Bicyclic amides

• US 20050203112A1
• Filed: 04/08/2003
• Published: 09/15/2005
• Est. Priority Date: 04/12/2002
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Lin, Linus S., Castonguay, Laurie A., Shah, Shrenik K., Hagmann, William K.
• Granted Patent: US 7,667,053 B2
• Time in Patent Office: Days
• US Class Current: 514/266.200
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 233/59 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 2602/08 the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 2602/10 the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 2602/12 the other ring being at least seven-membered
• CPC Class Codes: C07D 307/84 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 311/58 : other than with oxygen or sulphur atoms in position 2 or 4
• CPC Class Codes: C07D 319/20 : with substituents attached to the hetero ring
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links

Abstract

Novel compounds of the structural formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson'"'"'s disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, and cirrhosis of the liver.

Claims

1. A compound of structural formula I:

2. The compound according to claim 1, wherein R⁴ is selected from:

(1) hydrogen,

(2) C_1-4alkyl, and

(3) cyclopropyl,

wherein alkyl and cyclopropyl are optionally substituted with one, two or three R^a substituents;

and pharmaceutically acceptable salts thereof.

3. The compound according to claim 2, wherein R³ is selected from:

(1) methyl,

(2) trifluoromethyl, and

(3) cyclopropyl;

and pharmaceutically acceptable salts thereof.

4. The compound according to claim 3, R¹ is selected from:

(1) C_1-4alkyl,

(2) C_3-10cycloalkyl-,

(3) cycloheteroalkyl,

(4) phenyl, and

(5) pyridyl,

wherein each alkyl is optionally substituted with one R^a substituent, and each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is optionally substituted with one to three substituents independently selected from R^b;

and pharmaceutically acceptable salts thereof.

5. The compound according to claim 4, wherein R² is selected from:

R² is selected from;

(1) C_1-10alkyl,

(2) C_3-10cycloalkyl,

(3) cycloheteroalkyl,

(4) aryl,

(5) heteroaryl,

(6) —

OR^d,

(7) —

NR^cR^d, and

(8) —

CO₂R^d, and

wherein each alkyl is optionally substituted with one, two or three substituents independently selected from R^a, and each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is optionally substituted with one, two or three substitutents independently selected from R^b;

and pharmaceutically acceptable salts thereof.

6. The compound according to claim 5, wherein A is a yclopentyl, cyclohexyl, cycloheptyl, dioxanyl, tetrahydrofuranyl, or oxanyl, ring fused to a phenyl, or pyrrolyl ring, optionally fused to a phenyl ring to form a tricyclic ring wherein the A ring system is optionally substituted with one, two or three R^b substituents;

and pharmaceutically acceptable salts thereof.

7. The compound according to claim 1, wherein:

R¹ is selected from;

(1) isopropyl,

(2) isobutyl,

(3) n-propyl,

(4) cyclopropyl,

(5) cyclobutyl,

(6) cyclopentyl,

(7) cyclohexyl,

(8) piperidinyl,

(9) phenyl, and

(10) pyridyl,

wherein each alkyl is optionally substituted with one R^a substituent, and each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is optionally substituted with one to three substituents independently selected from R^b;

R² is selected from;

(1) cyclobutyl,

(2) cyclopentyl,

(3) cyclohexyl,

(4) pyrrolidinyl,

(5) pyrimidinyl,

(6) benzoxazolyl,

(7) dihydroindolyl,

(8) dihydroquinolinyl,

(9) benzotriazolyl,

(10) thiophenyl,

(11) indolyl,

(12) indazolyl,

(13) pyrrolidinyl,

(14) pyridazinyl

(15) triazolyl,

(16) azaindolyl,

(17) cyclobutylmethoxy,

(18) phenyl,

(19) pyridyl,

(20) —

NR^cR^d, and

(21) —

CO₂R^d,

wherein each alkyl is optionally substituted with one or two R^a substituents and each phenyl or pyridyl is independently with one to three R^b substituents.

