Claims
- 1. A CRF antagonist compound of formula I: ##STR22## or a pharmaceutically accetable salt thereof, wherein: A is N;
- X is H, OR.sup.1, S(O).sub.n R.sup.1, NR.sup.1 R.sup.2, CR.sup.1 R.sup.2 R.sup.3, phenyl (optionally substituted with 1-4 groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl);
- n is 0, 1 or 2;
- R.sup.1 is C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkoxyalkyl, C.sub.3 -C.sub.12 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, aryl-(C.sub.1 -C.sub.12 alkyl), C.sub.3 -C.sub.12 dialkylaminoalkyl, C.sub.2 -C.sub.13 cyanoalkyl, C.sub.2 -C.sub.5 carboalkoxy-(C.sub.1 -C.sub.12 alkyl), phenyl (optionally substituted with 1-4 (groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl), or heteroaryl (optionally substituted at one to all valence-allowed positions with groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl); R.sup.2 and R.sup.3 are independently chosen from H, C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkoxyalkyl, C.sub.3 -C.sub.12 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, aryl-(C.sub.1 -C.sub.12 alkyl), C.sub.3 -C.sub.12 dialkylaminoalkyl, C.sub.2 -C.sub.13 cyanoalkyl, C.sub.1 -C.sub.4 carboalkoxy, C.sub.2 -C.sub.12 carboalkoxyalkyl, C(.dbd.O)CH.sub.3, phenyl (optionally substituted with 1-4 groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl), or heteroaryl (optionally substituted at one to all valence-allowed positions with groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl);
- R.sup.4 is H, C.sub.1 -C.sub.12 alkyl, allyl, propargyl or benzyl (optionally substituted with 1-4 groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, nitro, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl);
- R.sup.1 and R.sup.4 may also optionally be taken together, along with the other four interconnected atoms, to form a ring of 5-9 total atoms, the structural sequence between the X group and the ring nitrogen atom consisting of the group (CH.sub.2).sub.p W(CH.sub.2).sub.q ;
- p and q are independently 0, 1 or 2;
- W is CH.sub.2, C(CH.sub.3).sub.2, C(.dbd.O), O, S or NCH.sub.3 ;
- R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are independently chosen from H, straight-chained C.sub.1 -C.sub.4 alkyl, allyl, propargyl, phenyl (optionally substituted with 1-4 groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl) or benzyl (optionally substituted with 1-4 groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl);
- R.sup.9 is phenyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.2 -C.sub.5 carboalkoxy or cyano), pyridyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.2 -C.sub.5 carboalkoxy or cyano), or pyrimidyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.2 -C.sub.5 carboalkoxy or cyano);
- R.sup.10 is H, C.sub.1 -C.sub.4 alkyl or cyano;
- R.sup.11 is H, C.sub.1 -C.sub.4 alkyl or halogen;
- R.sup.12 is H, C.sub.1 -C.sub.4 alkyl or phenyl;
- aryl is phenyl, biphenyl or naphthyl; and
- heteroaryl is pyridyl, pyrimidinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl or pyrazolyl.
- 2. A compound of claim 1 wherein:
- X is OR.sup.1, NR.sup.1 R.sup.2, CR.sup.1 R.sup.2 R.sup.3,
- R.sup.1 is C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkoxyalkyl, C.sub.3 -C.sub.12 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, aryl-(C.sub.1 -C.sub.12 alkyl), C.sub.3 -C.sub.12 dialkylaminoalkyl, or phenyl (optionally substituted with 1-4 groups independently chosen from halogen, haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl);
- R.sup.4 is H or C.sub.1 -C.sub.4 alkyl;
- R.sup.5 and R.sup.6 are either H or C.sub.1 -C.sub.4 alkyl;
- R.sup.9 is phenyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.2 -C.sub.5 carboalkoxy or cyano), 3-pyridyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.2 -C.sub.5 carboalkoxy or cyano), or 5-pyrimidyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.2 -C.sub.5 carboalkoxy or cyano);
- R.sup.10 is CH.sub.3 ;
- and R.sup.11 is H.
- 3. A compound of claim 2 wherein:
- X is NR.sup.1 R.sup.2 or CR.sup.1 R.sup.2 R.sup.3 ;
- R.sup.1 is C.sub.1 -C.sub.6 alkyl or C.sub.2 -C.sub.8 alkoxyalkyl;
- R.sup.2 and R.sup.3 are independently H, C.sub.1 -C.sub.6 alkyl or C.sub.2 -C.sub.8 alkoxyalkyl;
- R.sup.4 is H;
- R.sup.5 and R.sup.6 are H;
- R.sup.7 and R.sup.8 are independently H or CH.sub.3 ; and
- R.sup.9 is phenyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.2 -C.sub.5 carboalkoxy or cyano).
- 4. A compound of claim 3 selected from:
- 8-(2-bromo-4-isopropylphenyl)-4-(ethylbutylamino)-2-methyl-5,6,7,8-tetrahydropteridine;
- 8-(2-chloro-4,6-dimethoxyphenyl)-4-(ethylbutylamino)-2-methyl-5,6,7,8-tetrahydropteridine;
- 4-(ethylbutylamino)-2-methyl-8-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydropteridine; and
- 4-(1-methoxy-2-butyl)amino-2-methyl-8-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydropteridine.
- 5. A composition comprising a therapeutically effective amount of compound of claim 1 and a pharmaceutically suitable carrier.
- 6. A composition comprising a therapeutically effective amount of compound of claim 2 and a pharmaceutically suitable carrier.
- 7. A composition comprising a therapeutically effective amount of compound of claim 3 and a pharmaceutically suitable carrier.
- 8. A composition comprising a therapeutically effective amount of compound of claim 4 and a pharmaceutically suitable carrier.
Parent Case Info
This application claims the benefit of the filing date of the provisional application No. 60/018,198, filed May 23, 1996.
US Referenced Citations (7)
Foreign Referenced Citations (1)
Number |
Date |
Country |
8-92250 |
Apr 1996 |
JPX |