Patent EA-005137-B1 (EA)
Title: Novel cyclopropanes as cgrp antagonists
Inventor: EBERLEIN WOLFGANG
IPC: C07D471/04
Filed: 2000-10-21
Abstract: 1. Cyclopropanes of general formula (I) wherein: R denotes a mono unsaturated 5- to 7-membered diaza- or a thiadiaza heterocyclic group, whilst the above-mentioned heterocyclic groups are linked via a nitrogen atom and may contain a carbonyl group adjacent to a nitrogen atom, may be substituted at a carbon atom by a phenyl group or wherein an olefinic double bond of one of the above-mentioned unsaturated heterocyclic groups may be fused with a benzene, pyridine or quinoline ring, and contained in R phenyl groups, and the benzo, pyrido-fused heterocyclic groups in the carbon skeleton may additionally be mono- di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl, dialkylaminoalkoxy, nitro-, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkoxy-, hydroxycarbonylalkoxy-, carboxy-, hydroxy-, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, [N-alkyl-N-(dialkylaminoalkyl)amino]carbonyl, [(hydroxycarbonylalkyl)amino]carbonyl, [(alkoxycarbonylalkyl)amino]carbonyl, alkanoyl or trifluoromethoxy groups, by 5- to 7-membered alkyleneimino groups wherein a methylene group in the 3-or 4 position may be replaced by an oxygen atom or a methylimino group, for example 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl, 4-methyl-1,4-diazacyclohept-1-yl or 4-morpholinyl groups, alkoxy groups, which are in the omega position by a 5- to 7-membered heteroalicyclic group, where the heteroalicyclic group is linked via a carbon atom and in the position 2 and 2' contains an oxygen atom or linked via a carbon or nitrogen atom and contains one or two heteroatoms not directly connected separated from each other by at least one methylene group, for example methoxy-, ethoxy-, propoxy-, 2,5-dioxacyclopenthylmethoxy, 2,6-dioxacyclohexylmethoxy-, 2-(1-pyrrolidinyl)ethoxy-, 2-(1-piperidinyl)ethoxy-, 2-(4-methyl-1-piperazinyl)ethoxy- or 2-(4-morpholinyl)ethoxy groups, while multiple substitution by cyclic groups or those groups which contain a carbocyclic or heterocyclic group is excluded and wherein the substituents may be identical or different, and R<1> denotes a phenyl, which can be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, alkoxy, trifluoromethyl, nitro-, hydroxy- or amino groups, and the substituents may be identical or different, and all the above-mentioned alkyl and alkoxy groups and the alkyl or alkylene moieties present within the other groups specified may contain 1 to 3 carbon atoms, unless otherwise stated, the tautomers, diastereomers, enantiomers, mixtures thereof and the salts thereof. 2. Compounds of general formula I according to claim 1, wherein R denotes a 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl, 3,4-dihydro-2(1H)-oxopyrido[4,3-d]-pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl or 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl group, wherein the above-mentioned mono- and bicyclic heterocyclic groups may be mono- or disubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or may be monosubstituted by a 4-methyl-1-piperazinyl, 2,5-dioxacyclopentylmethoxy, methoxy, 2-(4-morpholinyl)ethoxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, methoxycarbonylmethoxy, hydroxycarbonylmethoxy, nitro, trifluoromethyl, methoxycarbonyl, carboxy, hydroxy, aminocarbonyl, diethylaminocarbonyl, [N-(2-dimethylaminoethyl)-N-methylamino]carbonyl, [(methoxycarbonylmethyl)amino]carbonyl or [(hydroxycarbonylmethyl)amino]carbonyl group, and R<1> denotes a phenyl group, which may be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by hydroxy or amino groups, wherein the substituents may be identical or different, for example the 4-chlorophenyl, 4-amino-3,5-dibromophenyl or 3,5-dibromo-4-hydroxyphenyl group, the tautomers, diastereomers, enantiomers and salts thereof. 