Di- and tri-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone

A compound of the formula:

• ##STR241## wherein:
• R.sub.1 is selected from the group consisting of:
• C.sub.1 -C.sub.10 alkyl, aryl, aryl(C.sub.1 -C.sub.6 alkyl), (C.sub.3 -C.sub.7 cycloalkyl)(C.sub.1 -C.sub.6 alkyl)-, (C.sub.1 -C.sub.5 alkyl)-K--(C.sub.1 -C.sub.5 alkyl)-, aryl(C.sub.0 -C.sub.5 alkyl)-K--(C.sub.1 -C.sub.5 alkyl)-, and (C.sub.3 -C.sub.7 cycloalkyl)(C.sub.0 -C.sub.5 alkyl)-K--(C.sub.1 -C.sub.5 alkyl)-, where K is O, S(O).sub.m, N(R.sub.2)C(O), C(O)N(R.sub.2), OC(O), C(O)O, --CR.sub.2 .dbd.CR.sub.2 --, or --C.tbd.C--, where aryl is selected from:
• phenyl, naphthyl, indolyl, azaindole, pyridyl, benzothienyl, benzofuranyl, thiazolyl, and benzimidazolyl, and R.sub.2 and alkyl may be further substituted by 1 to 9 halogen, S(O).sub.m R.sub.2a, 1 to 3 of OR.sub.2a or C(O)OR.sub.2a, and aryl may be further substituted by 1 to 3 of C.sub.1 -C.sub.6 alkyl, 1 to 3 of halogen, 1 to 2 of OR.sub.2, methylenedioxy, --S(O).sub.m R.sub.2, 1 to 2 of --CF.sub.3, --OCF.sub.3, nitro, --N(R.sub.2)C(O)(R.sub.2), --C(O)OR.sub.2, --C(O)N(R.sub.2)(R.sub.2), -1H-tetrazol-5-yl, --SO.sub.2 N(R.sub.2)(R.sub.2), --N(R.sub.2)SO.sub.2 phenyl, or --N(R.sub.2)SO.sub.2 R.sub.2 ;
• R.sub.2 is selected from:
• hydrogen, C.sub.1 -C.sub.6 alkyl, and C.sub.3 -C.sub.7 cycloalkyl, and where two C.sub.1 -C.sub.6 alkyl groups are present on one atom, they may be optionally joined to form a C.sub.3 -C.sub.8 cyclic ring;
• X is selected from:
• --C.tbd.N, --(CH.sub.2).sub.q N(R.sub.2)C(O)R.sub.2, --(CH.sub.2).sub.q N(R.sub.2)C(O)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q N(R.sub.2)SO.sub.2 (CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q N(R.sub.2)SO.sub.2 R.sub.2, --(CH.sub.2).sub.q N(R.sub.2)C(O)N(R.sub.2)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q N(R.sub.2)C(O)N(R.sub.2)(R.sub.2), --(CH.sub.2).sub.q C(O)N(R.sub.2)(R.sub.2), --(CH.sub.2).sub.q C(O)N(R.sub.2)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q C(O)OR.sub.2, --(CH.sub.2).sub.q C(O)O(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q OR.sub.2, --(CH.sub.2).sub.q OC(O)R.sub.2, --(CH.sub.2).sub.q OC(O)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q OC(O)N(R.sub.2)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q OC(O)N(R.sub.2)(R.sub.2), --(CH.sub.2).sub.q C(O)R.sub.2, --(CH.sub.2).sub.q C(O)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q N(R.sub.2)C(O)OR.sub.2, -- (CH.sub.2).sub.q N(R.sub.2)SO.sub.2 N(R.sub.2)(R.sub.2), --(CH.sub.2).sub.q S(O).sub.m R.sub.2, and --(CH.sub.2).sub.q S(O).sub.m (CH.sub.2).sub.t aryl, where an R.sub.2, (CH.sub.2).sub.q and (CH.sub.2).sub.t group may be optionally substituted by 1 to 2 C.sub.1 -C.sub.4 alkyl, hydroxyl, C.sub.1 -C.sub.4 lower alkoxy, carboxyl, CONH.sub.2, S(O).sub.m CH.sub.3, carboxylate C.sub.1 -C.sub.4 alkyl esters, or 1H-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl, or 1H-tetrazol-5-yl groups which may be optionally substituted by 1 to 3 halogen, 1 to 3 --OR.sub.2, --CON(R.sub.2)(R.sub.2), --C(O)OR.sub.2, 1 to 3 C.sub.1 -C.sub.4 alkyl, --S(O).sub.m R.sub.2, or 1H-tetrazol-5-yl;
