US 7,842,808 B2 · Anti-migraine spirocycles

Abstract

The present invention relates to compounds of Formula (I) as antagonists of calcitonin gene-related peptide receptors (“CGRP-receptor”), pharmaceutical compositions comprising them, methods for identifying them, methods of treatment using them and their use in therapy for treatment of neurogenic vasodilation, neurogenic inflammation, migraine and other headaches, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and other conditions the treatment of which can be effected by the antagonism of CGRP-receptors.

A compound according to Formula (I)

or a pharmaceutically acceptable salt thereof
wherein
V is —N(R1)(R2) or OR4;
R4 is H, C1-6alkyl, C1-4haloalkyl or (C1-4alkylene)0-1R4′
R4′ is C3-7cycloalkyl, phenyl, adamantyl, quinuclidyl, azabicyclo[2.2.1]heptyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino or dioxolanyl;
and
R4′ is optionally substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, hydroxy, amino, C3-7cycloalkyl, C1-3 alkylamino, C1-3dialkylamino, (C1-3alkyl)0-2ureido, phenyl and benzyl;
and
R4′ optionally contains 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the ring structure of R4′;
R1 and R2 are each independently L1, wherein L1 is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, —C1-6alkylene-amino (C1-3alkyl)2, C3-7cycloalkyl, phenyl, azetidinyl, adamantyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and dioxolanyl;
and
R1 and R2 are each optionally and independently substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, hydroxy, amino, C3-7cycloalkyl, C1-3alkylamino, C1-3dialkylamino, (C1-3alkyl)0-2ureido, phenyl and benzyl;
R1 and R2 optionally and independently contain 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the heterocycles comprising R1 and R2;
or
R1 and R2 together with the nitrogen to which they are attached form X,
wherein X is azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino;
wherein X is optionally substituted with Y, wherein Y is dioxolanyl, C1-9alkyl, C2-9alkenyl, C2-9 alkynyl, C1-4alkylamino, C1-4dialkylamino, C1-4alkoxy, C3-7cycloalkyl, phenyl, azetidinyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazolidinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, pyridyl, pyrimidinyl, dihydrobenzimidazolonyl, piperazinyl, piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or thiomorpholino;
and wherein X and Y are
optionally interrupted with Z, wherein Z is —NHC(O)O—, —NHC(O)NH—, NC(O)NH2, —NH—, —C1-3alkylene-, —C2-3alkenylene -—NHC(O)O—C1-3alkylene-;
and
optionally and independently substituted with 1 or 2 of the same or different substituents selected from the group consisting of C1-4alkyl, amino, C1-3alkylamino, —C1-6alkylene-amino(C1-3 alkyl)2, (C1-3alkyl)0-2ureido, phenyl and benzyl;
X and Y optionally and independently contain 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the heterocycles comprising X and Y;
provided that if X is substituted with Y, and if X and Y are not interrupted with Z, then
X and Y optionally share one carbon atom and together form a spirocyclic moiety;
Q is Q′ or Q″;
wherein
Q′ is (Sy)sR3;
and
Q″ is NH(Sy)sR3, NHC(O)(Sy)sR3, NHC(O)O(Sy)sR3, NHC(O)NH(Sy)sR3, O(Sy)sR3, (Sy)sNHR3, (Sy)sNHC(O)R3, (Sy)sNHC(O)OR3, (Sy)sNHC(O)NHR3 or (Sy)sOR3;
wherein Sy is C1-3alkylene or C2-3alkylidene and s is 0 or 1;
U is CH2 or NH;
provided that if Q is Q″, then U is CH2;
R3 is R3a or R3b
wherein
R3a is
(i) a heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to five of the same or different heteroatoms selected from the group consisting of O, N and S and said heterocycle optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of said fused rings;
(ii) a 4 to 6 membered heterocycle containing one to three of the same or different heteroatoms selected from the group consisting of O, N and S, optionally containing 1 to 2 carbonyls, wherein the carbon atom of said carbonyl is a member of said 4 to 6 membered heterocycle;
(iii) C3-7cycloalkyl;
(iv) carbazolyl, fluorenyl, phenyl, —O-phenyl, —O—C1-4alklylene-phenyl, or napthyl;
or
(v) C1-8alkyl, C2-7alkenyl, —C(O)R3′, CHC(O)O—R3′, CH(CH3)C(O)O—R3′, —C(O)O—R3′ or C2-7alkynyl;
and
wherein R3a is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, —O-phenyl, —O—C1-3alkylenephenyl, —C1-3alkylene-OC(O)-phenyl, cyano, amino, nitro, halo, C1-6alkyl, C1-3mono-bi-tri-haloalkyl, C1-3mono-bi-tri-haloalkyloxy, (C1-3 alkyl)1-2amine, —OR3′, —C(O)R3′, —C(O)O—R3′, —O—C(O)R3′, —N(R3′)2, —C(O)N(R3′)2, —N(R3′)C(O)(R3′)2, —N(R3′)C(O)N(R3′)2, —N(R3′)C(O)OR3′, —O—C(O)N(R3′)2, —N(R3′)SO2R3′, —SO2N(R3′)2 and —SO2R3′;
R3′ is H or —C1-6alkyl;
provided that if R3a is, —C(O)R3′, CHC(O)O—R3′, CH(CH3)C(O)O—R3′ or —C(O)O—R3′, then said —C(O)R3′, CHC(O)O—R3′, CH(CH3)C(O)O—R3′ or —C(O)O—R3′ are unsubstituted;
R3b is R3a but is not phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol -3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl;
optionally substituted in the carbon skeleton with mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by branched or unbranched alkyl groups, C3-8-cycloalkyl groups, phenylalkyl groups, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkoxy, hydroxy, nitro, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, methylsulphonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups;
wherein said substituents may be the same or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom, or by an alkyl, trifluoromethyl, amino or acetylamino group;
D is O, NCN or NSO2C1-3alkyl;
A is C;
m and n are each 1;
E is N, CH or C;
p is 0;
G, J and E together form Ax;
Ax is a fused heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to four of the same or different heteroatoms selected from the group consisting of O, N and S;
and
optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of said fused heterocycle;
and further provided that
if Q is Q″, then R3 is R3a;
and
if Q is Q′, then
R3 is R3b.

59 more elements

Anti-migraine spirocycles

Life of this patent

Anti-migraine spirocycles

Life of this patent

Abstract

Claims36