine, cellulose, magnesium carbonate and the like. These organic bases as isopropylamine, trimethylamine, histidine, compositions take the form of Solutions, Suspensions, tab procaine and the like. lets, pills, capsules, Sustained release formulations or pow The carrier can also be a solvent or dispersion medium ders. containing, for example, water, , polyol (for example, In certain defined embodiments, oral pharmaceutical glycerol, propylene glycol, and liquid polyethylene glycol, compositions will comprise an inert diluent or assimilable and the like), suitable mixtures thereof, and vegetable oils. 10 edible carrier, or they may be enclosed in hard or soft shell The proper fluidity can be maintained, for example, by the gelatin capsule, or they may be compressed into tablets, or use of a coating, such as lecithin, by the maintenance of the they may be incorporated directly with the food of the diet. required particle size in the case of dispersion and by the use For oral therapeutic administration, the active compounds of Surfactants. The prevention of the action of microorgan may be incorporated with excipients and used in the form of isms can be brought about by various antibacterial and 15 ingestible tablets, buccal tables, troches, capsules, elixirs, antifungal agents, for example, parabens, chlorobutanol, Suspensions, syrups, wafers, and the like. Such compositions phenol, Sorbic acid, thimerosal, and the like. In many cases, and preparations should contain at least 0.1% of active it will be preferable to include isotonic agents, for example, compound. The percentage of the compositions and prepa Sugars or sodium chloride. Prolonged absorption of the rations may, of course, be varied and may conveniently be injectable compositions can be brought about by the use in between about 2 to about 75% of the weight of the unit, or the compositions of agents delaying absorption, for preferably between 25-60%. The amount of active com example, aluminum monostearate and gelatin. pounds in Such therapeutically useful compositions is such Sterile injectable solutions are prepared by incorporating that a suitable dosage will be obtained. the active compounds in the required amount in the appro The tablets, troches, pills, capsules and the like may also priate solvent with various of the other ingredients enumer 25 contain the following: a binder, as gum tragacanth, acacia, ated above, as required, followed by filtered sterilization. cornstarch, or gelatin; excipients, such as dicalcium phos Generally, dispersions are prepared by incorporating the phate; a disintegrating agent, such as corn starch, potato various sterilized active ingredients into a sterile vehicle starch, alginic acid and the like; a lubricant, Such as mag which contains the basic dispersion medium and the nesium Stearate; and a Sweetening agent, such as Sucrose, required other ingredients from those enumerated above. In 30 lactose or saccharin may be added or a flavoring agent, Such the case of sterile powders for the preparation of sterile as peppermint, oil of wintergreen, or cherry flavoring. When injectable solutions, the preferred methods of preparation the dosage unit form is a capsule, it may contain, in addition are vacuum-drying and freeze drying techniques which yield to materials of the above type, a liquid carrier. Various other a powder of the active ingredient plus any additional desired materials may be present as coatings or to otherwise modify ingredient from a previously sterile-filtered solution thereof. 35 the physical form of the dosage unit. For instance, tablets, The preparation of more, or highly, concentrated Solutions pills, or capsules may be coated with shellac, Sugar or both. for direct injection is also contemplated, where the use of A syrup of elixir may contain the active compounds Sucrose DMSO as solvent is envisioned to result in extremely rapid as a Sweetening agent methyl and propylparabensas preser penetration, delivering high concentrations of the active Vatives, a dye and flavoring, Such as cherry or orange flavor. agents to a small area. 40 The pharmaceutical compositions of this invention may Upon formulation, solutions will be administered in a be used in the form of a pharmaceutical preparation, for manner compatible with the dosage formulation and in Such example, in Solid, semisolid or liquid form, which contains amount as is therapeutically effective. The formulations are one or more of the compound of the invention, as an active easily administered in a variety of dosage forms, such as the ingredient, in admixture with an organic or inorganic carrier type of injectable solutions described above, but drug 45 or excipient Suitable for external, enteral or parenteral appli release capsules and the like can also be employed. cations. The active ingredient may be compounded, for For parenteral administration in an aqueous solution, for example, with the usual non-toxic, pharmaceutically accept example, the solution should be suitably buffered if neces able carriers for tablets, pellets, capsules, Suppositories, sary and the liquid diluent first rendered isotonic with Solutions, emulsions, Suspensions, and any other form Suit Sufficient saline or glucose. These particular aqueous solu 50 able for use. The carriers which can be used are water, tions are especially suitable for intravenous, intramuscular, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, Subcutaneous and intraperitoneal administration. In this con magnesium trisilicate, talc, corn starch, keratin, colloidal nection, sterile aqueous media which can be employed will silica, potato starch, urea and other carriers suitable for use be known to those of skill in the art in light of the present in manufacturing preparations, in Solid, semisolid, or liquid disclosure. 55 form, and in addition auxiliary, stabilizing, thickening and In addition to the compounds formulated for parenteral coloring agents and perfumes may be used. The active object administration, such as intravenous or intramuscular injec compound is included in the pharmaceutical composition in tion, other pharmaceutically acceptable forms include, e.g., an amount sufficient to produce the desired effect upon the tablets or other solids for oral administration; liposomal process or condition of the disease. formulations; time-release capsules; and any other form 60 For preparing Solid compositions such as tablets, the currently used, including cremes. principal active ingredient is mixed with a pharmaceutical Additional formulations suitable for other modes of carrier, e.g., conventional tableting ingredients such as corn administration include Suppositories. For Suppositories, tra starch, lactose, Sucrose, Sorbitol, talc, Stearic acid, magne ditional binders and carriers may include, for example, sium Stearate, dicalcium phosphate or gums, and other polyalkylene glycols or triglycerides; Such Suppositories 65 pharmaceutical diluents, e.g., water, to form a solid prefor may be formed from mixtures containing the active ingre mulation composition containing a homogeneous mixture of dient in the range of 0.5% to 10%, preferably 1%–2%. a compound of the invention, or a non-toxic pharmaceuti US 7,153,858 B2 29 30 cally acceptable salt thereof. When referring to these pre For treating clinical conditions and diseases noted above, formulation compositions as homogeneous, it is meant that the compound of this invention may be administered orally, the active ingredient is dispersed evenly throughout the topically, parenterally, by inhalation spray or rectally in composition so that the composition may be readily Subdi dosage unit formulations containing conventional non-toxic vided into equally effective unit dosage forms such as pharmaceutically acceptable carriers, adjuvants and tablets, pills and capsules. This solid preformulation com position is then Subdivided into unit dosage forms of the type vehicles. The term parenteral as used herein includes sub described above containing from 0.1 to about 500 mg of the cutaneous injections, intravenous, intramuscular, intrastemal active ingredient of the invention. The tablets or pills of the injection or infusion techniques. novel composition can be coated or otherwise compounded 10 Methods for preparing the compounds of this invention to provide a dosage form affording the advantage of pro- are illustrated in the following Example(s). The following longed action. For example, the tablet or pill can comprise examples are given for the purpose of illustrating the inven an inner dosage and an outer dosage component, the latter tion, but not for limiting the scope or spirit of the invention. being in the form of an envelope over the former. The two components can be separated by an enteric layer which 15 Synthesis of Arylpiperazinyl Sulfonamide Compounds serves to resist disintegration in the stomach and permits the Arylpiperazinyl Sulfonamide compounds of the invention inner component to pass intact into the duodenum or to be were synthesized by the following schemes. delayed in release. A variety of materials can be used for Such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids 20 SCHEME 1. with Such materials as shellac, cetyl alcohol and cellulose R acetate. YC SOCI The liquid forms in which the compositions of the inven- \ / 2 tion may be incorporated for administration orally or by Ho1N11 NH injection include aqueous solution, Suitably flavored syrups, 25 Et3N f CH2Cl2 aqueous or oil suspensions, and emulsions with acceptable 1 R2 oils such as cottonseed oil, Sesame oil, coconut oil or peanut O. O O. O oil, or with a solubilizing- or emulsifying agent Suitable for \WSn -SVW intravenous use, as well as elixirs and similar pharmaceu- N 1N-1 n N tical vehicles. Suitable dispersing or Suspending agents for 30 Ri i l --R aqueous Suspensions include synthetic and natural gums 2 2 21 Such as tragacanth, acacia, alginate, dextran, Sodium car- 2 boxymethylcellulose,ymelnyce methylcellulose,y polyvinylpyrrolipoly V1nylpy R4-6 \ / N 2 / EtN (THF done or gelatin. 7 N NH Compositions for inhalation or insufflation include solu- 35 RS V / Or 2 / EtN / CHCN tions and Suspensions in pharmaceutically acceptable, aque ous or organic solvents, or mixtures thereof, and powders. 3 The liquid or Solid compositions may contain Suitable phar- O. O maceutically acceptable excipients as set out above. Prefer- R4-6 \ / V -SV/ ably the compositions are administered by the oral or nasal 40 ( N 1N-1N N respiratory route for local or systemic effect. Compositions R’so \ / l --R in preferably sterile pharmaceutically acceptable solvents 2 2 may be nebulized by use of inert gases. Nebulized solutions 4 may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or 45 R=CH, CHCH, F intermittent positive pressure breathing machine. Solution, Suspension or powder compositions may be administered, R=H, CH, CHCH, CHCHCH c-CHs preferably orally or nasally, from devices which deliver the R. R. NO, CHO, CHCHO, CH, CHCH formulation in an appropriate manner. CHCHCH, CHCHCHCH (CH),C, (CH) CH, H

SCHEME 2 V / NA VNH Ho-2 / EtN / THF NA VN 1-1a N -S N \ / Or 2 / EtN / CH3CN \ / o R R 21 ON 5 ON 6

SnCl2 HCl ( MeOH Or H / Pd/C / EtOH / AcOH

US 7,153,858 B2 43 44 R=CH, CHCH, CHCHCH, CHCHCHCH (CH), To a solution of the product of Example 1 (150 mg 0.35 CH. (CH) CHCH (CH) C. c-CHCH. c-CH, mmol) in dichloromethane (0.5 ml) at ambient temperature c-C5Ho, c-CH7, c-CHs. was added 2 ml of 2M hydrochloride ether solution. The R=H, CH, CHCH, CHCHCH, CHCHCHCH precipitate was collected by filtration, washed with ether and (CH),CH, (CH),CHCH (CH) C. c-CHCH dried under vacuum overnight to give the salt of the product c-CH1, c-C5Ho, c-CH7, c-CHs. of Example 1, a white solid product (168 mg, 95% yield). X, Y=CH, N H NMR (400 MHz, CDOD): 8 (ppm) 7.83(s, 1H), 7.76 7.72(m, 3H), 7.51 (t, 1H), 7.447.38(m, 3H), 4.00(d, 2H), 3.69(m, 2H), 3.30 3.15(m, 6H), 2.90(t, 2H), 2.42(s, Preparation 1 10 3H), 1.88(m, 2H), 1.59(m, 2H); MS (APCI): m/z. 433 (MH: CH 100%) O O V/ H Sn O 1N1 nu-Nn S Preparation 2 15 O O CH H3C H N N 1N1N1 Nn S To an ice-cooled solution of amino alcohol 1 (1.0 g, 11.0 \ / 4 mmol) in anhydrous methylene chloride (25 mL) under N was added Et-N (6.1 mL, 44.0 mmol), followed by tosyl HN chloride (5.3.g. 28.0 mmol). The mixture was stirred at 0°C. for 3 h and then quenched with cold aqueous Saturated To a solution of tin chloride (3.5 g. 18.5 mmol) in NaHCO, solution (15 mL), and the organic phase was methanol (50 ml) and concentrated hydrochloride (10 ml) washed with water (3x15 mL). The organic layer was dried 25 was added a solution of the product of Example 1 (800 mg. over MgSO and filtered, and the solvent was removed under 1.85 mmol) in methanol (50 ml) in one portion at -10° C. reduced pressure to give a brownish-red residue. The crude The reaction mixture was allowed to warm to ambient material was used for next step without further purification. temperature and stirred until the reaction was complete as determined by TLC. The reaction was quenched by adding 30 10% sodium carbonate solution (200 ml) and extracted with CH dichloromethane (3x200 ml). The combined extracts were H dried over sodium sulfate and evaporated under reduced N 1n-1N-Nns pressure. The residue was separated by flash chromatogra \ / MV 35 phy on silica gel using dichloromethane-methanol (100:2) as O O an eluent to give the titled compound, 3-(4-(4-(tosylamino) ON butyl)piperazin-1-yl)benzenamine, (670 mg. 90% yield). The reduction was also done by hydrogenation with Pd/C as A mixture of 1-(3-nitro-phenyl)-piperazine (3.4 g. 16.4 catalyst. It gave the desired product. mmol); the product of Preparation 1.4-(tosylamino)butyl 40 "H NMR (400 MHz, CDC1): 8 (ppm) 7.75 (d. 2H), 7.29 4-methylbenzenesulfonate; (7.8 g. 19.6 mmol); triethyl (d. 2H), 7.09 (t, 1H), 6.41 (d. 1H), 6.30 (s, 1H), 6.28 (d. 1H), amine (2.4g, 23.7 mmol) in THF or CHCN (500 ml) was 3.65 (sb, 2H), 3.25–3.22 (m, 4H), 3.00 (t, 2H), 2.63–2.61 (m, stirred under nitrogen at ambient temperature for 48 hours. 4H), 2.45 (s, 3H), 2.41 (t, 2H), 1.64–1.60 (m, 4H); MS The reaction mixture was diluted with dichloromethane and (APCI): m/z 403 (MH"; 100%). washed with 10% aqueous sodium carbonate solution 45 (2x200 ml) and water (2x200 ml), dried over sodium sulfate. After removal of sodium sulfate, solvent was evaporated CH3 under reduced pressure. The residue was purified by flash H chromatography on silica gel using dichloromethane-metha N 1S-1N-Nns nol (100:2) as an eluent to give 5.4 g (76% yield) of the title 50 A V compound, 4-Methyl-N-(4-4-(3-nitro-phenyl)-piperazin-1- \ / O O yl-butyl-benzenesulfonamide. HN "H NMR (400 MHz, CDC1): 8 (ppm) 7.747.66 (m, 4H), O 7.40 (t, 1H), 7.29 (d. 2H), 7.22 7.20 (m, 1H), 3.34–3.2 (m, 4H), 2.99 (t, 1H), 2.63–2.61 (m, 4H), 2.42 (s, 3H), 2.39 (t, 55 2H), 1.61–1.59 (m, 4H); MS (APCI); m/z 433 (MH: 100%). To a solution of the product of Preparation 2 (31 mg, 0.077 mmol) in dichloromethane (3 ml) and pyridine (2 ml) CH 60 was added cyclopropanecarbonyl chloride (8.1 mg 0.077 mmol) at 0°C. The mixture was stirred at ambient tempera A V ~-N O ture overnight and the volatiles were removed under reduced N N S pressure. The residue was diluted with dichloromethane, V / 4. washed with 10% aqueous sodium carbonate solution ON 65 (2x100 ml) and water (2x100 ml), dried over sodium sulfate, purified with flash chromatography on silica gel (elunt: MeOH/CHCl2=1:100) to give the titled compound, Cyclo

