Pyrrolidine modulators of chemokine receptor activity

• US 6,399,619 B1
• Filed: 04/04/2000
• Issued: 06/04/2002
• Est. Priority Date: 04/06/1999
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Lynch, Christopher, Willoughby, Christopher, Berk, Scott, Hale, Jeffrey, MacCoss, Malcolm, Caldwell, Charles G., Mills, Sander G., Chapman, Kevin T.
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): Patel, Sudhaker B.
• Application Number:
  US09/542,898
• Time in Patent Office: 791 Days
• Field of Search: 514/255.05, 514/340, 514/422, 514/426, 514/429, 544/359, 544/372, 546/193, 546/207, 548/517, 548/518, 548/566, 548/570, 548/577
• US Class Current: 514/255.05
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• 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 259/06 having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings

Abstract

The present invention is directed to pyrrolidine compounds of the formula I:

(wherein R¹, R², R³, R⁴, R⁵, R⁶ and n are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-5 and/or CCR-3.

Claims

1. A compound of the formula I:

wherein;

R² is

wherein R⁷ is selected from;

(1) hydrogen,

(2) C_1-6 alkyl, which is unsubstituted or substituted with 1-4 substituents where the substituents are independently selected from;

hydroxy, cyano, and halo,

(3) cyano,

(4) hydroxy, and

(5) halo,

wherein X is —

(C_0-6 alkyl)-Y—

(C_0-6 alkyl)-,

where the alkyl is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from;

(a) halo,

(b) hydroxy,

(c) —

O—

C_1-3 alkyl, and

(d) trifluoromethyl,

and where Y is selected from;

—

(CO)—

, —

(CO)O—

, —

O(CO)—

, —

(CO)NR¹⁰—

, —

NR¹⁰(CO)—

, —

O(CO)NR¹⁰—

, —

NR¹⁰(CO)O—

, and —

NR¹⁰(CO)NR⁹—

,

and where R¹⁰ is independently selected from;

hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, benzyl, phenyl, and C_1-6 alkyl-C_3-6 cycloalkyl,

which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from;

halo, C_1-3 alkyl, C_1-3 alkoxy and trifluoromethyl,

and wherein R⁸ is selected from;

phenyl, naphthyl, biphenyl, and heterocycle,

which is unsubstituted or substituted with 1-7 of R¹¹ where R¹¹ is independently selected from;

(a) halo,

(b) cyano,

(c) hydroxy,

(d) C_1-6 alkyl, which is unsubstituted or substituted with 1-5 of R¹² where R¹² is independently selected from;

halo, cyano, hydroxy, C_1-6 alkoxy, —

CO₂H, —

CO₂(C_1-6 alkyl), phenyl, trifluoromethyl, and —

NR⁹R¹⁰,

(e) —

O—

C_1-6 alkyl, which is unsubstituted or substituted with 1-5 of R¹²,

(f) —

CF₃,

(g) —

CHF₂,

(h) —

CH₂F,

(i) —

NO₂,

(j) phenyl,

(k) —

CO₂R⁹,

(l) tetrazolyl,

(m) —

NR⁹R¹⁰,

(n) —

NR⁹—

COR¹⁰,

(o) —

NR⁹—

CO₂R¹⁰,

(p) —

CO—

NR⁹R¹⁰,

(q) —

OCO—

NR⁹R¹⁰,

(r) —

NR⁹CO—

NR⁹R¹⁰,

(s) —

S(O)_m—

R⁹, wherein m is an integer selected from 0, 1 and 2,

(t) —

S(O)₂—

NR⁹R¹⁰,

(u) —

NR⁹S(O)₂—

R¹⁰, and

(v) —

NR⁹S(O)₂—

NR⁹R¹⁰;

R³ is selected from the group consisting of;

phenyl and thienyl,

which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from;

(a) halo,

(b) trifluoromethyl,

(c) hydroxy,

(d) C_1-3 alkyl,

(e) —

O—

C_1-3 alkyl,

(f) —

CO₂R⁹,

(g) —

NR⁹R¹⁰, and

(h) —

CONR⁹R¹⁰;

R⁴ is selected from;

C_1-10 alkyl, C_3-8 cycloalkyl, —

(C_1-3 alkyl)-C_3-8 cycloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, phenyl, —

(C_1-6 alkyl)-phenyl, naphthyl, biphenyl, heterocycle, hydrogen, cyclohexenyl, dihydronaphthyl, tetrahydronaphthyl, and octahydronaphthyl,

which is unsubstituted or substituted with 1-7 of R¹¹ where R¹¹ is independently as defined above;

R⁵ is selected from;

hydrogen or C_1-6 alkyl, wherein the alkyl is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from;

(a) halo,

(b) trifluoromethyl,

(c) hydroxy,

(d) C_1-3 alkyl,

(e) —

O—

C_1-3 alkyl,

(f) —

CO₂R⁹,

(g) —

NR⁹R¹⁰, and

(h) —

CONR⁹R¹⁰,

or where R⁴ and R⁵ may be joined together to form a C_3-8 cycloalkyl ring which may be unsubstituted or substituted with 1-7 of R¹¹;

and pharmaceutically acceptable salts thereof and individual diastereomers thereof.

