US 7,479,488 B2 · Selected CGRP—antagonists, process for preparing them and their use as pharmaceutical compositions

Abstract

The present invention relates to the CGRP antagonists of general formula wherein A, X, D, E, G, M, Q and R1 to R3 are defined as in claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates thereof, the mixtures thereof and the salts thereof and the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids, pharmaceutical compositions containing these compounds, the use thereof and processes for the preparation thereof.

A compound of the formula I

wherein
A denotes an oxygen or sulphur atom,
X denotes an oxygen or sulphur atom,
(a) D, E independently of one another in each case denote a methyne group or the nitrogen atom and
G denotes a methyne group substituted by the group Ra,
M denotes a methyne group substituted by the group Rb,
Q denotes a methyne group substituted by the group Rc,
while one or two of the groups G, M and Q in each case may also represent a nitrogen atom,
or
(b) D and E in each case denote a methyne group, while one of the groups D and E may also represent a nitrogen atom, and
G, M and Q in each case denote a nitrogen atom,
while Ra, Rb and Rc independently of one another in each case denote a hydrogen or halogen atom, a C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, cyclo-C3-7-alkyl, cyclo-C3-7-alkenyl, cyano, hydroxy, hydroxy-C1-6-alkyl, hydroxy-C3-6-alkenyl, hydroxy-C3-6-alkynyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxy-C3-6-alkenyl, C1-6-alkoxy-C3-6-alkynyl, C3-6-alkenoxy-C1-6-alkyl, C3-6-alkenoxy-C3-6-alkenyl, C3-6-alkenoxy-C3-6-alkynyl, C3-6-alkynoxy-C1-6-alkyl, C3-6-alkynoxy-C3-6-alkenyl, C3-6-alkynoxy-C3-6-alkynyl, thiohydroxy, C1-6-alkylthio, C3-6-alkenylthio, C3-6-alkynylthio, amino, C1-6-alkyl-amino, C3-6-alkenyl-amino, C3-4-alkynyl-amino, di-(C1-6-alkyl)-amino, di-(C3-6-alkenyl)-amino, di-(C3-6-alkynyl)-amino, amino-C1-6-alkyl, C1-3-alkyl-amino-C1-6-alkyl, di(C1-3-alkyl)-amino-C1-6-alkyl, amino-C3-6-alkenyl, C1-3-alkyl-amino-C3-6-alkenyl, di-(C1-3-alkyl)-amino-C3-6-alkenyl, amino-C3-6-alkynyl, C1-3-alkyl-amino-C3-6-alkynyl, di-(C1-3-alkyl)-amino-C3-6-alkynyl, hydroxycarbonyl, phenylcarbonyl, pyridylcarbonyl, C1-6-alkyl-carbonyl, C2-6-alkenyl-carbonyl, C2-6-alkynyl-carbonyl, formyl, C1-6-alkoxy-carbonyl, C3-6-alkenoxy-carbonyl, C3-6-alkynoxy-carbonyl, aminocarbonyl, C1-6-alkyl-aminocarbonyl, C3-6-alkenyl-aminocarbonyl, C3-6-alkynyl-aminocarbonyl, di-(C1-6-alkyl)-aminocarbonyl, di-(C3-6-alkenyl)-aminocarbonyl, di-(C3-6-alkynyl)-aminocarbonyl, formylamino, C1-6-alkyl-carbonylamino, C2-6-alkenyl-carbonylamino, C2-6-alkynyl-carbonylamino, formyl-C1-6-alkyl-amino, formyl-C3-6-alkenyl-amino, formyl-C3-6-alkynyl-amino, C1-6-alkyl-carbonyl-C1-6-alkyl-amino, C2-6-alkenyl-carbonyl-C1-6-alkyl-amino, C2-6-alkynyl-carbonyl-C1-6-alkyl-amino, C1-6-alkyl-carbonyl-C3-6-alkenyl-amino, C2-6-alkenyl-carbonyl-C3-6-alkenyl-amino, C2-6-alkynyl-carbonyl-C3-6-alkenyl-amino, C1-6-alkyl-carbonyl-C3-6-alkynyl-amino, C2-6-alkenyl-carbonyl-C3-6-alkynyl-amino, C2-6-alkynyl-carbonyl-C3-6-alkynyl-amino, C1-6-alkyl-sulphonyl, C2-6-alkenyl-sulphonyl, C2-6-alkynyl-sulphonyl, C1-6-alkyl-sulphinyl, C2-6-alkenyl-sulphinyl, C2-6-alkynyl-sulphinyl, C1-6-alkyl-sulphonylamino, C2-6-alkenyl-sulphonylamino, C2-6-alkynyl-sulphonylamino, C1-6-alkyl-sulphonyl-C1-6-alkylamino, C1-6-alkyl-sulphonyl-C3-6-alkenylamino, C1-6-alkyl-sulphonyl-C3-6-alkynylamino, C2-6-alkenyl-sulphonyl-C1-6-alkylamino, C2-6-alkenyl-sulphonyl-C3-6-alkenylamino, C2-6-alkenyl-sulphonyl-C3-6-alkynylamino, C2-6-alkynyl-sulphonyl-C1-6-alkylamino, C2-6-alkynyl-sulphonyl-C3-6-alkenylamino, C2-6-alkynyl-sulphonyl-C3-6-alkynylamino, aminosulphonyl, C1-6-alkylaminosulphonyl, di-(C1-6-alkyl)-aminosulphonyl, C3-6-alkenylaminosulphonyl, di-(C3-6-alkenyl)-aminosulphonyl, C3-6-alkynylaminosulphonyl or di-(C3-6-alkynyl)-aminosulphonyl group