US 7,153,858 B2 47 48 Reaction of the product of Preparation 2 with acetyl To a mixture of the product of Preparation 2 (31 mg, 0.077 chloride in dichloromethane as described in Example 3 gave mmol) and pyridine (2 ml) in dichloromethane (5 ml) was the desired product, N-(3-4-4-(Toluene-4-sulfonylamino)- added methanesulfonyl chloride (0.008 ml, 0.10 mmol) at 0° butyl-piperazin-1-yl)-phenyl)-acetamide, as a white solid. C. The mixture was stirred at ambient temperature overnight "H NMR (400 MHz, CDC1): 8 (ppm) 7.96 (d. 2H), 7.60 and concentrated on vacuum to dryness. The resulting (d. 1H), 7.44 (m,3H), 7.04 (d. 1H), 6.88 (t, 1H), 3.32 (t, 4H), residue was diluted with dichloromethane and washed with 3.04 (t, 2H), 2.68 (t, 4H), 2.46 (s, 3H), 2.42 (t, 2H), 2.28 (s, aqueous sodium carbonate solution, water, dried over 3H), 1.64 (m, 4H); MS (APCI); m/z. 445.8 (MH"; 100%). sodium sulfate, filtered, and concentrated. Purification by 10 silica gel chromatography (methanol/dichloromethane) gave EXAMPLE 9 36 mg (97%) of the desired product, N-(4-4-(3-Methane CH3 sulfonylamino-phenyl)-piperazin-1-yl)-butyl-4-methyl benzenesulfonamide, as a white Solid. H H NMR (400 MHz, CDC1): 7.71 (d. 2H), 7.27 (d. 2H), N --O 15 7.22 (t, 1H), 6.81 (s, 1H), 6.74 (d. 1H), 6.67 (d. 1H), 3.25 (t, - 4. \, 4H), 3.01 (s, 3H), 2.96 (t, 2H), 2.59 (t, 4H), 2.41 (s, 3H), HN 2.37 (t, 2H), 1.61–1.57 (m, 4H); MS (APCI); m/z 481 (MH: 100%).

EXAMPLE 12 Reaction of the product of Example 8 and hydrogen chloride in ether as described in Example 2 gave the desired white solid product, a salt of the compound of Example 8. H NMR (400 MHz, CDOD): 8 (ppm) 7.74 (d. 2H), 7.46 25 (d. 1H), 7.40 (d. 2H), 7.24 (t, 1H), 6.98 (d. 1H), 6.80 (t, 1H), 3.82 (t, 2H), 3.66 (t, 2H), 3.22 (m, 6H), 2.90 (t, 2H), 2.42 (s, 3H), 2.12 (s.3H), 1.86 (t, 2H), 1.58 (t, 2H); MS (APCI); m/z 445.8 (MH"; 100%). 30

EXAMPLE 10 CH Reaction of the product of Preparation 2 with propane 35 2-sulfonyl chloride in dichloromethane as described in H Example 11 gave the desired product, 4-Methyl-N-(4-4-3- N - O (propane-2-sulfonylamino)-phenyl-piperazin-1-yl)-butyl)- H 4. \, benzenesulfonamide, as a white Solid. HN H NMR (400 MHz, CDC1): 8 (ppm) 7.72(d. 2H), 7.26 40 (d. 2H), 7.18 (t, 1H), 6.85–6.84 (m. 1H), 6.71–6.67 (m, 2H), )—o 3.36–3.30 (m. 1H), 3.243.22 (m, 4H), 2.96 (t, 2H), 2.59–2.56 (m, 4H), 2.41 (s, 3H), 2.36 (t, 2H), 1.58–1.56 (m, Reaction of the product of Preparation 2 with propionyl 4H), 1.38 (d. 6H); MS (APCI); m/z 509 (MH"; 100%). chloride in dichloromethane as described in Example 3 gave the desired product, N-(3-4-4-(Toluene-4-sulfonylamino)- 45 butyl-piperazin-1-yl)-phenyl)-propionamide, as a white EXAMPLE 13 solid. CH3 "H NMR (400 MHz, CDC1): 8 (ppm) 8.30 (s, 1H), 7.72 - H (d. 2H), 7.40 (s, 1H), 7.32 (m, 3H), 6.84 (d. 1H), 6.62 (d. 50 1H), 3.26 (t, 4H), 2.94 (t, 2H), 2.62 (t, 4H), 2.40 (s.3H), 2.38 N N 11a-Na R O (m, 4H), 1.59(m, 4H), 1.24 (t, 3H); MS (APCI): m/z 459.4 (MH"; 100%). HNYé 55 / So EXAMPLE 11 Reaction of the product of Preparation 2 with ethanesulfo nyl chloride in dichloromethane as described in Example 11 11a-NH gave the desired product, N-(4-4-(3-Ethanesulfonylamino N N 2\ 60 phenyl)-piperazin-1-yl)-butyl-4-methyl-benzenesulfona mide, as a white Solid. NHV2O "H NMR (400 MHz, CDC1): 7.72 (d. 2H), 7.29 (d. 2H), /so 7.22 (t, 1H), 6.83 (t, 1H), 6.74 (d. 1H), 6.64 (d. 1H), 3.30 (t, CH 65 4H), 3.14 (q, 2H), 2.98 (t, 2H), 2.67 (t, 4H), 2.46 (t, 2H), 2.42 (s.3H), 1.62(t, 4H), 1.37 (t,3H); MS (APCI): m/z 495.5 (MH"; 100%). US 7,153,858 B2 49 50 Reaction of 1-pyridin-2-yl-piperazine and the product of Preparation 1 as described in Example 1 gave the desired EXAMPLE 14 product, 4-Methyl-N-4-(4-pyridin-2-yl-piperazin-1-yl)-bu CH3 tyl-benzenesulfonamide. 5 "H NMR (400 MHz, CDC1): 8 (ppm) 8.20 (d. 1H), 7.72 (d. 2H), 7.51–7.47 (m, 1H), 7.26 (d. 2H), 6.66–6.23 (m, 2H), KX- y-n-n-n S O 3.59 (t, 4H), 2.97 (t, 2H), 2.56 (t, 4H), 2.41 (s, 3H), 2.37 (t, \ / 4. \, 2H), 1.60–1.58 (m, 4H); MS (APCI); m/z 389 (MH: 100%). 10 Reaction of 1-phenyl-piperazine and the product of Prepa ration 1 as described in Example 1 gave the desired product, EXAMPLE 1.8 4-Methyl-N-4-(4-phenyl-piperazin-1-yl)-butyl-benzene CH3 Sulfonamide. "H NMR (400 MHz, CDC1): 8 (ppm) 7.72 (d. 2H), 15 o H 7.29 7.24 (m, 4H), 6.93 (d. 2H), 6.87 (t, 1H), 3.21 (t, 4H), ()- --O 2.96 (t, 2H), 2.58 (t, 4H), 2.39 (s. 3H), 2.53 (t, 2H), N \ / 1.62–1.54 (m, 4H); MS (APCI): m/z 388 (MH; 100%). 3HCI

EXAMPLE 1.5 Reaction of the product of Example 17 and hydrogen CH3 chloride in ether as described in Example 2 gave the desired white solid product, a salt of the compound of Example 17. N H 25 H NMR (400 MHz, CDOD): 8 (ppm) 8.17–8.08(m, 2H), 7.76(d. 2H), 7.48(d. 1H), 7.39(d. 2H), 7.15(t, 1H), (=N ) (\ /)-n-n- uC 4.41(m, 2H), 3.76(m, 4H), 3.33–3.23(m, 4H), 2.89(t, 2H), 2.43(s, 3H), 1.94–1.86(m, 2H), 1.63–1.56(m, 2H); MS (APCI): m/z 389 (MH"; 100%). Reaction of 2-piperazin-1-yl-pyrimidine and the product 30 of Preparation 1 as described in Example 1 gave the desired product, 4-Methyl-N-4-(4-pyrimidin-2-yl-piperazin-1-yl)- Preparation 3 butyl-benzenesulfonamide. ON "H NMR (400 MHz, CDC1): 8 (ppm) 8.36 (d. 2H), 7.78 (d. 2H), 7.34 (d. 2H), 6.52 (t, 1H), 3.90 (t, 4H), 3.00 (t, 2H), 35 N NH 2.54 (t, 4H), 2.42 (s, 3H), 2.36 (t, 2H), 1.60 (m, 4H); MS (APCI): m/z 390.2 (MH; 100%). OCH

EXAMPLE 16 40 A mixture of 2-methoxy-5-nitro-phenylamine (16.8 g., 0.1 CH3 mol), bis-(2-chloro-ethyl)-amine hydrochloride (17.8 g., 0.1 mol) and potassium carbonate (69 g, 0.5 mol) in chloroben N Zene (300 ml) was refluxed for 48 h, washed by water. The / )-N --O 45 water phase was extracted with dichloromethane. The FN \ / /\, organic layers were combined, dried over Sodium sulfate, purified with flash chromatography on silica gel (CH2Cl2/ MeOH) to give the desired product, 1-(2-methoxy-5-nitro phenyl)piperazine (10.7 g 45%). Reaction of the product of Example 15 and hydrogen 50 H NMR (400 MHz, CDC1): 8 (ppm) 7.95 (dd. 1H), 7.79 chloride in ether as described in Example 2 gave the desired (d. 1H), 6.90 (d. 1H), 3.98 (s.3H), 3.09 (s, 8H), 1.96 (s, 1H). white solid product, a salt of the compound of Example 15. MS (APCI): m/z 238 (MH"; 100%). "H NMR (400 MHz, CDOD): 8 (ppm) 9.28 (d. 2H), 8.22 (brs, 1H), 7.92 (d. 2H), 7.74 (t, 1H), 7.10 (brs, 1H), 4.26 55 EXAMPLE19 (t, 4H), 3.96 (t, 4H), 3.34 (m, 4H), 2.38 (s, 3H), 1.96 (m, 4H); MS (APCI): m/z 390.2 (MH; 100%). ON CH3 H N Y1\-1N-Nns EXAMPLE 17 AV 60 \ / 4. \, CH

Reaction of the product of Preparation 3 and the product 65 of Preparation 1 as described in Example 1 gave the desired product, N-(4-4-(2-Methoxy-5-nitro-phenyl)-piperazin-1- yl-butyl-4-methyl-benzenesulfonamide. US 7,153,858 B2 51 52 "H NMR (400 MHz, CDC1): 8 (ppm) 7.97 (dd. 1H), 7.8 (d. 1H), 7.74 (d. 2H), 7.32 (d. 2H), 6.91 (d. 1H), 3.98 (s.3H), 3.22–3.16 (m, 4H), 2.99 (t, 2H), 2.68–2.62 (m, 4H), 2.44 (s, Preparation 5 3H), 2.41 (t, 2H), 1.63–1.58 (m, 4H); MS (APCI): m/z 447 (MH"; 100%).

Preparation 4 HC O. O 10 VW no CH Reaction of (4-hydroxy-butyl)-carbamic acid tert-butyl N ester and tosyl chloride as described in 1 gave the desired H3C Ns/ \, 15 compound which was used without further purification. Preparation 6 Reaction of tosyl chloride and piperidin-4-yl-methanol as H described in Preparation 1 gave the desired compound, A V 1N1\-N O (1-tosylpiperidin-4-yl)methyl 4-methylbenzenesulfonate, which was used without further purification. V / rkO ON