2. The compound of claim 1 wherein R³ is selected from the group consisting of:

phenyl and thienyl,

which may be unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from;

(a) halo,

(b) trifluoromethyl,

(c) hydroxy,

(d) C_1-3 alkyl, and

(e) —

O—

C_1-3 alkyl.

3. The compound of claim 1 wherein R³ is selected from the group consisting of:

phenyl and thienyl,

which may be unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from;

(a) fluoro,

(b) chloro,

(c) trifluoromethyl,

(d) hydroxy, and

(e) C_1-3 alkyl.

4. The compound of claim 1 wherein R³ is selected from the group consisting of:

phenyl, which may be unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from;

(a) fluoro, and

(b) chloro; and

unsubstituted thienyl.

5. The compound of claim 1 wherein R³ is unsubstituted phenyl, (3-fluoro)phenyl or 3-thienyl.

6. The compound of claim 1 wherein R⁴ is C_1-10 alkyl, C_3-8 cycloalkyl, or —

(C_1-3 alkyl)-C_3-8 cycloalkyl,

which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from;

(a) halo,

(b) hydroxy,

(c) —

C_1-6 alkyl, which is unsubstituted or substituted with halo, cyano, —

CO₂H, hydroxy or trifluoromethyl,

(d) —

O—

C_1-6 alkyl, which is unsubstituted or substituted halo, cyano, —

CO₂H, hydroxy or trifluoromethyl,

(e) —

CF₃,

(f) —

CHF₂,

(g) —

CH₂F, and

(h) —

CO₂H.

7. The compound of claim 1 wherein R⁴ is selected from:

isopropyl, isobutyl, sec-butyl, t-butyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, —

CH₂-cyclohexyl, —

CH₂-cyclopentyl, —

CH₂-cyclobutyl, and —

CH₂-cyclopropyl.

8. The compound of claim 1 wherein R⁴ is selected from:

isopropyl, sec-butyl, t-butyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, —

CH₂-cyclobutyl, and —

CH₂-cyclopropyl.

9. The compound of claim 1 wherein R⁴ is selected from:

cyclohexyl, isopropyl, sec-butyl, t-butyl, —

CH₂-cyclobutyl and —

CH₂-cyclopropyl.

10. The compound of claim 1 wherein R⁵ is hydrogen.

11. The compound of claim 1 wherein R⁷ is hydrogen, fluoro, hydroxy or C_1-6 alkyl.

12. The compound of claim 1 wherein R⁷ is hydrogen or fluoro.

13. The compound of claim 1 wherein R⁷ is hydrogen.

14. The compound of claim 1 wherein X is:

—

(C_0-4 alkyl)-Y—

(C_0-4 alkyl)-,

where the alkyl is unsubstituted or substituted with 1-4 substituents where the substituents are independently selected from;

(a) halo,

(b) hydroxy,

(c) —

O—

C_1-3 alkyl, and

(d) trifluoromethyl,

and where Y is selected from;

—

(CO)NR¹⁰—

, —

NR¹⁰(CO)—

, —

O(CO)NR¹⁰—

, —

NR¹⁰(CO)O—

, and —

NR¹⁰O(CO)NR⁹—

,

and where R¹⁰ is independently selected from;

hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, benzyl, phenyl, and C_1-6 alkyl—

C_3-6 cycloalkyl,

which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from;

halo, C_1-3 alkyl, C_1-3 alkoxy and trifluoromethyl.

15. The compound of claim 1 wherein X is:

—

(C_0-2 alkyl)-Y—

(C_0-2 alkyl)-,

where the alkyl is unsubstituted or substituted with 1-4 substituents where the substituents are independently selected from;

(a) halo,

(b) hydroxy,

(c) —

O—

C_1-3 alkyl, and

(d) trifluoromethyl,

and where Y is selected from;

—

(CO)NR¹⁰—

, —

NR¹⁰(CO)—

, —

O(CO)NR¹⁰—

, —

NR¹⁰(CO)O—

, and —

NR¹⁰(CO)NR⁹—

,

where R⁹ is independently selected from;

hydrogen and C_1-6 alkyl, and

R¹⁰ is independently selected from;

hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, benzyl, phenyl, and C_1-6 alkyl-C_3-6 cycloalkyl,

which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from;

halo, C_1-3 alkyl, C_1-3 alkoxy and trifluoromethyl.

