Substituted piperidine compounds

1. A compound of formula I:

wherein:

R 1 is —C(═O)OR 5 , —C(═O)NR 6 R 7 , —NR 6 R 7 , or —CH 2 OR 5 ;

R 2 and R 3 are each independently alkyl or alkenyl;

R 4 is:

cycloalkyl,

heterocycloalkyl, or

C 1-10 alkyl which is substituted with at least one:

substituted aryl, wherein at least one of said aryl substituents is other than OH, nitro, amino, halo, CN, CH 2 CN, CONH 2 , C 1-4 alkyl, C 1-4 alkoxy, or C 1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms),

aryloxyaryl,

-aryl-N(H)R b ,

-aryl-N(R b )R b ,

heteroarylaryl,

alkoxyaryl, wherein the carbon chain of said alkoxy is interrupted by a nitrogen atom,

substituted alkoxyaryl, provided that when one or more substituents are present on the alkoxy group, at least one of said substituents is other than halo,

substituted cycloalkyl,

RS(═O) p substituted heteroaryl,

RS(═O) p substituted heterocycloalkyl,

RS(═O) p substituted aryl,

heterocycloalkylheteroaryl,

heteroarylheteroaryl,

bicycloalkyl,

bicycloalkenyl,

carboxy,

—CO 2 R a ,

—C(═O)N(R 6a )—R 6b —CO 2 H,

—C(═O)N(R 6a )—R 6b —CO 2 R,

—C(═O)N(R 6a )—R 6b —C(═O)NR 7a R 7b ,

—N(R 7c )C(═O)R 7d ,

aralkoxyaryl,

substituted arylheteroaryl, or

substituted alkoxyheteroaryl, provided that when one or more substituents are present on the alkoxy group, at least one of said substituents is other than halo;

p is 0, 1, or 2;

R is alkyl, aralkyl, or aryl;

R a is H, alkyl, alkenyl, cycloalkyl, aryl, or heteroaryl, provided that R a is not C 1-6 alkyl;

each R b is independently alkyl, cycloalkyl, aralkyl, or aryl,

R 6a is H, alkyl, aralkyl, cycloalkyl, alkenyl, aryl, heteroaralkyl, or heteroaryl;

R 6b is lower alkylene, or lower aralkylene or, together with the nitrogen atom to which they are attached, R 6a and R 6b form a 4- to 7-membered heterocycloalkyl ring;

R 7a and R 7b are each independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aralkyl, or aryl, or together with the nitrogen atom to which they are attached, R 7a and R 7b form a 4- to 7-membered heterocycloalkyl ring, provided that at least one of R 7a and R 7b is other than H;

R 7c and R 7d are each independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aralkyl, or aryl;

R 5 is H or alkyl; and

each R 6 and R 7 is independently H, alkyl, or —C(═O)R, or, together with the nitrogen atom to which they are attached, R 6 and R 7 form a 4- to 7-membered heterocycloalkyl ring, provided that no more than one of R 6 and R 7 is —C(═O)R, and provided that when R 1 is NR 6 R 7 , R 4 can also be aralkyl;

or a stereoisomer, pharmaceutically acceptable salt, acid or N-oxide thereof, provided that R 2 and R 3 are not in the cis stereoisomer conformation when both R 2 and R 3 are methyl.

2. A compound according to claim 1 , wherein:

R 4 is:

cycloalkyl,

heterocycloalkyl, or

C 1-10 alkyl which is substituted with at least one:

substituted aryl, wherein said aryl substituent is other than OH, nitro, amino, halo, CN, CH 2 CN, CONH 2 , C 1-4 alkyl, C 1-4 alkoxy, or C 1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms),

aryloxyaryl,

-aryl-N(H)R b ,

-aryl-N(R b )R b ,

heteroarylaryl,

alkoxyaryl, wherein the carbon chain of said alkoxy is interrupted by a nitrogen atom,

substituted alkoxyaryl, provided that when one or more substituents are present on the alkoxy group, at least one of said substituents is other than halo,

substituted cycloalkyl,

RS(═O) p substituted heteroaryl,

RS(═O) p substituted heterocycloalkyl,

RS(═O) p substituted aryl,

heterocycloalkylheteroaryl,

heteroarylheteroaryl,

bicycloalkyl,

bicycloalkenyl,

carboxy,

—CO 2 R a ,

—C(═O)N(R 6a )—R 6b —CO 2 H,

—C(═O)N(R 6a )—R 6b —CO 2 R,

—C(═O)N(R 6a )—R 6b —C(═O)NR 7a R 7b ,

—N(R 7c )C(═O)R 7d ,

aralkoxyaryl,

substituted arylheteroaryl, or

substituted alkoxyheteroaryl, provided that when one or more substituents are present on the alkoxy group, at least one of said substituents is other than halo.