EXAMPLE 20 25 Reaction of 1-(3-nitro-phenyl)-piperazine and the product of Preparation 5 as described in Example 1 gave the desired / \, CH3 compound, tert-butyl 4-(4-(3-nitrophenyl)piperazin-1-yl) butylcarbamate. & CO 30 "H NMR (400 MHz, CDC1): 8 (ppm) 7.78 (s, 1H), 7.67 (d. 1H), 7.41 (t, 1H), 7.21 (d. 1H), 5.21 (bs, 1H), 3.39–3.21 (m, 4H), 2.68 (m, 4H), 2.23 (m, 2H), 2.17 (m, 2H), 1.78–142 (m, 4H), 1.44 (s, 9H); MS (APCI): m/z. 379 MH: 100%) 35 Reaction of 1-(2-methoxy-phenyl)-piperazine and the Preparation 7 product of Preparation 4 as described in Example 1 gave the desired product, 1-(2-Methoxy-phenyl)-4-1-(toluene-4-sul N y1\-1S-1 NH2 fonyl)-piperidin-3-ylmethyl-piperazine. 40 \ / "H NMR (400 MHz, CDC1): 8 (ppm) 7.64 (d. 2H), 7.31 (d. 2H), 6.90 (m, 21H), 6.85 (d. 2H), 3.84 (s, 3H), 3.80 (t, ON 4H), 3.47 (d. 2H), 3.03 (t, 2H), 2.54 (t, 2H), 2.43 (s, 3H), 2.24 (m, 2H), 1.80 (t, 2H), 1.60 (m. 1H), 1.34 (m, 4H); MS 45 To a solution of the product of Preparation 6 (14.0 g, (APCI): m/z 444.2 (MH; 100%). 0.037 mol) in dichloromethane (100 mL) at 0 C, trifluoro acetic acid (10 mL, 0.13 mol) was added. The resultant solution was stirred for additional 2 hours. Solvent was EXAMPLE 21 evaporated under reduced pressure. Residue was washed with diethyl ether (100 mL). Precipitate was dried to obtain / \, CH3 50 product, 4-(4-(3-nitrophenyl)piperazin-1-yl)butan-1-amine (16.85g) in 90% yield. & CO H NMR (400 MHz, CDOD): 8 (ppm) 10.05 (bs, 1H), 7.79 7.42 (m, 4H), 4.07 3.48 (m, 4H), 3.25 (bs, 3H), 2.83 55 (m, 4H), 2.17 (m, 2H), 1.99–142 (m, 6H); MS (APCI): m/z 279 MH; 100%). The reaction was also done by using hydrogen chloride in dioxane to give the desired product. Reaction of the product of Example 20 and hydrogen chloride in ether as described in Example 2 gave the desired 60 Preparation 8 white solid product, a salt of the compound of Example 20. H "H NMR (400 MHz, CDOD): 8 (ppm) 7.82 (d. 2H), 7.44 N 1N1a-Ns (m. 1H), 7.38 (d. 2H), 7.16 (m, 3H), 4.01 (t, 4H), 3.80 (s, A- / \, 3H), 3.78 (t, 2H), 3.49 (d. 2H), 3.03 (t, 2H), 2.41 (s, 3H), 65 ON 2.19 (m, 2H), 1.96 (t, 2H), 1.63 (m. 1H), 1.30 (m, 4H); MS (APCI): m/z 444.2 (MH; 100%). US 7,153,858 B2 53 54 To a solution of the product of Preparation 7 (0.5 mmol) Reaction of the product of Preparation 10 and hydrogen in dichloromethane (25 ml) and triethylamine (0.75 mmol) chloride in ether as described in Example 2 gave the desired was added cyclohexyl-methanesulfonyl chloride (0.5 mmol) white solid product, a salt of the compound of Preparation at 0° C. The mixture was allowed to stir at 0° C. for 2–3 h 10. and the volatiles were removed under reduced pressure. The H NMR (400 MHz, CDOD): 8 (ppm) 7.50 (t, 1H), 7.27 residue was diluted with dichloromethane, washed with 10% (t, 1H), 7.02 (d. 1H), 6.85 (d. 1H), 3.88 (t, 2H), 3.74 (t, 2H), aqueous sodium carbonate solution (2x15 ml) and water 2.46 (t, 2H), 2.45 (t, 2H), 2.98 (d. 2H), 2.15 (s.3H), 1.99 (m, (2x15 ml) and dried over sodium sulfate. After removal of Solvent, the residue was purified with flash chromatography 6H), 1.68 (m, 6H), 1.33–1.02 (m, 7H); MS (APCI): m/z on silica gel (2% MeOH/CHCl) to give the titled com 10 451.3 (MH"; 100%) pound (75–88% yield). "H NMR (400 MHz, CDC1): 8 (ppm) 7.45 (s, 1H), 7.21 Preparation 11 (t, 1H), 6.97 (d. 1H), 6.75 (d. 1H), 3.85 (m, 2H), 3.63 (m 2H), 3.28–3.05 (m. 14H), 1.99–1.39 (m, 12H); MS (APCI): H m/z. 439 MH; 100%) 15 N \1-1-nu-Nns - / \, Preparation 9 HN O H N 1--1a-Nns a- 4. \, HN Reaction of the product of Preparation 9 with cyclopro 25 panecarbonyl chloride in dichloromethane as described in Reaction of the product of Preparation 9 and tin chloride Example 3 gave the desired product, Cyclopropanecarboxy or hydrogenation with Pd/C as catalyst as described in lic acid {3-4-(4-cyclohexylmethanesulfonylamino-butyl)- Preparation 2 gave the desired product. piperazin-1-yl-phenyl-amide, as a white solid. H NMR (400 MHz, CDC1): 8 (ppm) 7.50 (s, 1H), 7.11 "H NMR (400 MHz, CDC1): 8 (ppm) 741-7.17 (m, 2H), (t, 1H), 6.89 (d. 1H), 6.69 (d. 1H), 3.85 (bs, 2H), 3.63 (m 30 6.82 (d. 1H), 6.65 (d. 1H), 3.24(m, 4H), 3.05 (m, 4H), 2.87 2H), 3.35 3.02 (m, 16H), 2.01–144 (m, 12H); MS (APCI): (m, 4H), 2.62 (m, 4H), 2.41 (m. 2H) 1.95–1.49 (m. 13H), m/z 409 MH; 100%) 1.38 0.91 (m, 5H); MS (APCI): m/z 477 (MH; 100%)

Preparation 10 35 EXAMPLE 23 H NA vN ~-N \ N \1-1-1Ns \ / / WO A- / \, 40 HN HN )—o O Reaction of the product of Preparation 9 with acetyl 45 chloride in dichloromethane as described in Example 3 gave Reaction of the product of Preparation 11 and hydrogen the desired product, N-3-4-(4-Cyclohexylmethanesulfo chloride in ether as described in Example 2 gave the desired nylamino-butyl)-piperazin-1-yl)-phenyl)-acetamide, as a white solid product, a salt of the product of Preparation 11. white solid. 50 H NMR (400 MHz, CDOD): 8 (ppm) 7.48 (s, 1H), 7.27 "H NMR (400 MHz, CDC1): 8 (ppm) 7.44 (s, 1H), 7.30 (t, 1H), 6.92 (d. 1H), 6.71 (d. 1H), 4.84 (bs, 4H), 3.90 (m, (s, 1H), 7.20 (t, 1H), 6.93 (d. 1H), 6.70 (brs, 1H), 6.68 (d. 2H), 3.68 (m 2H), 3.34–3.02 (m, 15H), 1.95–1.49 (m. 10H), 1H), 3.27 (t, 4H), 3.15 (t, 2H), 2.89 (d. 2H), 2.46 (t, 4H), 1.38 0.91 (m, 5H); MS (APCI): m/z 477 (MH; 100%) 2.45 (t, 2H), 2.19 (s, 3H), 1.99 (t, 2H), 1.68 (m, 7H), 1.33–1.02 (m, 6H); MS (APCI): m/z 451.3 (MH"; 100%) 55 Preparation 12

EXAMPLE 22 H H N \1\-1N-Ns N 1N1a-Nns 60 H / \, - / \, ON HN

65 Reaction of propane-2-sulfonyl chloride and the product )-o of Preparation 7 as described in Preparation 8 gave the desired product. US 7,153,858 B2 55 56 "H NMR (400 MHz, CDOD): 8 (ppm) 7.81-7.69(m, 3.41–3.31(m,9H), 2.17(t,3H), 1.97-191(m, 2H), 1.72-1.65 2H), 7.447.22(m, 2H), 6.60(sb, 1H), 3.44–3.33(m, 4H), (m. 2H), 1.38(d. 6H), MS (APCI); m/z 397 (MH"; 100%). 3.243.13(m, 3H), 2.75–2.64(m, 4H), 2.58–2.50(m, 2H), 1.77–1.70(m, 4H), 1.40(d. 6H); MS (APCI): m/z 385 (MH: 100%). Preparation 15 H Preparation 13 N 1N1-S-Ns H / \, 10 N ----- ON H / \, HN 15 Reaction of 2-methyl-propane-1-sulfonyl chloride and the product of Preparation 7 as described in Preparation 8 gave the desired product. The crude mixture was used for reduc Reaction of the product of Preparation 9 and tin chloride tion without further purification. as described in Preparation 2 gave the desired product. "H NMR (400 MHz, CDOD): 8 (ppm)7.04(t, 1H), 6.36 MS (APCI); m/z 399 (MH"; 100%). (d. 1H), 6.26–6.21 (m, 2H), 3.60(sb, 2H), 3.22–3.01(m, 7H), 2.63–2.61 (m, 4H), 2.44(t, 2H), 1.70—1.64(m, 4H), 1.34(d. 6H), MS (APCI); m/z. 355 (MH"; 100%). Preparation 16 25 A V -N-N-N Preparation 14 N\ /N /\,(1 H HN N y-s-s 30 V- / \, Reaction of the product of Preparation 15 and tin chloride HN or hydrogenation or the product of Preparation 15 by using Pd/C as catalyst as described in Preparation 2 gave the 35 desired product. )—o H NMR (400 MHz, CDC1): 8 (ppm) 7.03(t, 1H), 6.37–6.34(m, 1H), 6.25-6.20(m, 2H), 3.21–3.18(m, 4H), 3.08(t, 2H), 2.85(d. 2H), 2.61–2.85(m, 4H), 2.42(t, 2H), 40 2.27 2.16(m, 1H), 1.68–1.61 (m, 4H), 1.08(d. 6H), MS Reaction of the product of Preparation 13 with acetyl chloride in dichloromethane as described in Example 3 gave (APCI): m/z. 369 (MH"; 100%). the desired product, N-(3-4-4-(Propane-2-sulfonylamino)- butyl-piperazin-1-yl)-phenyl)-acetamide, as a white solid. Preparation 17 "H NMR (400 MHz, CDC1): 8 (ppm) 7.32 7.21(m, 2H), 45 6.92(d. 1H), 6.71 (d. 2H), 3.29–3.11(m, 7H), 2.67–2.66(m, H 4H), 2.50 2.48(m, 2H), 2.22(s, 3H), 1.77–1.66(m, 4H), N N1-1\-Nns 1.39(d. 6H); MS (APCI); m/z 397 (MH; 100%). H / \, HN 50 EXAMPLE 24 )—o

55 Reaction of the product of Preparation 16 and acetyl chloride in dichloromethane as described in Example 3 gave the desired product, N-(3-4-4-(2-Methyl-propane-1-sulfo 60 nylamino)-butyl-piperazin-1-yl)-phenyl)-acetamide, as a white solid. Reaction of the product of Preparation 14 and hydrogen "H NMR (400 MHz, CDC1): 8 (ppm) 7.02(t, 1H), 6.36(d, chloride in ether as described in Example 2 gave the desired 1H), 6.24(t, 1H), 6.21 (d. 1H), 3.21–3.18(m, 4H), 3.08(t, white solid product, a salt of the product of Preparation 14. 65 2H), 2.85(d. 2H), 2.61–2.59(m, 4H), 2.42(t, 2H), 2.27 2.20 "H NMR (400 MHz, CD,OD): 8 (ppm) 7.50(s, 1H), (m. 1H), 1.68–1.61 (m, 4H), 1.08(d. 6H); MS (APCI): m/z 7.27(m, 1H), 7.02(d. 1H), 6.84(d. 1H), 3.903.72(m, 4H), 411 (MH"; 100%). US 7,153,858 B2 57 58

EXAMPLE 25 Preparation 19 H N N1)-1\-Nns s a- / \, ()- N1)n-1\-1Ne, HN

2HC 10 ON

Reaction of 1-(3-nitro-phenyl)-piperazine and toluene-4- Reaction of the product of Preparation 17 and hydrogen sulfonic acid 4-(tert-butoxycarbonyl-methyl-amino)-butyl chloride in ether as described in Example 2 gave the desired ester as described in Example 1 gave the desired compound. white solid product, a salt of the product of Preparation 17. 15 "H NMR (400 MHz, CDOD): 8 (ppm) 7.5(s, 1H), 7.22(t, H NMR (400 MHz, CDC1): 8 (ppm) 7.75 (s, 1H), 7.63 1H), 6.95(d. 1H), 6.78(d. 1H), 3.83(d. 2H), 3.67(d. 2H), (dd. 1H), 7.34 (t, 1H), 7.19 (dd. 1H), 3.47 (m, 4H), 2.68 (m, 3.28–3.22(m, 4H), 3.14–3.05(m, 4H), 2.95(d. 2H), 4H), 2.37 (s.3H), 2.23 (m, 2H), 2.17 (m, 2H), 1.88-1.45 (m, 2.23–2.15(m, 1H), 2.12(s, 3H), 1.94–1.86(m, 2H), 4H), 1.44 (s, 9H); MS (APCI); m/z 393 MH; 100%) 1.67–1.61(m, 2H), 1.10(d. 6H); MS (APCI); m/z 411 (MH: 100%). Preparation 20 H Preparation 18 N 1\-1\-ne, 25 \ / 1N1 S-1 N ON N N 7\ \ / /\, 30 Reaction of the product of Preparation 19 and TFA as HN described in Preparation 7 gave the desired product. "H NMR (400 MHz, CD,OD): 8 (ppm) 7.75 (s, 1H), 7.53 (t, 1H), 7.25 (d. 1H), 7.09 (d. 1H), 4.56 (bs, 3H), 3.48 (m, 35 4H), 2.78 (m, 4H), 2.27 (s.3H), 2.13 (m, 2H), 1.99–145 (m, 6H), MS (APCI); m/z 293 MH"; 100%) Reaction of cyclohexanesulfonic acid (4-4-(3-amino phenyl)-piperazin-1-yl)-butyl-amide and acetyl chloride in dichloromethane as described in Example 3 gave the desired Preparation 21 product, N-3-4-(4-Cyclohexanesulfonylamino-butyl)-pip erazin-1-yl)-phenyl)-acetamide, as a white solid. 40 "H NMR (400 MHz, CDC1): 8 (ppm) 7.36 (t, 1H), 7.28 N N 1N1\1 N n S (t, 1H), 6.91 (d. 1H), 6.73 (d. 1H), 3.28 (t, 4H), 3.16 (t, 2H), 2.86 (m. 1H), 2.66 (t, 4H), 2.49 (t, 2H), 2.21 (s, 3H), - / \, 1.99-1.12 (m. 14H); MS (APCI): m/z 437.3 (MH; 100%) 45 ON

EXAMPLE 26 Reaction of cyclohexyl-methanesulfonyl chloride and the product of Preparation 20 as described in Preparation 8 gave the desired product. H NMR (400 MHz, CDC1): 8 (ppm) 7.35 (s, 1H), 7.23 (t, 1H), 6.94 (d. 1H), 6.81 (d. 1H), 3.87 (n, 2H), 3.68 (m 2H), 3.25–3.03 (m. 14H), 2.17 (s.3H), 1.96-1.34 (m. 11H): MS (APCI); m/z 453 MH"; 100%) 55

