WO2005097798A1 - Novel 2-amino-imidazo[4,5-d]pyridazin-4-ones and 2-amino-imidazo[4,5-c]pyridin-4-ones, production and use thereof as medicaments - Google Patents

Abstract

The invention relates to 2-amino-imidazo[4,5-d]pyridazin-4-ones and 2-amino-imidazo[4,5-c]pyridin-4-ones of general formula (I), where R1 to R4 and X are as defined in claims 1 to 6, the tautomers, enantiomers, diastereomers, mixtures and salts thereof with useful pharmacological properties, in particular an inhibitory effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).

Description

 New 2-amino-imidazo [4,5-d] pyridazin-4-ones and 2-amino-imidazo [4,5-c] pyridin-4-ones, their preparation and their use as medicines

The present invention relates to new substituted imidazo [4,5-d] pyridazin-4-ones and 2-amino-imidazo [4,5-c] pyridin-4-ones of the general formula

their tautomers, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically tolerable salts with inorganic or organic acids, which have valuable pharmacological properties, in particular an inhibitory effect on the activity of the enzyme dipeptidyl peptidase-IV (DPP-IV), the Production, their use for the prevention or treatment of diseases or conditions which are associated with increased DPP-IV activity or which can be prevented or alleviated by reducing the DPP-IV activity, in particular of type I or type II diabetes mellitus, the a compound of the general formula (I) or a physiologically tolerable salt thereof medicament and method for the production thereof.

WO 03/104229 discloses imidazo [4,5-d] pyridazin-4-one and imidazo [4,5-c] - pyridin-4-one, which are substituted in position 2 by cyclic groups.

In the above formula I mean R ^{1 is} an arylmethyl or arylethyl group,

a heteroarylmethyl or heteroarylethyl group,

an arylcarbonylmethyl group,

a heteroarylcarbonylmethyl group or

an arylprop-2-enyl or heteroarylprop-2-enyl group, in which the propenyl chain by 1 to 4 fluorine atoms or a cyan, Cι. ₃ -alkyloxy-carbonyl or nitro group can be substituted,

X is a nitrogen atom or a CR ⁵ group, where R ^{5 is} a hydrogen atom or a Cι_ ₃ alkyl group,

R ^{2 is} a hydrogen atom,

a C ₆ alkyl group,

an aryl or heteroaryl group,

a C ₆ -alkyl group substituted by a group R _a , where

R _{a is} a C ₃ - ₇ cycloalkyl group in which one or two methylene groups independently of one another each through an oxygen or sulfur atom, through a -NH- or -N (Cι_ ₃ -alkyl) group or through a carbonyl, sulfinyl or sulfonyl group can be replaced, or a trifluoromethyl, aryl, heteroaryl, cyano, carboxy, Cι. ₃ -alkoxy-carbonyl-, aminocarbonyl-, Cι_ ₃ -alkylamino-carbonyl-, di- (Cι. ₃ -alkyl) -amino-carbonyl-, pyrrolidin-1-ylcarbonyl-, piperidin-1-ylcarbonyl-, morpholin-4 -ylcar- bonyl-, piperazin-1-ylcarbonyl-, 4- (Cι- ₃ -alkyl) -piperazin-1-ylcarbonyl-, aryl- carbonyl, heteroarylcarbonyl, Cι. ₃ -Alkylsulfinyl-, Cι_ ₃ -alkylsulfonyl-, hydroxy-, -Cι-3-alkoxy-, Cι. ₃ -Alkylsulfanyl-, Amino-, Cι- -alkylamino-, Di- (Cι- ₃ -alkyl) -amino-, Pyrrolidin-1-yl-, Piperidin-1-yl-, MorphoIin-4-yl-, Piperazin- 1-yl- or 4- (-Cι. ₃ alkyl) - piperazin-1-yl group means

a trifluoromethyl, carboxy, Cι. ₄ -alkoxy-carbonyl-, aminocarbonyl-, Cι_ ₃ -alkylamino-carbonyl-, di- (Cι. ₃ -alkyl) -amino-carbonyl-, pyrrolidin-1-ylcarbonyl-, piperidin-1-ylcarbonyl-, morpholine -4-ylcarbonyl-, piperazin-1-ylcarbonyl-, 4- (Cι- ₃ -alkyl) -piperazin- 1-ylcarbonyl-, arylcarbonyl-, heteroarylcarbonyl-, Cι_ ₃ -alkylsulfinyl-, Cι. ₃ -Alkylsulfonyl-, -CC 4-alkoxy, -C. -Alkylsulfanyl-, Amino-, -CC. ₃ -alkylamino- or di- (Cι_ ₃ -alkyl) - amino-, pyrrolidin-1-yl-, piperidin-1-yl-, morpholin-4-yl-, piperazin-1-yl- or 4- (Cι_ _3rd Alkyl) piperazin-1-yl group,

