DIPEPTIDE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM FOR INCREASING LEVELS OF ENDOGENOUS GROWTH HORMONE IN A HUMAN OR OTHER ANIMALS

摘要

Compounds for increasing levels of endogenous growth hormone of the formula 998 י" ב בסיון התשס" ד - June 1, 2004 the racemic-diastereomeric mixtures and optical isomers of said compounds and the pharmaceutcally-acceptable salts and prodrugs thereof, wherein e is 0 or 1; n and w are each independently 0, 1 or 2; provided that w and n cannot both be 0 at the same time; Y is oxygen or sulfur; where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4) alkyl, hydroxyl, (C1-C4) alkoxy, carboxyl, -CONH2, -S(O)m ((C1-C6) alkyl, -CO2(C1-C4) alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y1 is O, S(O)m, -C(O)NX6-, -CH=CH-, -C:C-, N(X6)C(O)-, -C(O)NX6-, -C(O)O-, -OC(O)N(X6)- or -OC(O)-; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH2)q group and (CH2)t group may each be optionally substituted with hydroxyl, (C1-C4) alkoxy, carboxyl, -CONH2, -S(O)m(C1-C6) alkyl, -CO2(C1-C4) alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (C1-C4) alkyl; R2 is hydrogen, (C1-C8) alkyl, -(C0-C3) alkyl-(C3-C8) cycloalkyl, -(C1-C4) alkyl-A1 or A1; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxyl, -C(O)OX6, -C(O)N(X6)(X6), -N(X6)(X6), -S(O)m -(C1-C6) alkyl, -C(O)A1, -C(O)(X6), 999 י" ב בסיון התשס" ד - June 1, 2004 CF3, CN or 1, 2 or 3 halogen; R3 is A1, (C1-C10) alkyl, -(C1-C6) alkyl-A1, -(C1-C6) alkyl -(C3-C7) cycloalkyl, -(C1-C5) alkyl-X1-(C1-C5) alkyl, -(C1-C5) alkyl-X1-(C0-C5) alkyl-A1 or -(C1-C5) alkyl-X1- (C1-C5) alkyl-(C3-C7) cycloalkyl; where the alkyl groups in the definition of R3 are optionally substituted with -S(O)m-(C1-C6) alkyl, -C(O)OX3, 1, 2, 3, 4 or 5 halogens, or 1, 2 or 3 OX3; X1 is O, S (O)m, -N(X2)C(O)-, -C(O) N(X2)-, -OC(O)-, -C(O)O-, -CX2=CX2-, -N(X2)C(O)O-, -OC(O)N(X2)- or -C:C-; R4 is hydrogen, (C1-C6) alkyl or (C3-C7) cycloalkyl, or R4 is taken together with R3 and the carbon atom to which they are attached and form (C5-C7) cycloalkyl, (C5-C7) cycloalkenyl, a partialy saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or is a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, fused to a partially saturated, fully unsaturated or fully saturated 5 to 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; X4 is hydrogen or (C1-C6) alkyl or X4 is taken together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached and form a five to seven membered ring; R6 is a bond or is where a and b are independently 0, 1, 2 or 3; X5 and X5a are each independently selected from the group consisting of hydrogen, trifluoromethyl, A1 and optionally substituted (C1-C6) alkyl; the optionally substituted (C1-C6) alkyl in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, OX2, -S(O)m(C1-C6) alkyl, -C(O)OX2, (C3-C7 cycloalkyl, -N(X2)(X2) and -C(O) N(X2)(X2); or the carbon bearing X5 or X5a forms one or two alkylene bridges with the nitrogen atom bearing R7 and R8 wherein each alkylene bridge contains 1 to 5 carbon atoms, provided that when one alkylene bridge is formed then X5 or X5a but not both may be on the carbon atom and R7 or R8 but not both may be on the nitrogen atom and further provided that when two alkylene bridges are formed then X5 and X5a cannot be on the carbon atom and R7 and R8 cannot be on the nitrogen atom; or X5 is taken together with X5a and the carbon atom to which they are attached and form a partially saturated or fully saturated 3- to 7-membered ring, or a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from 1000 י" ב בסיון התשס" ד - June 1, 2004 the group consisting of oxygen, sulfur and nitrogen; or X5 is taken together with X5a and the carbon atom to which they are attached and form a bicyclic ring system consisting of a partially saturated of fully saturated 5- or 6-membered ring, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; Z1 is a bond, O or N-X2, provided that when a and b are both 0 then Z1 is not N-X2 or O; R7 and R8 are independently hydrogen or optionally substituted (C1-C6) alkyl; where the optionally substituted (C1-C6) alkyl in the definition of R7 and R8 is optionally independently sub