Patent EA-002089-B1 (EA)
Title: Method for treating insulin resistance with grwth hormone secretagogues
Inventor: CARPINO PHILIP ALBERT
IPC: A61K38/05
Filed: 1998-06-05
Abstract: m a partially saturated or fully saturated 3- to 7-membered ring, or a partially saturated or fully ammal, which comprises administering to said mammaroatoms independently selected from the group cons or the stereoisomeric mixtures, diastereomerically enriched, diastereomerically pure, enantiomericahich they are attached and form a bicyclic ring system consisting of a partially saturated or fully  thereof, wherein e is 0 or 1; n and w are each independently 0, 1 or 2; provided that w and n can not both be 0 at the same time; Y is oxygen or sulf fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionaCH2)t-A<1>, -(CH2)qN(X<6>)SO2X<6>, -(CH2)qN(X<6>)C(O)N(X<6>)(CH2)t-A<1>, -(CH2)qN(X<6>)C(O)N(X<6>)(Xnd oxygen; Z<1> is a bond, O or N-X<2>, provided t(CH2)t-A<1>, -(CH2)qC(O)OX<6>, -(CH2)qC(O)O(CH2)t-> or O; R<7> and R<8> are independently hydrogen o(CH2)t-A<1>, -(CH2)qOC(O)N(X<6>)(CH2)t-A<1>, -(CH2ptionally substituted (C-C6)alkyl in R<7> and R<8> is optionally independently substituted with A<1>, -C(O)O-(C1-C6)alkyl, -S(O)m(C1-C6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 -O-C(O)(C1-C10)al(C3-C7)cycloalkyl, -(CH2)q-Y<1>-(C1-C6)alkyl, -(CHbe taken together to form -(CH2)r-L-(CH2)r-; where) cycloalkyl; where the alkyl and cycloalkyl groups in the definition of R<1> are optionally substit, phenyl or a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro atoms; Y<1> is O, S(O)m, -C(O)NX<6>-, -CH=CH-, -C [triple bond] C-, -N(X<6>)C(O)-, -C(O)NX<6>-, -C(O)O partially saturated, fully unsaturated or fully s; t is 0, 1, 2 or 3; said (CH2)q group and (CH2)t group may each be optionally substituted with hydrgroup consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionall<2> is hydrogen, (C1-C8)alkyl, -(C0-C3)alkyl-(C3-C from the group consisting of nitrogen, sulfur ande alkyl groups and the cycloalkyl groups in the de optionally substituted, in one or optionally both rings if A<1> is a bicyclic ring system, with up to three substituents, each substituent independen CF3, CN or 1, 2 or 3 halogen; R<3> is A<1>, (C1-Cr, I, OCF3, OCF2H, CF3, CH3, OCH3, -OX<6>, -C(O)N()cycloalkyl, -(C1-C5)alkyl-X<1>-(C1-C5)alkyl, -(C1 cyano, benzyl, -S(O)m(C1-C6)alkyl, 1H-tetrazol-5-X<1>-(C1-C5)alkyl-(C3-C7)cycloalkyl; where the alkyl groups in the definition of R<3> are optionally -SO2N(X<6>)(X<6>), -N(X<6>)SO2-phenyl, -N(X<6>)SO1, 2, 3, 4 or 5 halogens, or 1, 2 or 3 OX<3>; X<1><12>, -NX<6>CONX<11>X<12>, -NX<6>SO2NX<11>X<12>, --, -C(O)O-, -CX<2>=CX<2>-, -N(X<2>)C(O)O-, OC(O)N(X<2>)- or -C [triple bond] C-; R<4> is hydrogen, (C1-C6)alkyl or (C3-C7)cycloalkyl, or R<4> is takented with one methylenedioxy; where X<11> is hydroghey are attached and form (C5-C7)cycloalkyl, (C5-Cionally substituted (C1-C6)alkyl defined for X<11> is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, -S(O)m(C1-C6)aing of oxygen, sulfur and nitrogen, or is a bicyclC10)alkanoyloxy or 1 to 3 (C1-C6)alkoxy; X<12> is  or fully saturated 5- or 6-membered ring, fused tlyl, furyl or thienyl, provided that when X<12> isy saturated 5- or 6-membered ring, optionally havih one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCn; X<4> is hydrogen or (C1-C6)alkyl or X<4> is taken together with R<4> and the nitrogen atom to which X<4> is attached and the carbon atom to which R<4> is attached and form a five to seven membered ence is independently hydrogen, optionally substituted (C1-C6)alkyl, or optionally substituted (C3-Cndependently selected from the group consisting of hydrogen, trifluoromethyl, A<1> and optionally substituted (C1-C6)alkyl; the optionally substituted (C1-C6)alkyl in the definition of X<5> and X<5a> is optionally substituted with a substituent selecch occurrence is independently hydrogen or (C1-C6))m(C1-C6)alkyl, -C(O)OX<2>, (C3-C7)cycloalkyl, -N(X<2>)(X<2>) and -C(O)N(X<2>)(X<2>); or the carbon bearing X<5> or X<5a> forms one or two alkylene bridges with the nitrogen atom bearing R<7> and R<8> wherein each alkylene bridge contains 1 to 5 carbon atoms, provided that when one alkylene bridge is formed then X<5> or X<5a> but not both may be on, hydroxyl, (C1-C4)alkoxy, carboxyl, CONH2, -S(O)m be on the nitrogen atom and further provided thatzol-5-yl; or when there are two X<6> groups on oned X<5a> cannot be on the carbon atom and R<7> and R<8> cannot be on the nitrogen atom; or X<5> is taken together with X<5a> and the carbon atom to whiX<6> groups are attached, form a 4- to 9- membered ring optionally having oxygen, sulfur or NX<7>; X<7> is hydrogen or (C1-C6)alkyl optionally substitered ring having 1 to 4 heteroatoms independently ndependently 0, 1 or 2; with the proviso that: X<6ur and nitrogen; or X<5> is taken together with X<is attached to C(O) or SO2 in the form C(O)X<6>, C and form a bicyclic ring system consisting of a pbond then L is N(X<2>) and each r in -(CH2)r-L-(CH2)r- is independently 2 or 3. 