with the provisos that, if none of the groups D, E, G, M and Q denotes a nitrogen atom,
(i) Ra does not denote a hydrogen atom, if both Rb and Rc in each case denote a C1-6-alkyl group,
(ii) Rc does not denote a hydrogen atom if both Ra and Rb in each case denote a C1-6-alkyl group,
(iii) Ra does not take on the meanings of a hydrogen, fluorine, chlorine, bromine or iodine atom or a difluoro- or trifluoromethyl group if Rc denotes a C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl group and Rb denotes a chlorine or bromine atom, an amino, methylamino or hydroxy group,
(iv) Rc does not take on the meanings of a hydrogen, fluorine, chlorine, bromine or iodine atom or a difluoro- or trifluoromethyl group if Ra denotes a C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl group and Rb denotes a chlorine or bromine atom, an amino, methylamino or hydroxy group,
R1 denotes a 1,3,4,5-tetrahydro-1,3-benzodiazepin-2-on-3-yl group,
R2 denotes the hydrogen atom,
a phenylmethyl group or a C2-7-alkyl group which may be substituted in the ω position by a cyclo-C3-7-alkyl, cyclo-C3-7-alkenyl, phenyl, pyridinyl, diazinyl, hydroxy, amino, C1-6-alkylamino, di-(C1-6-alkyl)-amino, C3-6-alkenylamino, di-(C3-6-alkenyl)amino, C3-6-alkynylamino, di-(C3-6-alkynyl)amino, hydroxycarbonyl, C1-6-alkoxycarbonyl, aminocarbonyl, aminocarbonylamino, C1-6-alkylcarbonylamino, C2-6-alkenylcarbonylamino, C2-6-alkynylcarbonylamino, 4-morpholinyl, [bis-(2-hydroxyethyl)]amino, 4-(C1-6-alkyl)-1-piperazinyl or 4-(ω-hydroxy-C2-7-alkyl)-1-piperazinyl group,
a phenyl or pyridinyl group,
while the phenyl, pyridinyl and diazinyl groups mentioned in the groups defined hereinbefore for R2 or contained as substituents may additionally be mono-, di- or trisubstituted in the carbon skeleton by halogen, by C1-3-alkyl, C2-3-alkenyl, C2-3-alkynyl, C1-3-alkoxy, hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, amino-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, C1-3-alkylcarbonylamino, C1-3-alkylcarbonylamino-C1-3-alkyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, cyano, aminosulphonyl, C1-3-alkyl-aminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, C1-3-alkyl-thio, C1-3-alkyl-sulphinyl or C1-3-alkyl-sulphonyl and the substituents may be identical or different,
R3 denotes the hydrogen atom or a C1-3-alkyl group substituted by a phenyl or pyridinyl group,
while the C1-3-alkyl group may be connected to an alkyl group contained in R2 or to a phenyl or pyridyl ring contained in R2 including the nitrogen atom to which R2 and R3 are bound, forming a 4- to 7-membered ring,
or
R2 and R3 together with the enclosed nitrogen atom denote a group of the formula II
wherein
Y1 denotes the carbon atom or, if R5 denotes a pair of free electrons, it may also denote the nitrogen atom,
q and r, if Y1 denotes the carbon atom, denote the numbers 0, 1 or 2, or
q and r, if Y1 denotes the nitrogen atom, denote the numbers 1 or 2,
