Imidazopyridazinediones, their preparation and their use as pharmaceutical compositions
The invention relates to substituted imidazopyridazinediones of general formula wherein R 1 to R 4 are defined as in claim 1 , the tautomers, the enantiomers, the diastereomers, 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. A method for treating type I or type II diabetes mellitus or obesity, the method comprising the step of administering to a patient a pharmaceutical composition comprising a compound of formula I
wherein
R 1 is:
an arylmethyl group,
a heteroarylmethyl group,
an arylcarbonylmethyl group,
a heteroarylcarbonylmethyl group, or
an arylprop-2-enyl or heteroarylprop-2-enyl group, wherein the propenyl chain may be substituted by 1 to 4 fluorine atoms or a cyano, C 1-3 -alkyloxy-carbonyl or nitro group,
R 2 is:
a C 1-6 -alkyl group,
an aryl or heteroaryl group,
a C 1-6 -alkyl group substituted by a group R a ,
where R a is
a fluorine, chlorine or bromine atom,
a C 3-7 -cycloalkyl group, wherein one or two methylene groups, independently of one another, may each be replaced by an oxygen or sulphur atom or by an —NH or —N(C 1-3 -alkyl)- group, or by a carbonyl, sulphinyl, or sulphonyl group, or
a trifluoromethyl, aryl, heteroaryl, cyano, carboxy, C 1-3 -alkoxy-carbonyl, aminocarbonyl, C 1-3 -alkylamino-carbonyl, or di-(C 1-3 -alkyl)-amino-carbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C 1-3 -alkyl)-piperazin-1-ylcarbonyl, arylcarbonyl, heteroarylcarbonyl, C 1-3 -alkylsulphinyl or C 1-3 -alkylsulphonyl group,
a C 2-6 -alkyl group substituted by a group R b , wherein
R b is isolated from the cyclic nitrogen atom by at least two carbon atoms, and
R b denotes a hydroxy, C 1-3 -alkoxy, C 1-3 -alkylsulphanyl, amino, C 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, or 4-(C 1-3 -alkyl)-piperazin-1-yl group,
a C 3-6 -cycloalkyl group, or
a C 3-6 -alkenyl or C 3-6 -alkynyl group, while the multiple bond is isolated from the cyclic nitrogen atom by at least one carbon atom,
R 3 is
a C 5-7 -cycloalkenylmethyl group optionally substituted by a C 1-3 -alkyl group,
an arylmethyl or heteroarylmethyl group,
a straight-chain or branched C 2-8 -alkenyl group which may be substituted by 1 to 15 fluorine atoms or by a cyano, nitro or C 1-3 -alkoxy-carbonyl group, or
a straight-chain or branched C 3-6 -alkynyl group which may be substituted by 1 to 9 fluorine atoms or by a cyano, nitro or C 2-8 -alkoxy-carbonyl group,
and R 4 is
a pyrrolidin-1-yl or azetedin-1-yl group that is substituted in the 3 position by an amino or C 1-3 -alkylamino group and may additionally be substituted by one or two C 1-3 -alkyl groups,
a piperidin-1-yl or hexahydroazepin-1-yl group which is substituted in the 3 position or in the 4 position by an amino group or C 1-3 -alkylamino group and may additionally be substituted by one or two C 1-3 -alkyl groups,
a piperazin-1-yl or homopiperazin-1-yl group which may be substituted by one or two C 1-3 -alkyl groups,
an amino group substituted by the groups R 15 and R 16 wherein
R 15 denotes a hydrogen atom, a C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, aryl or aryl-C 1-3 -alkyl group, and
R 16 denotes a R 17 -C 2-3 -alkyl group, while the C 2-3 -alkyl moiety is straight-chain and may be substituted by 1 to 4 C 1-3 -alkyl groups, which may be identical or different, and R 17 denotes an amino or C 1-3 -alkylamino group,
an amino group substituted by the groups R 15 and R 18 , wherein
R 15 is as hereinbefore defined, and
R 18 denotes a C 3-6 -cycloalkyl-methyl group substituted by R 19 in the 1 position of the cycloalkyl group or a C 3-6 -cycloalkyl group substituted by a R 19 —CH 2 — group in the 1 position, while R 19 denotes an amino or C 1-3 -alkylamino group,
an amino group substituted by the groups R 15 and R 20 wherein
R 15 is as hereinbefore defined, and
R 20 denotes an azetidin-3-yl, azetidin-2-ylmethyl, azetidin-3-ylmethyl, pyrrolidin-3yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-3-yl, piperidin-4-yl, piperidin-2-ylmethyl, piperidin-3-ylmethyl or piperidin-4-ylmethyl group, while the groups mentioned for R 20 may each be substituted by one or two C 1-3 -alkyl groups,
an amino group substituted by the groups R 15 and R 21 wherein
R 15 is as hereinbefore defined, and
R 21 denotes a C 3-7 -cycloalkyl group substituted in the 2 or 3 position by an amino or C 1-3 -alkylamino group, which may additionally be substituted by one or two C 1-3 -alkyl groups,
while, unless otherwise stated, the above-mentioned alkyl, alkenyl, and alkynyl groups may be straight-chain or branched,
the tautomers, enantiomers, diastereomers, the mixtures thereof, and the salts thereof, or a physiologically acceptable salt thereof.
