US 5,672,596 AGranted

Benzo-fused lactams promote release of growth hormone

AssigneeMerck & Co., Inc.

InventorsMatthew Wyvratt, Robert DeVita, Richard Bochis, William Schoen

Life of this patent

Estimating the term…

Abstract

There are disclosed certain novel compounds identified as benzo-fused lactams which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. Growth promoting compositions containing such benzo-fused lactams as the active ingredient therefore are also disclosed.

Claims22

Dependent claims

A compound having the formula:

##STR474## where L is ##STR475## p is 0 to 3;
q is 0 to 4;
w is 0 or 1;
R.sup.1, R.sup.2, R.sup.1a, R.sup.2a, R.sup.1b and R.sup.2b are independently hydrogen, halogen, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.3 perfluoroalkyl, C.sub.1 -C.sub.3 perfluoroalkoxy, --S(O).sub.m R.sup.7a, cyano, nitro, R.sup.7b O(CH.sub.2).sub.v --, R.sup.7b COO(CH.sub.2).sub.v --, R.sup.7b OCO(CH.sub.2).sub.v, R.sup.4 R.sup.5 N(CH.sub.2).sub.v --, R.sup.7b CON(R.sup.4)(CH.sub.2).sub.v --, R.sup.4 R.sup.5 NCO(CH.sub.2).sub.v --, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, or hydroxy;
R.sup.7a and R.sup.7b are independently hydrogen, C.sub.1 -C.sub.3 perfluoroalkyl, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, where the substituents are phenyl or substituted phenyl;
phenyl or substituted phenyl where the phenyl substituents are from 1 to 3 of halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, or hydroxy and v is 0 to 3;
R.sup.3a and R.sup.3b are independently hydrogen, R.sup.9, C.sub.1 -C.sub.6 alkyl substituted with R.sup.9, phenyl substituted with R.sup.9, or phenoxy substituted with R.sup.9 with the proviso that either R.sup.3a or R.sup.3b must be a substituent other than hydrogen;
R.sup.9 is
R.sup.4b R.sup.12b NCON(R.sup.12a)(CH.sub.2).sub.v --,
R.sup.4b R.sup.12b NCSN(R.sup.12a)(CH.sub.2).sub.v --,
R.sup.4b R.sup.12c NN(R.sup.12b)CSN(R.sup.12a)(CH.sub.2).sub.v --,
R.sup.4b R.sup.12c NN(R.sup.12b)CON(R.sup.12a)(CH.sub.2).sub.v --,
R.sup.4b R.sup.12c NN(R.sup.12b)COO(CH.sub.2).sub.v --, R.sup.4b R.sup.12b NCOO(CH.sub.2).sub.v --,
or R.sup.13 OCON(R.sup.12a)(CH.sub.2).sub.v --, where v is 0 to 3;
R.sup.12a, R.sup.12b and R.sup.12c are independently R.sup.5a, OR.sup.5a, or COR.sup.5a. R.sup.12a and R.sup.12b, or R.sup.12b and R.sup.12c, or R.sup.12a and R.sup.12c, or R.sup.12b and R.sup.4b, or R.sup.12c and R.sup.4b, or R.sup.13 and R.sup.12a can be taken together to form --(CH.sub.2).sub.r --B--(CH.sub.2).sub.s -- where B is CHR.sup.1, O, S(O).sub.m or NR.sup.10, m is 0, 1 or 2, r and s are independently 0 to 3 and R.sup.1 and R.sup.10 are as defined;
R.sup.13 is:
C.sub.1 -C.sub.3 perfluoroalkyl, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, where the substitutents are hydroxy, NR.sup.10 R.sup.11, carboxy, phenyl or substituted phenyl;
phenyl or substituted phenyl where the substituents on the phenyl are from 1 to 3 of halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy or hydroxy;
and v is as defined above;
R.sup.4, R.sup.4b, R.sup.5 and R.sup.5a are independently hydrogen, phenyl, substituted phenyl, C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, substituted C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, or substituted C.sub.3 -C.sub.10 alkynyl where the substituents on the phenyl, alkyl, alkenyl or alkynyl are from 1 to 5 of hydroxy, C.sub.1 -C.sub.6 alkoxy, C.sub.3 -C.sub.7 cycloalkyl, fluoro, R.sup.1, R.sup.2 independently disubstituted phenyl C.sub.1 -C.sub.3 alkoxy, R.sup.1, R.sup.2 independently disubstituted phenyl, C.sub.1 -C.sub.20 -alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy, formyl or --NR.sup.10 R.sup.11 where R.sup.10 and R.sup.11 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl, phenyl C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.5 -alkoxycarbonyl or C.sub.1 -C.sub.5 -alkanoyl-C.sub.1 -C.sub.6 alkyl;
or R.sup.4 and R.sup.5 can be taken together to form --(CH.sub.2).sub.r --B--(CH.sub.2).sub.s -- where B is CHR.sup.1, O, S(O).sub.m or N--R.sup.10, r and s are independently 1 to 3 and R.sup.1 and R.sup.10 are as defined above;
R.sup.6 is hydrogen, C.sub.1 -C.sub.10 alkyl, phenyl or phenyl C.sub.1 -C.sub.10 alkyl;
A is ##STR476## where x and y are independently 0-3;
R.sup.8 and R.sup.8a are independently hydrogen, C.sub.1 -C.sub.10 alkyl, trifluoromethyl, phenyl, substituted C.sub.1 -C.sub.10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(O).sub.m R.sup.7a, C.sub.1 -C.sub.6 alkoxy, C.sub.3 -C.sub.7 cycloalkyl, R.sup.1, R.sup.2 independently disubstituted phenyl C.sub.1 -C.sub.3 alkoxy, R.sup.1, R.sup.2 independently disubstituted phenyl, C.sub.1 -C.sub.5 -alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy, formyl, or --NR.sup.10 R.sup.11 where R.sup.10 and R.sup.11 are as defined above;
or R.sup.8 and R.sup.8a can be taken together to form --(CH.sub.2).sub.t -- where t is 2 to 6;
and R.sup.8 and R.sup.8a can independently be joined to one or both of R.sup.4 and R.sup.5 to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms;
and pharmaceutically acceptable salts thereof.