3. A compound according to claim 2 :

wherein:

R 4 is:

cycloalkyl,

heterocycloalkyl, or

C 1-10 alkyl which is substituted with at least one:

aryloxyaryl,

-aryl-N(H)R b ,

-aryl-N(R b )R b ,

heteroarylaryl,

alkoxyaryl, wherein the carbon chain of said alkoxy is interrupted by a nitrogen atom,

substituted cycloalkyl,

RS(═O) p substituted heteroaryl,

RS(═O) p substituted heterocycloalkyl,

RS(═O) p substituted aryl,

heterocycloalkylheteroaryl,

heteroarylheteroaryl,

bicycloalkyl,

bicycloalkenyl,

carboxy,

—CO 2 R a ,

—C(═O)N(R 6a )—R 6b —CO 2 H,

—C(═O)N(R 6a )—R 6b —CO 2 R,

—C(═O)N(R 6a )—R 6b —C(═O)NR 7a R 7b ,

—N(R 7c )C(═O)R 7d ,

aralkoxyaryl, or

substituted arylheteroaryl.

4. A compound according to claim 1 , wherein said compound is a compound of formula Ia:

5. A compound according to claim 4 , wherein R 2 is methyl.

6. A compound according to claim 5 , wherein R 3 is methyl.

7. A compound according to claim 6 , wherein said compound is a compound of formula IIa:

wherein:

R 8 is alkyl, aralkyl, cycloalkyl, alkylcycloalkyl, aryl, heteroaryl, or heteroaralkyl;

R 9 is H, alkyl, alkenyl, cycloalkyl, aryl, or heteroaryl provided that R 9 is not C 1-6 alkyl; and

n is an integer from 1 to 3.

8. A compound according to claim 7 , wherein said compound is a compound of formula IIIa:

9. A compound according to claim 6 , wherein said compound is a compound of formula IVa:

wherein:

R 8 is alkyl, aralkyl, cycloalkyl, alkylcycloalkyl, aryl, heteroaryl, or heteroaralkyl;

R 10 is —R 6b —CO 2 H, —R 6b —CO 2 R 10a , or —R 6b —C(═O)NR 10b R 10c ;

R 11 is H, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl, or together with the nitrogen atom to which they are attached, R 6b and R 11 form a 4- to 7-membered heterocycloalkyl ring;

R 10a is alkyl or aralkyl;

R 10b and R 10c are each independently H or alkyl, or together with the nitrogen atom to which they are attached, R 10b and R 10c form a 4- to 7-membered heterocycloalkyl ring, provided that at least one of R 10b and R 10c is other than H; and

n is an integer from 1 to 3.

10. A compound according to claim 9 , wherein said compound is a compound of formula Va:

wherein:

R 12 is H, lower alkyl, or aralkyl;

R 13 is H, alkyl, cycloalkyl, or aryl, or together with the nitrogen and carbon atoms to which they are respectively attached, R 12 and R 13 form a 4- to 7-membered heterocycloalkyl ring;

each R 14 independently is H, alkyl, cycloalkyl or aryl;

R 15 is —OR 16 or —NR 17 R 18 ;

R 16 , R 17 , and R 18 are each, independently H, or alkyl or, together with the nitrogen atom to which they are attached, R 17 and R 18 form a 4- to 7-membered heterocycloalkyl ring, provided that at least one of R 17 and R 18 is other than H; and

m is an integer from 0 to 3.

11. A compound according to claim 6 , wherein said compound is a compound of formula VIa:

wherein:

R 8 is alkyl, aralkyl, cycloalkyl, alkylcycloalkyl, or aryl;

R 19 is H, alkyl, cycloalkyl, or aryl;

R 20 is —C(═O)R 21 , or —S(═O) 2 R 21 ;

R 21 is alkyl, cycloalkyl, heterocycloalkyl, aralkyl, aryl, or heteroaryl;

m is an integer from 0 to 3; and

n is an integer from 1 to 3.

12. A compound according to claim 11 , wherein said compound is a compound of formula VIIa:

wherein:

R 19 is H or alkyl.

13. A compound according to claim 1 , wherein

R 1 is —C(═O)OR 5 , —C(═O)NR 6 R 7 , or —NR 6 R 7 ; and

R 4 is C 1-10 alkyl, which is substituted with —N(R 7c )C(═O)R 7d , —C(═O)N(R 6a )R 6b —CO 2 H, or —C(═O)N(R 6a )—R 6b —CO 2 R.