a C ₃ - ₇ cycloalkyl group in which one or two methylene groups independently of one another each through an oxygen or sulfur atom, through a -NH or -N (Cι- ₃ alkyl) group, or through a carbonyl, sulfinyl or sulfonyl group can be replaced, or

a C ₃ . ₆ alkenyl or C ₃ . ₆ -alkynyl group,

R ^{3 is} a C ₅ optionally substituted by a C ₃ alkyl group. _7- cycloalkenylmethyl group,

an arylmethyl or heteroarylmethyl group,

a straight-chain or branched C ₂ . _8- alkenyl group, which can be substituted by 1 to 15 fluorine atoms or a cyano, nitro or Cι- ₃ alkoxycarbonyl group,

or a straight-chain or branched C ₃ - ₈ alkynyl group, which has 1 to 9 fluorine atoms or a cyano, nitro or Cι. ₃ -alkoxy-carbonyl group can be substituted, and

R is an amino group substituted by the radicals R ^lü and R, in which R ^{15 is} a hydrogen atom, a Cι. ₆ -alkyl-, C ₃ . ₆ -cycloalkyl-, C ₃ . _6- cycloalkyl-C ₁ . ₃ - alkyl, aryl or aryl -C ₃ alkyl group and

R ^{16 is} R ¹⁷ -C ₂ . ₃ -alkyl group, the C ₂ . ₃ -Alkylt.eil is straight-chain and can be substituted by 1 to 4 Cι_ ₃ alkyl groups, which may be the same or different, and wherein the C ₂ - ₃ alkyl group can be linked from position 2 with R ¹⁷ , and

R ^{17 represents} an amino or C ₃ alkylamino group,

an amino group substituted by the radicals R ⁵ and R ⁸ , in which

R ¹⁵ is defined as mentioned above and R ^{18 is} a C ₃ .io-cycloalkyl-C ₂ -alkyl group substituted in the 1 position of the cycloalkyl radical by R ¹⁹ or a 1- or 2-position by an R ¹⁹ -Cι- ₂ alkyl group substituted C ₃ .ι ₀ cycloalkyl group, where R ^{19 is} an amino or Cι. ₃ -alkylamino group,

an amino group substituted by the radicals R ¹⁵ and R ²⁰ , in which

R ^{15 is} as defined above and R ^{20 is} a C ₄ - or C ₈ -ιo-cycloalkyl group, in which a methylene group from position 3 of the C ₄ - or C ₈ -ιo-cycloalkyl group by an -NH- group is replaced represents

or an amino group substituted by the radicals R ¹⁵ and R ²¹ , in which R ¹⁵ is defined as mentioned above and R ^{21 is} a C ₃ - ₄ - substituted in the 2- or 3-position by an amino or C ₃ alkyl alkyl group or Represents C ₈ -o-cycloalkyl group, where the abovementioned radicals R ¹⁸ , R ²⁰ and R ²¹ can be mono- or disubstituted by R _b , where the substituents can be the same or different and R is a fluorine atom, a C ₃ alkyl, trifluoromethyl or cyano -, Amino-, Cι. ₃ alkyl ~ amino, hydroxy or Cι. ₃ -Alkyloxygruppe, and in which one or two methylene groups of the cycloalkyl radical independently of one another each by an oxygen or sulfur atom or by an -NH- or -N (Cι. ₃ -alkyl) group, or by a carbonyl, sulfinyl or sulfonyl group can be replaced,

whereby the aryl groups mentioned in the definition of the abovementioned radicals are to be understood as meaning phenyl or naphthyl groups which can be mono-, di- or tri-substituted independently of one another by R _h , where the substituents can be identical or different and R _{h is} one Fluorine, chlorine, bromine or iodine atom, a trifluoromethyl, cyan, nitro, amino, aminocarbonyl, Cι-3-alkoxy-carbonyl, aminosulfonyl, methylsulfonyl, acetylamino, methylsulfonylamino , C ₁ -3- alkyl, cyclopropyl, ethenyl, ethinyl, morpholinyl, hydroxy, Cι- ₃ alkyloxy, difluoromethoxy or trifluoromethoxy group, and in which each hydrogen atom is additionally represented by a fluorine atom can be replaced