Preparation 22

Reaction of the product of Preparation 18 and hydrogen 60 chloride in ether as described in Example 2 gave the desired white solid product, a salt of the product of Preparation 18. "H NMR (400 MHz, CDOD): 8 (ppm) 7.69 (t, 1H), 7.42 HN (t, 1H), 7.22 (d. 1H), 7.13 (d. 1H), 3.78 (t, 2H), 3.62 (t, 2H), 3.46 (t, 2H), 3.01 (m. 1H), 2.98 (t, 4H), 2.49 (t, 2H), 2.19 (s. 65 3H), 2.14 (t, 2H), 1.99–1.12 (m. 14H); MS (APCI): m/z Reaction of the product of Preparation 21 and tin chloride 437.3 (MH"; 100%) as described in Preparation 2 gave the desired product. US 7,153,858 B2 59 60 "H NMR (400 MHz, CDC1): 8 (ppm) 7.25 (m, 2H), 6.937 2H), 3.29–302 (m. 14H), 2.17 (s, 3H), 1.97-1.34 (m, 7H): (d. 1H), 6.30 (d. 1H), 3.85 (bs, 2H), 3.63 (m 2H), 3.28–3.05 MS (APCI): m/z 413 MH; 100%) (m. 16H), 2.17 (s, 3H), 1.99–1.39 (m. 11H); MS (APCI): m/z 423 MH; 100%) Preparation 25 Preparation 23 - t CH3 N N 1N1 Su-Nn S N 1a1n-Nns 10 \ / (1 - 4. \, HN HN Reaction of the product of Preparation 24 and tin chloride )—o 15 or hydrogenation of the product of Preparation 24 by using Pd/C as catalyst as described in Preparation 2 gave the desired product. "H NMR (400 MHz, CDC1): 8 (ppm) 7.27 (s, 1H), 7.13 Reaction of the product of Preparation 22 and acetyl (t, 1H), 6.95 (d. 1H), 6.74 (d. 1H), 3.95 (bs, 2H), 3.65 (m chloride in dichloromethane as described in Example 3 gave 2H), 3.29–3.03 (m, 16H), 2.17 (s, 3H), 1.99–1.39 (m, 5H): the desired product, N-(3-4-4-(Cyclohexylmethanesulfo MS (APCI); m/z 383 MH"; 100%) nyl-methyl-amino)-butyl-piperazin-1-yl)-phenyl)-aceta mide, as a white solid. 25 Preparation 26 "H NMR (400 MHz, CDC1): 8 (ppm) 7.37 (s, 1H), 7.15 (t, 1H), 6.98 (d. 1H), 6.71 (d. 1H), 3.43–3.25 (m, 6H), CH3 2.97–147 (m 301H); MS (APCI): m/z. 465 (MH"; 100%) N 1)N-1N-Ns 30 \ / / \, EXAMPLE 27 HN N Y1-1a-Nns )—o - / \, 35 HN )—o Reaction of the product of Preparation 25 and acetyl 40 chloride in dichloromethane as described in Example 3 gave the desired product, N-(3-4-1-(Propane-2-sulfonyl)-pip eridin-4-ylmethyl-piperazin-1-yl)-phenyl)-acetamide, as a white solid. Reaction of the product of Preparation 23 and hydrogen chloride in ether as described in Example 2 gave the desired 45 H NMR (400 MHz, CDC1): 8 (ppm) 7.47 (s, 1H), 7.23 white solid product, a salt of the product of Preparation 23. (t, 1H), 6.98 (d. 1H), 6.73 (d. 1H), 3.43–3.25 (m, 6H), "H NMR (400 MHz, CDC1): 8 (ppm) 7.42 (s, 1H), 7.21 2.97–1.17 (m. 26H); MS (APCI): m/z 425 (MH"; 100%). (t, 1H), 6.97 (d. 1H), 6.75 (d. 1H), 4.84 (bs, 4H), 3.85 (m, 2H), 3.63 (m 2H), 3.28–3.05 (m. 13H), 2.07 (s, 3H), 50 CH 1.99–1.15 (m. 14H); MS (APCI); m/z 465 (MH; 100%).

Preparation 24 CH 55 ()-Orr N 1N1\-Nns - / \, )—o ON 60

Reaction of 2-methyl-propane-1-sulfonyl chloride and the Reaction of the product of Preparation 26 and hydrogen product of Preparation 20 as described in Preparation 8 gave chloride in ether as described in Example 2 gave the desired the desired product. 65 white solid product, a salt of the product of Preparation 26. "H NMR (400 MHz, CDC1): 8 (ppm) 7.26 (s, 1H), 7.12 H NMR (400 MHz, CDOD): 8 (ppm) 7.45 (s, 1H), 7.26 (t, 1H), 6.96 (d. 1H), 6.77 (d. 1H), 3.89 (m, 2H), 3.65 (m (t, 1H), 6.97 (d. 1H), 6.85 (d. 1H), 4.87 (bs, 4H), 3.87 (m, US 7,153,858 B2 61 62 2H), 3.73 (m 2H), 3.38 3.05 (m, 12H), 2.07 (s, 3H), 1.99–1.15 (m, 1H); MS (APCI): m/z 425 (MH; 100%) Preparation 29 Preparation 27 N y-n-n-Ns, H 1N1N1 N O \ / SO N N r K N O V OMe 10 Reaction of {3-4-(4-amino-butyl)-piperazin-1-yl)-phe Reaction of 1-(2-methoxy-phenyl)-piperazine and the nyl)-dimethyl-amine and cyclohexyl-methanesulfonyl chlo product of Preparation 5 as described in Example 1 gave the ride as described in Preparation 8 gave desired compound, desired compound. 15 C-Cyclohexyl-N-(4-4-(3-dimethylamino-phenyl)-piper "H NMR (400 MHz, CDC1): 8 (ppm) 7.02 (m, 4H), 3.92 azin-1-yl)-butyl-methanesulfonamide. (s.3H), 3.21 (t, 6H), 2.76 (t, 4H), 2.44 (t, 2H), 1.60 (m, 4H), "H NMR (400 MHz, CDC1): 8 (ppm) 7.12 (t, 1H), 6.33 1.41 (s, 9H); MS (APCI); m/z. 364.5 (MH"; 100%) (t, 2H), 6.30 (s, 1H), 3.24 (t, 2H)3.03 (t, 2H), 2.92 (s, 6H), 2.88 (d. 2H), 2.64 (t, 4H), 2.44 (t, 2H), 1.95 (m, 3H), 1.67 (m, 8H), 1.32-1.01 (m, 6H); MS (APCI); m/z 437.5 (MH"; Preparation 28 100%). N '1N1a- NH2 \ / EXAMPLE 31 OMe 25 H N 1N1a-Nns Reaction of the product of Preparation 27 and TFA as \- 4. \, described in Preparation 7 gave the desired product. -N "H NMR (400 MHz, CDOD): 8 (ppm) 7.29 (m, 2H), 6.64 30 V (m. 2H), 3.90 (s, 3H), 3.28 (t, 2H), 3.19 (t, 2H), 3.01 (t, 2H), 2.62 (t, 4H), 2.39 (t, 2H), 1.55 (m, 4H); MS (APCI): m/z 264.3 (MH"; 100%) Reaction of the product of Preparation 29 and hydrogen chloride in ether as described in Example 2 gave the desired 35 white solid product, a salt of the product of Preparation 29. H "H NMR (400 MHz, CDOD): 8 (ppm) 749 (t, 1H), 7.34 N Y1a1n-Nns (m. 1H), 7.19 (m, 2H), 4.02 (t, 2H)3.72 (t, 2H), 3.70 (t, 6H), V- / \, 3.12 (s, 6H), 3.13 (t, 2H), 2.95 (d. 2H), 1.93 (m, 5H), 1.74 (m, 4H), 1.44–1.01 (m, 6H); MS (APCI): m/z 437.5 (MH"; OMe 40 100%). Reaction of cyclohexyl-methanesulfonyl chloride and the product of Preparation 28 as described in Preparation 8 gave Preparation 30 the desired product, C-Cyclohexyl-N-(4-4-(2-methoxy phenyl)-piperazin-1-yl)-butyl-methanesulfonamide. 45 "H NMR (400 MHz, CDC1): 8 (ppm) 6.98 (m, 4H), 3.86 (s, 3H), 3.10 (t, 6H), 2.85 (d. 2H), 2.64 (t, 2H), 2.49 (t, 2H) /FN \ Cr-rk 198(m, 3H), 1.67 (m, 8H), 1.26–0.91 (m, 6H); MS (APCI): m/z 424.2 (MH; 100%). Reaction of 1-pyridin-2-yl-piperazine and the product of 50 Preparation 5 as described in Example 1 gave the desired compound. EXAMPLE 30 H NMR (400 MHz, CDC1): 8 (ppm) 8.20–8.18(m. 1H), 7.50 7.45(m, 1H), 6.66–6.61(m, 2H), 5.40(sb, 1H), 55 3.58–3.56(m, 4H), 3.16(m, 2H), 2.57–2.54(m, 4H), 2.40(t, 2H), 1.60–1.56(m, 4H), 1.43(s, 9H); MS (APCI): m/z 335 (MH"; 100%).

Preparation 31 Reaction of the product of Example 29 and hydrogen 60 chloride in ether as described in Example 2 gave the desired white solid product, a salt of the product of Example 29. / \, \ \-N-N-NH. "H NMR (400 MHz, CDOD): 8 (ppm) 7.91 (d. 1H), 7.48 \ / (m. 1H), 7.22 (d. 2H), 3.80 (s.3H), 3.52 (t, 4H), 3.41 (t, 2H), 2.91 (d. 2H), 2.89 (t, 2H), 2.77 (t, 2H) 2.51 (t, 2H), 1.62 (m, 65 TFA 9H), 1.29–0.86 (m, 6H); MS (APCI): m/z 424.2 (MH"; 100%). US 7,153,858 B2 63 64 Reaction of the product of Preparation 30 and TFA as H NMR (400 MHz, CDC1): 8 (ppm) 7.80 7.77 (m, 2H), described in Preparation 7 gave the desired product. 723-7.10 (m, 3H), 6.33–6.27 (m, 3H), 3.80 (d. 2H), 3.14 (t, "H NMR (400 MHz, CDOD): 8 (ppm) 8.15-8.13(m, 4H), 2.92 (s, 6H), 2.50 (t, 4H), 2.27 (t, 2H), 2.20 (d. 2H), 1H), 7.84 7.80(m, 1H), 7.13(d. 1H), 6.95(t, 1H), 3.92–3.84 1.85 (d. 2H), 1.50-1.42 (m. 1H), 1.34–1.27 (m, 2H); MS (m, 4H), 3.48–3.40(m, 4H), 3.24-322(m, 2H), 3.00(t, 2H), 5 1.90–1.84(m, 2H), 1.76–172(m, 2H); MS (APCI); m/z 235 (APCI): m/z 461 (MH"; 100%). (MH"; 100%) EXAMPLE 33

Preparation 32 10

()- -n-n-N/ (H3C)NS-Oro A V Or 3HC O O \ / \ / / 15

Reaction of cyclohexyl-methanesulfonyl chloride and the Reaction of the product of Preparation 33 and hydrogen product of Preparation 31 as described in Preparation 8 gave chloride in ether as described in Example 2 gave the desired the desired product, C-Cyclohexyl-N-4-(4-pyridin-2-yl white solid product, a salt of the product of Preparation 33. piperazin-1-yl)-butyl-methanesulfonamide. "H NMR (400 MHz, CDC1): 8 (ppm) 10.78(sb, 1H), "H NMR (400 MHz, CDC1): 8 (ppm) 8.198.18 (m, 1H), 7.92–7.88(m, 2H), 7.58(t, 2H), 7.39 7.36(m. 1H), 7.20–6.90 7.50 7.46 (m. 1H), 6.66–6.61 (m, 2H), 3.61–3.59(m, 4H), 25 3.10(t, 2H), 2.86(d. 2H), 2.60 2.58(m, 4H), 2.44(t, 2H), (m, 3H), 3.86(d. 2H), 3.71–3.34(m, 6H), 3.10(m, 9H), 11.96–1.92(m, 3H), 1.71–1.62(m, 7H), 1.30-1.03(m, 5H): 2.31(t, 2H), 2.03–195(m, 3H), 1.37-1.30(m, 3H); MS MS (APCI); m/z 395 (MH"; 100%). (APCI): m/z 461 (MH"; 100%).

