IP Library › Granted Patent US 7,579,466
Granted Patent B2
US 7,579,466 · App. 11/679,042 · Granted Aug 25, 2009

Pyrimidinyl sulfonamide compounds which inhibit leukocyte adhesion mediated by VLA-4

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Quick Facts
Patent No.
US 7,579,466
App. No.
11/679,042
Granted
Aug 25, 2009
Kind
B2
Abstract

Disclosed are compounds, which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a human or animal subject such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Claims (79)

1. A compound of formula I:

wherein:

R 1 is selected from the group consisting of C 1 to C 4 alkyl and C 1 to C 4 haloalkyl; and

R 2 is selected from the group consisting of C 1 to C 4 alkyl, C 2 to C 4 alkenyl, C 2 to C 4 alkynyl, and C 3 -C 6 cycloalkyl;

or a pharmaceutically acceptable salt thereof;

or an ester thereof, wherein the ester is an ester of the —COOH group.

2. The compound according to claim 1 , wherein R 1 is C 1 to C 2 alkyl.

3. The compound according to claim 1 , wherein R 1 is methyl or trifluoromethyl.

4. The compound according to claim 1 , wherein R 1 is methyl.

5. The compound according to claim 1 , wherein R 2 is C 1 to C 4 alkyl.

6. The compound according to claim 1 , wherein R 2 is C 1 to C 3 alkyl.

7. The compound according to claim 6 , wherein R 2 is methyl or ethyl.

8. The compound according to claim 6 , wherein R 2 is isopropyl.

9. The compound according to claim 1 , wherein R 2 is C 3 to C 6 cycloalkyl.

10. The compound according to claim 9 , wherein R 2 is cyclopentyl.

11. The compound according to claim 1 , wherein R 2 is C 2 to C 4 alkenyl.

12. The compound according to claim 11 , wherein R 2 is allyl.

13. The compound according to claim 1 , wherein R 2 is C 2 to C 4 alkynyl.

14. The compound according to claim 13 , wherein R 2 is propargyl.

15. A compound of formula II:

wherein:

R 1 is selected from the group consisting of C 1 to C 4 alkyl and C 1 to C 4 haloalkyl; and

R 2 is selected from the group consisting of C 1 to C 4 alkyl, C 2 to C 4 alkenyl, C 2 to C 4 alkynyl, and C 3 -C 6 cycloalkyl;

or pharmaceutically acceptable salt thereof;

or an ester thereof, wherein the ester is an ester of the —COOH group.

16. The compound according to claim 15 , wherein R 1 is C 1 to C 2 alkyl.

17. The compound according to claim 15 , wherein R 1 is methyl or trifluoromethyl.

18. The compound according to claim 15 , wherein R 1 is methyl.

19. The compound according to claim 15 , wherein R 2 is C 1 to C 4 alkyl.

20. The compound according to claim 15 , wherein R 2 is C 1 to C 3 alkyl.

21. The compound according to claim 20 , wherein R 2 is methyl or ethyl.

22. The compound according to claim 20 , wherein R 2 is isopropyl.

23. The compound according to claim 16 , wherein R 2 is C 3 to C 6 cycloalkyl.

24. The compound according to claim 23 , wherein R 2 is cyclopentyl.

25. The compound according to claim 15 , wherein R 2 is C 2 to C 4 alkenyl.

26. The compound according to claim 25 , wherein R 2 is allyl.

27. The compound according to claim 15 , wherein R 2 is C 2 to C 4 alkynyl.

28. The compound according to claim 27 , wherein R 2 is propargyl.

29. A compound selected from the group consisting of:

(S)-2-(2-(diethylamino)-5-(N-ethyl-1,1,1-trifluoromethylsulfonamido)pyrimidin-4-ylamino)-3-(4-(pyrrolidine-1-carbonyloxy)phenyl)propanoic acid;

(S)-2-(2-(diethylamino)-5-(N-isopropylmethylsulfonamido)pyrimidin-4-ylamino)-3-(4-(pyrrolidine-1-carbonyloxy)phenyl)propanoic acid;

(S)-2-(5-(N-cyclopentylmethylsulfonamido)-2-(diethylamino)pyrimidin-4-ylamino)-3-(4-(pyrrolidine-1-carbonyloxy)phenyl)propanoic acid;