the heteroaryl groups mentioned in the definition of the abovementioned radicals are to be understood as a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group,

or a pyrrolyl, furanyl, thienyl or pyridyl group in which one or two methine groups are replaced by nitrogen atoms,

or an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group in which one to three methine groups are replaced by nitrogen atoms and the above-mentioned heteroaryl groups can be mono- or disubstituted by R, where the substituents are the same or can be different and R _h is defined as mentioned above, the monocyclic and polycyclic ring systems are to be understood in the definition of the cycloalkyl radicals mentioned above, where the multiple cycles can be fused, spiro-linked or bridged, for example decalin, octahydroindene, norbornane, spiro [4.4] nonane, spiro are among the multiple cycles [4.5] decane, bicyclo [2.1.1] hexane, bicyclo [2.2.2] octane, bicyclo [3.2.1] octane, bicyclo [3.2.23nonane, bicyclo [3.3.1] nonane, bicyclo [3.3.2] decane or to understand Adamantan

unless stated otherwise, the alkyl, alkenyl and alkynyl groups mentioned above can be straight-chain or branched,

their tautomers, enantiomers, diastereomers, their mixtures, their prodrugs and their salts.

The carboxy groups mentioned in the definition of the abovementioned radicals can be replaced by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions,

Furthermore, the amino and imino groups mentioned in the definition of the abovementioned radicals can be substituted by a radical which can be split off in vivo. Such groups are described, for example, in WO 98/46576 and by N.M. Nielsen et al. in International Journal of Pharmaceutics 39, 75-85 (1987).

A group which can be converted into a carboxy group in vivo is, for example, a hydroxymethyl group, a carboxy group esterified with an alcohol, in which the alcoholic part preferably contains a Ci- _δ- alkanoI, a phenyl-Cι- ₃ -alkanol, a C ₃ .g- Cycloalkanol, where a C ₅ . _8- Cycloalkanol additionally by one or two C-ι. ₃ alkyl groups can be substituted, a Cs-s-cycloalkanol in which a methylene group in the 3- or 4-position by an oxygen atom or by an optionally by a Cι. ₃ -alkyl, phenyl -CC. ₃ -alkyl-, phenyl-Cι_ ₃ -alkoxycarbonyl- or C ₂ - ₆ -alkanoyl group substituted imino group is replaced and the cycloalkanol part additionally by one or two Cι. ₃ alkyl groups can be substituted, a C ₄ . _7- cycloalkenol, a C ₃ . _5- alkenol, a phenyl-C ₃ . ₅ -alkenol, a C ₃ . ₅ -Alkinol or phenyl-C ₃ _ ₅ -alkinoI with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond, a C ₃ - ₈ cycloalkyl-Cι- ₃ alkanol, a Bicycloalkanol with a total of 8 to 10 carbon atoms, which in the bicycloalkyl part can additionally be substituted by one or two C ₃ alkyl groups, a 1, 3-dihydro-3-oxo-1-isobenzfuranol or an alcohol of the formula R _p -CO-O - (R _q CR _r ) -OH,

by doing

R _p a Cι. ₈ alkyl, C ₅ - ₇ cycloalkyl, C _{8 8} alkyloxy, C _{5 7} cycloalkyloxy, phenyl or phenyl C ₃ alkyl group,

R _{q is} a hydrogen atom, a Cι. -Alkyl-, Cs- ₇ -cycloalkyl or phenyl group and

R _{r is} a hydrogen atom or a Cι. Represent ₃ alkyl group,

under a group that is negatively charged under physiological conditions, such as a tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, Cι_ ₆ alkylsulfonylamino, phenylsulfonylamino, benzylsulfonylamino, trifluoromethylsulfonylamino, Cι. ₆ -Alkylsulfonylaminocarbonyl-, Phenylsulfonylaminocarbonyl-, Benzylsulfonylaminocarbonyl- or Perfluor-Cι- ₆ -alkylsulfonylaminocarbonylgruppe