14. A compound according to claim 13 , wherein R 4 is C 1-10 alkyl, which is substituted with —N(R 7c )C(═O)R 7d .

15. A compound according to claim 14 wherein R 5 , R 6 , and R 7 are H.

16. A compound according to claim 13 , wherein R 4 is C 1-10 alkyl, which is substituted with —C(═O)N(R 6a )—R 6b —CO 2 H.

17. A compound according to claim 16 , wherein R 5 , R 6 , and R 7 are H.

18. A compound of claim 13 , wherein R 4 is C 1-10 alkyl, which is substituted with —C(═O)N(R 6a )—R 6b —CO 2 R.

19. A compound according to claim 18 , wherein R 5 , R 6 , and R 7 are H.

20. A compound according to claim 6 , wherein

R 1 is —C(═O)OR 5 , —C(═O)NR 6 R 7 , or —NR 6 R 7 ; and

R 4 is C 1-10 alkyl, which is substituted with —N(R 7c )C(═O)R 7d , —C(═O)N(R 6a )—R 6b —CO 2 H, or —C(═O)N(R 6a )—R 6b —CO 2 R.

21. A compound according to claim 20 , wherein R 4 is C 1-10 alkyl, which is substituted with —N(R 7c )C(═O)R 7d .

22. A compound according to claim 21 wherein R 5 , R 6 , and R 7 are H.

23. A compound according to claim 20 , wherein R 4 is C 1-10 alkyl substituted with —C(═O)N(R 6a )—R 6b —CO 2 H.

24. A compound according to claim 23 , wherein R 5 , R 6 , and R 7 are H.

25. A compound of claim 20 , wherein R 4 is C 1-10 alkyl substituted with —C(═O)N(R 6a )—R 6b —CO 2 R.

26. A compound of claim 25 , wherein R 5 , R 6 , and R 7 are H.

27. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier; and

an effective amount of a compound according to claim 1 .

28. A pharmaceutical composition according to claim 27 , further comprising an effective amount of at least one opioid.

29. A pharmaceutical composition according to claim 28 , wherein said opioid is selected from alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil, tramadol or mixtures thereof.

30. A method for treating gastrointestinal dysfunction caused by an endogenous or exogenous opioid, comprising the step of:

administering to a mammal in need of such treatment, a composition comprising an effective amount of a compound according to claim 1 .

31. A method for treating post-operative or opioid-induced ileus, comprising the step of:

administering to a mammal in need of such treatment, a composition comprising an effective amount of a compound according to claim 1 .

32. A method for treating at least one side effect associated with an opioid, comprising the step of:

administering to a mammal in need of such treatment, a composition comprising an effective amount of a compound according to claim 1 ;

wherein said side effect is selected from the group consisting of constipation, nausea, and vomiting.

33. A method according to claim 32 , wherein said composition further comprises an effective amount of at least one opioid.

34. A method according to claim 32 , wherein said administering step occurs before, during or after a step of administering at least one opioid.

35. A method of treating pain, comprising the step of:

administering to a mammal in need thereof, a composition, comprising:

an effective amount of an opioid; and

an effective amount of a compound according to claim 1 .

36. A method according to claim 33 or 35 , wherein said opioid is selected from alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil, tramadol or mixtures thereof.

37. A compound selected from the group consisting of:

3-(1-cyclohexyl-3R,4R-dimethyl-piperidin-4-yl)-benzoic acid;

3-[1-(3-benzyloxy-benzyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoic acid;

3-(1-biphenyl-4-ylmethyl-3R,4R-dimethyl-piperidin-4-yl)-benzoic acid;

3-[3R,4R-dimethyl-1-(3-phenoxy-benzyl)-piperidin-4-yl]-benzoic acid;

3-[1-(4-dimethylamino-benzyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoic acid;

3-[3R,4R-dimethyl-1-(2-pyridin-4-yl-benzyl)-piperidin-4-yl]-benzoic acid;

3-{1-[4-(4-fluoro-phenoxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}-benzoic acid;

3-[3R,4R-dimethyl-1-(4-pyrimidin-5-yl-benzyl)-piperidin-4-yl]-benzoic acid;

3-[3R,4R-dimethyl-1-(4-pyridin-3-yl-benzyl)-piperidin-4-yl]-benzoic acid;

3-[3R,4R-dimethyl-1-(4-pyridin-4-yl-benzyl)-piperidin-4-yl]-benzoic acid;

3-{1-[4-(3-dimethylamino-propoxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}-benzoic acid;

3-{1-[4-(4-fluoro-benzyloxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}-benzoic acid;

3-[1-(4′-fluoro-biphenyl-4-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoic acid;

3-[1-(4′-fluoro-biphenyl-3-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoic acid;

3-[1-(2-ethoxycarbonyl-cyclopropylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoic acid;