R³ is methyl;

R⁴ is selected from hydrogen and methyl;

R⁶ is selected from;

(1) hydrogen,

(2) methyl,

(3) hydroxyl,

(4) halogen, and

(5) —

CN;

A is selected from;

(1) benzodioxanyl,

(2) indanyl,

(3) 1,2,3,4-tetrahydronaphthyl,

(4) 6,7,8,9-tetrahydro[a][7]annulenyl,

(5) chromanyl,

(6) 2,3-dihydrobenzyl furanyl,

(7) 1,2,3,4-tetrahydroquinolinyl,

(8) 1,2,3,4-tetrahydroisoquinolinyl,

(9) 1,2,3,4-tetrahydro-1,4-quinazolinyl, and

(10) 1,2,3,4-tetrahydrocarbolinyl,

each optionally substituted with one, two, or three groups independently selected from R^b;

each R^b is independently selected from;

(1) methoxy,

(2) halogen,

(3) —

SH,

(4) —

SCH₃,

(5) —

NH₂,

(6) —

C(O)CH₃,

(7) —

CO₂H,

(8) —

CO₂CH₃,

(9) —

CF₃,

(10) —

OCF₃,

(11) C_3-6 cycloalkyl,

(12) C_1-4alkyl,

(13) phenyl,

(14) benzyl, and

(15) heteroaryl;

and pharmaceutically acceptable salts thereof.

17. A method of treating a disease mediated by the Cannabinoid-1 receptor comprising administration to a patient in need of such treatment of a therapeutically effective amount of a compound according to claim 1.

18. The method according to claim 17 wherein the disease mediated by the Cannabinoid-1 receptor is selected from:

psychosis, memory deficit, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders, cerebral vascular accidents, head trauma, anxiety disorders, stress, epilepsy, Parkinson'"'"'s disease, schizophrenia, substance abuse disorders, constipation, chronic intestinal pseudo-obstruction, cirrhosis of the liver, asthma, obesity, and other eating disorders associated with excessive food intake.

19. The method according to claim 18 wherein the disease mediated by the Cannabinoid-1 receptor is an eating disorder associated with excessive food intake.

20. The method according to claim 19 wherein the eating disorder asssociated with excessive food intake is selected from obesity, bulimia nervosa, and compulsive eating disorders.

21. The method according to claim 20 wherein the eating disorder associated with excessive food intake is obesity.

22. A method of preventing obesity in a person at risk for obesity comprising administration to said person of about 0.001 mg to about 100 mg per kg of a compound according to claim 1.

23. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

8. A compound of structural formula IA:

9. The compound according to claim 8, wherein R⁴ is selected from:

(1) hydrogen,

(2) C_1-4alkyl, and

(3) cyclopropyl,

wherein alkyl and cyclopropyl are optionally substituted with one, two or three R^a substituents;

and pharmaceutically acceptable salts thereof.

10. The compound according to claim 9, wherein R³ is selected from:

(1) methyl,

(2) trifluoromethyl, and

(3) cyclopropyl;

and pharmaceutically acceptable salts thereof.

11. The compound according to claim 10, wherein R¹ is selected from:

(1) phenyl, and

(2) pyridyl;

wherein phenyl and pyridyl are optionally substituted with one or two R^b substituents;

and pharmaceutically acceptable salts thereof.

12. The compound according to claim 11, wherein R² is selected from:

(1) phenyl, and

(2) pyridyl;

wherein phenyl and pyridyl are optionally substituted with one or two R^b substituents.

and pharmaceutically acceptable salts thereof.

13. The compound according to claim 12, wherein A is a cyclopentyl, cyclohexyl, cycloheptyl, dioxanyl, tetrahydrofuranyl, or oxanyl, ring fused to a phenyl, or pyrrolyl ring, optionally fused to a phenyl ring to form a tricyclic ring wherein the A ring system is optionally substituted with one, two or three R^b substituents;

and pharmaceutically acceptable salts thereof.

14. The compound according to claim 8, wherein:

R¹ is selected from phenyl and 4-chlorophenyl;

R² is selected from;

(1) phenyl, and

(2) pyridyl,

wherein phenyl and pyridyl are optionally substituted with one or two halogen substituents;

R³ is methyl;

R⁴ is selected from hydrogen and methyl;

A is selected from;

(1) benzodioxanyl,

(2) indanyl,

(3) 1,2,3,4-tetrahydronaphthyl,

(4) 6,7,8,9-tetrahydro[a][7]annulenyl,

(5) chromanyl,

(6) 2,3-dihydrobenzyl furanyl,

(7) 1,2,3,4-tetrahydroquinolinyl,

(8) 1,2,3,4-tetrahydroisoquinolinyl,

(9) 1,2,3,4-tetrahydro-1,4-quinazolinyl, and

(10) 1,2,3,4-tetrahydrocarbolinyl,

each optionally substituted with one, two, or three groups independently selected from R^b;

each R^b is independently selected from;

(1) methoxy,

(2) halogen,

(3) —

SH,

(4) —

SCH₃,

(5) —

NH₂,

(6) —

C(O)CH₃,

(7) —

CO₂H,

(8) —

CO₂CH₃,

(9) —

CF₃,

(10) —

OCF₃,

(11) C_3-6 cycloalkyl,

(12) C_1-4alkyl,

(13) phenyl,

(14) benzyl, and

(15) heteroaryl;

and pharmaceutically acceptable salts thereof.

