IP Library › Patent Application 12299855

Patent Application

App. No. 12/299,855

IMIDAZOAZEPINONE COMPOUNDS

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Patent No.: US None
App. No.: 12/299,855

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Abstract

The invention relates to compounds of formula (I): along with pharmaceutical compositions containing the same and methods of use thereof.

Claims (139)

1 . A compound of formula I:

wherein:

Q is —C(R 1 )(R 2 )— or —CH═CH— (cis or trans);

R 1 and R 2 are independently selected from H, C 1-3 alkyl, C 2-4 alkenyl, or taken together are C 1-6 alkylidene or C 2-4 alkenylenidene;

each of R 3 , R 4 , R 6 , and R 7 is independently selected from hydrogen and methyl;

X is methylene, ethylene, or propenylene;

R 5 is phenyl, quinolinyl, isoquinolinyl, indolyl, furyl, thienyl, pyrazolyl, quinoxalinyl, naphthyl, or pyrrolyl, and substituted with between 0 and 5 substituents independently selected from C 1-3 alkyl, C 1-3 alkoxy, hydroxyl, C 1-3 alkylthio, cyclopropyl, cyclopropylmethyl, and halo;

R 8 is H, methyl, ethyl, propenyl, (C 1-3 alkoxy)C 1-3 alkyl, (C 1-3 alkylthio)C 1-3 alkyl, C 1-3 hydroxyalkyl, phenyl, benzyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isooxazolyl, pyridyl, and thienyl;

wherein R 8 is substituted with between 0 and 3 substituents independently selected from methyl, ethyl, halo, C 1-3 alkoxy, C 1-3 alkylthio, (C 1-3 alkoxy)C 1-3 alkyl, (C 1-3 alkylthio)C 1-3 alkyl, C 1-3 hydroxyalkyl, (C 1-3 mercaptoalkyl)phenyl, benzyl, furyl, imidazolyl, pyrazolyl, pyrrolyl, isothiazolyl, isooxazolyl, pyridyl, thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, and cyclopropyl; and

each of R a , R b , and R c is independently selected from hydrogen, hydroxyl, methoxy, benzyloxy, fluoro, chloro, amino, methylamino, dimethylamino, and phenoxy;

or one pair selected from R a and R b , and R b and R c , taken together, is —O—(CH 2 )—O— or —O—CH 2 —CH 2 —O—;

or a pharmaceutically acceptable salt, a C 1-4 alkyl ester or amide, or a C 2-6 alkenyl ester or amide thereof.

2 . The compound of claim 1 , wherein:

Q is —C(R 1 )(R 2 )— or —CH═CH— (cis or trans);

R 1 and R 2 are independently selected from H, methyl, ethyl or propyl, or taken together are CH 2 ═, allylidene, propylidene, propenylidene, or ethylidene;

each of R 3 , R 4 , R 6 , and R 7 is hydrogen;

X is methylene, ethylene, or propenylene;

R 5 is phenyl, quinolinyl, isoquinolinyl, indolyl, furyl, thienyl, pyrazolyl, quinoxalinyl, naphthyl, or pyrrolyl, and substituted with between 0 and 3 substituents independently selected from methyl, methoxy, ethyl, hydroxyl, bromo, fluoro, and chloro;

R 8 is H, methyl, ethyl, propenyl, methoxyethyl, hydroxyethyl, or benzyl,

wherein R 8 is substituted with between 0 and 3 substituents independently selected from methyl, ethyl, halo, C 1-3 alkoxy, 1, C 1-3 hydroxyalkyl, benzyl, furyl, imidazolyl, pyrazolyl, pyrrolyl, isothiazolyl, isooxazolyl, pyridyl, thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, and cyclopropyl;

or R a and R b taken together is —O—(CH 2 )—O—;

each of R a , R b , and R c is independently selected from hydrogen, hydroxyl, methoxy, benzyloxy, fluoro, and chloro;

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 2 , wherein:

R 1 and R 2 are independently selected from H and methyl, or taken together are CH 2 ═;

X is methylene, ethylene, or propenylene;

R 5 is phenyl, quinolinyl, isoquinolinyl, indolyl, quinoxalinyl, naphthyl, or pyrrolyl, and substituted with between 0 and 3 substituents independently selected from, fluoro, methyl, methoxy, hydroxyl, and bromo;

R 8 is H, methyl, ethyl, hydroxyethyl, or benzyl; wherein benzyl is optionally substituted with pyrrolyl or pyrazolyl; and

each of R a , R b , and R c is independently selected from hydrogen, methoxy, and fluoro;

or a pharmaceutically acceptable salt thereof.