30 EXAMPLE32 Preparation 34 / N / \, O ()-\ \ \ / -n-n-N4/ 35 - O

40 Reaction of 1-pyridin-2-yl-piperazine and 4-fluoro-ben Zenesulfonic acid 1-(4-fluoro-benzenesulfonyl)-piperidin-4- Reaction of the product of Preparation 32 and hydrogen ylmethyl ester as described in Example 1 gave the desired chloride in ether as described in Example 2 gave the desired product, 1-1-(4-Fluoro-benzenesulfonyl)-piperidin-4-ylm white solid product, a salt of the product of Preparation 32. ethyl-4-pyridin-2-yl-piperazine. "H NMR (400 MHz, CDOD): 8 (ppm) 8.21-8.17(m, 45 H NMR (400 MHz, CDC1): 8 (ppm) 8.01 (d. 1H), 7.91 1H), 8.09(d. 1H), 7.52(d. 1H), 7.18(t, 1H), 4.41 (d. 2H), 3.80 3.70(m, 4H), 3.35–3.29(m, 4H), 3.12(t, 2H), 2.95(d, (d. 1H), 7.77 (t, 2H), 7.62 (d. 1H), 7.02 (t, 2H), 6.95 (t, 1H), 2H), 1.96–1.90(m, 5H), 1.77–1.64(m, 5H), 1.42–1.11(m, 3.75 (t, 4H), 3.41 (t, 2H), 3.22 (t, 2H), 3.13 (t, 2H), 2.21 (t, 5H); MS (APCI); m/z 395 (MH"; 100%). 2H), 1.77 (m, 3H), 1.39 (m, 4H); MS (APCI): m/z. 419.6 50 (MH"; 100%). Preparation 33 EXAMPLE 34 55 / N / \, O (H3C)NS-Oro AV Or O O - no

60 Reaction of dimethyl-(3-piperazin-1-yl-phenyl)-amine Reaction of the product of Preparation 34 and hydrogen and 4-fluoro-benzenesulfonic acid 1-(4-fluoro-benzene chloride in ether as described in Example 2 gave the desired sulfonyl)-piperidin-4-ylmethyl ester as described in white solid product, a salt of the product of Preparation 34. Example 1 gave the desired product, (3-4-1-(4-Fluoro 65 benzenesulfonyl)-piperidin-4-ylmethyl-piperazin-1-yl)- "H NMR (400 MHz, CDOD): 8 (ppm) 8.16 (t, 1H), 8.08 phenyl)-dimethyl-amine. (d. 1H), 7.85 (t, 2H), 7.50 (d. 1H), 7.36 (t, 2H), 7.15 (t, 1H), US 7,153,858 B2 65 66 3.83 (t, 4H), 3.35 (t, 2H), 3.25 (t, 2H), 3.17 (t, 2H), 2.36 (t, the desired product, N-(3-4-1-(4-Fluoro-benzenesulfo 2H), 1.98 (m, 3H), 1.43 (m, 4H); MS (APCI): m/z. 419.6 nyl)-piperidin-4-ylmethyl-piperazin-1-yl)-phenyl)-aceta (MH"; 100%). mide, as a white Solid. "H NMR (400 MHz, CDC1): 8 (ppm) 7.80 7.76(m, 2H), 7.32 7.13(m, 5H), 6.78(d. 1H), 6.63(d. 1H), 3.79(d. 2H), 3.14(t, 4H), 2.47(t, 4H), 2.28–2.10(m, 7H), 1.83(d. 2H), Preparation 35 1.47–1.43(m, 1H), 1.33–123(m, 2H); MS (APCI); m/z 457 (MH"; 100%). 10 N N OC F EXAMPLE 35 15

Reaction of 1-(3-nitro-phenyl)-piperazine and 4-fluoro ()-O r n O F benzenesulfonic acid 1-(4-fluoro-benzenesulfonyl)-piperi din-4-ylmethyl ester as described in Example 1 gave the )- O /\, desired compound. "H NMR (400 MHz, CDOD): 8 (ppm) 7.81–7.77(m, 2H), 7.69 7.63(m, 2H), 7.36(t, 1H), 7.24 7.15(m, 3H), 25 Reaction of the product of Preparation 37 and hydrogen 3.81 (d. 2H), 3.25–3.22(m, 4H), 2.53–2.51(m, 4H), chloride in ether as described in Example 2 gave the desired 2.30 2.21 (m, 4H), 1.86–1.83(m, 2H), 1.49–144(m, 1H), white solid product, a salt of the product of Preparation 37. 1.35–1.25(m, 2H); MS (APCI); m/z. 363 (MH"; 100%). "H NMR (400 MHz, CDOD): 8 (ppm) 7.88 7.84(m, 2H), 7.48 7.5(sb 1H), 7.37(t, 2H), 7.22(t, 1H), 6.95(d. 1H), 30 6.77(d. 1H), 3.81 (t, 4H), 3.64(d. 2H), 3.26–3.13(m, 6H), 2.37(t, 2H), 2.11(s.3H), 1.91 (d. 2H), 1.43–1.37(m, 3H); MS Preparation 36 (APCI): m/z 457 (MH"; 100%).

35 N N F Preparation 38 COO F H 40 N - O \ / 4 ON Reaction of the product of Preparation 35 and tin chloride as described in Preparation 2 gave the desired product. 45 Reaction of 1-(3-nitro-phenyl)-piperazine and 4-fluoro "H NMR (400 MHz, CDOD): 8 (ppm) 7.81–7.77(m, benzenesulfonic acid 4-(4-fluoro-benzenesulfonylamino)- 2H), 7.28 7.20(m, 2H), 7.06 7.02(m. 1H), 6.35(d. 1H), butyl ester as described in Example 1 gave the desired 6.24–6.21 (m, 2H) 3.80(d. 2H), 3.60(sb, 2H), 3.19(m, 4H), compound. 2.39(m, 4H), 2.29–2.19(m, 4H), 1.85(d. 2H), 1.47(m, 1H), 50 H NMR (400 MHz, CDC1): 8 (ppm) 7.85 (m, 2H), 1.35–1.28(m, 2H); MS (APCI); m/z. 433 (MH"; 100%). 7.75 7.63 (m, 2H), 7.22 7.06 (m, 4H), 3.38 (m, 4H), 2.95 (m. 2H), 2.45 (m, 4H), 2.05 (m, 1H), 1.61 (m, 4H); MS (APCI): m/z 437 (MH"; 100%).

55 Preparation 37 Preparation 39 F

H ()-O CuC F 60 N Y1a1n- Ns O \ / 4 )- S. HN

65 Reaction of the product of Preparation 36 and acetyl Reaction of the product of Preparation 38 and tin chloride chloride in dichloromethane as described in Example 3 gave as described in Preparation 2 gave the desired product. US 7,153,858 B2 67 68 "H NMR (400 MHz, CDC1): 8 (ppm) 7.95 (m, 2H), 7.45–6.95 (m, 4H), 6.51–6.19 (m, 2H), 3.95–2.83 (m, 8H), 2.65-2.31 (m, 7H), 1.61 (m, 4H); MS (APCI): m/z 407 Preparation 42

(MH"; 100%). 5 A w O. O N N V/

Preparation 40 \ / roy HN F 10 H Reaction of the product of Preparation 41 and tin chloride N - O as described in Preparation 2 gave the desired product. \ / 4. \, H NMR (400 MHz, CDC1): 8 (ppm) 7.92-7.10(m, 4H), HN 3.98-1.11 (m. 26H), MS (APCI); m/z 411 (MH"; 100%).

)—o Preparation 43 Reaction of the product of Preparation 39 and acetyl chloride in dichloromethane as described in Example 3 gave 2O the desired product, N-(3-4-4-(4-Fluoro-benzenesulfony ()-Croy lamino)-butyl-piperazin-1-yl)-phenyl)-acetamide, as a HN - white solid. "H NMR (400 MHz, CDC1): 8 (ppm) 7.45 7.16 (m, 4H), 25 )—o 6.81 (d. 2H), 6.65 (d. 2H), 3.48 (s, 1H), 3.28 (m, 4H), 2.95 (m. 2H), 2.62 (m, 5H), 2.35 (m, 2H), 2.08 (s.3H), 1.65 (m, Reaction of the product of Preparation 42 and acetyl 4H); MS (APCI): m/z 449 (MH; 100%). chloride in dichloromethane as described in Example 3 gave 30 the desired product as a white solid. EXAMPLE 36 H NMR (400 MHz, CDC1): 8 (ppm) 7.40–6.60(m, 4H), F 3.99–1.20 (m. 29H); MS (APCI); m/z 423 (MH"; 100%).

35 EXAMPLE 37 ()- V / -n-n-sMV O O HN )—o 40 HN()-Croy - O 2HC Reaction of the product of Preparation 40 and hydrogen chloride in ether as described in Example 2 gave the desired 45 white solid product, a salt of the product of Preparation 40. Reaction of the product of Preparation 43 and hydrogen "H NMR (400 MHz, CDOD): 8 (ppm) 7.99 (m, 2H), chloride in ether as described in Example 2 gave the desired 7.61–7.45 (m, 2H) 7.01 (d. 2H), 6.81 (d. 2H), 5.01 (bs, 4H), white solid product, N-(3-4-1-(Propane-2-sulfonyl)-pip 3.99 (m. 1H), 3.75 (m. 1H), 3.45–3.21 (m, 8H), 2.18 (s.3H), eridin-4-ylmethyl-piperazin-1-yl)-phenyl)-acetamide. 2.01 (m, 2H), 1.89–1.65 (m, 4H); MS (APCI): m/z 449 50 "H NMR (400 MHz, CDC1): 8 (ppm) 7.50–6.80(m, 4H), (MH"; 100%). 4.00-1.25 (m. 29H); MS (APCI); m/z 423 (MH"; 100%).

Preparation 41 Preparation 44 55

A w O. O N\ /N royVW ON()-Croy ->

Reaction of 1-(3-nitro-phenyl)-4-piperidin-4-ylmethyl Reaction of 1-(3-nitro-phenyl)-4-piperidin-4-ylmethyl piperazine TFA salt and propane-2-sulfonyl chloride as piperazine TFA salt and cyclohexyl-methanesulfonyl chlo described in Preparation 8 gave the desired product. 65 ride as described in Preparation 8 gave the desired product. H NMR (400 MHz, CDC1): 8 (ppm) 7.89 7.02(m, 4H), H NMR (400 MHz, CDC1): 8 (ppm) 7.90 7.20(m, 4H), 3.90–1.09(m, 26H); MS (APCI); m/z 411 (MH"; 100%). 3.900.90 (m, 32H); MS (APCI); m/z. 465 (MH"; 100%). US 7,153,858 B2 69 70 Ethanesulfonylamino-phenyl)-piperazin-1-yl)-butyl-4- methyl-benzenesulfonamide: 4-Methyl-N-(4-4-3- Preparation 45 (propane-2-sulfonylamino)-phenyl-piperazin-1-yl)-butyl)- benzenesulfonamide: 4-Methyl-N-(4-4-(3-nitro-phenyl)- piperazin-1-yl)-butyl-benzenesulfonamide: 4-Methyl-N- N N V/ 4-(4-pyridin-2-yl-piperazin-1-yl)-butyl \ / Oy () benzenesulfonamide: N-(4-4-(2-Methoxy-5-nitro-phenyl)- HN piperazin-1-yl)-butyl-4-methyl-benzenesulfonamide; 4-Methyl-N-4-(4-pyrimidin-2-yl-piperazin-1-yl)-butyl 10 benzenesulfonamide: N-(4-4-(3-Methoxy-phenyl)-piper Reaction of the product of Preparation 44 and tin chloride azin-1-yl)-butyl-4-methyl-benzenesulfonamide: N-(4-4- as described in Preparation 2 gave the desired product. (3-Ethanesulfonylamino-phenyl)-piperazin-1-yl-butyl-4- "H NMR (400 MHz, CDC1): 8 (ppm) 7.79–6.20(m, 4H), methyl-benzenesulfonamide: N-4-4-(3- 4.00-1.00 (m, 32H); MS (APCI); m/z 435 (MH"; 100%). Methanesulfonylamino-phenyl)-piperazin-1-yl)-butyl-4- 15 methyl-benzenesulfonamide: 4-Methyl-N-(4-4-(3-pyrazin 2-yl-phenyl)-piperazin-1-yl)-butyl-benzenesulfonamide: Preparation 46 and N-4-(4-Biphenyl-3-yl-piperazin-1-yl)-butyl-4-methyl benzenesulfonamide, N-4-(4-Biphenyl-3-yl-piperazin-1- N N V / yl)-butyl-4-methyl-benzenesulfonamide, 4-Methyl-N-4- (4-phenyl-piperazin-1-yl)-butyl-benzenesulfonamide, \ / Oy () C-Cyclohexyl-N-(4-4-(2-methoxy-phenyl)-piperazin-1- HN yl-butyl-methanesulfonamide, N-(3-4-4-(Toluene-4-sul fonylamino)-butyl-piperazin-1-yl)-phenyl)-acetamide, )- N-(3-4-4-(Toluene-4-sulfonylamino)-butyl-piperazin-1- 25 yl-phenyl)-propionamide, (3-4-1-(4-Fluoro-benzene Reaction of the product of Preparation 45 and acetyl sulfonyl)-piperidin-4-ylmethyl-piperazin-1-yl)-phenyl)- chloride in dichloromethane as described in Example 3 gave dimethyl-amine, 1-1-(4-Fluoro-benzenesulfonyl)- the desired product, N-3-4-(1-Cyclohexylmethanesulfo piperidin-4-ylmethyl-4-pyridin-2-yl-piperazine, nyl-piperidin-4-ylmethyl)-piperazin-1-yl)-phenyl)-aceta C-Cyclohexyl-N-(4-4-(3-dimethylamino-phenyl)-piper 30 azin-1-yl)-butyl-methanesulfonamide, C-Cyclohexyl-N- mide, as a white solid. 4-(4-pyridin-2-yl-piperazin-1-yl)-butyl-methanesulfona H NMR (400 MHz, CDC1): 8 (ppm) 7.26–6.70(m, 4H), mide, N-(3-4-1-(4-Fluoro-benzenesulfonyl)-piperidin-4- 3.79–1.05 (m, 35H); MS (APCI); m/z 477 (MH"; 100%). ylmethyl-piperazin-1-yl)-phenyl)-acetamide, N-(3-4-4- (4-Fluoro-benzenesulfonylamino)-butyl-piperazin-1-yl)- 35 phenyl)-acetamide, N-3-4-(4- EXAMPLE 38 Cyclohexylmethanesulfonylamino-butyl)-piperazin-1-yl)- A V O. O phenyl)-acetamide, N-3-4-(1- N N \/ Cyclohexylmethanesulfonyl-piperidin-4-ylmethyl)- \ / 1n ( ) piperazin-1-yl-phenyl)-acetamide, 40 Cyclopropanecarboxylic acid {3-4-(4-cyclohexylmethane HN sulfonylamino-butyl)-piperazin-1-yl)-phenyl-amide, N-(3- {4-1-(Propane-2-sulfonyl)-piperidin-4-ylmethyl-piper )—o azin-1-yl)-phenyl)-acetamide, N-(3-4-4-(Propane-2- sulfonylamino)-butyl-piperazin-1-yl)-phenyl)-acetamide, Reaction of the product of Preparation 46 and hydrogen 45 N-3-4-(4-Cyclohexanesulfonylamino-butyl)-piperazin-1- chloride in ether as described in Example 2 gave the desired yl-phenyl-acetamide, N-(3-4-4-(Cyclohexylmethane white solid product, a salt of the product of Preparation 46. sulfonyl-methyl-amino)-butyl-piperazin-1-yl)-phenyl)-ac "H NMR (400 MHz, CDC1): 8 (ppm) 7.50–6.79(m, 4H), etamide, N-(3-4-4-(2-Methyl-propane-1-sulfonylamino)- 3.90–1.10 (m, 35H); MS (APCI); m/z 477 (MH"; 100%). butyl-piperazin-1-yl)-phenyl)-acetamide, N-3-(4-4- 50 Methyl-(2-methyl-propane-1-sulfonyl)-amino-butyl piperazin-1-yl)-phenyl-acetamide, N-(3-piperazin-1-yl EXAMPLE 39 phenyl)-acetamide, Cyclopropanecarboxylic acid (3-piperazin-1-yl-phenyl)-amide, and 1-(2-Methoxy-phe Activity of arylpiperazinyl Sulfonamide Compounds nyl)-4-1-(toluene-4-Sulfonyl)-piperidin-3-ylmethyl-pip Arylpiperazinyl Sulfonamide compounds of the invention 55 erazine. were made according to the synthesis noted above, and their These compounds were found to be active (e.g., at con activity and selectivity was determined. These compounds centrations from about 0.1 to about 10 uM) and selective are 4-Methyl-N-(4-4-(3-nitro-phenyl)-piperazin-1-yl)-bu 5-HT modulators. Test data is shown in Table 1. The tyl-benzenesulfonamide: 4-Methyl-N-(4-4-(3-nitro-phe compounds accordingly are expected to be useful as 5-HT nyl)-piperazin-1-yl-butyl-benzenesulfonamide HCl salt; 60 receptor modulators, e.g., in the treatment of a wide variety Cyclopropanecarboxylic acid (3-4-4-(toluene-4-Sulfony of clinical conditions which are characterized by serotonin lamino)-butyl-piperazin-1-yl)-phenyl)-amide, N-(3-4-4- excess or absence, e.g., serotonergic hypofunction or hyper (Toluene-4-sulfonylamino)-butyl-piperazin-1-yl)-phenyl)- function. Such conditions include eating disorders, Schizo butyramide: 2,2-Dimethyl-N-(3-4-4-(toluene-4- phrenia, neuralgia, and addiction disorders; obsessive com sulfonylamino)-butyl-piperazin-1-yl)-phenyl)- 65 pulsive disorders, panic disorders, sexual dysfunctions propionamide; N-(3-4-4-(Toluene-4-sulfonylamino)- caused by the central nervous system and disturbances in butyl-piperazin-1-yl)-phenyl)-isobutyramide: N-(4-4-(3- sleep and the absorption of food, alcoholism, pain, memory US 7,153,858 B2 71 72 deficits, unipolar depression, dysthymia, bipolar depression, multiple etiologies; Parkinson's disease and other extra treatment-resistant depression, depression in the medically pyramidal movement disorders such as medication-induced ill, panic disorder, obsessive-compulsive disorder, eating movement disorders, for example, neuroleptic-induced par disorders, social phobia, premenstrual dysphoric disorder, kinsonism, neuroleptic malignant syndrome, neuroleptic mood disorders, such as depression or more particularly induced acute dystonia, neuroleptic-induced acute akathisia, depressive disorders, for example, single episodic or recur neuroleptic-induced tardive dyskinesia and medication-in rent major depressive disorders and dysthymic disorders, or duced postural tremor, Substance-related disorders arising bipolar disorders, for example, bipolar I disorder, bipolar II from the use of alcohol, amphetamines (or amphetamine disorder and cyclothymic disorder; anxiety disorders, such like Substances) caffeine, cannabis, cocaine, hallucinogens, as panic disorder with or without agoraphobia, agoraphobia 10 inhalants and aerosol propellants, nicotine, opioids, phe without history of panic disorder, specific phobias, e.g., nylglycidine derivatives, sedatives, hypnotics, and anxiolyt specific animal phobias, social phobias, stress disorders ics, which substance-related disorders include dependence including post-traumatic stress disorder and acute stress and abuse, intoxication, withdrawal, intoxication delirium, disorder, and generalized anxiety disorders; Schizophrenia withdrawal delirium, persisting dementia, psychotic disor and other psychotic disorders, for example, Schizophreni 15 ders, mood disorders, anxiety disorders, sexual dysfunction form disorders, schizoaffective disorders, delusional disor and sleep disorders; epilepsy; Down's syndrome; demyeli ders, brief psychotic disorders, shared psychotic disorders nating diseases such as MS and ALS and other neuropatho and psychotic disorders with delusions or hallucinations; logical disorders such as peripheral neuropathy, for example delirium, dementia, and amnestic and other cognitive or diabetic and chemotherapy-induced neuropathy, and post neurodegenerative disorders, such as Alzheimer's disease, therapeutic neuralgia, trigeminal neuralgia, segmental or senile dementia, dementia of the Alzheimer's type, vascular intercostal neuralgia and other neuralgias; and cerebral dementia, and other dementias, for example, due to HIV vascular disorders due to acute or chronic cerebrovascular disease, head trauma, Parkinson's disease, Huntington's damage such as cerebral infarction, Subarachnoid hemor disease, Pick's disease, Creutzfeldt-Jakob disease, or due to rhage or cerebral edema.