24 more elements

A compound which is selected from the group consisting of:

2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!propana mide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-7-trifluoro-methyl-2-oxo-1H-benzazepin-3(R)-yl!butana mide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanam ide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanam ide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl! -4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!propanam ide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!-amino!methyl!1,1'-b iphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanami de;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanami de;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!-methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(ethylamino)carbonyl!amino!methyl!1,1'-bi phenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanami de;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!methyl !1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!methyl !1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!propanam ide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!methyl !1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!propana mide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!methyl !1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!prop anamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!methyl !1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl !propanamide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!methyl !1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!methyl !1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanami de;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!methyl !1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanam ide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!methyl !1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!buta namide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!methyl !1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl !butanamide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!methyl !1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!methyl !1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanami de;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!methyl !1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanam ide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!methyl !1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!buta namide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!methyl !1,1'-bi-phenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-y l!butanamide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!-methy l!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!-methy l!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanam ide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!-methy l!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butana mide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!-methy l!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!but anamide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(hydroxyethyl)amino!carbonyl!amino!-methy l!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-y l!butanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-2-(methylamino)carbonyl!amino!prop-2-yl!1 ,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-1-(methylamino)carbonyl!amino!ethyl!1,1'- biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(methoxycarbonyl)amino!methyl!1,1'-bipheny l!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methoxycarbonyl)amino!methyl!1,1'-bipheny l!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methoxycarbonyl)amino!methyl!1,1'-bipheny l!-4-yl!-methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methoxycarbonyl)amino!methyl!1,1'-bipheny l!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
2-Amino-2-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!oxy!methyl!1,1'-bip henyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;
3-Amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!oxy!methyl!1,1'-bip henyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!oxy!methyl!1,1'-bip henyl!-4-yl!-methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
3-2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1-2'-(methylamino)carbonyl!oxy!methyl!1,1'-bip henyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;
or a pharmaceutically accepteble salt thereof.

88 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/392,961Filed 18 Apr 1995 · continuation in part
Priority: 28 Aug 1992
Granted: 30 Sep 1997
Term ends: Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 223/16
Condensed with carbocyclic rings or ring systems: benzazepines; Hydrogenated benzazepines
A23K 20/132
Heterocyclic compounds: containing only one nitrogen as hetero atom
A23K 20/137
Heterocyclic compounds: containing two hetero atoms, of which at least one is nitrogen
A61K 38/25
Hormones: growth hormone-releasing factor [GH-RF], i.e. somatoliberin

Family

Serial936,975Parent of this continuation-in-part · filed 28 Aug 1992
US 5,283,241 AParent of this continuation-in-part
US 5,672,596 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound having the formula:

