Piperazin-1-yl and 2-([1,4]diazepan-1-yl)-imidazo[4,5-d]-pyridazin-4-ones, the preparation thereof and their use as pharmaceutical compositions
The present invention relates to substituted imidazo[4,5-d]pyridazin-4-ones of general formula wherein R 1 to R 3 and n are defined as in claims 1 to 8 , the tautomers, enantiomers, diastereomers, 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 compound formula (I):
wherein
R 1 denotes a heteroaryl-C 1-3 -alkyl group,
where the term heteroaryl denotes a pyridinyl, pyrimidinyl, phenylpyridinyl, phenylpyrimidinyl, benzoxazolyl, 1-methyl-1H-benzotriazolyl, benzo[1,2,5]thiadiazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, or naphthyridinyl group, and each heteroaryl group is substituted by R 10 and R 11 ,
where R 10 denotes a fluorine, chlorine or bromine atom or a difluoromethyl, trifluoromethyl, cyano, methoxy, difluoromethoxy, trifluoromethoxy, amino, methylamino, dimethylamino, pyrrolidin-1-yl, piperidin-1-yl or morpholin-4-yl group, and
R 11 denotes a methoxy or cyano group
or R 1 denotes a naphthyl-C 1-3 -alkyl group wherein the naphthyl moiety is substituted by R 13
wherein R 13 denotes a difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy group,
R 2 denotes a hydrogen atom or a methyl group,
R 3 denotes a 2-butyn-1-yl group or a 1-buten-1-yl, 2-buten-1-yl or 3-methyl-2-buten-1-yl group,
and n denotes the number 1 or 2,
or a tautomer, enantiomer, diastereomer, mixture or salt thereof,
with the exception of the compounds:
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(pyridin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(pyridin-3-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(pyridin-4-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(2-methoxy-pyridin-3-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(6-amino-pyridin-3-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(5-amino-pyridin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(2-fluoro-pyridin-3-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(2-fluoro-pyridin-4-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(6-fluoro-pyridin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one.
2. A compound of formula I according to claim 1 , wherein:
R 1 denotes a heteroarylmethyl group,
where the term heteroaryl denotes a pyridinyl, pyrimidinyl, benzoxazolyl, 1-methyl-1H-benzotriazolyl, benzo[1,2,5]thiadiazolyl, [1,2,4]-triazolo[4,3-a]pyridinyl, quinolinyl, iso-quinolinyl, quinazolinyl, quinoxalinyl, or naphthyridinyl-group, and each heteroaryl group is substituted by R 10 , R 11 and R 12 ,
while R 10 denotes a fluorine atom or a difluoromethyl, trifluoromethyl, cyano, methoxy, difluoromethoxy, trifluoromethoxy, dimethylamino, pyrrolidin-1-yl, piperidin-1-yl or
morpholin-4-yl group, and
R 11 denotes a cyano group,
or R 1 denotes a naphthylmethyl group wherein the naphthyl moiety is substituted by R 13 ,
where R 13 denotes a difluoromethyl, trifluoromethyl, difluoromethoxy or
trifluoromethoxy group,
R 2 denotes a hydrogen atom or a methyl group,
R 3 denotes a 2-butyn-1-yl group or a 1-buten-1-yl, 2-buten-1-yl or 3-methyl-2-buten-1-yl group,
and n denotes the number 1 or 2,
or a tautomer, mixture or salt thereof,
with the exception of the compounds:
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(pyridin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(pyridin-3-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(pyridin-4-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(2-methoxy-pyridin-3-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(2-fluoro-pyridin-3-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(2-fluoro-pyridin-4-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(6-fluoro-pyridin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one.