TABLE 1.

5-HT1A (K) C1 C2 Compoun nM % inhibition % inhibition 4-Methyl-N-(4-4-(3-nitro-phenyl)-piperazin-1- 125 56 14 yl)-butyl-benzenesulfonamide 4-Methyl-N-(4-4-(3-nitro-phenyl)-piperazin-1- 105 61 23 yl)-butyl-benzenesulfonamide HCI 4-Methyl-N-(4-4-3-(propane-2- 78 15 &10 Sulfonylamino)-phenyl-piperazin-1-yl)-butyl)- benzenesulfonamide N-4-4-(3-Ethanesulfonylamino-phenyl)- 141 47 14 piperazin-1-yl)-butyl-4-methyl benzenesulfonamide 4-Methyl-N-(4-(4-phenyl-piperazin-1-yl)-butyl- 40 98 90 benzenesulfonamide N-(3-4-4-(Toluene-4-sulfonylamino)-butyl- 47 47 2 piperazin-1-yl)-phenyl)-isobutyramide N-4-4-(3-Methanesulfonylamino-phenyl)- 46 51 21 piperazin-1-yl)-butyl-4-methyl benzenesulfonamide 4-Methyl-N-(4-(4-pyrimidin-2-yl-piperazin-1- 26 &10 6 yl)-butyl-benzenesulfonamide 4-Methyl-N-(4-(4-pyrimidin-2-yl-piperazin-1- 30 35 7 yl)-butyl-benzenesulfonamide HCl Cyclopropanecarboxylic acid (3-4-4-(toluene- 21 40 5 4-sulfonylamino)-butyl-piperazin-1-yl)- phenyl)-amide HC N-4-4-(2-Methoxy-5-nitro-phenyl)-piperazin- 415 28 O 1-yl)-butyl-4-methyl-benzenesulfonamide N-(3-4-4-(Toluene-4-sulfonylamino)-butyl- 56 12 2 piperazin-1-yl)-phenyl)-butyramide 2,2-Dimethyl-N-(3-4-4-(toluene-4- 1360 O 1 Sulfonylamino)-butyl-piperazin-1-yl)-phenyl)- propionamide 4-Methyl-N-(4-(4-pyridin-2-yl-piperazin-1-yl)- 10 81 63 butyl-benzenesulfonamide 4-Methyl-N-(4-(4-pyridin-2-yl-piperazin-1-yl)- 7.7 8O 72 butyl-benzenesulfonamide HCl 1-(2-Methoxy-phenyl)-4-1-(toluene-4- 9.2 74 57 Sulfonyl)-piperidin-3-ylmethyl-piperazine C-Cyclohexyl-N-(4-4-(2-methoxy-phenyl)- 3.9 98 86 piperazin-1-yl-butyl-methanesulfonamide C-Cyclohexyl-N-(4-4-(2-methoxy-phenyl)- 3.2 98 87 piperazin-1-yl)-butyl-methanesulfonamide HCl N-(3-4-4-(Toluene-4-sulfonylamino)-butyl- 16 22 43 piperazin-1-yl)-phenyl)-acetamide N-(3-4-4-(Toluene-4-sulfonylamino)-butyl- 6.8 10 15 piperazin-1-yl-phenyl)-acetamide HCl US 7,153,858 B2 73 74

TABLE 1-continued 5-HT1A (K) C1 C2 Compound nM % inhibition % inhibition N-(3-4-4-(Toluene-4-sulfonylamino)-butyl- 213 O 31 piperazin-1-yl)-phenyl)-propionamide (3-4-1-(4-Fluoro-benzenesulfonyl)-piperidin- 507 74 O 4-ylmethyl-piperazin-1-yl-phenyl)-dimethyl amine HCI 1-1-(4-Fluoro-benzenesulfonyl)-piperidin-4- 21 42 68 ylmethyl-4-pyridin-2-yl-piperazine HCI C-Cyclohexyl-N-(4-4-(3-dimethylamino- 110 85 25 phenyl)-piperazin-1-yl-butyl methanesulfonamide HCI C-Cyclohexyl-N-(4-(4-pyridin-2-yl-piperazin-1- 6.5 81 51 yl)-butyl-methanesulfonamide HCI N-(3-4-1-(4-Fluoro-benzenesulfonyl)- 13 49 &10 piperidin-4-ylmethyl-piperazin-1-yl)-phenyl)- acetamide HCI N-(3-4-4-(4-Fluoro-benzenesulfonylamino)- 18 39 &10 butyl-piperazin-1-yl)-phenyl)-acetamide N-3-4-(4-Cyclohexylmethanesulfonylamino- 5.1-11 &25 &10 butyl)-piperazin-1-yl)-phenyl-acetamide (K = 1600 nM) N-3-4-(1-Cyclohexylmethanesulfonyl- 10 13 &10 piperidin-4-ylmethyl)-piperazin-1-yl)-phenyl acetamide Cyclopropanecarboxylic acid 3-4-(4- 8.9 22 &10 cyclohexylmethanesulfonylamino-butyl)- piperazin-1-yl)-phenyl-amide N-(3-4-1-(Propane-2-sulfonyl)-piperidin-4- 112 &10% &10 ylmethyl-piperazin-1-yl)-phenyl)-acetamide N-(3-4-4-(Propane-2-sulfonylamino)-butyl- 24 &10 2 piperazin-1-yl)-phenyl)-acetamide N-3-4-(4-Cyclohexanesulfonylamino-butyl)- 40 &10 2 piperazin-1-yl)-phenyl-acetamide N-(3-4-4-(Cyclohexylmethanesulfonyl- 1.3 37 47 methyl-amino)-butyl-piperazin-1-yl-phenyl)- (Ki = 616 nM) acetamide N-(3-4-4-(2-Methyl-propane-1- 11 5 O Sulfonylamino)-butyl-piperazin-1-yl)-phenyl)- acetamide N-(3-Piperazin-1-yl-phenyl)-acetamide HCI 2.9 O 35 Cyclopropanecarboxylic acid (3-piperazin-1-yl- 4.6 O 14 phenyl)-amide HCl

