Bicyclic imidazole derivatives, the preparation thereof and their use as pharmaceutical compositions
The present invention relates to bicyclic imidazole compounds of general formula wherein R 1 to R 3 and A are defined as in claims 1 to 8 , the tautomers, the enantiomers, the stereoisomers, the mixtures thereof and the salts thereof, which have valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).
1. Compounds of general formula
wherein
R 1 denotes a pyridinyl, phenylpyridinyl, (pyridinylphenyl)carbonyl, quinolinyl, phenylquinolinyl, isoquinolinyl, phenylisoquinolinyl, phenanthridinyl, pyridazinyl, phenylpyridazinyl, (pyridazinylphenyl)carbonyl, pyrimidinyl, phenylpyrimidinyl, (pyrimidinylphenyl)carbonyl, (pyrazinylphenyl)carbonyl, quinolinyl, phenylquinolinyl, quinazolinyl, phenylquinazolinyl, phthalazinyl, phenyl -phthalazinyl, quinoxalinyl, phenylquinoxalinyl, naphthyridinyl or phenylnaphthyridinyl substituted by the groups R 10 to R 12 , while at least one nitrogen atom of the above-mentioned groups is substituted by an oxygen atom, and R 10 denotes hydrogen, fluorine, chlorine, bromine, or iodine, C 1-4 -alkyl, hydroxyl, C 1-4 -alkyloxy, nitro, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, C 1-3 -alkyl-carbonylamino, N—(C 1-3 -alkyl)—C 1-3 -alkyl-carbonylamino, C 1-3 -alkylsulphonylamino, N—(C 1-3 -alkyl)—C 1-3 -alkyl-sulphonylamino, C 1-3 -alkyl-carbonyl, cyano, aminocarbonyl, (C 1-3 -alkylamino)carbonyl, [di-(C 1-3 -alkyl)amino]carbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, methyl, methoxy substituted by 1 to 3 fluorine atoms, C 1-3 -alkylsulphanyl, C 1-3 -alkylsulphinyl, C 1-3 -alkylsulphonyl, C 2-4 -alkenyl, C 2-4 -alkynyl group, C 3-4 -alkenyloxy, C 3-4 -alkynyloxy, C 3-6 -cycloalkyl, C 3-6 -cycloalkyloxy, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 3-6 -cycloalkyl-C 1-3 -alkyloxy, aryl, aryloxy, aryl-C 1-3 -alkyl, or aryl-C 1-3 -alkyloxy, and R 11 and R 12 , which may be identical or different, represent hydrogen, fluorine, chlorine, bromine, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, or cyano,
R 2 denotes 2-methyl-2-propen-1-yl, 2-chloro-2-propen-1-yl, or 3-bromo-2-propen-1-yl, 1-buten-1-yl, 3-methyl-1-buten-1-yl, 3-methyl-2-buten-1-yl, 2-buten-1-yl, 2-methyl-2-buten-1-yl, 2,3-dimethyl-2-buten-1-yl, 2-butyn-1-yl, 1-cyclopenten-1-ylmethyl, benzyl, 2-fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl-, or 2-cyanobenzyl,
R 3 denotes 3-aminopiperidin-1-yl, 3-amino-azepan-1-yl, piperazin-1-yl, [1,4]-diazepan-1-yl, or an amino group substituted by the groups R 4 and R 5 , wherein R 4 denotes a methyl or ethyl group and R 5 denotes a 2-aminoethyl group, while the ethyl moiety of the 2-aminoethyl group may be substituted by one or two methyl groups,
A denotes a —CO—N(R 6 )— group, while the nitrogen atom of this group is linked to the imidazo ring of general formula I, and R 6 denotes hydrogen, C 1-4 -alkyl, C 3-6 -cycloalkyl, or an aryl group, or A denotes —CH═CH— substituted by R 6 , where R 6 is as hereinbefore defined, or A denotes —C(R 7 )═N—, where the nitrogen atom of this group is linked to the imidazo ring of general formula I, and R 7 denotes hydrogen, C 1-4 -alkyl, C 3-6 -cycloalkyl, or an aryl group, or A denotes —N═C(R 7 ), while the carbon atom of this group is linked to the imidazo ring of general formula I, and R 7 is as hereinbefore defined,
while by the aryl groups mentioned in the definition of the above groups is meant a phenyl group substituted by R 10 and R 11 as hereinbefore defined,
and the above-mentioned alkyl and alkenyl groups may be straight-chain or branched,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.
2. Compounds of general formula I according to claim 1 , wherein
R 1 denotes a pyridinyl, phenylpyridinyl, (pyridinylphenyl)carbonyl, quinolinyl, phenylquinolinyl, isoquinolinyl, phenylisoquinolinyl, phenanthridinyl, pyrimidinyl, phenylpyrimidinyl, (pyrimidinylphenyl)carbonyl, quinazolinyl, phenylquinazolinyl, quinoxalinyl, phenylquinoxalinyl, or naphthyridinyl substituted by the groups R 10 and R 11 , while at least one nitrogen atom of the above-mentioned groups is substituted by oxygen, and R 10 and R 11 , which may be identical or different, denote hydrogen, fluorine, chlorine, bromine, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, or cyano,
R 2 denotes a 2-butyn-1-yl group,
R 3 denotes a 3-aminopiperidin-1-yl, piperazin-1-yl or [1,4]-diazepan-1-yl group, or an amino group substituted by the groups R 4 and R 5 , wherein R 4 denotes methyl or ethyl, and R 5 denotes 2-aminoethyl, while the ethyl moiety of the 2-aminoethyl group may be substituted by one or two methyl groups,
A denotes —CO—N(R 6 ), while the nitrogen atom of this group is linked to the imidazo ring of general formula I, and R 6 denotes methyl, ethyl, propyl, isopropyl, cyclopropyl, or phenyl, or A denotes —N═C(R 7 )—, while the carbon atom of this group is linked to the imidazo ring of general formula I, and R 7 denotes hydrogen or methyl,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.
