US 5,536,716 A · Spiro piperidines and homologs which promote release of growth hormone

Abstract

There are disclosed certain novel compounds identified as spiro piperidines and homologs 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 treat physiological or medical conditions characterized by a deficiency in growth hormone secretion, such as short stature in growth hormone deficient children, and to treat medical conditions which are improved by the anabolic effects of growth hormone. Growth hormone releasing compositions containing such spiro compounds as the active ingredient thereof are also disclosed.

A compound of the formula ##STR38## 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)-,
wherein K is --O--, --S(O).sub.m --, --N(R.sub.2)C(O)--, --C(O)N(R.sub.2)--, --OC(O)--, --C(O)O--, or --CR.sub.2 .dbd.CR.sub.2 --, or --C.tbd.C--, where the R.sub.2 and alkyl groups may be futher substituted by 1 to 9 halogen, S(O)mR.sub.2a, 1 to 3 OR.sub.2a or C(O)OR.sub.2a, and where the aryl groups may be further substituted by phenyl, phenoxy, halophenyl, 1 to 3 C.sub.1 -C.sub.6 alkyl, 1 to 3 halogen, 1 to 2--OR.sub.2, methylenedioxy, --S(O).sub.m R.sub.2, 1 to 2 --CF.sub.3, --OCF.sub.3, nitro, --N(R.sub.2)(R.sub.2), --N(R.sub.2)C(O)R.sub.2, --C(O)OR.sub.2, --C(O)N(R.sub.2)(R.sub.2), --SO.sub.2 N(R.sub.2)(R.sub.2), --N(R.sub.2)S(O).sub.2 aryl, or --N(R.sub.2)SO.sub.2 R.sub.2 ;
R.sub.2 is selected from the group consisting of:
hydrogen, C.sub.1 -C.sub.6 alkyl, 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 optionally including oxygen, sulfur, or NR.sub.2a ;
R.sub.2a is hydrogen or C.sub.1 -C.sub.6 alkyl;
R.sub.3a and R.sub.3b are independently selected from the group consisting of:
hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, --OR.sub.2, cyano, --OCF.sub.3, methylenedioxy, nitro, --S(O).sub.m R.sub.2, --CF.sub.3 and --C(O)OR.sub.2, and when R.sub.3a and R.sub.3b are in an ortho arrangement, they may be joined to form a C.sub.5 to C.sub.8 aliphatic or aromatic ring optionally including 1 or 2 heteroatoms selected from oxygen, sulfur, or nitrogen;
R.sub.4 and R.sub.5 are independently selected from the group consisting of:
hydrogen, C.sub.1 -C.sub.6 alkyl, and substituted C.sub.1 -C.sub.6 alkyl where the substituents on alkyl are 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, phenoxy, 2-furyl, C.sub.1 -C.sub.6 alkoxycarbonyl, or 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.r L.sub.a (CH.sub.2).sub.s --, where L.sub.a is --C(R.sub.2).sub.2 --, --O--, --S(O).sub.m --, or --N(R.sub.2)--, where r and s are independently 1, 2 or 3;
R.sub.6 is hydrogen or C.sub.1 -C.sub.6 alkyl;
A is:
##STR39## wherein x and y are independently 0, 1, 2, or 3;
Z is N--R.sub.2 or O;
R.sub.7 and R.sub.7a are independently selected from the group consisting of:
hydrogen, --C.sub.1 -C.sub.6 alkyl, --OR.sub.2, trifluoromethyl, phenyl, substituted C.sub.1 -C.sub.6 alkyl where the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl,--OR.sub.2, 1 to 3 fluoro, --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), and --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 the 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;
B, D, E, and F are independently selected from the group consisting of:
--C(R.sub.8)(R.sub.10)--, --O--, C.dbd.O, --S(O).sub.m --, and --NR.sub.9 --, wherein one or two of B, D, E, or F may be optionally absent to provide a 5, 6, or 7 membered ring, provided that one of B, D, E or F is --O--, --S(O).sub.m --, or --NR.sub.9 --, and at least one of the remaining B, D, E or F is --C(R.sub.8)(R.sub.10)-- or C.dbd.O;
or B and D taken together may be --N.dbd.CR.sub.10 -- or --CR.sub.10 .dbd.N--, if E or F is --O--,--S(O).sub.m --, or--NR.sub.9 --, or D and E taken together may be --N.dbd.CR.sub.10 -- or --CR.sub.10 .dbd.N--, if B or F is --O--,--S(O).sub.m --, or --NR.sub.9 --, or B and D taken together may be --CR.sub.8 .dbd.CR.sub.10 --, if E or F is --O--, --S(O).sub.m --, or --NR.sub.9 --, or D and E taken together may be --CR.sub.8 .dbd.CR.sub.10 --, if B or F is --O--, --S(O).sub.m --, or --NR.sub.9 --;
R.sub.8 and R 10 are independently selected from the group consisting of:
hydrogen, --R.sub.2, --OR.sub.2, --(CH.sub.2).sub.q -aryl, --(CH.sub.2).sub.q --C(O)OR.sub.2, --(CH.sub.2).sub.q --C(O)O(CH.sub.2).sub.q -aryl, and --(CH.sub.2).sub.q -(1H-tetrazol-5-yl), where the aryl is optionally substituted by 1 to 3 halo, 1 to 2 C.sub.1 -C.sub.8 alkyl, 1 to 3 --OR.sub.2, or 1 to 2 --C(O)OR.sub.2 ;
R.sub.9 is selected from the group consisting of:
--R.sub.2, --(CH.sub.2).sub.q -aryl, --C(O)R.sub.2, --C(O)(CH.sub.2).sub.q -aryl, --SO.sub.2 R.sub.2, --SO.sub.2 (CH.sub.2).sub.q -aryl, --C(O)N(R.sub.2)(R.sub.2), --C(O)N(R.sub.2)(CH.sub.2).sub.q -aryl, --C(O)OR.sub.2, 1-H-tetrazol-5-yl, --SO.sub.3 H,--SO.sub.2 NHC.tbd.N, --SO.sub.2 N(R.sub.2)aryl, and --SO.sub.2 N(R.sub.2)(R.sub.2), where the (CH.sub.2).sub.q is optionally substituted by 1 to 2 C.sub.1 -C.sub.4 alkyl, and R.sub.2 and aryl are optionally further substituted by 1 to 3 --OR.sub.2a, --O(CH.sub.2).sub.q aryl, 1 to 2 --C(O)OR.sub.2a, 1 to 2 --C(O)O(CH.sub.2)q aryl, 1 to 2 --C(O)N(R.sub.2a)(R.sub.2a), 1 to 2 --C(O)N(R.sub.2a)(CH.sub.2).sub.q aryl, 1 to 5 halogen, 1 to 3 C.sub. 1 -C.sub.4 alkyl, 1,2,4-triazolyl, 1H-tetrazol-5-yl, --C(O)NHSO.sub.2 R.sub.2a, --S(O).sub.m R.sub.2a, --C(O)NHSO.sub.2 (CH.sub.2).sub.q -aryl, --SO.sub.2 NHC.tbd.N, --SO.sub.2 NHC(O)R.sub.2a, --SO.sub.2 NHC(O)(CH.sub.2).sub.q aryl, --N(R.sub.2)C(O)N(R.sub.2a)(R.sub.2a), --N(R.sub.2a)C(O)N(R.sub.2a)(CH.sub.2).sub.q -aryl, --N(R.sub.2a)(R.sub.2a), --N(R.sub.2a)C(O)R.sub.2a, --N(R.sub.2a)C(O)(CH.sub.2).sub.q aryl,--OC(O)N(R.sub.2a)(R.sub.2a), --OC(O)N(R.sub.2a)(CH.sub.2).sub.q aryl, or --SO.sub.2 (CH.sub.2).sub.q CONH--(CH.sub.2).sub.w NHC(O)R.sub.11, where w is 2 to 6 and R 11 is biotin, aryl, or aryl substituted by 1 or 2 --OR.sub.2, 1 to 2 halogen, azido, or nitro;
m is 0, 1 or 2;
n is 1 or 2;
q is 0, 1, 2, 3, or 4;
and
G, H, I and J are carbon, nitrogen, sulfur or oxygen atoms, such that one or two is a heteroatom, and where one of G, H, I or J may be optionally absent to afford a 5 or 6 membered heterocyclic aromatic ring;
and the pharmaceutically acceptable salts and individual diastereomers thereof.

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Spiro piperidines and homologs which promote release of growth hormone

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Spiro piperidines and homologs which promote release of growth hormone

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Abstract

Claims19