2. The method according to claim 1 , wherein
R 3 is:
a 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enyl-methyl, furanyl-methyl, thienylmethyl, chlorobenzyl, bromobenzyl, iodobenzyl, methoxybenzyl, or cyanobenzyl group,
and R 4 is:
an N-(2-aminoethyl)-N-methyl-amino group which may be substituted in the ethyl moiety by one or two C 1-3 -alkyl groups, or
a 3-aminopiperidin-1-yl, piperazin-1-yl or homopiperazin-1-yl group, while the above-mentioned groups may each additionally be substituted by one or two C 1-3 -alkyl groups,
the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.
3. The method according to claim 1 , wherein
R 1 is:
a phenylmethyl, phenylcarbonylmethyl, phenylprop-2-enyl, pyridinylmethyl, pyrimidinylmethyl, naphthylmethyl, quinolinylmethyl, isoquinolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl, phenanthridinylmethyl, naphthyridinylmethyl, or benzotriazolylmethyl group, while all the above-mentioned aryl and heteroaryl groups may be substituted by one or two fluorine, chlorine, bromine atoms, or one or two cyano, nitro, amino, C 1-3 -alkyl, C 1-3 -alkyloxy, and morpholinyl groups, while the substituents are identical or different,
R 2 is:
a C 1-6 -alkyl group that may be substituted by a fluorine atom or a cyano, carboxy, C 1-3 -alkyloxy-carbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, C 1-3 -alkylsulphonyl, aryl or heteroaryl group, while the aryl or heteroaryl group is as hereinbefore defined,
a C 2-6 -alkyl group a substituted by a group R b , where
R b is isolated from the cyclic nitrogen atom by at least two carbon atoms and R b is a hydroxy or C 1-3 -alkyloxy group, or
a C 3-6 -alkenyl or C 3-6 -alkynyl group, while the multiple bond is isolated from the cyclic nitrogen atom by at least one carbon atom,
R 3 is:
a 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enyl-methyl, furanyl-methyl, thienylmethyl, chlorobenzyl, bromobenzyl, iodobenzyl or cyanobenzyl group,
and R 4 is:
an N-(2-aminoethyl)-N-methylamino, N-(2-aminopropyl)-N-methyl-amino, 3-aminopiperidin-1-yl, piperazin-1-yl, or homopiperazin-1-yl group,
the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.