and under a residue which can be split off from an imino or amino group in vivo, for example a hydroxyl group, an acyl group such as one optionally substituted by fluorine, chlorine, bromine or iodine atoms, by C ₃ alkyl or C 1-4 alkoxy groups mono- or disubstituted Phenylcarbonyl group, where the substituents can be the same or different, a pyridinoyl group or a Cι_ι ₆ alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl or allyloxycarbonyl group, a Cι. ₁₆ -alkoxycarbonyl- or Cι.ι ₆ alkylcarbonyloxy group, in which hydrogen atoms can be replaced in whole or in part by fluorine or chlorine atoms, such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl -, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy, 2,2,2-trichloroethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy tert-Butylcarbonyloxy-, Pentylcarbonyloxy-, Hexylcarbonyloxy-, Octylcarbonyloxy-, Nonylcarbonyloxy-, Decylcarbonyloxy-, Undecylcarbonyloxy-, Dodecylcarbonyloxy- or Hexadecylcarbonyloxygruppe, a Phenyl-Cι-6-alkoxycarbonyl group like the Benzyloxycarbonyl-, Phenylinooxy- phenyl, phenylethoxy-, Phenylethoxy-, Phenylethoxy-, phenylethoxy-, phenylethoxy group -propionyl group in which the amino group by Cι- ₆ alkyl or C ₃ - ₇ cycloalkyl groups mono- or disubstitu iert and the substituents can be the same or different, a Cι. _3- alkylsulfonyl-C ₂ . ₄ -alkoxycarbonyl-, Cι- ₃ -alkoxy- C ₂ - ₄ -alkoxy-C ₂ - ₄ -alkoxycarbonyl-, R _p -CO-O- (R _q CR _r ) -O-CO-, C ^ e-alkyl -CO-NH-

(R _s CRt) -O-CO- or Cι. ₆ -alkyl-CO-O- (R _s CRt) - (RsCRt) -O-CO group, in which R _p to R _r are defined as mentioned above,

R _s and Rt, which may be the same or different, represent hydrogen atoms or C ₃ alkyl groups,

to understand.

Furthermore, the saturated alkyl and alkoxy parts which contain more than 2 carbon atoms and, unless otherwise stated, mentioned in the definitions above and below also include their branched isomers such as the isopropyl, tert-butyl, isobutyl group etc. ,

For R ¹ comes for example the meaning of a 2-cyanobenzyl, 3-fluorobenzyl, 3-methoxybenzyl, 4-bromo-2-cyanobenzyl, 3-chloro-2-cyanobenzyl, 2-cyan-4-fluorobenzyl, 3.5 -Dimethoxybenzyl-, 2,6-dicyanbenzyl-, 5-cyanfuranylmethyl-, oxazolylmethyl-, isoxazolylmethyl-, 5-methoxycarbonylthienylmethyl-, pyridinylmethyl-, 3-cyanopyridine- 2-ylmethyl-, 6-cyanopyridin-2-ylmethyl-, 6-fluoropyridin-2-ylmethyl-, 3- (2-cyanophenyl) prop-2-enyl-, 3- (pyridin-2-yl) prop- 2-enyl-, 3- (pentafluorophenyl) prop-2-enyl-, phenylcarbonylmethyl-, 3-methoxyphenylcarbonylmethyl-, naphthyl-1-methyl-, 4-cyano-naphth-1-ylmethyl-, quinolin-1- ylmethyl-, 4-cyanoquinolin-1-ylmethyl-, isoquinolin-1-ylmethyl-, 4-cyanisoquinolin-1-ylmethyl-, 4-cyanisoquinolin-3-ylmethyl-, 3-methyl-isoquinolin-1 -ylmethyl-, quinazoline- 2-ylmethyl-, 4-methylquinazolin-2-ylmethyl-, [1, 5] naphthiridin-2-ylmethyl-, [1, 5] naphthiridin-3-ylmethyl-, quinoxalin-6-ylmethyl- or 2,3-dimethyl -quinoxalin-6-ylmethyl group into consideration.

R ² is, for example, the meaning of a hydrogen atom, a methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, 2-propen-1-yl, 2-propyn-1-yl, cyclopropylmethyl, phenyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-hydroxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2- (dimethylamino) ethyl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl, piperazin-1-yl, carboxy, methoxycarbonyl -, ethoxycarbonyl, carboxymethyl, (methoxycarbonyl) methyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, (aminocarbonyl) methyl, (methylaminocarbonyl) methyl, (dimethylaminocarbonyl) methyl, (pyrrolidinocarbonyl) methyl, (piperidinocarbonyl) methyl, (morpholinocarbonyl) methyl, cyanomethyl, 2-cyanoethyl or pyridinyl group.

For R ³ , for example, the meaning of 2-propen-1-yl, 2-methyl-2-propen-1-yl, 1-buten-1-yl, 2-buten-1-yl, 3- Buten-1-yl, 2-methyl-2-buten-1-yl, 3-methyl-2-buten-1-yl, 2,3-dimethyl-2-buten-1-yl, 3- Methyl-3-buten-1-yl-, 1-cyclopenten-1-ylmethyl-, (2-methyl-1-cyclopenten-1-yl) methyl-, 1-cyclohexen-1 -ylmethyl-, 2-propyne -1-yl-, 2-butyn-1-yl, 3-butyn-1-yl, 2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl, 2-cyanobenzyl, 3-fluorobenzyl, 2-methoxybenzyl -, 2-furanylmethyl, 3-furanylmethyl, 2-thienylmethyl or 3-thienylmethyl group into consideration.

