IP Library › Granted Patent US 7,618,979
Granted Patent B2
US 7,618,979 · App. 10/532,633 · Granted Nov 17, 2009

Pyridopyrrolizine and pyridoindolizine derivatives

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Quick Facts
Patent No.
US 7,618,979
App. No.
10/532,633
Granted
Nov 17, 2009
Kind
B2
Abstract

Pyridopyrrolizine and pyridoindolizine derivatives are prostaglandin receptor antagonists useful for the treatment of prostaglandin-mediated diseases such as allergic rhinitis, nasal congestion and asthma.

Claims (466)

1. A compound having the formula I

and pharmaceutically acceptable salts thereof, wherein:

A is selected from C 1-3 alkyl optionally substituted with one to four halogen atoms, O(CH 2 ) 1-2 , and S(CH 2 ) 1-2 ;

Ar is selected from phenyl, 2-, 3-, 4-chlorophenyl, 2-, 3-, 4-bromophenyl, 2-, 3-, 4-fluorophenyl, 3,4-dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 2-cyanophenyl, 4-methylphenyl, 4-isopropylphenyl, 4-trifluoromethylphenyl, biphenyl, naphthyl, 3-methoxyphenyl, 3-carboxyphenyl, 2-carboxamidophenyl, 4-methoxyphenyl, 3-phenoxyphenyl, 4-(4-pyridyl)phenyl, 4-methylsulfonylphenyl, 3-dimethylaminophenyl, 5-tetrazolyl, 1-methyl-5-tetrazolyl, 2-methyl-5-tetrazolyl, 2-benzothienyl, 2-benzofuranyl, 2-indolyl, 2-quinolinyl, 7-quinolinyl, 2-benzothiazolyl, 2-benzimidazolyl, 1-benzotriazolyl, 2-furanyl, 3-furanyl, 2-imidazolyl, 5-imidazolyl, 5-isoxazolyl, 4-isoxazolyl, 4-isothiazolyl, 1,2,4-oxadiazol-5-yl, 2-oxazolyl, 4-oxazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyridyl, 3-pyridyl, 2-pyrazinyl, 5-pyrimidinyl, 2-pyrrolyl, 4-thiazolyl, 1,2,4-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, 1,2,3-thiadiazol-4-yl, 1,2,5-oxadiazol-4-yl, 1,2,3-oxadiazol-4-yl, 1,2,4-triazol-5-yl, 1,2,3-triazol-4-yl, 3-thienyl, 1,2,4-triazol-5-yl, pyrrolopyridine, furo[3,2-b]pyridin-2-yl, thieno[2,3-b]pyridin-2-yl, 5(H)-2-oxo-4-furanyl, 5(H)-2-oxo-5-furanyl, (1H-4H)-5-oxo-1,2,4-triazol-3-yl, 4-oxo-2-benzopyranyl;

Q is COOH,

one of X 1 , or X 3 is nitrogen and the others are independently selected from CH and C—R g and R g is selected from 1) C 1-6 alkyl optionally substituted with OR a , or 2) S(O) n C 1-6 alkyl;

X 2 is CH;

X 4 is CH or C—R g , where R g is selected from 1) C 1-6 alkyl optionally substituted with OR a or 2) S(O) n C 1-6 alkyl;

Y 1 is S;

Y 2 is selected from (CR d R e ) m and CR d ═CR e ;

R 1 is H;

R 2 is H;

R 3 is H;

R a is independently selected from H and C 1-10 alkyl;

R d and R e are independently H, halogen, C 1-6 alkyl or haloC 1-6 alkyl;

m is 1 or 2; and

n is 0, 1 or 2.

2. A compound of claim 1 wherein A-Q is CH 2 CO 2 H.

3. A compound of claim 1 wherein one of X 1 and X 3 is nitrogen and the other is CH, X 2 is CH, and X 4 is C—S(O) n —C 1-6 alkyl or C—C 1-6 alkyl optionally substituted with OR a .

4. A compound of claim 1 wherein Y 2 is selected from CH 2 and CH 2 CH 2 .

5. A compound of claim 1 represented by the formula Ia:

wherein X 2 and X 3 are independently CH or C—R g , A, Ar, Q, Y 1 , R 1 , R 2 , m and R g are as defined in claim 1 .

