Dihydropyrrolo[1,2-a]indole and tetrahydropyrido[1,2-a]-indole derivatives as prostaglandin d2 receptor antagonists
View Patent ↗Dihydropyrroloindoles and tetrahydropyridoindoles are prostaglandin receptor antagonists useful for the treatment of prostaglandin-mediated diseases such as allergic rhinitis, nasal congestion and asthma.
1. A compound having the formula I:
and pharmaceutically acceptable salts and hydrates thereof, wherein:
R 1 , R 2 and R 3 are each independently selected from hydrogen and R g ;
R 4 is selected from H, CN, C 1-6 alkyl optionally substituted with one to six halogen, OR a and S(O) n C 1-6 alkyl;
R 5 is selected from H and C 1-6 alkyl optionally substituted with one to six halogen; or
R 4 and R 5 together represent an oxo;
R 6 is selected from H and C 1-6 alkyl optionally substituted with one to six groups independently selected from OR a and halogen,
Ar is aryl optionally substituted with one to four groups independently selected from R g ;
A is C 1-3 alkyl optionally substituted with one to four halogen atoms, O(CH 2 ) 1-2 , or S(CH 2 ) 1-2 ;
Q is selected from:
(1) COOH,
(2) CONR a R b ,
(3) C(O)NHSO 2 R c ,
(4) SO 2 NHR a ,
(5) SO 3 H, and
(6) PO 3 H 2
Y 1 is —(CR d R e ) a —X—(CR d R e ) b —, phenylene, C 3-6 cycloalkylidene or C 3-6 cycloalkylene, wherein a and b are integers 0–1 such that the sum of a and b equals 0, 1 or 2;
X is a bond, O, S, NR a , C(O), OC(O), C(O)O, C(O)NR a , OC(O)NR a , NR a C(O), CR d ═CR e or C≡C;
Y 2 is CR d R e , CR d R e —CR d R e , or CR d ═CR e ,
R a and R b are independently selected from H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl and aryl-C 1-10 alkyl wherein alkyl, alkenyl, alkynyl and aryl are optionally substituted with one to six substituents independently selected from halogen, amino, carboxy, C 1-4 alkyl, C 1-4 alkoxy, aryl, aryl C 1-4 alkyl, hydroxy, CF 3 , OC(O)C 1-4 alkyl, OC(O)NR i R j , and aryloxy;
R c is selected from C 1-6 alkyl optionally substituted with one to six halogen and aryl optionally substituted with halogen, OC 1-6 alkyl, C 1-6 alkyl and wherein said alkyl is optionally substituted with one to six halogen;
R d and R e are independently H, halogen, aryl, C 1-6 alkyl or haloC 1-6 alkyl;
R f is selected from H, C 1-6 alkyl, haloC 1-6 alkyl, aryl, C(O)C 1-6 alkyl, C(O)haloC 1-6 alkyl, and C(O)-aryl;
R g is selected from
(1) halogen,
(2) CN,
(3) C 1-6 alkyl optionally substituted with one to eight groups independently selected from aryl, halogen, NR a R b , C(O)R a , C(OR a )R a R b , SR a and OR a , wherein aryl is optionally substituted with one to six groups independently selected from halogen, CF 3 , and COOH,
(4) C 2-6 alkenyl optionally substituted with one to six groups independently selected from halogen and OR a ,
(5) aryl, optionally substituted with one to eight groups independently selected from halogen, C(O)R a , OR a , C 1-3 alkyl, aryl and CF 3 ;
(6) C(O)R a ,
(7) C(O)OR a ,
(8) CONR a R b ,
(9) OCONR a R b ,
(10) OC 1-6 alkyl, wherein alkyl is optionally substituted with one to six substituents selected from halogen, aryl, OH and OC(O)R a ,
(11) O-aryl
(12) S(O) n C 1-6 alkyl, wherein alkyl is optionally substituted with one to six substituents selected from halogen, aryl, OH, and OC(O)R a ,
(13) S(O) n aryl,
(14) —NR a S(O) n R b ,
(15) —NR a R b ,
(16) —NR a C(O)R b ,
(17) —NR a C(O)OR b ,
(18) —NR a C(O)NR a R b ,
(19) S(O) n NR a R b ,
(20) NO 2 , and
C 5-8 cycloalkenyl;
R i and R j are independently selected from hydrogen, C 1-10 alkyl, aryl and aryl-C 1-10 alkyl
n is 0, 1 or 2.
2. A compound of claim 1 wherein Y 1 is selected from a bond, O, S, NR a , CHR d , CHR d CHR d , C(O), C(O)CHR d , phenylene, and C 3-6 cycloalkylidene.