4. A method for treating type I or type II diabetes mellitus or obesity, the method comprising the step of administering to a patient a pharmaceutical composition comprising a compound of formula I
wherein
R 1 is:
an arylmethyl group,
a heteroarylmethyl group,
an arylcarbonylmethyl group,
a heteroarylcarbonylmethyl group, or
an arylprop-2-enyl or heteroarylprop-2-enyl group, wherein the propenyl chain may be substituted by 1 to 4 fluorine atoms or a cyano, C 1-3 -alkyloxy-carbonyl or nitro group,
R 2 is:
a C 1-6 -alkyl group,
an aryl or heteroaryl group,
a C 1-6 -alkyl group substituted by a group R a ,
where R a is
a fluorine, chlorine or bromine atom,
a C 3-7 -cycloalkyl group, wherein one or two methylene groups, independently of one another, may each be replaced by an oxygen or sulphur atom or by an —NH or —N(C 1-3 -alkyl)- group, or by a carbonyl, sulphinyl, or sulphonyl group, or
a trifluoromethyl, aryl, heteroaryl, cyano, carboxy, C 1-3 -alkoxy-carbonyl, aminocarbonyl, C 1-3 -alkylamino-carbonyl, or di-(C 1-3 -alkyl)-amino-carbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C 1-3 -alkyl)-piperazin-1-ylcarbonyl, arylcarbonyl, heteroarylcarbonyl, C 1-3 -alkylsulphinyl or C 1 -3-alklysulphonyl group,
a C 2-6 -alkyl group substituted by a group R b , wherein
R b is isolated from the cyclic nitrogen atom by at least two carbon atoms, and
R b denotes a hydroxy, C 1-3 -alkoxy, C 1-3 -alkylsulphanyl, amino, C 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, or 4-(C 1-3 -alkyl)-piperazin-1-yl group,
a C 3-6 -cycloalkyl group, or
a C 3-6 -alkenyl or C 3-6 -alkynyl group, while the multiple bond is isolated from the cyclic nitrogen atom by at least one carbon atom,
R 3 is
a C 5-7 -cycloalkenylmethyl group optionally substituted by a C 1-3 -alkyl group,
an arylmethyl or heteroarylmethyl group,
a straight-chain or branched C 2-8 -alkenyl group which may be substituted by 1 to 15 fluorine atoms or by a cyano, nitro or C 1-3 -alkoxy-carbonyl group, or
a straight-chain or branched C 3-6 -alkynyl group which may be substituted by 1 to 9 fluorine atoms or by a cyano, nitro or C 2-8 -alkoxy-carbonyl group,
and R 4
a pyrrolidin-1-yl or azetedin-1-yl group that is substituted in the 3 position by an amino or C 1-3 -alkylamino group and may additionally be substituted by one or two C 1-3 -alkyl groups,
a piperidin-1-yl or hexahydroazepin-1-yl group which is substituted in the 3 position or in the 4 position by an amino group or C 1-3 -alkylamino group and may additionally be substituted by one or two C 1-3 -alkyl groups,
a piperazin-1-yl or homopiperazin-1-yl group which may be substituted by one or two C 1-3 -alkyl groups,
an amino group substituted by the groups R 15 and R 16 wherein
R 15 denotes a hydrogen atom, a C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, aryl or aryl-C 1-3 -alkyl group, and
R 16 denotes a R 17 —C 2-3 -alkyl group, while the C 2-3 -alkyl moiety is straight-chain and may be substituted by 1 to 4 C 1-3 -alkyl groups, which may be identical or different, and R 17 denotes an amino or C 1-3 -alkylamino group,
an amino group substituted by the groups R 15 and R 18 , wherein
R 15 is as hereinbefore defined, and
R 18 denotes a C 3-6 -cycloalkyl-methyl group substituted by R 19 in the 1 position of the cycloalkyl group or a C 3-6 -cycloalkyl group substituted by a R 19 —CH 2 — group in the 1 position, while R 19 denotes an amino or C 1-3 -alkylamino group,
an amino group substituted by the groups R 15 and R 20 wherein
R 15 is as hereinbefore defined, and
R 20 denotes an azetidin-3-yl, azetidin-2-ylmethyl, azetidin-3-ylmethyl, pyrrolidin-3-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-3-yl, piperidin-4-yl, piperidin-2-ylmethyl, piperidin-3-ylmethyl or piperidin-4-ylmethyl group, while the groups mentioned for R 20 may each be substituted by one or two C 1-3 -alkyl groups,
an amino group substituted by the groups R 15 and R 21 wherein
R 15 is as hereinbefore defined, and
R 21 denotes a C 3-7 -cycloalkyl group substituted in the 2 or 3 position by an amino or C 1-3 -alkylamino group, which may additionally be substituted by one or two C 1-3 -alkyl groups,
while, unless otherwise stated, the above-mentioned alkyl, alkenyl, and alkynyl groups may be straight-chain or branched,
the tautomers, enantiomers, diastereomers, the mixtures thereof, and the salts thereof, or a physiologically acceptable salt thereof.