To further demonstrate the suitability of compounds of the 40 As opposed to the reference compound chlordiazepoxide invention as 5-HT agonists, e.g., 5-HT agonists, an and buspirone, Compound A did not alter general motor arylpiperazinyl Sulfonamide compound of the invention, activity as demonstrated by a lack of effect in the open field N-3-4-(4-Cyclohexylmethanesulfonylamino-butyl)-piper and the elevated plus-maze, Suggesting that Compound A azin-1-yl)-phenyl)-acetamide (“Compound A'), was evalu may exhibit a preferable profile in these models. ated in laboratory animals using several standard tests, 45 which are set forth below. Material and Methods EXAMPLE 40 Animals Young adult male C57B 16/J mice from Jackson Labora Activity of a Representative Arylpiperazinyl 50 tory, Bar Harbor, Me. were used in the Elevated Plus Maze; Sulfonamide Compound In Vivo Anxiety and 129 Svev mice from Taconic, Germantown, N.Y. were used Motor Activity Assessments in the Stress-induced Hyperthermia, Open Field, and the Tail In this experiment, a compound of the invention, N-3- Suspension tests, and DBA/2J mice from Jackson Labora 4-(4-Cyclohexylmethanesulfonylamino-butyl)-piperazin 55 tory, Bar Harbor, Me. were used in the Forced Swim test. All 1-yl-phenyl-acetamide HCl (“Compound A') was evalu mice were received at the age of 6 weeks and were assigned ated in animal models of anxiety and motor activity in mice. unique identification numbers. Animals were housed 4 per The effect of the compound was investigated after acute oral cage in polycarbonate cages with filter tops, cagemate administration. Compound A administered orally in mice identification maintained by tail marks. Animals were accli exhibited an anxiolytic like-effect measured behaviorally 60 mated for 7 days and given food and water ad libitum. Mice and physiologically by the elevated plus-maZe and the were examined prior to initiation of the study at 8 weeks of stress-induced hyperthermia test, respectively. The highest age to assure adequate health and Suitability. During the dose of Compound A (i.e., 20 mg/kg) was effective in the course of the study, 12-hour light/12-hour dark cycles were stress-induced hyperthermia test whereas a lower dose (i.e., maintained with the light on at 7:00 a.m. The room tem 3 mg/kg) was effective in the elevated plus-maze test. This 65 perature was maintained between 20 and 23° C. with a may suggest that different doses of the compound may target relative humidity maintained between 30% and 70%. Chow different aspects of the stress-induced anxiety. and water were provided ad libitum. US 7,153,858 B2 75 76 In each test, animals were randomly assigned across pean Journal of Pharmacology 342(2–3): 177-82, 1998). treatment groups and balanced by cage number. Ten animals Anxiolytics are known to decrease this hyperthermic were used in each treatment group. Mice for the Open Field response to stress. This test involves two measures of rectal and Stress-induced hyperthermia studies were handled once temperature repeated in the same animal within a 10 min daily for 2 consecutive days prior to the testing. Mice period. On the day prior to testing, animals were brought to assigned to the Elevated plus maze experiment were not the experimental room 1 hr prior to scheduled lights out and handled to increase the stress level at the time of the testing. singly housed overnight with food and water ad libitum. On the morning of the experiment, animals were first injected Drugs with treatment compound or vehicle. One hr post treatment, The following compounds were used for this study: 10 the animal was removed from the holding cage and held in Test Compound: a Supine position and had rectal temperature measured by N-3-4-(4-Cyclohexylmethanesulfonylamino-butyl)- using a rectal probe attached to a PhysiTemp thermometer piperazin-1-yl-phenyl-acetamide HCl (“Compound (Fisher Scientific). For each animal tested, the rectal probe A’) (1, 3, and 20 mg/kg) (Lot 0 DC-006-022-L2, was cleaned with an alcohol pad and lubricated with sterile CHNOSHCL, doses expressed in mg of salt). 15 K-Yjelly and slowly inserted into the animals rectum at a Reference Compounds: length of approximately 3–5 mm. The probe remained Buspirone (3, 10 and 20 mg/kg, Sigma, Lot 0 101 H0402) within the animals rectum for approximately 5 sec or until Sertraline Hydrocloride salt (5, 20 mg/kg, received as a body temperature reached stability, and the baseline rectal gift from Pfizer CP-51,974-01, Lot -0047451-029-19) temperature (T1) was recorded. The animal was immedi Chlordiazepoxide (CDP, 10 mg/kg, Sigma, Lot :0 ately placed back to the holding cage and after a 10-min 94H1023). interval a second rectal temperature (T2) was taken using the All compounds were dissolved in sterile injectable water, same procedure as T1. The animal was then returned to the which served as the vehicle control. All solutions were home cage and at the completion of the experiment returned prepared on the day of the experiments. Compound A were to the colony room. given to animals orally (PO) in all tests in a volume of 10 25 Open Field (OF) ml/kg body weight; all reference compounds were given to The open field activity monitor system (Med Associates, animals intraperitoneally (IP) to the exception of Buspirone Inc.) measured general motor activity. The test was per which was given orally in the elevated plus maze (EPM) test formed under normal lighting conditions (400 lux). Mice and the open field (OF) tests. In all tests except for the tail were brought into the experimental room and allowed at Suspension (TS) test, drugs were administered acutely; in the 30 least 1 hr of acclimation. Thirty min after treatment, each TS test, Compound A was administered once daily for 3 days mouse was placed into the testing enclosure (lxwxh: 27 (test day inclusive) prior to testing. Thirty minutes pretreat cmx27 cmx20 cm) with an infrared beam array that auto ment time was used in all tests except for SIH in which case matically monitors the animals activity. Eight animals of compounds were given to the animals one hr before the test. balanced treatment were tested at one time. The test session 35 Methods lasted 40 min and animals were returned to the home cages All experiments were carried out in ambient temperature at the end of the session. The critical measures of this test under light cycle between 9:00 a.m. and 5:00 p.m. during a includes locomotion (total distance traveled), rearing (ver forty-day period. Results were recorded automatically and tical activity), number of center entries and percent time processed by microcomputer; or manually on individual data 40 spent in the center area of the OF arena. sheets, transcribed and verified item by item. Statistical Analysis Elevated Plus Maze (EPM) All data were analyzed by comparing the groups treated The elevated plus maze is a test commonly used to assess with the test substance to the vehicle control or reference anxiety in rodents. The maze consists of two closed arms treated groups. Statistical analysis was performed by (1xwxh: 15 cmx6 cmx30 cm) and two open arms (6 cm 45 ANOVA followed by Fisher's post-hoc test where appropri wx30 cm l) forming a cross, with a square center platform ate. Pless than 0.05 were considered to be significantly (6x6 cm). Rodents naturally fear open spaces and tend to different. Data are represented as the means and standard spend more time in the closed arms. Anxiolytics will attenu error to the mean (S.e.m). ate this fear of open spaces and will increase the number of Results time spent in open arms. All visible Surfaces are made of a 50 black acrylic. Each arm of the maze is placed on a Support Elevated Plus Maze column 50 cm above the floor. The light intensity was ~100 The reference compound CDP and the test substance lux above the open arms and -70 lux above the closed arms. Compound A exhibited an anxiolytic-like effects as mea Animals were brought to the experimental room at least 1 hr Sured by an increase in the time spent in open arms and an before the test in the home cage (food and water available). 55 increase in the number of entries into the open arms (FIGS. Mice were placed in the center of the elevated plus maze 1 and 2). Note that, in FIG. 1, an increase in Proportion of facing an open arm, tested once, one at a time for a 5 min Open Arm Entries compared to Vehicle treatment represents test. The time in the open/closed arms and the number of an anxiolytic-like effect. *P-0.05 vs vehicle-treated group entries in the open/closed arms were recorded via video (water). ANOVA revealed significant main effect for Treat 60 ment (p=0.0029). Fisher's PLSD for paired comparison camera and used as a measure of anxiety. Mice were indicated that the anxiolytic reference compound CDP, but returned to the home cage after testing and then to the colony not buspirone, significantly increased percentage of entries OO. into the open arms (p=0.011), an effect consistent with Stressed Induced Hyperthermia (SIH) CDP's clinical anxiolytic effects. Compound A in 3 mg/kg Mice have a natural hyperthermic response to stress, 65 dose induced a significant anxiolytic-like effect (p=0.039). which has been proposed as a measure of stress-induced Higher doses of Compound A (10 and 20 mg/kg) showed anxiety (Olivier, Zethof, Ronken & van der Heyden, Euro similar tendency but it did not reach statistical significance US 7,153,858 B2 77 78 (p=0.279 and p=0.074, respectively). In FIG. 2, an increase significantly decreased (p=0.044) basal rectal temperature. in Open Arm Time compared to Vehicle treatment represents Similarly, Compound A in 20 mg/kg dose resulted in sig an anxiolytic-like effect. *P-0.05 vs vehicle-treated group nificant decrease (p=0.0023). Lower dose of the drug did not (water). ANOVA revealed a significant effect for Treatment show significant effects (p=0.808 and p=0.326, for 1 and 3 (p=0.04). Fisher's PLSD for paired comparison indicated mg/kg of Compound A, respectively). In FIG. 6, note the that the anxiolytic reference compound CDP produced a increase in rectal temperature in vehicle-treated animals nearly significant increase in Open Arm Time (p=0.0554): (stress-induced hyperthermia) and the blocking effect of buspirone had no effect. Compound A in 3 mg/kg dose buspirone (20 mg/kg, P-0.05 vs vehicle-treated group) and induced a significant anxiolytic-like effect (p=0.048). Compound A (20 mg/kg; P-0.01 vs vehicle-treated group). Higher doses of Compound A (10 and 20 mg/kg) showed 10 ANOVA revealed significant effect of Treatment similar tendency but it did not reach statistical significance (p=0.0009). Follow-up Fisher's PLSD for paired compari (p=0.467 and p=0.543, respectively). son showed that buspirone (20 mg/kg) significantly Buspirone, however, failed to produce a significant anxi decreased (p=0.024) stress-induced hyperthermia. Similarly, olytic-like effect in the EPM. This lack of buspirone effect Compound A in 20 mg/kg dose resulted in significant has been previously reported in the literature. The anxiolytic 15 decrease (p=0.0067). Lower dose of the drug did not show effect of Compound A was specific as the compound did not significant effects (p=0.618 and p=0.2911, for 1 and 3 mg/kg alter locomotor activity as measured by a lack of effect on of Compound A, respectively). the number of entries in the closed arms or total number of entries in the closed and open arms (FIGS. 3 and 4). In FIG. Open Field 3. *P<0.05 vs vehicle-treated group (water). ANOVA Compound A did not alter locomotor activity as measured revealed significant effect for Treatment (p=0.0028). Fish by the total distance traveled (FIG. 7), the number of rearing er's PLSD for paired comparison indicated that the reference (FIG. 8) and the distance traveled in the center (FIG. 9–11). compound buspirone, but not CDP or Compound A, signifi In FIG. 7, time bins represent 5 min intervals with total cantly decreased number of entries into the closed arms testing time of 40 min. Bar graph represents cumulative total (p=0.0012) at 20 mg/kg dose. In FIG.4, note that an increase 25 distance traveled during the period of 40 min. Repeated or a decrease in Total Entries compared to Vehicle treatment measures ANOVA revealed no significant main effect for represents an increased or decreased locomotor activity. Treatment (p=0.2736). However, a significant-Distance X *p-0.05, **p-0.01 vs vehicle-treated group (water). Treatment interaction was identified (p<0.0001). Follow-up ANOVA revealed a significant main effect for Treatment Fisher's PLSD for paired comparison revealed no significant (p=0.0001). Follow-up Fisher's PLSD for paired compari 30 difference as compared to the Water-treated controls. In FIG. son revealed a significant effect of CDP compared to Vehicle 8, ANOVA did not exhibit a significant effect for Treatment (p=0.021) indicating slight increase in motor activity. High (p=0.087). Compound A did not alter vertical activity sig est dose of buspirone (20 mg/kg) resulted in a significant nificantly in any of the doses used as opposed to Buspirone decrease in total number of entries (p=0.0014). Compound which decreased the number of rears. In FIG. 9, ANOVA A did not alter total number of entries. 35 revealed no significant main effect for Treatment (p=0.923) Therefore, Compound A did not affect locomotor activity effects. These results indicated that neither buspirone nor in this test. Interestingly, CDP produced a slight increase Compound Aalter percent distance traveled in the center. In whereas high dose of buspirone (20 mg/kg) resulted in a FIG. 10, ANOVA revealed no significant main effect for decrease in total number of entries. Treatment (p=0.834) effects. These results indicated that 40 neither buspirone nor Compound A alter percent time trav Stress-Induced Hyperthermia eled in the center. In FIG. 11, time bins represent 5 min Both reference compound buspirone and Compound A intervals with total testing time of 40 min. Bar graph exerted a dose-dependent anxiolytic-like effect as measured represents cumulative total distance traveled during the by a decrease in the hyperthermic response to stress at the period of 40 min. Repeated measures ANOVA revealed no high dose tested (i.e., 20 mg/kg). This effect was also 45 significant main effect for Treatment (p=0.492) or Time X accompanied by a change in basal rectal temperature (FIG. Treatment interaction (p=0.659). These results indicated that 5–6). This phenomenon may also be associated with an neither buspirone nor Compound A alter Zone crossing anxiolytic-like profile as it is commonly reported with activity (between periphery and center). clinically used anxiolytics. In FIG. 5, *p-0.05, *p-0.01 vs. vehicle-treated group (water). ANOVA revealed a significant 50 Discussion effect of Treatment (p=0.0109). Follow-up Fisher's PLSD The results of these studies are summarized in Table 2, for paired comparison showed that buspirone (20 mg/kg) below.

TABLE 2

Test Ref. Cmp. Compound A Elevated Plus Maze CDP/Buspirone 3 mg/kg 10 mg/kg 20 mg/kg Proportion Open Arm Entries increase (CDP) increase no change no change Open Arm Time increase (CDP) increase no change no change Closed Arm Entries decrease (BUS, 20) no change no change no change Total Entries increase (CDP) no change no change no change decrease (BUS, 20) Stress-Induced Hyperthermia Buspirone 1 mg/kg 3 mg/kg 20 mg/kg US 7,153,858 B2

TABLE 2-continued Test Ref. Cmp. Compound A Basal Rectal Temperature decrease no change no change decrease Temperature Change decrease no change no change decrease Open Field Buspirone 1 mg/kg 3 mg/kg 20 mg/kg Total Distance (Horizontal) no change No change no change no change Vertical Activity (Rearing) decrease No change no change no change Percent Distance in Center no change No change no change no change Percent Time in Center no change No change no change no change Frequency of Zone Crosses no change No change no change no change