15. The compound according to claim 8, selected from:

(1) N-(2,3-bis(4-chlorophenyl)-1-methylpropyl)-1,4-benzodioxane-2-carboxamide,

(2) N-(2,3-bis(4-chlorophenyl)-1-methylpropyl)-indane-1-carboxamide,

(3) N-(2,3-bis(4-chlorophenyl)-1-methylpropyl)-2,3-dihydrobenzofuran-2-carboxamide,

(4) N-(2,3-bis(4-chlorophenyl)-1-methylpropyl)-1 2,3,4-tetrahydrocarbazole-1-carboxamide,

(5) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-1,2,3,4-tetrahydro-2-naphthamide,

(6) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2,3-dihydrobenzofuran-2-carboxamide,

(7) N-[2,3-bis(4-chlorophenyl)-1-methypropyl]-2-methyl-2,3-dihydrobenzofuran-2-carboxamide,

(8) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2,3-dihydrobenzofuran-2-carboxamide,

(9) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-methyl-1,2,3,4-tetrahydro-2-naphthamide,

(10) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-1,2,3,4-tetrahydro-2-naphthamide,

(11) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-1,2,3,4-tetrahydro-2-naphthamide,

(12) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]chromane-2-carboxamide,

(13) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]chromane-2-carboxamide,

(14) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-methylchromane-2-carboxamide,

(15) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methylchromane-2-carboxamide,

(16) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]chromane-3-carboxamide,

(17) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]chromane-3-carboxamide,

(18) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-3-methylchromane-3-carboxamide,

(19) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-3-methylchromane-3-carboxamide,

(20) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide,

(21) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide,

(22) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2,3-dihydro-1,4-benzodioxane-2-carboxamide,

(23) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2,3-dihydro-1,4-benzodioxane-2-carboxamide,

(24) N-[3-(4-chlorophenyl)-1-methy-3-pyridylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide,

(25) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-6,7,8,9-tetrahydro-5H-benzo[a][7]annulene-6-carboxamide,

(26) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-6,7,8,9-tetrahydro-5H-benzo[a][7]annulene-6-carboxamide,

(27) N-[2,3-bis(4-chlorophenyl)-1-methypropyl]-6,7,8,9-tetrahydro-5H-benzo[a][7]annulene-7-carboxamide,

(28) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-6,7,8,9-tetrahydro-5H-benzo [a][7annulene-7-carboxamide,

(29) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide,

(30) N-[3-(4-chlorophenyl)-1-methy-3-pyridylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide,

(31) N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-3-methylchromane-3-carboxamide,

(32) N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide,

(33) N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-6-chloro-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide,

(34) N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-7-chloro-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide;

and pharmaceutically acceptable salts thereof.

16. The compound according to claim 8, selected from:

(1) N-(2,3-bis(4-chlorophenyl)-1-methylpropyl)-1,4-benzodioxane-2-carboxamide,

(2) N-(2,3-bis(4-chlorophenyl)-1-methylpropyl)-indane-1-carboxamide,

(3) N-(2,3-bis(4-chlorophenyl)-1-methylpropyl)-2,3-dihydrobenzofuran-2-carboxamide,

(4) N-(2,3-bis(4-chlorophenyl)-1-methylpropyl)-1,2,3,4-tetrahydrocarbazole-1-carboxamide,

(5) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-1,2,3,4-tetrahydro-2-naphthamide, diastereomer I,

(6) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-1,2,3,4-tetrahydro-2-naphthamide, diastereomer II,

(7) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-1,2,3,4-tetrahydro-2-naphthamide, diastereomer III,

(8) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-1,2,3,4-tetrahydro-2-naphthamide, diastereomer IV,

(9) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2,3-dihydrobenzofuran-2-carboxamide diastereomer I,

(10) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2,3-dihydrobenzofuran-2-carboxamide diastereomer II,

(11) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2,3-dihydrobenzofuran-2-carboxamide, diastereomers I and II (1;

1),

(12) N-[2,3-bis(4-chlorophenyl)-1-methypropyl]-2-methyl-2,3-dihydrobenzofuran-2-carboxamide diastereomer I,

(13) N-[2,3-bis(4-chlorophenyl)-1-methypropyl]-2-methyl-2,3-dihydrobenzofuran-2-carboxamide diastereomer II,

(14) N-[2,3-bis(4-chlorophenyl)-1-methypropyl]-²-methyl-2,3-dihydrobenzofuran-2-carboxamide, diastereomers I and II (1;