R4 denotes the hydrogen atom, an amino, C1-4-alkyl-amino, di-(C1-4-alkyl)-alkylamino, C1-6-alkyl, a cyclo-C3-7-alkyl or cyclo-C3-7-alkenyl group optionally substituted by a hydroxycarbonyl, C1-6-alkoxycarbonyl, hydroxycarbonyl-C1-3-alkyl or C1-6-alkoxycarbonyl-C1-3-alkyl group, an amino-C2-7-alkyl, C1-4-alkyl-amino-C2-7-alkyl, di-(C1-4-alkyl-amino)-C2-7-alkyl, aminoiminomethyl, aminocarbonylamino, C1-4-alkyl-aminocarbonylamino, di-(C1-4-alkyl)-aminocarbonylamino, C1-4-alkyl-aminocarbonyl-C1-4-alkyl-amino, di-(C1-4-alkyl)-aminocarbonyl-C1-4-alkyl-amino, phenylaminocarbonylamino, aminocarbonyl, C1-4-alkyl-aminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl, aminocarbonyl-C1-3-alkyl, C1-4-alkyl-aminocarbonyl-C1-3-alkyl, di-(C1-4-alkyl)-aminocarbonyl-C1-3-alkyl, aminocarbonylamino-C1-3-alkyl, C1-6-alkoxycarbonyl, C3-6-alkenoxycarbonyl, C3-6-alkynoxycarbonyl, C1-6-alkoxycarbonyl-C1-3-alkyl, C1-6-alkenoxycarbonyl-C1-3-alkyl, C1-6-alkynoxycarbonyl-C1-3-alkyl or hydroxycarbonyl-C1-3-alkyl group,
a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl or phenylcarbonyl group which may be mono-, di- or trisubstituted in each case in the carbon skeleton by halogen, by C1-3-alkyl, C2-3-alkenyl, C2-3-alkynyl, C1-3-alkoxy, hydroxy, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, amino-C1-3-alkyl, C1-4-alkyl-amino-C1-3-alkyl, di-(C1-4-alkyl)-amino-C1-3-alkyl, C1-4-alkylcarbonylamino, C1-4-alkylcarbonylamino-C1-3-alkyl, aminocarbonyl, C1-4-alkyl-aminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl, cyano, aminosulphonyl, C1-4-alkyl-aminosulphonyl, di-(C1 -4-alkyl)-aminosulphonyl, C1-4-alkyl-thio, C1-4-alkyl-sulphinyl, or C1-4-alkyl-sulphonyl and the substituents may be identical or different,
a heterocycle selected from a 4- to 10-membered azacycloalkyl group, a 6- to 10-membered oxaza-, thiaza-, S,S-dioxothiaza- and diazacycloalkyl group and a 6- to 10-membered azabicycloalkyl group,
a 1-alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl group,
while the above-mentioned mono- and bicyclic heterocycles are bound to Y1 in formula (II) via a nitrogen or a carbon atom,
in the above-mentioned mono- and bicyclic heterocycles a methyne group not directly linked to a nitrogen, oxygen or sulphur atom may be substituted by a fluorine atom and a methylene group not directly linked to a nitrogen, oxygen or sulphur atom may be substituted by one or two fluorine atoms,
the above-mentioned mono- and bicyclic heterocycles and the 1-(C1-6-alkyl)-4-piperidinylcarbonyl and 4-(C1-6-alkyl)-1-piperazinylcarbonyl group in the ring may be mono- to tetrasubstituted by hydroxy, C1-6-alkyl or hydroxy-C1-3-alkyl groups, or, optionally additionally, monosubstituted by a cyclo-C3-7-alkyl, hydroxy-C3-7-cycloalkyl, cyclo-C3-7-alkenyl, cyclo-C3-7-alkyl-C1-3-alkyl, phenyl-C1-3-alkyl, pyridyl-C1-3-alkyl, C1-6-alkylcarbonyl, C1-6-alkylcarbonyl-C1-3-alkyl, hydroxy, C1-6-alkoxy, amino, C1-4-alkylamino, di-(C1-4-alkyl)amino, phenylcarbonyl, pyridinylcarbonyl, C1-6-alkoxycarbonyl, hydroxycarbonyl-carbonyl, C1-6-alkoxycarbonyl-carbonyl, hydroxycarbonyl-C1-3-alkyl, C1-6-alkoxycarbonyl-C1-3-alkyl, hydroxycarbonyl-C1-3-alkylcarbonyl, C1-6-alkoxycarbonyl-C1-3-alkylcarbonyl, aminocarbonyl, C1-4-alkylaminocarbonyl, di-(C1-4-alkyl)aminocarbonyl, aminosulphonyl, C1-4-alkylaminosulphonyl, di-(C1-4-alkyl)aminosulphonyl, C1-3-alkylsulphonyl, cyclo-C3-7-alkylsulphonyl, aminocarbonyl-C1-3-alkyl, C1-4-alkylaminocarbonyl-C1-3-alkyl, di-(C1-4-alkyl)aminocarbonyl-C1-3-alkyl, hydroxyaminocarbonyl-C1-3-alkyl, C1-3-alkoxyaminocarbonyl-C1-3-alkyl or hydroxy-(C1-3-alkyl)-aminocarbonyl-C1-3-alkyl group, by a cyclo-C3-7-alkyl-carbonyl, azacyclo-C4-7-alkyl-carbonyl, diazacyclo-C5-7-alkyl-carbonyl or oxazacyclo-C5-7-alkyl-carbonyl group optionally C1-3-alkyl-substituted in the ring, while the substituents may be identical or different and may be bound to a cyclic carbon or cyclic nitrogen atom,