3. A compound of formula I according to claim 1 , wherein
R 1 denotes a heteroarylmethyl group,
where the term heteroaryl denotes a pyridinyl, pyrimidinyl, benzoxazolyl, 1-methyl-1H-benzotriazolyl, benzo[1,2,5]thiadiazolyl, [1,2,4]-triazolo[4,3-a]pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, or naphthyridinyl group, and each heteroaryl group is substituted by R 10 , R 11 and R 12 ,
where R 10 denotes a fluorine atom or a cyano, methoxy, dimethylamino, pyrrolidin-1-yl, piperidin-1-yl or morpholin-4-yl group, and
R 11 denotes a cyano group,
R 2 denotes a hydrogen atom,
R 3 denotes a 2-butyn-1-yl group
and n denotes the number 1 or 2,
or a tautomer, mixture or salt thereof,
with the exception of the compounds:
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(pyridin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(pyridin-3-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(pyridin-4-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(2-methoxy-pyridin-3-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(2-fluoro-pyridin-3-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(2-fluoro-pyridin-4-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(6-fluoro-pyridin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and
2-(piperazin-1-yl)-3-(butyn-1-yl)-5-[(isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one.
4. A compound of formula I according to claim 1 , wherein
R 1 denotes a methyl group which is substituted by a fluoronaphthyl, bromonaphthyl, methoxynaphthyl, cyanonaphthyl, dicyanonaphthyl, methylpyridinyl, cyanopyridinyl, dimethylpyrimidinyl, phenylpyrimidinyl, methylbenzoxazolyl, 1-methyl-1H-benzo-triazolyl, benzo[1,2,5]thiadiazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, quinolinyl, fluoroquinolinyl, methylquinolinyl, cyanoquinolinyl, methylisoquinolinyl, cyanoiso-quinolinyl, quinazolinyl, methylquinazolinyl, phenylquinazolinyl, (dimethylamino)-quinazolinyl, (morpholin-4-yl)-quinazolinyl, quinoxalinyl, dimethylquinoxalinyl, trimethylquinoxalinyl, or naphthyridinyl group,
R 2 denotes a hydrogen atom,
R 3 denotes a 2-butyn-1-yl group,
and n denotes the number 1 or 2,
or a tautomer, mixture or salt thereof.
5. A compound of formula I according to claim 1 , wherein
R 1 denotes a methyl group which is substituted by a cyanonaphthyl, methylbenzoxazolyl, 1-methyl-1H-benzotriazolyl, benzo[1,2,5]thiadiazolyl, methylisoquinolinyl, methyl-quinazolinyl or trimethylquinoxalinyl group,
R 2 denotes a hydrogen atom,
R 3 denotes a 2-butyn-1-yl group and
n denotes the number 1 or 2,
or a tautomer or salt thereof.
6. A compound of formula I according to claim 1 , wherein
n denotes the number 1,
or a tautomer or salt thereof.
7. A compound of formula I according to claim 1 , wherein
n denotes the number 2,
or a tautomer or salt thereof.
8. A compound of formula I according to claim 1 selected from:
(a) 2-(piperazin-1-yl)-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
(b) 2-([1,4]diazepan-1-yl)-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
(c) 2-(piperazin-1-yl)-3-(2-butyn-1-yl)-5-[(4-methyl-benzoxazol-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
(d) 2-([1,4]diazepan-1-yl)-3-(2-butyn-1-yl)-5-[(4-methyl-benzoxazol-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
or a tautomer or salt thereof.
9. A compound according to claim 1 in the form of a physiologically acceptable salt with an inorganic or organic acid.
10. A pharmaceutical composition comprising a compound according to claim 1 and one or more inert carriers and/or diluents.
11. A pharmaceutical composition comprising a physiologically acceptable salt according to claim 9 and one or more inert carriers and/or diluents.
12. A method of treating a disease selected from the list consisting of type I and type II diabetes mellitus and obesity in a mammal by administration of a pharmaceutically acceptable amount of a compound according to claim 1 .
13. A process for preparing a compound of formula I according to claim 1 comprising the step of reacting a compound of formula (II):
wherein R 1 to R 3 are defined in claim 1 and Z 1 denotes a leaving group,
with piperazine or [1,4]diazepan or a salt thereof.
14. A process for preparing a compound of formula I according to claim 1 comprising the step of de-protecting a compound of formula (III):
wherein R 1 , R 2 and R 3 are defined as in claim 1 .