3. Compounds of general formula I according to claim 1 , wherein
R 1 denotes a phenylpyridinyl, quinolinyl, isoquinolinyl, phenanthridinyl, phenylpyrimidinyl, quinazolinyl, quinoxalinyl, or naphthyridinyl substituted by the groups R 10 and R 11 , while the nitrogen atom of the above-mentioned groups is substituted by an oxygen atom , and R 10 denotes hydrogen, methyl, methoxy, or cyano, and R 11 denotes hydrogen or methyl,
R 2 denotes 2-butyn-1-yl,
R 3 denotes 3-aminopiperidin-1-yl, piperazin-1-yl, or [1,4]-diazepan-1-yl group, or an amino group substituted by the groups R 4 and R 5 , wherein R 4 denotes methyl and R 5 denotes 2-aminoethyl, while the ethyl moiety of the 2-aminoethyl group may be substituted by one or two methyl groups,
A denotes —CO—N(R 6 )—, while the nitrogen atom of this group is linked to the imidazo ring of general formula I, and R 6 denotes methyl, ethyl, isopropyl, cyclopropyl, or
phenyl, or A denotes —N═C(R 7 )—, while the carbon atom of this group is linked to the imidazo ring of general formula I, and R 7 denotes hydrogen or methyl,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.
4. Compounds according to general formula 1 of claim 1 wherein R 3 denotes 3-aminopiperidin-1-yl, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.
5. Compounds according to general formula 1 of claim 1 , wherein R 3 denotes piperazin-1-yl, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.
6. Compounds according to general formula 1 of claim 1 , wherein R 3 denotes [1,4]-diazepan-1-yl, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.
7. Compounds of general formula I according to claim 1 , wherein
R 1 is chosen from quinolinyl, isoquinolinyl, methylisoquinolinyl, phenanthridinyl, quinazolinyl, or methyiquinazolinyl, while the nitrogen atom of the above-mentioned groups is substituted by an oxygen atom, or a quinoxalinyl, wherein both nitrogen atoms are substituted by oxygen atoms,
R 2 denotes 2-butyn-1-yl,
R 3 denotes 3-aminopiperidin-1-yl or piperazin-1-yl,
A denotes —CO—N(R 6 )—, while the nitrogen atom of this group is linked to the imidazo ring of general formula I, and R 6 denotes a methyl group, or A denotes —N═C(R 7 )—, while the carbon atom of this group is linked to the imidazo ring of general formula I, and R 7 denotes hydrogen,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.
8. The following compounds of general formula I according to claim 1 chosen from:
(a) 1-[(4-methyl-3-oxy-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
(b) 1-[(1-oxy-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
(c) 1-[(3-methyl-2-oxy-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
(d) 1-[(5-oxy-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
(e) 1-[(3-oxy-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
(f) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(1-oxy-quinolin-2-yl)methyl)]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
(g) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(3-oxy-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
(h) 2-(piperazin-1-yl)-3-(2-butyn-1-yl)-5-[(4-methyl-3-oxy-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
(i) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(4-methyl-3-oxy-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
(j) 1-[(2-oxy-isoquinolin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine and
(k) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1 -yl)-5-(2-oxy-isoquinolin-3-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
as well as the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.
9. Physiologically acceptable salts of the compounds of general formula I according to claim 1 with inorganic or organic acids.
10. A pharmaceutical composition comprised of a compound of general formula I according to claim 1 or a physiologically acceptable salt thereof optionally together with one or more inert carriers and or diluents.
11. A method of treating a disease, disorder, or condition chosen from type I and II diabetes mellitus, obesity, and calcitonin-induced osteoporosis comprised of the steps of administering to a patient in need therof a therapeutically effective amount of a compound of general formula I according to claim 1 .
12. Process for preparing a pharmaceutical composition of general formula I according to claim 1 , comprised of the steps of incorporating said compound into one or more inert carriers and/or diluents by a non-chemical method.
13. Process for preparing the compounds of general formula I according to claim 1 , comprised of the step of reacting
a compound of general formula
wherein
R 1 , R 2 and A are defined as mentioned in claim 1 and
Z 1 denotes a leaving group such as a halogen atom, a substituted hydroxy,
mercapto, sulphinyl, sulphonyl or sulphonyloxy group,
with R 3 -H, the enantiomers or the salts thereof, where R 3 is as hereinbefore defined.
14. Process for preparing the compounds of general formula I according to claim 1 , comprised of the step of deprotecting
a compound of general formula
wherein R 1 , R 2 and A are defined as defined in claim 1 , and R 3′ denotes one of the groups mentioned in the definition of R 3 hereinbefore wherein the amino or imino group is protected by a protecting group;
and optionally cleaving any protecting groups used during the reaction;
and optionally resolving the compounds of general formula I thus obtained are into their enantiomers and/or diastereomers;
and optionally converting the compounds of general formula I into physiologically acceptable salts thereof with inorganic or organic acids.