3. A compound of claim 1 wherein Y 1 is selected from S, CH 2 , and C(O).
4. A compound of claim 1 wherein A is C 1-3 alkyl optionally substituted with one to four halogen atoms and Q is COOH.
5. A compound of claim 1 wherein A-Q is CH 2 COOH.
6. A compound of claim 1 wherein Y 2 is selected from CH 2 and CH 2 CH 2 .
7. A compound of claim 1 wherein Ar is phenyl or naphthyl optionally substituted wit one to three groups independently selected from halogen, aryl, S(O) n C 1-6 alkyl optionally substituted wit one to six halogen, C 1-6 alkyl optionally substituted with one to five halogen atoms, CN, CONR a R b , and C(O)R a , where R a and R b are as defined in claim 1 .
8. A compound of claim 1 wherein Ar is phenyl optionally substituted with one to three groups independently selected from halogen, aryl, S(O) n C 1-6 alkyl optionally substituted with one to six halogen, C 1-6 alkyl optionally substituted with one to five halogen atoms, (ZN, CONR a R b , and C(O)R a , where R a and R b are as defined in claim 1 .
9. A compound of claim 1 wherein Ar is 4-chlorophenyl optionally substituted with a second halogen atom.
10. A compound of claim 1 wherein R 4 and R 5 are each hydrogen.
11. A compound of claim 8 wherein Y 1 is selected from C(O), S and CH 2 , Y 2 is CH 2 or CH 2 CH 2 , R 4 and R 5 are each hydrogen, and A-Q is CH 2 COOH.
12. A compound of claim 9 wherein Y 1 is selected from C(O), S and CH 2 , Y 2 is CH 2 or CH 2 CH 2 , R 4 and R 5 are each hydrogen, and A-Q is CH 2 COOH.
13. A compound of claim 1 wherein R 1 , R 2 and R 3 are independently selected from (1) hydrogen, (2) CN, (3) halogen, (4) S(O) n C 1-3 alkyl, (5) OC 1-6 alkyl optionally substituted with one to six substituents selected from halogen, aryl OH and OC(O)R a , (6) C 1-6 alkyl (optionally substitued with one to eight groups selected from aryl, halogen, NR a R b , C(O)R a , C(OR a )R a R b , SR a , and OR a , wherein aryl is optionally substituted with one to six groups independently selected from halogen, CF 3 , and COOH, (7) aryl optionally substituted with one to eight groups independently selected from halogen, C(O)R a , OR a , C 1-3 alkyl, aryl, and CF 3 ; (8) C 2-6 alkenyl optionally substituted with one to six groups independently selected front halogen and OR a , (9) C(O)OC 1-3 alkyl, (10) S(O) n NR a R b , (11) C(O)R a , (12) C(OH)R a R b , (13) C 5-8 cycloalkenyl, and (14) C(OC 1-3 alkyl)R a R b , n=0, 1 or 2; R a and R b are independently selected from hydrogen arid C 1-6 alkyl optionally substituted with halogen.
14. A compound of claim 13 wherein one of R 1 , R 2 and R 3 is hydrogen.
15. A compound of claim 1 having the formula Ia:
16. A compound of claim 15 wherein R 1 , R 2 and R 3 are independently selected from (1) hydrogen, (2) CN, (3) halogen, (4) S(O) n C 1-3 alkyl, (5) OC 1-6 alkyl optionally substituted with one to six substituents selected from halogen, aryl, OH and OC(O)R a , (6) C 1-6 alkyl optionally substitued with one to eight groups selected from aryl, halogen, NR a R b , C(O)R a , C(OR a )R a R b , SR a , and OR a , wherein aryl is optionally substituted with one to six groups independently selected from halogen, CF 3 , and COOH, (7) aryl optionally substituted with one to eight groups independently selected from halogen, C(O)R a , OR a , C 1-3 alkyl, aryl and CF 3 ; (8) C 2-6 alkenyl optionally substituted with one to six groups independently selected from halogen and OR a , (9) C(O)OC 1-3 alkyl, (10) S(O) n NR a R b , (11) C(O)R a , (12) C(OH)R a R b , (13) C 5-8 cycloalkenyl, and (14) C(OC 1-3 alkyl)R a R b , n=0, 1 or 2; R a and R b are independently selected from hydrogen and C 1-6 alkyl optionally substituted with halogen.