4 . The compound of claim 2 , wherein:

R 1 and R 2 are independently selected from H, methyl, ethyl, or taken together are propylidene, allylidene, or CH 2 ═;

X is methylene or ethylene;

R 8 is H, methyl, ethyl, hydroxyethyl, or benzyl; wherein benzyl is optionally substituted with pyrrolyl or pyrazolyl;

or a pharmaceutically acceptable salt thereof.

5 . The compound of claim 2 , wherein R c is methoxy or fluoro.

6 . The compound of claim 1 , wherein R a and R c are methoxy or fluoro.

7 . The compound of claim 1 , wherein each of R 1 and R 2 is independently selected from H, methyl, and ethyl.

8 . The compound of claim 1 , wherein one of R 1 and R 2 is H, and the other is methyl or ethyl.

9 . The compound of claim 1 , wherein one of R 1 and R 2 is methyl and the other is H.

10 . The compound of claim 1 , wherein one of R 1 and R 2 is H.

11 . The compound of claim 1 , wherein R 1 and R 2 taken together are propylidene, vinylidene, or CH 2 ═.

12 . The compound of claim 1 , wherein each of R 3 , R 4 , R 6 , and R 7 is hydrogen.

13 . The compound of claim 1 , wherein R 5 is phenyl, 4-quinolinyl, 5-quinolinyl, 8-quinolinyl, 5-isoquinolinyl, 3-indolyl, N-methyl-3-indolyl, 5-quinoxalinyl, 1-naphthyl, or 2-naphthyl, and substituted or further substituted with between 0 and 3 substituents independently selected from methyl, methoxy, and bromo.

14 . The compound of claim 1 , wherein R 8 is benzyl, phenyl, (pyrrolyl)phenyl, or (pyrazolyl)phenyl.

15 . The compound of claim 1 , wherein R 8 is H, methyl, ethyl, hydroxyethyl, or methoxyethyl.

16 . The compound of claim 2 , wherein:

one of R 1 and R 2 is H and the other is methyl or ethyl;

R 5 is phenyl, having the following substituents: fluoro, methyl or hydroxyl at the 2-position; hydrogen, methyl, or methoxy at the 3-position; and hydrogen, methyl, or methoxy at the 5-position; and

R 8 is methyl, ethyl, methoxy, ethyl, or hydroxyethyl.

17 . The compound of claim 2 , wherein R 5 is 2-fluoro-3,5-dimethylphenyl, 2-fluoro-3,5-dimethoxyphenyl, 3,5-dimethylphenyl, 2-hydroxy-3,5-dimethoxyphenyl, 2,3-dimethyl, or 2-methyl-3,5-dimethoxyphenyl.

18 . The compound of claim 1 , selected from the group consisting of: ER-819724, ER-819755, ER-819750, ER-819749, ER-819735, and pharmaceutically acceptable salts thereof.

19 . The compound of claim 1 , selected from the group consisting of: ER-819543, ER-819549, ER-819543, ER-819701, ER-819544, ER-819594, ER-819647, ER-819657, ER-819659, ER-819592, and pharmaceutically acceptable salts thereof.

20 . The compound of claim 1 , selected from the group consisting of ER-819595, ER-819597, ER-819641, ER-819673, ER-819651, ER-819583, ER-819604, ER-819593, ER-819658, ER-819648, and pharmaceutically acceptable salts thereof.

21 . The compound of claim 1 , selected from the group consisting of ER-819602, ER-819689, ER-819646, ER-819655, ER-819703, ER-819667, ER-819601, ER-819605, ER-819652, ER-819688, ER-819603, ER-819642, ER-819628, and pharmaceutically acceptable salts thereof.

22 . The compound of claim 1 , selected from the group consisting of ER 819-891, ER-819772, ER-819771, ER-819770, ER-819769, ER-819768, ER-819767, and pharmaceutically acceptable salts thereof.

23 . The compound of claim 1 , selected from the group consisting of: ER-819556, ER-819557, ER-819558, ER-819752, and pharmaceutically acceptable salts thereof.

24 . The compound of claim 1 , selected from the group consisting of: ER-819877, ER-819878, ER-819879, ER-819882, and ER-819763, and pharmaceutically acceptable salts thereof.