15. A method according to Claim 1 wherein the condition associated with insulin resistance is type I diabetes, type II diabetes, hyperglycemia, impaired glucose tolerance or an insulin resistant syndrome or state. 16. A roatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; Z<1> is a bith obesity or old age. 17. A method of treating insulin resistance in a mammal which comprises admiare independently hydrogen or optionally substituted (C1-C6)alkyl; where the optionally substituted  growth hormone releasing peptide mimetic or a phaally independently substituted with A<1>, -C(O)O-(ss for the preparation of the compound of formula k,   wherein the compound of formula g   which comprises reacting the compound of free base (g), with the compound of formula j,   where Prt is an amine protecting group, in the presence of an organicnce is independently (C5-C7)cycloalkenyl, phenyl or a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally havind of formula k. 19. A process according to Claim 18 where the peptide coupling reagent is 1-propane phosphonic acid cyclic anhydride and the compound  saturated, fully unsaturated or fully saturated 5 or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a und of formula Z,   wherein the compound of formulturated 5 or 6-membered ring, optionally having 1 und (g) with the compound of formula j,   in the proup consisting of nitrogen, sulfur and oxygen; A<1> for each occurrence is independently optionally substituted, in one or optionally both rings if A<1> is a bicyclic ring system, with up to three sug the compound of formula k to yield the compound d from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, -OX<6>, -C(O)N(X<6>)(X<6>), -C(O)OX<6>, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, -S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl,nt is l-propane phosphonic acid cyclic anhydride and the compound of formula g has the R-configurati)(X<6>), -N(X<6>)SO2-phenyl, -N(X<6>)SO2X<6>, -CONX<11>X<12>, -SO2NX<11>X<12>, -NX<6>SO2X<12>, -NX<6Z has the 3a-(R),1-(R) configuration. 22. A proces12>, imidazolyl, thiazolyl and tetrazolyl, provided that if A<1> is optionally substituted with methylenedioxy then it can only be substituted with ont solvent at a temperature of about -50 degree C tnally substituted (C1-C6)alkyl; the optionally substituted (C1-C6)alkyl defined for X<11> is optionamula g. 23. A process for the preparation of the compound of formula c,   wherein the compound of fo5 halogens, 1 to 3 hydroxy, 1 to 3 (C1-C10)alkanoyloxy or 1 to 3 (C1-C6)alkoxy; X<12> is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X<12> is not hydrogen, X<12> is optionally substituted with one to thherein the compound of formula e,   is put into reroup consisting of Cl, F, CH3, OCH3, OCF3 and CF3; or X<11> and X<12> are taken together to form -(CH2)r-L<1>-(CH2)r-; where L<1> is C(X<2>)(X<2>), O,a   wherein Prt is hydrogen or an amine protectingndently 1, 2 or 3; X<2> for each occurrence is independently hydrogen, optionally substituted (C1-C6ng administering to said mammal an effective amounl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in theomerically pure, enantiomerically enriched or enanubstituted with -S(O)m(C1-C6)alkyl, -C(O)OX<3>, 1  acceptable salts and prodrugs thereof, wherein e ce is independently hydrogen or (C1-C6)alkyl; X<6> is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionall -CN, -(CH2)qN(X<6>)C(O)X<6>, -(CH2)qN(X<6>)C(O)(CH2)t-A<1>, -(CH2)qN(X<6>)SO2(CH2)t-A<1>, -(CH2)qN(alkyl and optionally substituted (C3-C7)cycloalkyl, -(CH2)qN(X<6>)C(O)N(X<6>)(X<6>), -(CH2)qC(O)N(X<y 1 or 2 (C1-C4)alkyl, hydroxyl, (C1-C4)alkoxy, carboxyl, CONH2, S(O)m(C1-C6)alkyl, -CO2(C1-C4) alkyCH2)qOC(O)X<6>, -(CH2)qOC(O)(CH2)t-A<1>, -(CH2)qOCo X<6> groups on one atom and both X<6> are indepe-(CH2)qC(O)X<6>, -(CH2)qC(O)(CH2)t-A<1>, -(CH2)qN(X<6>)C(O)OX<6>, -(CH2)qN(X<6>)SO2N(X<6>)(X<6>), -(CH2)qS(O)mX<6>, -(CH2)qS(O)m(CH2)t-A<1>, -(C1-C10) a 4- to 9- membered ring optionally having oxygen, sulfur or NX<7>; X<7> is hydrogen or (C1-C6)alky1> or -(CH2)q-Y<1>-(CH2)t-(C3-C7)cycloalkyl; whereach occurrence is independently 0, 1 or 2; with th of R<1> 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-tetraand when R<6> is a bond then L is N(X<2>) and each(O)NX<6>-, -CH=CH-, -C [triple bond] C-, -N(X<6>)C. A method according to Claim 1 wherein said compound of formula I is of the following formula   or the stereoisomeric mixtures, diastereomerically enriched, diastereomerically pure, enantiomerically