17. A compound of claim 16 wherein R 1 is hydrogen and A-Q is CH 2 COOH.
18. A compound of claim 17 wherein R 2 is selected from (1) halogen, (2) S(O) n C 1-3 alkyl, (3) OC 1-6 alkyl optionally substituted with aryl, (4) CN, (5) C 2-6 alkenyl and (6) C 1-6 alkyl.
19. A compound of claim 17 wherein R 3 is selected from (1) halogen, (2) S(O) n C 1-3 alkyl, (3) OC 1-6 alkyl, (4) C(O)R a , (5) C 1-6 alkyl optionally substitued with 3 to 6 halogen atoms, and 0 or 1 group selected from OR a , SR a , (6) C 2-6 alkenyl, (7) C 5-8 cycloalkenyl, (8) phenyl optionally substituted with a group selected from C 1-3 alkyl and OR a , and (9) naphthyl.
20. A compound of claim 1 having the formula Ib:
wherein Y 1 is O, S, C(O) or CH 2 , R 4 and R 5 are each hydrogen or R 4 and R 5 together represent oxo, and R 2 and R 3 represent one or two non-H substituent.
21. A compound of claim 20 , wherein R 4 and R 5 are each hydrogen, R 2 is selected from (1) halogen, (2) S(O) n C 1-3 alkyl, (3) OC 1-6 alkyl optionally substituted with aryl, (4) CN, (5) C 2-6 alkenyl and (6) C 1-6 alkyl, R 3 is selected from ( 1) halogen, (2) S(O) n C 1-3 alkyl, (3) OC 1-6 alkyl, (4) C(O)R a , (5) C 1-6 alkyl optionally substitued with 3 to 6 halogen atoms, and 0 or 1 group selected from OR a , SR a , (6) C 2-6 alkenyl, (7) C 5-8 cycloalkenyl, (8) phenyl optionally substituted with a group selected from C 1-3 alkyl and OR a , and (9) naphthyl, and Ar is selected from (1) 1- and 2-napthyl, and (2) phenyl optionally substituted with one to three groups independently selected from halogen, aryl, S(O) n C 1-6 alkyl optionally substituted with one to six halogen, C 1-6 alkyl optionally substituted with one to five halogen atoms, CN, CONR a R b , and C(O)R a , where R a and R b are as defined in claim 1 .
22. A compound of claim 1 having the formula Ic:
wherein Y 1 is C(O), CH 2 or S, B, and R′ are independently hydrogen, halogen, cyano, C 1-3 alkanoyl or CF 3 , R 2 is selected from (1) halogen, (2) S(O) n C 1-3 alkyl, (3) OC 1-6 alkyl optionally substituted with aryl, (4) CN, (5) C 2-6 alkenyl and (6) C 1-6 alkyl, and R 3 is selected from (1) halogen, (2) S(O) n C 1-3 alkyl, (3) OC 1-6 alkyl, (4) C(O)R a , (5) C 1-6 alkyl optionally substitued with 3 to 6 halogen atoms, and 0 or 1 group selected from OR a , SR a , (6) C 2-6 alkenyl, (7) C 5-8 cycloalkenyl, (8) phenyl optionally substituted with a group selected from C 1-3 alkyl and OR a , and (9) naphthyl.
23. A compound of claim 22 wherein R 2 is F, R is Cl, R′ is hydrogen, and R 3 is selected from (1) halogen, (2) S(O) n C 1-3 alkyl, (3) OC 1-6 alkyl, (4) C(O)R a , (5) C 1-6 alkyl optionally substitued with 3 to 6 halogen atoms, and 0 or 1 group selected from OR a , SR a , (6) C 2-6 alkenyl, (7) C 5-8 cycloalkenyl, (8) phenyl optionally substituted with a group selected from C 1-3 alkyl and OR a , and (9) naphthyl.