while the phenyl and pyridinyl groups contained in the groups defined above for R4 may in turn be mono-, di- or trisubstituted by halogen atoms, by C1-3-alkyl, C2-3-alkenyl, C2-3-alkynyl, C1-3-alkoxy, hydroxy, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, amino-C1-3-alkyl, C1-4-alkyl-amino-C1-3-alkyl, di-(C1-4-alkyl)-amino-C1-3-alkyl, C1-4-alkylcarbonylamino, C1-4-alkylcarbonylamino-C1-3-alkyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-C1-4-alkyl-aminocarbonyl, cyano, aminosulphonyl, C1-4-alkyl-aminosulphonyl, di-(C1-4-alkyl)-aminosulphonyl, C1-3-alkyl-thio, C1-3-alkyl-sulphinyl, or C1-3-alkyl-sulphonyl, while the substituents may be identical or different,
or also, if Y1 denotes the carbon atom, the hydroxycarbonyl, aminomethyl, C1-4-alkyl-aminomethyl or di-(C1-4-alkyl)-aminomethyl group,
R5 denotes a hydrogen atom or a hydroxy group,
a C1-4-alkyl group, while an unbranched alkyl group may be substituted in the ω position by a phenyl, pyridinyl, diazinyl, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, 4-C1-4-alkyl-1-piperazinyl or 4-morpholinyl group,
a C1-6-alkoxycarbonyl, cyano or aminocarbonyl group or also, if Y1 denotes a nitrogen atom, a pair of free electrons,
or, if Y1 denotes the carbon atom, it may also denote the fluorine atom, or
R4 together with R5 and Y1 denote a 4- to 7-membered cycloaliphatic ring wherein a methylene group may be replaced by a group —NH—, —N(C1-4-alkyl)-, —N(C3-4-alkenyl)-, —N(C3-4-alkynyl)-, —N(cyclo-C3-7-alkyl)-, —N(C3-7-cycloalkyl-C1-3-alkyl)-, —N(hydroxycarbonyl-C1-3-alkyl)— or —N(C1-6-alkoxycarbonyl-C1-3-alkyl)-,
while a hydrogen atom bound to a nitrogen atom in one of the groups defined for R4 hereinbefore may be replaced by a protecting group,
R6 and R7, which may be identical or different, in each case denote a hydrogen atom, a C1-4-alkyl group or also, if Y1 denotes a carbon atom, the fluorine atom, an amino, C1-4-alkylamino or di-(C1-4-alkyl)-amino group, while the two C1-4-alkyl groups may be joined together, forming a ring and
R8 and R9, which may be identical or different, in each case denote a hydrogen atom or a C1-3-alkyl group,
while, unless otherwise stated, all the alkyl, alkenyl and alkynyl groups mentioned or contained in the groups defined hereinbefore may be straight-chain or branched, every methyne group contained in the groups defined hereinbefore may be substituted by a fluorine atom, every methylene group may be substituted by up to 2 fluorine atoms and every methyl group may be substituted by up to 3 fluorine atoms and two alkyl and alkenyl groups bound to a nitrogen atom may be joined together forming a 4- to 7-membered, saturated or unsaturated heterocyclic ring,
all the aromatic and heteroaromatic groups mentioned or contained in the groups defined hereinbefore may additionally be mono-, di- or trisubstituted by halogen, by cyano or hydroxy groups and the substituents may be identical or different and
wherein a protecting group may be
a phenylalkoxycarbonyl group with 1 to 3 carbon atoms in the alkoxy moiety, optionally substituted in the phenyl nucleus by a halogen atom, by a nitro or phenyl group or by one or two methoxy groups,
an alkoxycarbonyl group with a total of 1 to 5 carbon atoms in the alkyl moiety,
the allyloxycarbonyl, 2,2,2-trichloro-(1,1-dimethylethoxy)carbonyl or 9-fluorenyl-methoxycarbonyl group or
the formyl, acetyl or trifluoroacetyl group;
or a tautomer or salt thereof.

52 more elements

Selected CGRP—antagonists, process for preparing them and their use as pharmaceutical compositions

Life of this patent

Selected CGRP—antagonists, process for preparing them and their use as pharmaceutical compositions

Life of this patent

Abstract

Claims28