R ⁴ is, for example, the meaning of a (2-aminocyclopropyl) amino, N- (2-aminocyclopropyl) -N-methylamino, (2-aminocyclobutyl) amino, N- (2-aminocyclobutyl) -N -methyl-amino-, N- (3-aminocyclobutyl) -N-methyl-amino-, N- (2-aminoethyl) -N- methyl-amino-, N- (1-aminoprop-2-yl) -N-methyl-amino-, N- (2-aminopropyl) -N-methyl-amino-, N- (1-amino-2-methyl- prop-2-yl) -N-methylamino-, N- (2-amino-2-methylpropyl) -N-methylamino-, N - [(1-aminocyclopropyl) methyl] -N-methyl- amino or N- (l-aminomethylcyclopropyl) -N-methylamino group into consideration.

Preferred compounds of the general formula I are those in which

R ¹ and R ⁴ are defined as mentioned above,

X is a nitrogen atom or a -CH group,

R ^{2 is} a hydrogen atom, a Cu alkyl, C ₃ - ₆ cycloalkyl or phenyl group and

R ^{3 is} a 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enylmethyl, furanylmethyl, thienylmethyl, chlorobenzyl, Bromobenzyl, iodobenzyl, methoxybenzyl or cyanbenzyl group,

their enantiomers, their diastereomers, their mixtures and their salts.

Those compounds of the general formula I in which

R ^{1 is} phenylmethyl, phenylcarbonylmethyl, phenylprop-2-enyl, pyridinylmethyl, pyrimidinylmethyl, naphthylmethyl, quinolinylmethyl, isoquinolinylmethyl, chinazolinylmethyl, quinoxalinylmethyl, naphthyridinylmethyl, or benzotriazole or two fluorine, chlorine, bromine atoms or one or two cyano, nitro, amino, C-ι- ₃ alkyl, Cι- ₃ alkyloxy and morpholinyl groups, where the substituents are the same or different .

X is a nitrogen atom or a -CH group, R is a hydrogen atom,

R ^{3 is} 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enylmethyl, furanylmethyl, thienylmethyl, chlorobenzyl, Bromobenzyl, iodobenzyl or cyanobenzyl group and

R ^{4 represents} an N- (2-aminoethyl) -N-methyl-amino group in which the ethyl group can be substituted by 1 to 4 methyl groups,

their tautomers, their mixtures and their salts.

Those compounds of the general formula I in which

R ^{1 is} an isoquinolinylmethyl, quinazolinylmethyl or benzyl group which can be substituted by a 'methyl or cyano group,

X is a nitrogen atom or a -CH group,

R ^{2 is} a hydrogen atom,

R ^{3 is} a 2-butyn-1-yl group and

R ^{4 is} an N- (2-aminoethyl) -N-methylamino, N- (2-aminopropyl) -N-methylamino or N- (2-amino-2-methylpropyI) -N-methylamino group mean,

their tautomers and their salts.

For example, the following preferred compounds are mentioned:

(a) 2- [N- (2-aminoethyl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(4-methyl-quinazolin-2-yl) methyl] - 3,5-dihydro-imidazo [4,5-d] pyridazin-4-one (b) 2- [N- (2-Aminoethyl) -N-methylamino] -3- (2-butyn-1-yi) -5 - [(3-methyl-isoquinolin-1-yl) methyl] - 3,5-dihydro-imidazo [4,5-d] pyridazin-4-one |

(c) S) -2- [N- (2-aminopropyl) -N-methylamino] -3- (2-butyn-1-yl) -5- (2-cyanophenylmethyl) -3,5- dihydro-imidazo [4,5-d] pyridazin-4-one | (d) 2- [N- (2-Amino-2-methylpropyl) -N-methylamino] -3- (2-butyn-1-yl) -5- (2-cyanophenylmethyl) -3.5 dihydro-imidazo [4,5-d] pyridazin-4-one]

(e) CS) -2- [N- (2-aminopropyl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(4-methyl-quinazoline-2- yl) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one |

(f) 2- [N- (2-Aminoethyl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(3-methyl-isoquinolin-1-yl) methyl] - 3,5-dihydro-imidazo [4,5-c] pyridine-4-one |

(g) (S) -2- [N- (2-aminopropyl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(4-cyano-isoquinoline-3 yl) methyl] -3,5-dihydro-imidazo [4,5-c] pyridin-4-one |

as well as their tautomers and their salts.