5. A method for treating type I or type II diabetes mellitus or or obesity, the method comprising the step of administering to a patient a pharmaceutical composition comprising a compound of formula I
wherein
R 1 is:
an arylmethyl group,
a heteroarylmethyl group,
an arylcarbonylmethyl group,
a heteroarylcarbonylmethyl group, or
an arylprop-2-enyl or heteroarylprop-2-enyl group, wherein the propenyl chain may be substituted by 1 to 4 fluorine atoms or a cyano, C 1-3 -alkyloxy-carbonyl or nitro group,
R 2 is:
a C 1-6 -alkyl group,
an aryl or heteroaryl group,
a C 1-6 -alkyl group substituted by a group R a ,
where R a is
a fluorine, chlorine or bromine atom,
a C 3-7 -cycloalkyl group, wherein one or two methylene groups, independently of one another, may each be replaced by an oxygen or sulphur atom or by an —NH or —N(C 1-3 -alkyl)- group, or by a carbonyl, sulphinyl, or sulphonyl group, or
a trifluoromethyl, aryl, heteroaryl, cyano, carboxy, C 1-3 -alkoxy-carbonyl, aminocarbonyl, C 1-3 -alkylamino-carbonyl, or di-(C 1-3 -alkyl)-amino-carbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C 1-3 -alkyl)-piperazin-1-ylcarbonyl, arylcarbonyl, heteroarylcarbonyl, C 1-3 -alkylsulphinyl or C 1 -3-alkylsulphonyl group,
a C 2-6 -alkyl group substituted by a group R b , wherein
R b is isolated from the cyclic nitrogen atom by at least two carbon atoms, and
R b denotes a hydroxy, C 1-3 -alkoxy, C 1-3 -alkylsulphanyl, amino, C 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, or 4-(C 1-3 -alkyl)-piperazin-1-yl group,
a C 3-6 -cycloalkyl group, or
a C 3-6 -alkenyl or C 3-6 -alkynyl group, while the multiple bond is isolated from the cyclic nitrogen atom by at least one carbon atom,
R 3 is
a C 5-7 -cycloalkenylmethyl group optionally substituted by a C 1-3 -alkyl group,
an arylmethyl or heteroarylmethyl group,
a straight-chain or branched C 2-8 -alkenyl group which may be substituted by 1 to 15 fluorine atoms or by a cyano, nitro or C 1-3 -alkoxy-carbonyl group, or
a straight-chain or branched C 3-6 -alkynyl group which may be substituted by 1 to 9 fluorine atoms or by a cyano, nitro or C 2-8 -alkoxy-carbonyl group,
and R 4
a pyrrolidin-1-yl or azetedin-1-yl group that is substituted in the 3 position by an amino or C 1-3 -alkylamino group and may additionally be substituted by one or two C 1-3 -alkyl groups,
a piperidin-1-yl or hexahydroazepin-1-yl group which is substituted in the 3 position or in the 4 position by an amino group or C 1-3 -alkylamino group and may additionally be substituted by one or two C 1-3 -alkyl groups,
a piperazin-1-yl or homopiperazin-1-yl group which may be substituted by one or two C 1-3 -alkyl groups,
an amino group substituted by the groups R 15 and R 16 wherein
R 15 denotes a hydrogen atom, a C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, aryl or aryl-C 1-3 -alkyl group, and
R 16 denotes a R 17 —C 2-3 -alkyl group, while the C 2-3 -alkyl moiety is straight-chain and may be substituted by 1 to 4 C 1-3 -alkyl groups, which may be identical or different, and R 17 denotes an amino or C 1-3 -alkylamino group,
an amino group substituted by the groups R 15 and R 18 , wherein
R 15 is as hereinbefore defined, and
R 18 denotes a C 3-6 -cycloalkyl-methyl group substituted by R 19 in the 1 position of the cycloalkyl group or a C 3-6 -cycloalkyl group substituted by a R 19 —CH 2 — group in the 1 position, while R 19 denotes an amino or C 1-3 -alkylamino group,
an amino group substituted by the groups R 15 and R 20 wherein
R 15 is as hereinbefore defined, and
R 20 denotes an azetidin-3-yl, azetidin-2-ylmethyl, azetidin-3-ylmethyl, pyrrolidin-3-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-3-yl, piperidin-4-yl, piperidin-2-ylmethyl, piperidin-3-ylmethyl or piperidin-4-ylmethyl group, while the groups mentioned for R 20 may each be substituted by one or two C 1-3 -alkyl groups,
an amino group substituted by the groups R 15 and R 21 wherein
R 15 is as hereinbefore defined, and
R 21 denotes a C 3-7 -cycloalkyl group substituted in the 2 or 3 position by an amino or C 1-3 -alkylamino group, which may additionally be substituted by one or two C 1-3 -alkyl groups,
while, unless otherwise stated, the above-mentioned alkyl, alkenyl, and alkynyl groups may be straight-chain or branched,
the tautomers, enantiomers, diastereomers, the mixtures thereof, and the salts thereof, or a physiologically acceptable salt thereof.