US 5,317,017 AGranted

N-biphenyl-3-amido substituted benzolactams stimulate growth hormone release

AssigneeMerck & Co., Inc.

InventorsHyun O. Ok, William R. Schoen, Matthew Wyvratt

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Abstract

There are disclosed certain compounds identified as N-biphenyl-3-amido substituted benzolactams 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 benzolactams as the active ingredient thereof are also disclosed.

Claims13

Dependent claims

A compound having the formula:

##STR51## where L is ##STR52## 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 ;
m is 0 to 2;
R.sup.9 is ##STR53## 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.7b CO(CH.sub.2).sub.v --, R.sup.7b (CH.sub.2).sub.v CO--, 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 --, R.sup.4 R.sup.5 NCS(CH.sub.2).sub.v --, R.sup.4 R.sup.5 NN(R.sup.5)CO(CH.sub.2).sub.v --, R.sup.4 R.sup.5 NN(R.sup.5)CS(CH.sub.2).sub.v --, R.sup.7b CON(R.sup.4)N(R.sup.5)CO(CH.sub.2).sub.v --, R.sup.7b CON(R.sup.4)N(R.sup.5)CS(CH.sub.2).sub.v --, R.sup.4 N(OR.sup.7b)CO(CH.sub.2).sub.v --, R.sup.7a CON(OR.sup.7b)CO(CH.sub.2).sub.v --, R.sup.4b R.sup.12a NCON(R.sup.12b)(CH.sub.2).sub.v --, R.sup.4b R.sup.12a NCSN(R.sup.12b)(CH.sub.2).sub.v --, R.sup.4b R.sup.12a NN(R.sup.12b)CSN(R.sup.12c)(CH.sub.2).sub.v --, R.sup.4b R.sup.12a NN(R.sup.12b)CON(R.sup.12c)(CH.sub.2).sub.v --, R.sup.4b R.sup.12a NN(R.sup.12b)COO(CH.sub.2).sub.v --, R.sup.4b R.sup.12a NCOO(CH.sub.2).sub.v -- or R.sup.13 OCON(R.sup.12b)(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.13 and R.sup.12b, or R.sup.12a and R.sup.4b when taken together 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;
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;
X is --CH.sub.2 CH(R.sup.20)--, --CH(R.sup.21)CH.sub.2 --, --CH(R.sup.21)CH(R.sup.20)--, --CH.dbd.C(R.sup.20)--, --C(R.sup.21).dbd.CH--, --C(R.sup.21).dbd.C(R.sup.20)--, --S(O).sub.m CH(R.sup.20)-- or --OCH(R.sup.20)--;
R.sup.20 and R.sup.21 are independently hydrogen, R.sup.1, R.sup.2 independently disubstituted phenyl, R.sup.1, R.sup.2 independently disubstituted thiophenyl, C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, substituted C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, substituted C.sub.2 -C.sub.10 alkynyl where the substituents on the alkyl, alkenyl, alkynyl are from 1 to 3 of hydroxy, C.sub.1 -C.sub.6 alkoxy, fluoro, R.sup.1 substituted phenyl, --NR.sup.10 R.sup.11, carboxy, C.sub.1 -C.sub.5 alkoxycarbonyl, formyl or R.sup.20 and R.sup.21 when taken together form --(CH.sub.2).sub.r B(CH.sub.2).sub.s -- where B, r, s, R.sup.1, R.sup.2, R.sup.10 and R.sup.11 are as defined above, with the proviso that R.sup.20 and R.sup.21 cannot both be hydrogen;
R.sup.4, R.sup.4a, 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 ;
or R.sup.4 and R.sup.5 when taken to form --(CH.sub.2).sub.r B(CH.sub.2).sub.s -- where B, r, s, R.sup.1, R.sup.2, R.sup.10 and R.sup.11 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 ##STR54## 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 when taken together form --(CH.sub.2).sub.t -- where t is 2 to 6;
and R.sup.8 and R.sup.8a when independently joined to one or both of R.sup.4 and R.sup.5 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;
or pharmaceutically acceptable salts thereof.

21 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound having the formula:

##STR51## where L is ##STR52## 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 ;
m is 0 to 2;
R.sup.9 is ##STR53## 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.7b CO(CH.sub.2).sub.v --, R.sup.7b (CH.sub.2).sub.v CO--, 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 --, R.sup.4 R.sup.5 NCS(CH.sub.2).sub.v --, R.sup.4 R.sup.5 NN(R.sup.5)CO(CH.sub.2).sub.v --, R.sup.4 R.sup.5 NN(R.sup.5)CS(CH.sub.2).sub.v --, R.sup.7b CON(R.sup.4)N(R.sup.5)CO(CH.sub.2).sub.v --, R.sup.7b CON(R.sup.4)N(R.sup.5)CS(CH.sub.2).sub.v --, R.sup.4 N(OR.sup.7b)CO(CH.sub.2).sub.v --, R.sup.7a CON(OR.sup.7b)CO(CH.sub.2).sub.v --, R.sup.4b R.sup.12a NCON(R.sup.12b)(CH.sub.2).sub.v --, R.sup.4b R.sup.12a NCSN(R.sup.12b)(CH.sub.2).sub.v --, R.sup.4b R.sup.12a NN(R.sup.12b)CSN(R.sup.12c)(CH.sub.2).sub.v --, R.sup.4b R.sup.12a NN(R.sup.12b)CON(R.sup.12c)(CH.sub.2).sub.v --, R.sup.4b R.sup.12a NN(R.sup.12b)COO(CH.sub.2).sub.v --, R.sup.4b R.sup.12a NCOO(CH.sub.2).sub.v -- or R.sup.13 OCON(R.sup.12b)(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.13 and R.sup.12b, or R.sup.12a and R.sup.4b when taken together 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;
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;
X is --CH.sub.2 CH(R.sup.20)--, --CH(R.sup.21)CH.sub.2 --, --CH(R.sup.21)CH(R.sup.20)--, --CH.dbd.C(R.sup.20)--, --C(R.sup.21).dbd.CH--, --C(R.sup.21).dbd.C(R.sup.20)--, --S(O).sub.m CH(R.sup.20)-- or --OCH(R.sup.20)--;
R.sup.20 and R.sup.21 are independently hydrogen, R.sup.1, R.sup.2 independently disubstituted phenyl, R.sup.1, R.sup.2 independently disubstituted thiophenyl, C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, substituted C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, substituted C.sub.2 -C.sub.10 alkynyl where the substituents on the alkyl, alkenyl, alkynyl are from 1 to 3 of hydroxy, C.sub.1 -C.sub.6 alkoxy, fluoro, R.sup.1 substituted phenyl, --NR.sup.10 R.sup.11, carboxy, C.sub.1 -C.sub.5 alkoxycarbonyl, formyl or R.sup.20 and R.sup.21 when taken together form --(CH.sub.2).sub.r B(CH.sub.2).sub.s -- where B, r, s, R.sup.1, R.sup.2, R.sup.10 and R.sup.11 are as defined above, with the proviso that R.sup.20 and R.sup.21 cannot both be hydrogen;
R.sup.4, R.sup.4a, 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 ;
or R.sup.4 and R.sup.5 when taken to form --(CH.sub.2).sub.r B(CH.sub.2).sub.s -- where B, r, s, R.sup.1, R.sup.2, R.sup.10 and R.sup.11 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 ##STR54## 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 when taken together form --(CH.sub.2).sub.t -- where t is 2 to 6;
and R.sup.8 and R.sup.8a when independently joined to one or both of R.sup.4 and R.sup.5 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;
or pharmaceutically acceptable salts thereof.

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