According to the invention, the compounds of the general formula I are obtained by processes known per se, for example by the following processes:

a) implementation of a compound of the general formula

in the

R ¹ to R ³ and X are defined as mentioned at the outset and Z represents a leaving group such as a halogen atom, a substituted hydroxyl, mercapto, sulfinyl, sulfonyl or sulfonyloxy group such as a chlorine or bromine atom, a methanesulfonyl or methanesulfonyloxy group R ⁴ -H or salts thereof, where R ^{4 is} as defined in the introduction. The reaction is advantageously carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulfolane, optionally in the presence of an inorganic or tertiary organic base, for example sodium carbonate, potassium carbonate or potassium hydroxide, a tertiary organic base , for example triethylamine, or in the presence of N-ethyldiisopropylamine (Hünig base), these organic bases can also serve as solvents at the same time, and if appropriate in the presence of a reaction accelerator such as an alkali metal halide or a palladium-based catalyst at temperatures between - 20 and 180 ° C, but preferably at temperatures between -10 and 120 ° C. However, the reaction can also be carried out without solvent in an excess of ethylenediamine derivative with conventional heating or in a microwave oven.

b) deprotection of a compound of the general formula

in which R ¹ , R ² , R ³ and X are defined as mentioned at the beginning and

Z ^{2 represents} one of the groups mentioned at the outset for R ⁴ which contains an amino group which is not bonded directly to the imidazopyridazinone backbone and which is Boc-protected in Z ² , where Boc stands for a tert-butyloxycarbonyl radical.

The tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with bromotrimethylsilane or iodotrimethylsilane, if appropriate using a solvent such as methylene chloride, ethyl acetate, dioxane, methanol, isopropanol or diethyl ether at temperatures between 0 and 80 ° C.

In the reactions described above, any reactive groups present, such as amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.

For example, come as protective residues for an amino, alkylamino or imino group, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group also includes the phthalyl group.

The subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl radical is cleaved off, for example, hydrogenolytically, for example using hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. However, a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole. A tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

A trifluoroacetyl radical is preferably split off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C. or by treatment with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C.

A phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.

Furthermore, the compounds of general formula I obtained, as already mentioned at the beginning, can be separated into their enantiomers and / or diastereomers. For example, cis / trans mixtures can be separated into their ice and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.

For example, the cis / trans mixtures obtained can be chromatographed into their cis and trans isomers, the compounds of general formula I obtained which occur in racemates, according to methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms on the basis of their physico-chemical differences according to methods known per se, for example by chromatography and / or fractionated crystallization, separate into their diastereomers, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above. The enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols, and Separation of the diastereomeric salt mixture or derivative obtained in this way, for example on the basis of different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids are, for example, the D and L forms of tartaric acid or dibenzoyl tartaric acid, di-op-toluoyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Examples of suitable optically active alcohol are (+) - or (-) - menthol and optically active acyl radicals in amides are, for example, (+) - or (-) - menthyloxycarbonyl.

Furthermore, the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids. Examples of suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the new compounds of formula I thus obtained, if they contain a carboxy group, can then, if desired, be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts. Suitable bases here are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds of general formulas II and III used as starting materials are either known from the literature or can be obtained by processes known per se from the literature (see Examples I to XI). As already mentioned at the beginning, the compounds of the general formula I according to the invention and their physiologically tolerable salts have valuable pharmacological properties, in particular an inhibitory action on the enzyme DPP-IV.

The biological properties of the new compounds were tested as follows:

The ability of the substances and their corresponding salts to inhibit DPP-IV activity can be demonstrated in an experimental setup in which an extract of the human colon carcinoma cell line Caco-2 is used as the DPP-IV source. The differentiation of the cells to induce the DPP-IV expression was carried out according to the description by Reiher et al. in an article entitled "Increased expression of intestinal cell line Caco-2", published in Proc. Natl. Acad. Be. Vol. 90, pages 5757-5761 (1993). The cell extract was obtained from cells solubilized in a buffer (10 mM Tris HCl, 0.15 M NaCl, 0.04 tiu aprotinin, 0.5% Nonidet-P40, pH 8.0) by centrifugation at 35000 g for 30 minutes at 4 ° C (to remove cell debris) won.