16. The compound of claim 1 wherein X is selected from:

—

(C_0-2 alkyl)-Y—

(C_0-2 alkyl)-, where the alkyl is unsubstituted,

and where Y is selected from;

—

(CO)NR¹⁰—

, —

NR¹⁰(CO)—

, —

O(CO)NR¹⁰—

, —

NR¹⁰(CO)O—

, and —

NR¹⁰(CO)NH—

,

where R¹⁰ is independently selected from;

hydrogen, C_1-3 alkyl, C_2-3 alkenyl, and C_2-3 alkynyl.

17. The compound of claim 1 wherein X is selected from:

(1) —

N(C_1-4 alkyl)(CO)O—

CH₂—

,

(2) —

N(allyl)(CO)O—

CH₂—

,

(3) —

N(C_1-4 alkyl)(CO)NH—

CH₂—

,

(4) —

N(allyl)(CO)NH—

CH₂—

, and

(5) —

N(CH₂CH₃)(CO)NH—

CH₂CH₂—

.

18. The compound of claim 1 wherein R⁸ is selected from:

phenyl, naphthyl, benzoimidazolyl, benzofurazanyl, isoxazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, and tetrazolopyridyl,

which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from;

(a) halo,

(b) cyano,

(c) hydroxy,

(d) C_1-6 alkyl, which is unsubstituted or substituted with 1-5 of R¹² where R¹² is independently selected from;

halo, cyano, hydroxy, C_1-6 alkoxy, —

CO₂H, phenyl, —

CO₂(C_1-6 alkyl), trifluoromethyl, and —

NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently selected from;

hydrogen, C_1-6 alkyl, C_5-6 cycloalkyl, benzyl or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from;

halo, C_1-3 alkyl, C_1-3 alkoxy and trifluoromethyl;

(e) —

O—

C_1-6 alkyl, which is unsubstituted or substituted with 1-5 of R¹²,

(f) —

CF₃,

(g) —

CHF₂,

(h) —

CH₂F,

(i) —

NO₂,

(j) phenyl,

(k) —

CO₂R⁹,

(l) tetrazolyl,

(m) —

NR⁹R¹⁰,

(n) —

NR⁹—

COR¹⁰,

(o) —

NR⁹—

CO₂R¹⁰,

(p) —

CO—

NR⁹R¹⁰,

(q) —

OCO—

NR⁹R¹⁰,

(r) —

NR⁹CO—

NR⁹R¹⁰,

(s) —

S(O)_m—

R⁹,wherein m is an integer selected from 0, 1 and 2,

(t) —

S(O)₂—

NR⁹R¹⁰,

(u) —

NR⁹S(O)₂—

R¹⁰, and

(v) —

NR⁹S(O)₂—

NR⁹R¹⁰.

19. The compound of claim 1 wherein R⁸ is selected from:

phenyl, benzofurazanyl, benzoimidazolyl, isoxazole, and pyridyl;

which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from;

(a) halo,

(b) cyano,

(c) —

NO₂,

(d) —

CF₃,

(e) —

CHF₂,

(f) —

CH₂F,

(g) tetrazolyl,

(h) C_1-6 alkyl, which is unsubstituted or substituted with phenyl, and

(i) —

O—

C_1-6 alkyl.

20. The compound of claim 1 wherein R⁸ is

phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:

(a) fluoro,

(b) chloro,

(c) cyano,

(d) —

NO₂, and

(e) —

CF₃.

21. The compound of claim 1 wherein R⁸ is selected from:

phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, 2,4,6-trifluorophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-chlorophenyl, 3-chlorophenyl, 4-trifluoromethylphenyl, and 3,5-bis(trifluoromethyl)phenyl.

22. The compound of claim 1 which is of the stereochemical configuration:

23. The compound of claim 1, which is a compound of formula (II):

wherein

R² is selected from the group consisting of

R⁴ is selected from the group consisting of

A is methyl, ethyl, propyl, butyl, or cyclopropylmethyl-; and

D¹ and D² are both fluoro;

or one of D¹ and D² is hydrogen and the other of D¹ and D² is fluoro, chloro, CN, CF₃, or SO₂CH₃; and

G is hydrogen or fluoro;

and pharmaceutically acceptable salts thereof and individual diastereomers thereof.

24. The compound according to claim 1, which is a compound selected from the group consisting of

and pharmaceutically acceptable salts thereof.

25. A compound according to claim 24, which is a compound selected from the group consisting of

and pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1.

27. A method for preventing infection by HIV, treating infection by HIV, delaying of the onset of AIDS, or treating AIDS comprising the administration to a patient of an effective amount of the compound of claim 1.

28. A method for the prevention or treatment of asthma or rheumatoid athritis which comprises tie administration to a patient of an effective amount of the compound of claim 1.