(S)-2-(2-(diethylamino)-5-(N-methylmethylsulfonamido)pyrimidin-4-ylamino)-3-(4-(pyrrolidine-1-carbonyloxy)phenyl)propanoic acid;

(S)-2-(2-(diethylamino)-5-(N-(prop-2-ynyl)methylsulfonamido)pyrimidin-4-ylamino)-3-(4-(pyrrolidine-1-carbonyloxy)phenyl)propanoic acid;

(S)-2-(2-(diethylamino)-5-(N-ethylmethylsulfonamido)pyrimidin-4-ylamino)-3-(4-(pyrrolidine-1-carbonyloxy)phenyl)propanoic acid;

(S)-2-(5-(N-allylmethylsulfonamido)-2-(diethylamino)pyrimidin-4-ylamino)-3-(4-(pyrrolidine-1-carbonyloxy)phenyl)propanoic acid; (S)-2-(2-(diethylamino)-5-(N-ethylbutylsulfonamido)pyrimidin-4-ylamino)-3-(4-(pyrrolidine-1-carbonyloxy)phenyl)-propanoic acid;

(S)-2-(5-(3-chloro-N-ethylpropylsulfonamido)-2-(diethylamino)-pyrimidin-4-ylamino)-3-(4-(pyrrolidine-1-carbonyloxy)phenyl)propanoic acid;

(S)-2-(5-(3-chloro-N-methylpropyl-sulfonamido)-2-(diethylamino)pyrimidin-4-ylamino)-3-(4-(pyrrolidine-1-carbonyloxy)phenyl)propanoic acid;

(S)-2-(2-(diethylamino)-5-(N-ethyl-3,3,3-trifluoropropylsulfonamido)-pyrimidin-4-ylamino)-3-(4-(pyrrolidine-1-carbonyloxy)phenyl)propanoic acid;

(S)-2-(2-(diethylamino)-5-(N-ethylpropylsulfonamido)pyrimidin-4-ylamino)-3-(4-(pyrrolidine-1-carbonyloxy)phenyl)-propanoic acid; and

(S)-2-(2-(diethylamino)-5-(N-ethyl-2-methylpropylsulfonamido)pyrimidin-4-ylamino)-3-(4-(pyrrolidine-1-carbonyloxy)-phenyl)propanoic acid;

or a pharmaceutically acceptable salt thereof;

or an ester thereof, wherein the ester is an ester of the propanoic acid.

30. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds as set forth in claim 1 .

31. A method for preparing a compound of formula I:

wherein:

R 1 is selected from the group consisting of C 1 to C 4 alkyl and C 1 to C 4 haloalkyl; and

R 2 is selected from the group consisting of C 1 to C 4 alkyl, C 2 to C 4 alkenyl, C 2 to C 4 alkynyl, and C 3 -C 6 cycloalkyl;

or a pharmaceutically acceptable salt thereof;

which method comprises:

a) contacting a compound of formula III

where Pg is a carboxyl protecting group;

with a C 1 to C 4 aldehyde or ketone, a C 2 to C 4 alkenyl aldehyde or ketone, C 2 to C 4 alkynyl aldehyde or ketone, C 3 -C 6 cycloalkyl ketone and benzaldehyde under reductive amination conditions to provide for a compound of formula IV:

b) contacting compound IV with a sulfonyl halide of the formula R 1 SO 2 Z where Z is halo under conditions to form a compound of formula V:

and

c) removing the carboxyl protecting group to provide for a compound of formula I.

32. A method for preparing a compound of formula I:

wherein:

R 1 is selected from the group consisting of C 1 to C 4 alkyl and C 1 to C 4 haloalkyl; and

R 2 is selected from the group consisting of C 1 to C 4 alkyl, C 2 to C 4 alkenyl, C 2 to C 4 alkynyl, and C 3 -C 6 cycloalkyl;

or a pharmaceutically acceptable salt thereof;

which method comprises;

a) contacting a compound of formula VI

where Pg is a carboxyl protecting group;

with an excess of R′SO 2 X to provide for a compound of formula VII:

b) selectively removing a single —SO 2 R′ group from the compound of formula VII to provide a compound of formula VIII:

c) contacting compound VIII with an alkylating agent with a formula R 2 —X, wherein X is halo, or with dimethylsulfate when R 2 is methyl, to form a compound of formula IX:

and

d) removing the carboxyl protecting group to provide for a compound of formula I.