The DPP-IV assay was carried out as follows:

50 μl substrate solution (AFC; AFC is amido-4-trifluoromethylcoumarin), final concentration 100 μM, were placed in black microtiter plates. 20 μl assay buffer (final concentrations 50 mM Tris HCl pH 7.8, 50 mM NaCl, 1% DMSO) were pipetted in. The reaction was started by adding 30 μl solubilized Caco-2 protein (final concentration 0.14 μg protein per well). The test substances to be checked were typically added pre-diluted in 20 μl, the assay buffer volume then being reduced accordingly. The reaction was carried out at room temperature, the incubation period was 60 minutes. The fluorescence was then measured in a Victor 1420 multilabel counter, the excitation wavelength being 405 nm and the emission wavelength 535 nm. Blank values (corresponding to 0% activity) were found in batches without Caco-2 protein (Volume replaced by assay buffer), control values (corresponding to 100% activity) were obtained in batches without added substance. The potency of the respective test substances, expressed as IC ₅₀ values, were calculated from dose-response curves, each of which consisted of 11 measuring points. The following results were obtained:

The compounds prepared according to the invention are well tolerated, since no changes in the behavior of the animals could be observed, for example, after oral administration of 10 mg / kg of the compound of Example 1 to rats.

With regard to the ability to inhibit DPP-IV activity, the compounds of general formula I according to the invention and their corresponding pharmaceutically acceptable salts are suitable for influencing all those conditions or diseases which can be influenced by inhibiting DPP-IV activity , It is therefore to be expected that the compounds according to the invention for the prevention or treatment of diseases or conditions such as type 1 and type 2 diabetes mellitus, diabetic complications (such as, for example, retinopathy, nephropathy or neuropathies), metabolic acidosis or ketosis, reactive hypoglycemia, insulin resistance , Metabolic syndrome, dyslipidemia of various origins, arthritis, atherosclerosis and related diseases, obesity, allograft transplantation and osteoporosis caused by calcitonin are suitable. In addition, these substances are suitable for preventing B cell degeneration such as apoptosis or necrosis of pancreatic B cells. The substances are further suitable for improving or restoring the functionality of pancreatic cells, in addition to increasing the number and size of pancreatic B cells. In addition and based on the role of the glucagon-like peptides, such as GLP-1 and GLP-2 and their linkage with DPP-IV inhibition, it is expected that the compounds according to the invention are suitable for achieving, among other things, a sedative or anxiolytic effect , to be able to influence catabolic conditions after operations or hormonal stress responses favorably or to reduce mortality and morbidity after myocardial infarction. In addition, they are suitable for the treatment of all conditions which are related to the above-mentioned effects and are mediated by GLP-1 or GLP-2. The compounds according to the invention can also be used as diuretics or antihypertensives and are suitable for the prevention and treatment of acute kidney failure. Furthermore, the compounds according to the invention can be used to treat inflammatory diseases of the respiratory tract. They are also suitable for the prevention and therapy of chronic inflammatory bowel diseases such as irritable bowel syndrome (IBS), Crohn's disease or ulcerative colitis as well as for pancreatitis. Furthermore, it is expected that they can be used for any kind of injury or impairment in the gastrointestinal tract, such as, for example, for colitis and enterids. In addition, it is expected that DPP-IV inhibitors and thus also the compounds according to the invention can be used to treat infertility or to improve fertility in humans or in the mammalian organism, in particular if the infertility in connection with an insulin resistance or with the poly- cystic ovarian syndrome. On the other hand, these substances are suitable for influencing sperm motility and can therefore be used as contraceptives for use in men. Furthermore, the substances are suitable for influencing growth hormone deficiency states that are associated with short stature, and can be used sensibly in all indications in which growth hormone can be used. Because of their inhibitory action against DPP IV, the compounds according to the invention are also suitable for the treatment of various autoimmune diseases such as, for example, rheumatoid arthritis, multiple sclerosis, thyroid disease and Graves' disease, etc. In addition, they can be used for viral diseases such as HIV infections, for stimulating blood formation, for benign prostatic hyperplasia, for gingivitis as well as for the treatment of neuronal defects and neurodegenerative diseases such as Alzheimer's disease. Compounds described can also be used for the therapy of tumors, in particular for changing tumor invasion, as well as metastatisation. Examples here are the use in T-cell lymphomas, acute lymphoblastic leukemia, cell-based thyroid carcinomas, basal cell carcinomas or breast carcinomas. Other indications are stroke, ischemia of various origins, Parkinson's disease and migraines. In addition, further areas of indication include follicular and epidermal hyperkeratosis, increased keratinocyte proliferation, psoriasis, encephalomyelitis, glomerulonephritis, lipodystrophy and psychosomatic, depressive and neuropsychiatric diseases of various origins.