• Y is selected from:
• C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q (C.sub.3 -C.sub.7 cycloalkyl), --(CH.sub.2).sub.q -K--(C.sub.1 -C.sub.6 alkyl), --(CH.sub.2).sub.q -K--(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q -K--(CH.sub.2).sub.t (C.sub.3 -C.sub.7 cycloalkyl containing O, NR.sub.2, S), and --(CH.sub.2).sub.q -K--(CH.sub.2).sub.t (C.sub.3 -C.sub.7 cycloalkyl), where K is O, S(O).sub.m, C(O)NR.sub.2, CH.dbd.CH, C.tbd.C, N(R.sub.2)C(O), C(O)NR.sub.2, C(O)O, or OC(O), and where the alkyl, R.sub.2, (CH.sub.2).sub.q and (CH.sub.2).sub.t groups may be optionally substituted by C.sub.1 -C.sub.4 alkyl, hydroxyl, C.sub.1 -C.sub.4 lower alkoxy, carboxyl, --CONH.sub.2 or carboxylate C.sub.1 -C.sub.4 alkyl esters, and aryl is phenyl, naphthyl, pyridyl, 1-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, or isothiazolyl which is optionally substituted by 1 to 3 halogen, 1 to 3 --OR.sub.2, --C(O)OR.sub.2, --C(O)N(R2)(R2), nitro, cyano, benzyl, 1 to 3 C.sub.1 -C.sub.4 alkyl, --S(O).sub.m R.sub.2, or 1H-tetrazol-5-yl;
• R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, or substituted C.sub.1 -C.sub.6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 C.sub.1 -C.sub.10 alkanoyloxy, 1 to 3 C.sub.1 -C.sub.6 alkoxy, phenyl, phenyloxy, 2-furyl, C.sub.1 -C.sub.6 alkoxycarbonyl, S(O).sub.m (C.sub.1 -C.sub.6 alkyl), or R.sub.4 and R.sub.5 may be taken together to form --(CH.sub.2).sub.d --L.sub.a (CH.sub.2).sub.e --where L.sub.a is --C(R.sub.2).sub.2 --, O, S(O).sub.m or N(R.sub.2), d and e are independently 1 to 3 and R.sub.2 is as defined above;
• A is:
• ##STR242## Where x and y are independently 0, 1, 2 or 3;
• Z is N--R.sub.6a or O, where R.sub.6a is hydrogen or C.sub.1 -C.sub.6 alkyl;
• R.sub.7 and R.sub.7a are independently hydrogen, C.sub.1 -C.sub.6 alkyl, trifluoromethyl, phenyl, or substituted C.sub.1 -C.sub.6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR.sub.2, S(O).sub.m R.sub.2, C(O)OR.sub.2, C.sub.3 -C.sub.7 cycloalkyl, N(R.sub.2)(R.sub.2), C(O)N(R.sub.2)(R.sub.2) , or R.sub.7 and R.sub.7a may independently be joined to one or both of R.sub.4 and R.sub.5 groups to form an alkylene bridge between the terminal nitrogen and the alkyl portion of the R.sub.7 or R.sub.7a groups, wherein the bridge contains 1 to 5 carbons atoms, or R.sub.7 and R.sub.7a can be joined to one another to form C.sub.3 -C.sub.7 cycloalkyl;
• with the proviso that if X or Y is unsubstituted phenyl, R.sub.4 is hydrogen, and R.sub.5 is hydrogen, then R.sub.7 and R.sub.7a are other than hydrogen or unsubstituted C.sub.1 -C.sub.6 alkyl;
• m is 0, 1 or 2;
• n is 2;
• q is 0, 1, 2, 3, or 4;
• t is 0, 1, 2, or 3;
• and pharmaceutically acceptable salts and individual diastereomers thereof.