15 In our experimental conditions, Compound A adminis transgene encoding SNAP-25 was bred into the Coloboma tered orally in mice exhibited an anxiolytic like-effect mea strain to complement the Snap deletion, the hyperactivity sured behaviorally and physiologically by the elevated plus expressed by these mice was rescued, returning these cor maZe and the stress-induced hyperthermia test, respectively. rected mice to normal levels of locomotor activity. Millet al. The highest dose of Compound A (i.e., 20 mg/kg) was (2002) also demonstrated in a linkage study that SNAP-25 effective in the stress-induced hyperthermia test whereas a may play a role in the genetic of etiology of ADHD although lower dose (i.e., 3 mg/kg) was effective in the elevated further work is required to confirm or reject this hypothesis. plus-maze test. This may suggest that different doses of the Altogether, these results supported the use of the Coloboma compound may target different aspects of the stress-induced mice as a model to mimic hyperactivity in rodents. anxiety. In other studies carried out under specific condi 25 In this experiment, the effect of the compound Compound tions, e.g., tail suspension and forced Swim test, Compound A was investigated after acute oral administration. Three A did not appear to have antidepressive properties. doses of the test compound was administered in the As opposed to the reference compound chlordiazepoxide Coloboma mice and their spontaneous activity was mea and buspirone, Compound A did not alter general motor Sured using an Open Field test. d-Amphetamine was used as activity as demonstrated by a lack of effect in the open field 30 a positive reference compound. and the elevated plus-maze, Suggesting that Compound A Material and Methods may exhibit a preferable profile in these models. Animals Overall these results suggest that Compound A exhibits a The mice used in the current study are the offspring of clear anxiolytic like-effect in the experimental conditions breeding pairs (C3H/HeSnj-Cm) originally purchased from employed. 35 Jackson Laboratory, Bar Harbor, Me. Of the 48 mice tested, 22 were male and 26 were female, at age between 12–20 EXAMPLE 41 weeks old. These animals were weaned at 21 days age and were housed in 2 to 4 littermates per cage in our animal Activity of a Representative Arylpiperazinyl facility where standard animal husbandry was maintained. Sulfonamide Compound In Vivo Hyperlocomotor 40 The colony room was kept under 12-hour light/12-hour dark Activity Assessments cycles with the lights on at 7:00 a.m. Temperature was maintained between 20 and 23°C. with a relative humidity In this experiment, a compound of the invention, N-3- maintained between 30% and 70%. Animals received food 4-(4-Cyclohexylmethanesulfonylamino-butyl)-piperazin chow and water provided ad libitum. 1-yl-phenyl-acetamide HCl (“Compound A') adminis 45 tered orally decreased the hyperlocomotor activity observed Drugs in the Coloboma mice at the doses of 1 and 20 mg/kg. The The following compounds were used for this study. effect was similar to the effect observed with d-Amphet Test Compound: amine. Overall, these results suggest that Compound A may N-3-4-(4-Cyclohexylmethanesulfonylamino-butyl)- normalize hyperactivity in the experimental conditions 50 piperazin-1-yl-phenyl-acetamide HCl (“Compound employed. A’) (1, 3, and 20 mg/kg) (Lot 0 DC-006-022-L2, The Coloboma mutant mice are considered as an animal CHNOSHCL, doses expressed in mg of salt). model of attention deficit hyperactivity disorder (ADHD) Reference Compound: due to their spontaneous high level of hyperactivity. Indeed, d-Amphetamine (4 mg/kg, Sigma, Lot 0 60K1909) hyperactivity syndromes are thought to account for a large 55 All compounds were dissolved in sterile injectable water, proportion of children diagnosed with learning disabilities, which served as the vehicle control. All solutions were therefore a great deal of attention has been focused on the prepared on the day of the experiments. Compound Aas well causes and the treatment of hyperactivity in children. as its vehicle (water) was given to animals orally (PO) in a The mouse mutant Coloboma exhibits profound sponta volume of 10 ml/kg body weight; the reference compound neous locomotor hyperactivity resulting from a deletion 60 was given to animals intraperitoneally (IP). Thirty minutes mutation. This deletion encompasses several genes includ pretreatment time was used for Compound A and vehicle ing Snap, which encodes SNAP-25, a nerve terminal protein whereas d-Amphetamine (AMPH) was given to animals 15 involved in neurotransmitter release. In 1996, Hess et al. demonstrated that amphetamine, a clinically-used agent that min before the test. normalize hyperactivity expressed in ADHD-affected chil 65 Methods dren, markedly reduced the locomotor activity in Coloboma The study was conducted over two consecutive days with mice but increased the activity of control mice. When a animals tested between 10:00 a.m. and 5:00 p.m. on each US 7,153,858 B2 81 82 day. Gender and age were balanced across five treatment spirit and scope of the invention as defined by the claims. groups and the testing day. Eight to 10 animals were Other aspects, advantages, and modifications are within the allocated per group. The results were recorded automatically scope of the invention. The contents of all references, issued and processed by microcomputer. patents, and published patent applications cited throughout The open field activity monitor system (Med Associates, this application are hereby incorporated by reference. The Inc.) measured general motor activity. The test was per appropriate components, processes, and methods of those formed under normal lighting conditions (400 lux). Mice patents, applications and other documents may be selected were brought into the experimental room and allowed at for the invention and embodiments thereof. least 1 hr of acclimation followed by drug administration. What is claimed is: After drug administration (i.e., 30 min after administration 10 of Compound A or vehicle, and 15 min after administration 1. A compound having the formula of d-Amphetamine), each mouse was placed into the testing enclosure (lxwxh: 27 cmx27 cmx20 cm) with an infrared beam array that automatically monitors the animals activity. (I) Eight animals of balanced treatment were tested at one time. 15 The test session lasted 40 min and animals were returned to N Y. the home cages at the end of the session. The critical N-1 Ys PYR measure of this test was the Distance Traveled. /\, Statistical Analysis All data were analyzed by comparing the groups treated with the test substance to the vehicle control or reference wherein treated groups. Statistical analysis was performed by R is unsubstituted alkyl or cycloalkyl: or cyclohexylm ANOVA followed by Fisher's post-hoc test where appropri ethyl or cyclohexylphenyl: ate. Pless than 0.05 were considered to be significantly R and R independently are hydrogen, nitro, lower 25 alkoxy, or —NRRs, provided that R and R are not different. Data are represented as the means and standard both hydrogen; error to the mean (S.e.m). Ra and Rs are independently H, lower alkyl: COR or Results SOR, where R is lower alkyl or cycloalkyl; Amphetamine significantly decreased locomotor activity Y is NH, N(lower alkyl) or as compared to the vehicle-treated group. Overall, the com 30 pound also significantly decreased the level of activity. Post-hoc analysis revealed that only the dose of 1 and 20 mg/kg of Compound A was significantly different from vehicle. Time bins represent 5 min intervals with total testing time 35 of 40 min. Bar graph represents cumulative total distance traveled during the period of 40 min. p-0.05 vs. Water m is 0, 1, 2, 3, 4, 5, or 6: treated controls. n is 1, 2, 3, 4, 5, or 6: Discussion p is 0, 1, 2, 3, or 4; and pharmaceutically acceptable salts From the data above, it can be seen that Compound A 40 thereof. administered orally decreased the hyperlocomotor activity 2. The compound of claim 1, wherein R is selected from observed in the Coloboma mice at the doses of 1 and 20 the group consisting of lower alkoxy; amino; nitro; NHCO mg/kg. The effect was similar to the effect observed with alkyl; NHCO-cycloalkyl; —N-(alkyl)-CO-alkyl; and d-Amphetamine. - NHSO-alkyl. As demonstrated in Example 3, Compound A does not 45 3. The compound of claim 2, wherein R is nitro, NHCO appear to alter general motor activity as demonstrated by a alkyl, —N-(alkyl)-CO-alkyl, or alkylamino; and R is H. lack of effect in the elevated plus-maze and the open field in 4. The compound of claim3, wherein said NHCO-alkyl is normal C57B 16/J mice and 129 Svev mice, respectively. NHCO-lower alkyl. Therefore, it is unlikely that the present effect is related to a 5. The compound of claim 4, wherein said NHCO-lower non-specific sedative effect. 50 alkyl is NHCO-(CH), NHCO (CHCH), NHCO Overall these results suggest that Compound A normal (CHCH-CH), or NHCO-(CH(CH). izes hyperactivity in the experimental conditions employed, 6. The compound of claim 3, wherein R is in the meta and therefore is expected to be a useful drug for treating position. attention-deficit related conditions like ADD and ADHD. 55 7. The compound of claim 1, wherein said lower alkyl or The above examples demonstrate the suitability of com alkoxy is lower (C-C). pounds of the invention as 5-HT agonists and their predicted 8. The compound of claim 1, wherein said cycloalkyl is effectiveness in treating indications described herein, e.g., (C-C). anxiety, ADD and ADHD. 9. The compound of claim 1, wherein R is n-butyl, Equivalents 60 s-butyl, i-butyl, or cycloalkyl. Those skilled in the art will recognize, or be able to 10. The compound of claim 1, wherein said cycloalkyl is ascertain using no more than routine experimentation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo numerous equivalents to the specific procedures described hexylmethyl, or cyclohexylphenyl. herein. Such equivalents are considered to be within the 11. The compound of claim 1, wherein m is 0. scope of the invention and are covered by the following 65 12. The compound of claim 1, wherein n is 1 or 4. claims. Various Substitutions, alterations, and modifications 13. A pharmaceutical composition comprising the com may be made to the invention without departing from the pound of claim 1, and a pharmaceutically-acceptable carrier. US 7,153,858 B2 83 84 14. 4-Methyl-N-(4-4-(3-nitro-phenyl)-piperazin-1-yl)- 35. A compound having the formula butyl-benzenesulfonamide; or pharmaceutically acceptable salts thereof. 15. 4-Methyl-N-(4-4-(3-nitro-phenyl)-piperazin-1-yl)- (II) butyl-benzenesulfonamide HC1. 16. N-(3-4-4-(Toluene-4-sulfonylamino)-butyl-piper R- rsrN- Y. azin-1-yl)-phenyl)-butyramide; or pharmaceutically accept N-1N PYR able salts thereof. O O 17. 2,2-Dimethyl-N-(3-4-4-(toluene-4-sulfonylamino)- 10 butyl-piperazin-1-yl)-phenyl)-propionamide; or pharma ceutically acceptable salts thereof. wherein 18. N-(3-4-4-(Toluene-4-sulfonylamino)-butyl-piper R is unsubstituted alkyl or cycloalkyl; or cyclohexylm azin-1-yl)-phenyl)-isobutyramide; or pharmaceutically ethyl or cyclohexylphenyl: 15 R selected from the group consisting of lower alkoxy; acceptable salts thereof. amino; nitro; NHCO-lower alkyl; NHCO-cycloalkyl; 19. N-(4-4-(3-Ethanesulfonylamino-phenyl)-piperazin —N-(alkyl)-CO-alkyl; alkylamino; and NHSO-alkyl: 1-yl)-butyl-4-methyl-benzenesulfonamide; or pharmaceu Y is NH, N(lower alkyl) or tically acceptable salts thereof. 20. 4-Methyl-N-(4-4-3-(propane-2-sulfonylamino)- phenyl-piperazin-1-yl)-butyl)-benzenesulfonamide: O pharmaceutically acceptable salts thereof. 21. 4-Methyl-N-(4-4-(3-nitro-phenyl)-piperazin-1-yl)- --O-- butyl-benzenesulfonamide; or pharmaceutically acceptable 25 salts thereof. m is 0, 1, or 2: 22. N-(4-4-(2-Methoxy-5-nitro-phenyl)-piperazin-1-yl)- n is 1, 2, 3, or 4; and butyl-4-methyl-benzenesulfonamide; or pharmaceutically p is 0 or 1; and pharmaceutically acceptable salts thereof. acceptable salts thereof. 36. The compound of claim 35, wherein said NHCO 23. N-(4-4-(3-Methoxy-phenyl)-piperazin-1-yl)-butyl 30 lower alkyl is NHCO (CH), NHCO-(CHCH), 4-methyl-benzenesulfonamide; or pharmaceutically accept NHCO-(CHCH-CH), or NHCO-(CH(CH). able salts thereof. 37. The compound of claim 35, wherein R is in the meta 24. N-(4-4-(3-Ethanesulfonylamino-phenyl)-piperazin position. 1-yl)-butyl-4-methyl-benzenesulfonamide; or pharmaceu 38. The compound of claim 35, wherein said lower alkyl tically acceptable salts thereof. 35 or alkoxy is lower C-C). 25. N-(4-4-(3-Methanesulfonylamino-phenyl)-piper 39. The compound of claim 35, wherein said cycloalkyl is azin-1-yl)-butyl-4-methyl-benzenesulfonamide; or phar (C-C). maceutically acceptable salts thereof. 40. The compound of claim 35, wherein R is n-butyl, 26. N-4-(4-Biphenyl-3-yl-piperazin-1-yl)-butyl-4-me s-butyl, i-butyl, or cycloalkyl. thyl-benzenesulfonamide; or pharmaceutically acceptable 40 41. The compound of claim 40, wherein said cycloalkyl is salts thereof. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo 27. 4-Methyl-N-4-(4-phenyl-piperazin-1-yl)-butyl-ben hexylmethyl, or cyclohexylphenyl. Zenesulfonamide; or pharmaceutically acceptable salts 42. The compound of claim 35, wherein m is 0. thereof. 43. The compound of claim 35, wherein n is 1 or 4. 28.1-cyclohexyl-N-(4-(4-(2-methoxyphenyl)piperazin-1- 45 44. The compound of claim 35, wherein p is 0 or 1. 45. Cyclopropanecarboxylic acid (3-4-4-(toluene-4-sul yl)butyl)methanesulfonamide; or pharmaceutically accept fonylamino)-butyl-piperazin-1-yl)-phenyl)-amide; or phar able salts thereof. maceutically acceptable salts. 29. N-(3-4-4-(Toluene-4-sulfonylamino)-butyl-piper 46. N-(3-4-4-(Toluene-4-sulfonylamino)-butyl-piper azin-1-yl)-phenyl)-propionamide; or pharmaceutically 50 azin-1-yl)-phenyl)-acetamide; or pharmaceutically accept acceptable salts thereof. able salts thereof. 30. (3-4-1-(4-Fluoro-benzenesulfonyl)-piperidin-4-yl 47. N-3-4-(4-Cyclohexylmethanesulfonylamino-butyl)- methyl-piperazin-1-yl)-phenyl)-dimethyl-amine; or phar piperazin-1-yl-phenyl)-acetamide; or pharmaceutically maceutically acceptable salts thereof. acceptable salts thereof. 31. 1-cyclohexyl-N-(4-(4-(3-(dimethylamino)phenyl)pip 55 48. N-3-4-(1-Cyclohexylmethanesulfonyl-piperidin-4- erazin-1-yl)butyl)methanesulfonamide; or pharmaceutically ylmethyl)-piperazin-1-yl)-phenyl)-acetamide; or pharma acceptable salts thereof. ceutically acceptable salts thereof. 32. N-(3-4-1-(4-Fluoro-benzenesulfonyl)-piperidin-4- 49. Cyclopropanecarboxylic acid {3-4-(4-cyclohexyl ylmethyl-piperazin-1-yl)-phenyl)-acetamide; or pharma 60 methanesulfonylamino-butyl)-piperazin-1-yl)-phenyl ceutically acceptable salts thereof. amide; or pharmaceutically acceptable salts thereof. 33. N-(3-4-4-(4-Fluoro-benzenesulfonylamino)-butyl 50. N-(3-4-1-(Propane-2-sulfonyl)-piperidin-4-ylm piperazin-1-yl)-phenyl)-acetamide; or pharmaceutically ethyl-piperazin-1-yl)-phenyl)-acetamide; or pharmaceuti acceptable salts thereof. cally acceptable salts thereof. 34. 1-(2-Methoxy-phenyl)-4-1-(toluene-4-sulfonyl)-pip 65 51. N-(3-4-4-(Propane-2-sulfonylamino)-butyl-piper eridin-3-ylmethyl-piperazine; or pharmaceutically accept azin-1-yl)-phenyl)-acetamide; or pharmaceutically accept able salts thereof. able salts thereof. US 7,153,858 B2 85 86 52. N-3-4-(4-Cyclohexanesulfonylamino-butyl)-piper 55. N-3-(4-4-Methyl-(2-methyl-propane-1-sulfonyl)- azin-1-yl)-phenyl)-acetamide; or pharmaceutically accept aminol-butyl-piperazin-1-yl)-phenyl)-acetamide; or phar able salts thereof. maceutically acceptable salts thereof. 53. N-(3-4-4-(Cyclohexylmethanesulfonyl-methyl 56. A pharmaceutical composition comprising the com amino)-butyl-piperazin-1-yl)-phenyl)-acetamide; or phar- 5 pound of claim 35, and a pharmaceutically-acceptable car maceutically acceptable salts thereof. 1. 54. N-(3-4-4-(2-Methyl-propane-1-sulfonylamino)-bu 57. The compound of claim 1, wherein p is 0 or 1. tyl-piperazin-1-yl)-phenyl)-acetamide; or pharmaceuti cally acceptable salts thereof. k k k k k