24. A compound selected from
(+/−)-[9-[(4-chlorophenyl)thio]-6-fluoro-8-(methylsulfonyl)-3-oxo-2,3-dihydro-1H-pvrrolo[1,2-a]indol-1-yl]acetic acid;
(+/−)-{8-bromo-9-[(4-chlorophenyl )sulfinyl]-6-fluoro-2,3-dihydro-1H -pyrrolo[1,2-a]indol-1-yl}(difluoro)acetic acid;
R 2
R 3
Y 1
Ar
p
H
H
CH 2
4-Cl—Ph
2
H
H
CH 2
4-Cl—Ph
1
H
H
S
4-Cl—Ph
2
CH 3 S(O) 2
H
S
4-Cl—Ph
2
H
CH 3 S(O)
—
4-Cl—Ph
2
H
CH 3 S(O)
CH 2
4-Cl—Ph
2
F
Br
S
4-Cl—Ph
1
F
Br
S
4-Cl—Ph
2
CH 3 S(O) 2
CH 3 O
S
4-Cl—Ph
2
F
CH 3 C(O)
S
4-Cl—Ph
1
F
CF 3 C(O)
S
4-Cl—Ph
1
F
CF 3 CH(OH)
S
4-Cl—Ph
1
F
(CH 3 ) 2 CHCH(OH)
S
4-Cl—Ph
1
F
CH 3 CH(OH)
S
4-Cl—Ph
1
F
CH 3 CH(OCH 3 )
S
4-Cl—Ph
1
F
CH 3 C(O)
S
Ph
1
F
CH 3 C(O)
S
3,4-diCl—Ph
1
F
CF 3 CH(OCH 3 )
S
4-Cl—Ph
1
F
CH 3 CH 2 CH(OH)
S
4-Cl—Ph
1
F
CH 3 CH 2 CH(OCH 3 )
S
4-Cl—Ph
1
F
CH 3 CH(SCH 3 )
S
4-Cl—Ph
1
CH 3 O
CH 3 S(O) 2
S
4-Cl—Ph
1
PhCH 2 O
CH 3 S(O) 2
S
4-Cl—Ph
1
CH 3 S
CH 3 S(O) 2
S
4-Cl—Ph
1
CH 3 S(O) 2
(CH 3 ) 2 CH
S
4-Cl—Ph
1
(CH 3 ) 2 CHO
CH 3 S(O) 2
S
4-Cl—Ph
1
PhCH 2 O
(CH 3 ) 2 CH
S
4-Cl—Ph
1
CH 3 O
(CH 3 ) 2 CH
S
4-Cl—Ph
1
4-Cl—Ph
CH 3 S(O) 2
S
4-Cl—Ph
1
I
Br
S
4-Cl—Ph
1
CN
Br
S
4-Cl—Ph
1
CN
CH 3 C(O)
S
4-Cl—Ph
1
F
CH 3 S(O) 2
S
4-Cl—Ph
1
F
CH 3 CH 2 S(O) 2
S
4-Cl—Ph
1
F
CH 3 CH 2 CH 2
S
4-Cl—Ph
1
F
CH 3 CH 2
S
4-Cl—Ph
1
F
CH 3 C(═CH 2 )
S
4-Cl—Ph
1
F
(CH 3 ) 2 CH
S
4-Cl—Ph
1
F
1-cyclopentenyl
S
4-Cl—Ph
1
F
(CH 3 CH═)(CH 3 CH 2 )C
S
4-Cl—Ph
1
F
(CH 3 CH 2 ) 2 CH
S
4-Cl—Ph
1
F
cyclopentyl
S
4-Cl—Ph
1
F
Ph
S
4-Cl—Ph
1
F
CH 2 ═CH
S
4-Cl—Ph
1
CH 2 ═CH
Br
S
4-Cl—Ph
1
F
(CF 3 ) 2 C(OH)
S
4-Cl—Ph
1
F
cyclopropyl
S
4-Cl—Ph
1
F
Br
CH 2
4-Cl—Ph
1
F
CH 3 S(O) 2
CO
4-Cl—Ph
1
F
CH 3 S(O) 2
CH 2
4-Cl—Ph
1
F
(CF 3 ) 2 C(OCH 3 )
S
4-Cl—Ph
1
F
(CH 3 ) 2 CH
C(O)
4-Cl—Ph
1
F
1-CH 3 -2-pyrrolyl
C(O)
4-Cl—Ph
1
F
(CH 3 ) 2 CH
CH 2
4-Cl—Ph
1
F
CH 3 S(O) 2
CH 2
2,4-diCl—Ph
1
F
CH 3 S(O) 2
CH 2
2,6-diCl—Ph
1
F
Br
C(O)
4-Cl—Ph
1
F
cyclopropyl
C(O)
4-Cl—Ph
1
F
(CH 3 O)(CH 3 CH 2 )CH
C(O)
4-Cl—Ph
1
F
Ph
C(O)
4-Cl—Ph
1
F
CH 3 S(O) 2
CH 2
2,4,6-triCl—Ph
1
F
CH 3 S(O) 2
S
2,4,5-triCl—Ph
1
F
CH 3 S(O) 2
C(O)
4-biphenyl
1
F
CH 3 S(O) 2
C(O)
2-naphthyl
1
F
Br
C(O)
2-naphthyl
1
F
CH 3 S(O) 2
C(O)
2,4-diCl—Ph
1
F
CH 3 S(O) 2
C(O)
4-Cl-2-
1
CH 3 S(O) 2 —Ph
F
Br
C(O)