3-[1-(1-benzenesulfonyl-1H-pyrrol-2-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoic acid; 3-{3R,4R-dimethyl-1-[1-(2-morpholin-4-yl-ethyl)-1H-pyrrol-2-ylmethyl]-piperidin-4-yl}-benzoic acid;

3-[1-(1-isoxazol-3-yl-1H-pyrrol-2-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoic acid;

3-(1-bicyclo [2.2.1 ]hept-5-en-2-ylmethyl-3R,4R-dimethyl-piperidin-4-yl)-benzoic acid;

3-[3R,4R-dimethyl-1-(4-methylsulfanyl-benzyl)-piperidin-4-yl]-benzoic acid;

3-(3R,4R,1′-trimethyl-[1,4′]bipiperidinyl-4-yl)-benzoic acid;

3-(1′-benzyl-3R,4R,3′-trimethyl-[1,4′]bipiperidinyl-4-yl)-benzoic acid;

3-[1-(1-benzyl-pyrrolidin-3-yl)-3R,4R-dimethyl-piperidin-4-yl]-benzoic acid;

3-(1-cyclopentyl-3R,4R-dimethyl-piperidin-4-yl)-benzoic acid;

3-[1-(2S-carboxy-3-phenyl-propyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoic acid;

[[2(R)-[[4(R)-(3-carboxyphenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenyipropyl]amino]acetic acid;

3-(1-{2-[3-(4-hydroxyphenyl)-propionylamino]-3-methyl-butyl}-3R,4R-dimethyl-piperidin-4-yl)benzoic acid;

3-(1-cyclohexyl-3R,4R-dimethyl-piperidin-4-yl)-benzamide;

3-[1-(3-benzyloxy-benzyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;

3-(1-biphenyl-4-ylmethyl-3R,4R-dimethyl-piperidin-4-yl)-benzamide;

3-[3R,4R-dimethyl-1-(3-phenoxy-benzyl)-piperidin-4-yl]-benzamide;

3-[1-(4-dimethylamino-benzyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;

3-[3R,4R-dimethyl-1-(2-pyridin-4-yl-benzyl)-piperidin-4-yl]-benzamide;

3-{1-[4-(4-fluoro-phenoxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}-benzamide;

3-[3R,4R-dimethyl-1-(4-pyrimidin-5-yl-benzyl)-piperidin-4-yl]-benzamide;

3-[3R,4R-dimethyl-1-(4-pyridin-3-yl-benzyl)-piperidin-4-yl]-benzamide;

3-[3R,4R-dimethyl-1-(4-pyridin-4-yl-benzyl)-piperidin-4-yl]-benzamide;

3-[1-(4′-fluoro-biphenyl-4-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;

3-{1-[4-(4-fluoro-benzyloxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}-benzamide;

3-{1-[4-(3-dimethylamino-propoxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}1-benzamide;

3-[1-(4′-fluoro-biphenyl-3-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;

3-[1-(2-ethoxycarbonyl-cyclopropylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;

3-[1-(1-benzenesulfonyl-1H-pyrrol-2-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;

3-{3R,4R-dimethyl-1-[1-(2-morpholin-4-yl-ethyl)-1H-pyrrol-2-ylmethyl]-piperidin-4-yl}-benzamide;

3-[1-(1-isoxazol-3-yl-1H-pyrrol-2-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;

3-(1-bicyclo [2.2.1 ]hept-5-en-2-ylmethyl-3R,4R-dimethyl-piperidin-4-yl)-benzamide;

3-[3R,4R-dimethyl-1-(4-methylsulfanyl-benzyl)-piperidin-4-yl]-benzamide;

3-(1′-benzyl-3R,4R,3′-trimethyl-[1,4′]bipiperidinyl-4-yl)-benzamide;

3-{1-[1-(5-chloro-pyridin-2-yl)-1H-pyrrol-2-ylmethyl]-3R,4R-dimethyl-piperidin-4-yl}-benzamide;

3-[1-(1-benzyl-pyrrolidin-3-yl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;

3-(1-cyclopentyl-3R,4R-dimethyl-piperidin-4-yl)-benzamide;

3-{3R,4R-dimethyl-1-[4-(2H-tetrazol-5-yl)-benzyl]-piperidin-4-yl}-benzamide;

3-[1-(5-benzyloxy-1H-indol-3-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;

3-{3R,4R-dimethyl-1-[5-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-thiophen-2-ylmethyl]-piperidin-4-yl}-benzamide;

[[2(R)-[[4(R)-(3-amidophenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid;

3-(1-{2-[3-(4-hydroxyphenyl)-propionylamino]-3-methyl-butyl}-3R,4R-dimethyl-piperidin-4-yl)benzamide;

[[2(R)-[[4(R)-(3-aminophenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid; and

pharmaceutically acceptable salts thereof.