3. Compounds of general formula I according to claim 1selected from the group of: (1) cis-3-{1-[2-(4-Chlorbenzoyl)-cyclopropancarbonyl]-4-pipridinyl}-3,4-dihydro-2(1H)-quinazolinon, (2) trans-1-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-1,3-dihydro-4-(3-methoxyphenyl)-2(2H)imidazolon. (3) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinon, (4) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-6-brom-3,4-dihydro-2(1H)-quinazolinon, (5) trans-1-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2(2H)-imidazolon, (6) trans-1-{1-[2-(4-Amino-3,5-dibrombenzoyl}-cyclopropancarbonyl]-4-piperidinyl}-1,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)-imidazolon, (7) trans-1-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-1,3-dihydro-4-(3-hydroxyphenyl)-2(2H)imidazolon, (8) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-3,4-dihydro-6-hydroxy-2(1H)-quinazolinon, (9) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-3,4-dihydro-6-[(1,3-dioxolan-2-yl)methoxy]-2(1H)-quinazolinon, (10) trans-1-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-4-(3,4-dichlorphenyl)-1,3-dihydro-2(2H)imidazolon, (11) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-pyrido[4,3-d]pyrimidinon, (12) trans-1-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-1,3-dihydro-4-(2-methoxyphenyl)-2(2H)imidazolon, (13) trans-1-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-4-(3-chlorophenyl)-1,3-dihydro-2(2H)imidazolon, (14) trans-1-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-1,3-dihydro-4-(3-nitrophenyl)-2(2H)imidazolon, (15) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-pyrido[3,4-d]pyrimidinon, (16) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-3,4-dihydro-6-[2-(dimethylamino)ethoxy]-2(1H)-chinazolinon, (17) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-3,4-dihydro-6-(4-methyl-1-piperazinyl)-2(1H)-quinazolinon, (18) trans-1-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-1,3-dihydro-4-[2-(trifluormethyl)phenyl]-2(2H)-imidazolon, (19) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-3,4-dihydro-6-[3-(dimethylamino)propoxy]-2(1H)-quinazolinon, (20) trans-3-{1-[2-(3,5-Dibrom-4-hydroxybenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinon, (21) trans-1-{1-[2-(3,5-Dibrom-4-hydroxybenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2(2H)-imidazolon, (22) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-3,4-dihydro-6-(methoxycarbonylmethoxy)-2(1H)-quinazolinon, (23) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-3,4-dihydro-6-(hydroxycarbonylmethoxy)-2(1H)-quinazolinon, 24) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-3,4-dihydro-6-[2-(4-morpholinyl)ethoxy]-2(1H)-quinazolinon, (25) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-3,4-dihydro-7-methoxy-2(1H)-quinazolinon, (26) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-3,4-dihydro-7-(methoxycarbonylmethoxy)-2(1H)-quinazolinon, (27) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-7-carboxy-3,4-dihydro-2(1H)-quinazolinon, (28) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-7-methoxycarbonyl-3,4-dihydro-2(1H)-quinazolinon, (29) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-1,3-dihydro-2(2H)-imidazo[4,5-c]quinolinon, (30) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-3,4-dihydro-7-{[(methoxycarbonylmethylamino]carbonyl}-2(1H)-quinazolinon, (31) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-3, 4-dihydro-7-{[N-(2dimethylaminoethyl)-N-methylamino] carbonyl}-2 (1H)-quinazolinon, (32) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-7-diethylaminocarbonyl-3,4-dihydro-2(1H)-quinazolinon, (33) trans-7-Aminocarbonyl-3-{1-[2-(4-amino-3,5-dibrombezoyl)-cyclopropancarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)quinazolinon, (34) trans-3-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-3,4-dihydro-7-{[(hydroxycarbonylmethylamino] carbonyl}-2 (1H)-quinazolinon, (35) trans-1-{1-[2-(4-Amino-3,5-dibrombenzoyl)-cyclopropancarbonyl]-4-piperidinyl}-2,4-dihydro-5-phenyl-3(3H)-1,2,4-triazolon, and salts thereof. 4. Compounds of general formula I according to claim 1 comprising: (a) traps-1-(1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-imidazolone, (b) traps-3-(1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone, (c) traps-1-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2(2H)-imidazolone, (d) traps-1-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-(3-hydroxyphenyl)-2(2H)-imidazolone, (e) traps-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-hydroxy-2(1H)-quinazolinone, (f) traps-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-[(1,3-dioxolan-2-yl)methoxy]-2(1H)-quinazolinone, (g) traps-1-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropanecarbonyl]-4-piperidinyl}-4-(3-chlorophenyl)-1,3-dihydro-2(2H)-imidazolone, (h) traps-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-[3-(dimethylamino)propoxy]-2(1H)-quinazolinone, (i) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-(methoxycarbonylmethoxy)-2(1H)-quinazolinone, (j) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)-