##STR474## where L is ##STR475## p is 0 to 3;
q is 0 to 4;
w is 0 or 1;
R.sup.1, R.sup.2, R.sup.1a, R.sup.2a, R.sup.1b and R.sup.2b are independently hydrogen, halogen, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.3 perfluoroalkyl, C.sub.1 -C.sub.3 perfluoroalkoxy, --S(O).sub.m R.sup.7a, cyano, nitro, R.sup.7b O(CH.sub.2).sub.v --, R.sup.7b COO(CH.sub.2).sub.v --, R.sup.7b OCO(CH.sub.2).sub.v, R.sup.4 R.sup.5 N(CH.sub.2).sub.v --, R.sup.7b CON(R.sup.4)(CH.sub.2).sub.v --, R.sup.4 R.sup.5 NCO(CH.sub.2).sub.v --, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, or hydroxy;
R.sup.7a and R.sup.7b are independently hydrogen, C.sub.1 -C.sub.3 perfluoroalkyl, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, where the substituents are phenyl or substituted phenyl;
phenyl or substituted phenyl where the phenyl substituents are from 1 to 3 of halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, or hydroxy and v is 0 to 3;
R.sup.3a and R.sup.3b are independently hydrogen, R.sup.9, C.sub.1 -C.sub.6 alkyl substituted with R.sup.9, phenyl substituted with R.sup.9, or phenoxy substituted with R.sup.9 with the proviso that either R.sup.3a or R.sup.3b must be a substituent other than hydrogen;
R.sup.9 is
R.sup.4b R.sup.12b NCON(R.sup.12a)(CH.sub.2).sub.v --,
R.sup.4b R.sup.12b NCSN(R.sup.12a)(CH.sub.2).sub.v --,
R.sup.4b R.sup.12c NN(R.sup.12b)CSN(R.sup.12a)(CH.sub.2).sub.v --,
R.sup.4b R.sup.12c NN(R.sup.12b)CON(R.sup.12a)(CH.sub.2).sub.v --,
R.sup.4b R.sup.12c NN(R.sup.12b)COO(CH.sub.2).sub.v --, R.sup.4b R.sup.12b NCOO(CH.sub.2).sub.v --,
or R.sup.13 OCON(R.sup.12a)(CH.sub.2).sub.v --, where v is 0 to 3;
R.sup.12a, R.sup.12b and R.sup.12c are independently R.sup.5a, OR.sup.5a, or COR.sup.5a. R.sup.12a and R.sup.12b, or R.sup.12b and R.sup.12c, or R.sup.12a and R.sup.12c, or R.sup.12b and R.sup.4b, or R.sup.12c and R.sup.4b, or R.sup.13 and R.sup.12a can be taken together to form --(CH.sub.2).sub.r --B--(CH.sub.2).sub.s -- where B is CHR.sup.1, O, S(O).sub.m or NR.sup.10, m is 0, 1 or 2, r and s are independently 0 to 3 and R.sup.1 and R.sup.10 are as defined;
R.sup.13 is:
C.sub.1 -C.sub.3 perfluoroalkyl, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, where the substitutents are hydroxy, NR.sup.10 R.sup.11, carboxy, phenyl or substituted phenyl;
phenyl or substituted phenyl where the substituents on the phenyl are from 1 to 3 of halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy or hydroxy;
and v is as defined above;
R.sup.4, R.sup.4b, R.sup.5 and R.sup.5a are independently hydrogen, phenyl, substituted phenyl, C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, substituted C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, or substituted C.sub.3 -C.sub.10 alkynyl where the substituents on the phenyl, alkyl, alkenyl or alkynyl are from 1 to 5 of hydroxy, C.sub.1 -C.sub.6 alkoxy, C.sub.3 -C.sub.7 cycloalkyl, fluoro, R.sup.1, R.sup.2 independently disubstituted phenyl C.sub.1 -C.sub.3 alkoxy, R.sup.1, R.sup.2 independently disubstituted phenyl, C.sub.1 -C.sub.20 -alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy, formyl or --NR.sup.10 R.sup.11 where R.sup.10 and R.sup.11 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl, phenyl C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.5 -alkoxycarbonyl or C.sub.1 -C.sub.5 -alkanoyl-C.sub.1 -C.sub.6 alkyl;
or R.sup.4 and R.sup.5 can be taken together to form --(CH.sub.2).sub.r --B--(CH.sub.2).sub.s -- where B is CHR.sup.1, O, S(O).sub.m or N--R.sup.10, r and s are independently 1 to 3 and R.sup.1 and R.sup.10 are as defined above;
R.sup.6 is hydrogen, C.sub.1 -C.sub.10 alkyl, phenyl or phenyl C.sub.1 -C.sub.10 alkyl;
A is ##STR476## where x and y are independently 0-3;
R.sup.8 and R.sup.8a are independently hydrogen, C.sub.1 -C.sub.10 alkyl, trifluoromethyl, phenyl, substituted C.sub.1 -C.sub.10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(O).sub.m R.sup.7a, C.sub.1 -C.sub.6 alkoxy, C.sub.3 -C.sub.7 cycloalkyl, R.sup.1, R.sup.2 independently disubstituted phenyl C.sub.1 -C.sub.3 alkoxy, R.sup.1, R.sup.2 independently disubstituted phenyl, C.sub.1 -C.sub.5 -alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy, formyl, or --NR.sup.10 R.sup.11 where R.sup.10 and R.sup.11 are as defined above;
or R.sup.8 and R.sup.8a can be taken together to form --(CH.sub.2).sub.t -- where t is 2 to 6;
and R.sup.8 and R.sup.8a can independently be joined to one or both of R.sup.4 and R.sup.5 to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms;
and pharmaceutically acceptable salts thereof.

24 more elements

Facts

Application

08/392,961Filed 18 Apr 1995 · continuation in part

Priority

28 Aug 1992

Granted

30 Sep 1997

Term ends

Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 223/16
Condensed with carbocyclic rings or ring systems: benzazepines; Hydrogenated benzazepines
A23K 20/132
Heterocyclic compounds: containing only one nitrogen as hetero atom
A23K 20/137
Heterocyclic compounds: containing two hetero atoms, of which at least one is nitrogen
A61K 38/25
Hormones: growth hormone-releasing factor [GH-RF], i.e. somatoliberin