4-Cl-2-I—Ph
1
F
Br
C(O)
4-Cl-2-
1
CONH 2 —Ph
F
CH 3 S(O) 2
C(O)
4-Cl-2-CN—Ph
1
F
(CH 3 ) 2 CH
C(O)
4-Cl-2-I—Ph
1
F
(CH 3 ) 2 CH
C(O)
4-Cl-2-
1
CH 3 S(O) 2 —Ph
F
CH 3 S(O) 2
S
4-CF 3 —Ph
1
F
CH 3 S(O) 2
S
4-CH 3 S(O) 2 —Ph
1
F
CH 3 S(O) 2
CH(CH 3 )
4-Cl—Ph
1
F
CH 3 S(O) 2
C(O)CH 2 **
4-Cl—Ph
1
F
(CH 3 ) 2 CH
S
1-naphthyl
1
F
(CH 3 ) 2 CH
S
2-naphthyl
1
F
CH 3 S(O) 2
CH 2 CH 2
4-Cl—Ph
1
F
(CH 3 ) 2 CH
C(O)
2-naphthyl
1
F
CH 3 S(O) 2
S
2-naphthyl
1
F
(CH 3 ) 2 CH
S
4-Cl-2-F—Ph
1
F
CH 3 S(O) 2
S
4-Cl-2-F—Ph
1
F
2-CH 3 —Ph
S
4-Cl—Ph
1
F
2-OCH 3 —Ph
S
4-Cl—Ph
1
F
3,4-diCl—Ph
S
4-Cl—Ph
1
F
2-naphthyl
S
4-Cl—Ph
1
F
CN
S
4-Cl—Ph
1
F
(CH 3 ) 2 CH
C(O)
1-naphthyl
1
F
(CH 3 ) 2 CH
C(O)
3,4-diCl—Ph
1
F
(CH 3 ) 2 CH
S
4-Cl—Ph
2
F
(CH 3 ) 2 CH
C(O)
2-naphthyl
2
F
(CH 3 ) 2 CH
C(O)
4-Cl—Ph
2
F
CH 3 S(O) 2
S
4-Cl—Ph
2
F
CH 3 S(O) 2
1,4-
Ph
1
phenylene
F
CH 3 S(O) 2
—
2-naphthyl
1
F
CH 3 S(O) 2
1,3-
Ph
1
phenylene
CN
(CH 3 ) 2 CH
S
4-Cl—Ph
1
CH 3 S(O) 2
CH 3 S(O) 2
S
4-Cl—Ph
1
F
CH 3 S(O) 2
C(O)
4-Cl—Ph
2
F
CH 3 S(O) 2
C(O)
2-naphthyl
2
F
(CH 3 ) 2 CH
C(O)
3-Br-4-Cl—Ph
2
F
(CH 3 ) 2 CH
CH 2
4-Cl—Ph
2
F
(CH 3 ) 2 CH
S
3-Br-4-Cl—Ph
2
F
(CH 3 )(CH 2 ═)C
C(O)
4-Cl—Ph
2
F
CH 3 S(O) 2
C(O)
3,4-diCl—Ph
2
F
CH 3 S(O) 2
C(O)
4-nBu—Ph
2
F
CH 3 S(O) 2
C(O)
4-Ph—Ph
2
PhCH 2 O
CH 3 S(O) 2
S
4-Cl—Ph
2
PhCH 2 S
CH 3 S(O) 2
S
4-Cl—Ph
1
F
CH 3 S(O) 2
C(O)
4-Cl—Ph
2
**Y 1 —Ar = —C(O)—CH 2 —(4-Cl—Ph),
and
R 1
R 2
R 3
A—Q
F
F
CH 3 S(O) 2
CH 2 CO 2 H
F
F
S-(4-Cl-Ph)
CH 2 CO 2 H
CH 3 S(O) 2
F
CH 3 S(O) 2
CH 2 CO 2 H
CH 3 S(O) 2
CH 3 O
CH 3 S(O) 2
CH 2 CO 2 H
F
H
CH 3 S(O) 2
CH 2 CO 2 H
H
F
Br
CF 2 CO 2 H
H
F
CH 3 S(O) 2
CF 2 CO 2 H.
25. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
26. The composition of claim 25 further comprising a second active ingredient selected from an antihistamine, a leukotriene antagonist and a leukotriene biosynthesis inhibitor.
27. A method for the treatment of nasal congestion which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 .
28. A method for the treatment of allergic asthma which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 .
29. A method for the treatment of allergic rhinitis which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 .