6. A compound of claim 5 wherein X 2 and X 3 are each CH, R 1 and R 2 are each H, and A-Q is CH 2 CO 2 H.

7. A compound of claim 5 wherein Y 1 —Ar is S-phenyl optionally substituted with 1 or 2 groups independently selected from halogen, C 1-6 alkyl and trifluoromethyl.

8. A compound of claim 1 represented by the formula Ib:

wherein X 1 and X 2 are independently CH or C—R g , A, Ar, Q, Y 1 , R 1 , R 2 , m and R g are as defined in claim 1 .

9. A compound of claim 8 wherein X 1 and X 2 are each CH, R 1 and R 2 are each H, and A-Q is CH 2 CO 2 H.

10. A compound of claim 9 wherein Y 1 —Ar is S-phenyl optionally substituted with 1 or 2 groups independently selected from halogen, C 1-6 alkyl and trifluoromethyl.

11. A compound of claim 1 represented by the formula Ic:

wherein one of X 1 and X 3 is N and the other is CH, X 4 is CH, X 4 is CR g , m is 1 or 2, and Ar, Y 1 and m are as defined in claim 1 .

12. A compound of claim 11 wherein Ar is phenyl optionally substituted with 1 or 2 groups independently selected from halogen, C 1-3 alkyl and trifluoromethyl.

13. A compound of claim 11 wherein X 4 is selected from C—S(O) n C 1-6 alkyl and C—C 1-6 alkyl optionally substituted with OR a .

14. A compound of claim 11 wherein Y 1 —Ar is S-phenyl optionally substituted with 1 or 2 groups independently selected from halogen, C 1-6 alkyl and trifluoromethyl; X 1 and X 2 are each CH, X 3 is N, m is 1 or 2, and X 4 is C—SO 2 —-C 1-6 alkyl or C—C 1-6 alkyl.

15. A compound of claim 1 selected from:

X 1

X 2

X 3

X 4

Ar

Y 1

m

N

CH

CH

C(SO 2 CH 3 )

4-Cl—Ph

S

2

N

CH

CH

C(SCH 3 )

4-Cl—Ph

S

2

N

CH

CH

C(SO 2 CH 3 )

3,4-diCl—Ph

S

2

N

CH

CH

C(SO 2 CH 3 )

4-Br—Ph

S

2

CH

CH

N

C(SO 2 CH 3 )

3,4-diCl—Ph

S

1

CH

CH

N

C(SO 2 CH 3 )

3,4-diCl—Ph

S

2

N

CH

CH

C(SO 2 CH 3 )

4-CF 3 —Ph

S

2

N

CH

CH

C(SO 2 CH 3 )

2-Cl-4-F—Ph

S

2

N

CH

CH

C(SO 2 CH 3 )

2-naphthyl

S

2

N

CH

CH

C(SO 2 CH 3 )

2,3-diCl—Ph

S

2

N

CH

CH

C(SO 2 CH 3 )

4-CH 3 —Ph

S

2

N

CH

CH

C(SO 2 CH 3 )

Ph

S

2

N

CH

CH

C(SO 2 CH 3 )

2,4-diCl—Ph

S

2

CH

CH

N

C(SO 2 CH 3 )

4-Cl—Ph

S

2

N

C(CH3)

CH

C(SO 2 CH 3 )

4-Cl—Ph

S

2

N

CH

C(CH3)

C(SO 2 CH 3 )

4-Cl—Ph

S

2

CH

C(CH3)

N

C(SO 2 CH 3 )

4-Cl—Ph

S

2

C(CH3)

CH

N

C(SO 2 CH 3 )

4-Cl—Ph

S

2

N

CH

CH

C(CH(CH 3 ) 2 )

4-F—Ph

S

2

N

CH

CH

C(CH(CH 3 ) 2 )

4-Cl—Ph

S

2

N

CH

CH

C(CH(CH 3 ) 2 )

2,4-diCl—Ph

S

2

N

CH

CH

C(CH(CH 3 ) 2 )

4-Br—Ph

S

2

N

CH

CH

C(CH(CH 3 ) 2 )

2-Cl-4-F—Ph

S

2

N

CH

CH

C(CH(CH 3 ) 2 )