1),

(15) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2,3-dihydrobenzofuran-2-carboxamide diastereomer I,

(16) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2,3-dihydrobenzofuran-2-carboxamide diastereomer II,

(17) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2,3-dihydrobenzofuran-2-carboxamide, diastereomers I and II (1;

1),

(18) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-methyl-1,2,3,4-tetrahydro-2-naphthamide diastereomer I,

(19) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-methyl-1,2,3,4-tetrahydro-2-naphthamide, diastereomer II,

(20) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-1,2,3,4-tetrahydro-2-naphthamide diastereomers I and II (1;

1),

(21) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-1,2,3,4-tetrahydro-2-naphthamide diastereomer I,

(22) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-1,2,3,4-tetrahydro-2-naphthamide diastereomer II,

(23) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-1,2,3,4-tetrahydro-2-naphthamide diastereomers I and II (1;

1),

(24) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]chromane-2-carboxamide diastereomers I and II (1;

1),

(25) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]chromane-2-carboxamide diastereomers I and II (1;

1),

(26) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-²-methylchromane-2-carboxamide diastereomer I,

(27) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-²-methylchromane-2-carboxamide diastereomer II,

(28) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-methylchromane-2-carboxamide diastereomers I and II (1;

1),

(29) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methylchromane-2-carboxamide diastereomer I,

(30) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methylchromane-2-carboxamide diastereomer II,

(31) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methylchromane-2-carboxamide diastereomers I and II (1;

1),

(32) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]chromane-3-carboxamide diastereomers I and II (1;

1),

(33) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]chromane-3-carboxamide diastereomers I and II (1;

1),

(34) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-3-methylchromane-3-carboxamide diastereomers I and II (1;

1),

(35) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-3-methylchromane-3-carboxamide diastereomers I and II (1;

1),

(36) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomer I,

(37) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomer II,

(38) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomers I and II (1;

1),

(39) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomer 1,

(40) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2carboxamide diastereomer II,

(41) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomers I and II (1;

1),

(42) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2,3-dihydro-1,4-benzodioxane-2-carboxamide, diastereomer III,

(43) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomer IV,

(44) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomer I,

(45) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomer II,

(46) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomers I and II (1;

1),

(47) N-[3-(4-chlorophenyl)-1-methy-3-pyridylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomers I and II (3;

1),

(48) N-[3-(4-chlorophenyl)-1-methy-3-pyridylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomers I and II (1;

1),

(49) N-[3-(4-chlorophenyl)-1-methy-3-pyridylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomer II,

(50) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-6,7,8,9-tetrahydro-5H-benzo[a][7]annulene-6-carboxamide diastereomer I,

(51) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-6,7,8,9-tetrahydro-5H-benzo[a][7]annulene-6-carboxamide diastereomer II,

(52) N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-6,7,8,9-tetrahydro-5H-benzo[a][7]annulene-6-carboxamide diastereomers I and II (1;

1),

(53) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-6,7,8,9-tetrahydro-5H-benzo[a][7]annulene-6-carboxamide diastereomer I,

(54) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-6,7,8,9-tetrahydro-5H-benzo[a][7]annulene-6-carboxamide diastereomer II,

(55) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-6,7,8,9-tetrahydro-5H-benzo[a][7]annulene-6-carboxamide diastereomers I and II (1;

1),

(56) N-[2,3-bis(4-chlorophenyl)-1-methypropyl]-6,7,8,9-tetrahydro-5H-benzo[a][7]annulene-7-carboxamide diastereomers I and II (1;

1),

(57) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-6,7,8,9-tetrahydro-5H-benzo[a][7]annulene-7-carboxamide diastereomers I and II (1;

     1),

(58) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomer I enantiomer A,

(59) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomer I enantiomer B,

(60) N-[3-(4-chlorophenyl)-1-methy-3-pyridylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomer I, enantiomer A,

(61) N-[3-(4-chlorophenyl)-1-methy-3-pyridylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomer I, enantiomer B,

(62) N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-3-methylchromane-3-carboxamide diastereomer I,

(63) N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-3-methylchromane-3-carboxamide diastereomer II,

(64) N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomer I,

(65) N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomer II,

(66) N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-6-chloro-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomer I,

(67) N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-7-chloro-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomer I,

(68) N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-6-chloro-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomer II,

(69) N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-7-chloro-2-methyl-2,3-dihydro-1,4-benzodioxane-2-carboxamide diastereomer II,

and pharmaceutically acceptable salts thereof.

24-29. -29. (canceled)