25 . A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

26 . The composition of claim 25 , wherein:

Q is —C(R 1 )(R 2 )— or —CH═CH— (cis or trans);

R 1 and R 2 are independently selected from H, methyl, ethyl or propyl, or taken together are CH 2 ═, allylidene, propylidene, propenylidene, or ethylidene;

each of R 3 , R 4 , R 6 , and R 7 is hydrogen;

X is methylene, ethylene, or propenylene;

R 8 is H, methyl, ethyl, propenyl, methoxyethyl, hydroxyethyl, or benzyl,

or R a and R b taken together is —O—(CH 2 )—O—;

each of R a , R b , and R c is independently selected from hydrogen, hydroxyl, methoxy, benzyloxy, fluoro, and chloro;

or a pharmaceutically acceptable salt thereof.

27 . The composition of claim 25 , wherein said compound is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

28 . The composition of claim 25 , wherein said compound is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

29 . A method for treating multiple sclerosis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of claim 1 .

30 . The method of claim 29 , wherein:

Q is —C(R 1 )(R 2 )— or —CH═CH— (cis or trans);

R 1 and R 2 are independently selected from H, methyl, ethyl or propyl, or taken together are CH 2 ═, allylidene, propylidene, propenylidene, or ethylidene;

each of R 3 , R 4 , R 6 , and R 7 is hydrogen;

X is methylene, ethylene, or propenylene;

R 8 is H, methyl, ethyl, propenyl, methoxyethyl, hydroxyethyl, or benzyl,

or R a and R b taken together is —O—(CH 2 )—O—;

each of R a , R b , and R c is independently selected from hydrogen, hydroxyl, methoxy, benzyloxy, fluoro, and chloro;

or a pharmaceutically acceptable salt thereof.

31 . The method of claim 29 , wherein said compound is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

32 . The method of claim 29 , wherein said compound is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

33 . Use of a compound of claim 1 in the manufacture of a medicament for the treatment of multiple sclerosis.

34 . The use of claim 33 , wherein:

Q is —C(R 1 )(R 2 )— or —CH═CH— (cis or trans);

R 1 and R 2 are independently selected from H, methyl, ethyl or propyl, or taken together are CH 2 ═, allylidene, propylidene, propenylidene, or ethylidene;

each of R 3 , R 4 , R 6 , and R 7 is hydrogen;

X is methylene, ethylene, or propenylene;

R 8 is H, methyl, ethyl, propenyl, methoxyethyl, hydroxyethyl, or benzyl,

or R a and R b taken together is —O—(CH 2 )—O—;

each of R a , R b , and R c is independently selected from hydrogen, hydroxyl, methoxy, benzyloxy, fluoro, and chloro;

or a pharmaceutically acceptable salt thereof.

35 . The use of claim 33 , wherein said compound is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

36 . The use of claim 33 , wherein said compound is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

37 . A method for treating rheumatoid arthritis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of claim 1 .

38 . The method of claim 37 , wherein:

Q is —C(R 1 )(R 2 )— or —CH═CH— (cis or trans);

R 1 and R 2 are independently selected from H, methyl, ethyl or propyl, or taken together are CH 2 ═, allylidene, propylidene, propenylidene, or ethylidene;

each of R 3 , R 4 , R 6 , and R 7 is hydrogen;

X is methylene, ethylene, or propenylene;

R 8 is H, methyl, ethyl, propenyl, methoxyethyl, hydroxyethyl, or benzyl,

or R a and R b taken together is —O—(CH 2 )—O—;

each of R a , R b , and R c is independently selected from hydrogen, hydroxyl, methoxy, benzyloxy, fluoro, and chloro;

or a pharmaceutically acceptable salt thereof.

39 . The method of claim 37 , wherein said compound is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

40 . The method of claim 37 , wherein said compound is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

41 . Use of a compound of claim 1 in the manufacture of a medicament for the treatment of rheumatoid arthritis.

42 . The use of claim 41 , wherein:

Q is —C(R 1 )(R 2 )— or —CH═CH— (cis or trans);

R 1 and R 2 are independently selected from H, methyl, ethyl or propyl, or taken together are CH 2 ═, allylidene, propylidene, propenylidene, or ethylidene;

each of R 3 , R 4 , R 6 , and R 7 is hydrogen;

X is methylene, ethylene, or propenylene;

R 8 is H, methyl, ethyl, propenyl, methoxyethyl, hydroxyethyl, or benzyl,

or R a and R b taken together is —O—(CH 2 )—O—;

each of R a , R b , and R c is independently selected from hydrogen, hydroxyl, methoxy, benzyloxy, fluoro, and chloro;

or a pharmaceutically acceptable salt thereof.

43 . The use of claim 41 , wherein said compound is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

44 . The use of claim 41 , wherein said compound is a compound of the formula:

or a pharmaceutically acceptable salt thereof.