3,4-diCl—Ph

S

2

CH

CH

N

C(CH(CH 3 ) 2 )

4-F—Ph

S

2

CH

CH

N

C(CH(CH 3 ) 2 )

4-Cl—Ph

S

2

CH

CH

N

C(CH(CH 3 ) 2 )

2,4-diCl—Ph

S

2

CH

CH

N

C(CH(CH 3 ) 2 )

4-Br—Ph

S

2

CH

CH

N

C(CH(CH 3 ) 2 )

2-Cl4-F—Ph

S

2

CH

CH

N

C(CH(CH 3 ) 2 )

3,4-diCl—Ph

S

2

CH

CH

N

C(CH(CH 3 ) 2 )

4-F—Ph

S

1

CH

CH

N

C(CH(CH 3 ) 2 )

4-Cl—Ph

S

1

CH

CH

N

C(CH(CH 3 ) 2 )

2,4-diCl—Ph

S

1

CH

CH

N

C(CH(CH 3 ) 2 )

4-Br—Ph

S

1

CH

CH

N

C(CH(CH 3 ) 2 )

2-Cl-4-F—Ph

S

1

CH

CH

N

C(CH(CH 3 ) 2 )

3,4-diCl—Ph

S

1

N

CH

CH

C(CH(OCH 3 )

4-Cl—Ph

S

2

(CH 2 CH 3 ))

N

CH

CH

C(CH(OCH 3 )

4-Cl—Ph

S

1

(CH 2 CH 3 ))

CH

CH

N

C(CH(OCH 3 )

4-Cl—Ph

S

2

(CH 2 CH 3 ))

CH

CH

N

C(CH(OCH 3 )

4-Cl—Ph

S

1

(CH 2 CH 3 ))

N

CH

CH

C(C(CH 3 ) 3 )

4-Cl—Ph

S

2

N

CH

CH

C(C(CH 3 ) 3 )

3,4-diCl—Ph

S

2

N

CH

CH

C(C(CH 3 ) 3 )

4-Br—Ph

S

2

N

CH

CH

C(C(CH 3 ) 3 )

4-CF 3 —Ph

S

2

N

CH

CH

C(C(CH 3 ) 3 )

2-Cl-4-F—Ph

S

2

N

CH

CH

C(C(CH 3 ) 3 )

2-naphthyl

S

2

N

CH

CH

C(C(CH 3 ) 3 )

2,3-diCl—Ph

S

2

N

CH

CH

C(C(CH 3 ) 3 )

4-CH 3 —Ph

S

2

N

CH

CH

C(C(CH 3 ) 3 )

Ph

S

2

N

CH

CH

C(C(CH 3 ) 3 )

2,4-diCl—Ph

S

2

Ar

Y 1

5-tetrazolyl

S

2-pyrroly

S

1,2,4-triazoly-3-yl

S

1,2,3-triazol-4-yl

S

5-imidazolyl

S

4-pyrazolyl

S

5-pyrazolyl

S

(1H,4H)-5-oxo-1,2,4-triazol-3-yl

S

4-isothiazolyl

S

1,2,5-thiadiazol-5-yl

S

1,2,5-oxadiazol-5-yl

S

3-furanyl

S

1,2,3-thiadiazol-4-yl

S

1,2,3-oxadiazol-4-yl

S

4-isoxazolyl

S

3-thienyl

S

4-oxazolyl

S

4-thiazolyl

S

(5H)-2-oxo-5-furanyl

S

(5H)-2-oxo-4-furanyl

S

1,2,4-oxadiazol-5-yl

S

3-pyridyl

S

2-pyrazinyl

S

5-pyrimidinyl

S

2-indolyl

S

2-benzothienyl

S

2-benzofuranyl

S

4-oxo-benzopyran-2-yl

S

2-quinolinyl

S

2-benzimidazolyl

S

2-benzoxazolyl

S

2-benzothiazolyl

S

1-benzotriazolyl

CH 2 S

thieno[2,3-b]pyridin-2-yl

S.

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

Assignments (1)
CHANGE OF NAME Recorded Jun 25, 2013
From: MERCK FROSST CANADA LTD.
To: MERCK CANADA INC.
Reel/Frame 030681/0784 →