The compounds according to the invention can also be used in combination with other active ingredients. Therapeutics suitable for such a combination include, for example, antidiabetic agents such as metformin, sulfonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinedione (e.g. rosiglitazone, pioglitazone), PPAR-gamma agonists (e.g. Gl 262570) and antagonists, PPAR-gamma / alpha modulators (eg KRP 297), alpha-glucose inhibitors (eg acarbose, Voglibose), other DPPIV inhibitors, alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin. In addition, SGLT2 inhibitors such as T-1095 or KGT-1251 (869682), inhibitors of protein tyrosine phosphatase 1, substances which influence deregulated glucose production in the liver, such as inhibitors of glucose-6-phosphatase, or fructose-1, 6- bisphosphatase, the glycogen phosphorylase, glucagon receptor antagonists and inhibitors of the phosphoenolpyruvate carboxykinase, the glycogen synthase kinase or the pyruvate dehydrokinase, lipid-lowering agents such as HMG-CoA reductase inhibitor (e.g. simvastatin, deribibrate, fennafate, forafate (eg -alpha agonists, PPAR-delta agonists, ACAT inhibitors (eg Avasimibe) or cholesterol absorption inhibitors such as ezetimibe, bile acid binding substances such as for example colestyramine, inhibitors of ileal bile acid transport, HDL-increasing compounds such as, for example, inhibitors of CETP or regulators of ABC1 or active substances for the treatment of obesitas, such as sibutramine or tetrahydrolipstatin, dexfenfluramine, axokines, antagonists of the cannbinoidl receptor, MCH Receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or ß ₃ agonists such as SB-418790 or AD-9677 as well as agonists of the 5HT2c receptor.

In addition, a combination with drugs to influence high blood pressure such as All antagonists or ACE inhibitors, diuretics, β-blockers, Ca antagonists and others or combinations thereof are suitable.

The dosage required to achieve a corresponding effect is expediently 1 to 100 mg, preferably 1 to 30 mg for intravenous administration, and 1 to 1000 mg, preferably 1 to 100 mg, in each case 1 to 4 times a day for oral administration. For this purpose, the compounds of formula I prepared according to the invention, optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures, in conventional galenical preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.

The following examples are intended to explain the invention in more detail: Preparation of the starting compounds:

Example I

2-Bromo-1 - (2-butyn-1-yl) -1 H -imidazole-4,5-dicarboxylic acid dimethyl ester A solution of 15.0 g of 2-bromo-imidazole-4,5-dicarboxylic acid dimethyl ester, 5.15 ml of 1-bromo-2-butyne and 50 ml of N, N-diisopropylethylamine in 280 ml of tetrahydrofuran are heated to reflux for one hour. The mixture is evaporated, the residue is mixed with about 100 ml of water and extracted three times with 70 ml of ethyl acetate. The extracts are washed with 50 ml of water, dried and concentrated. The crude product thus obtained is purified by column chromatography on silica gel with methylene chloride / ethanol (1: 0-> 49: 1) as the eluent. Yield: 13.50 g (75% of theory) R _f value: 0.82 (silica gel, methylene chloride / ethanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 315/317 (Br) [M + H] ⁺

Example II

2-bromo-3- (2-butyn-1-yl) -5-formyl-3H-imidazole-4-carboxylic acid methylester

To a solution of 13.5 g of 2-bromo-1- (2-butyn-1-yl) -1 H-imidazole-4,5-dicarboxylic acid dimethyl ester in 220 ml of tetrahydrofuran under an argon atmosphere at -70 ° C 43 ml of a 1 M solution of diisobutylaluminum hydride in tetrahydrofuran were added dropwise within 20 minutes. The mixture is stirred for a further four hours at -70 ° C., then 20 ml of a mixture of 1 M hydrochloric acid and tetrahydrofuran are added dropwise. After warming to room temperature, about 200 ml of water are added and extracted three times with 70 ml of ethyl acetate. The combined extracts are dried and concentrated. The crude product thus obtained is purified by column chromatography on silica gel using petroleum ether / ethyl acetate (4: 1-> 1: 1) as the eluent. Yield: 6.40 g (52% of theory) mass spectrum (ESI ⁺ ): m / z = 285/287 (Br) [M + H] ⁺ Example III

2-bromo-3- (2-butyn-1-yl) -3.5-dihvdro-imidazor4.5-dlpyridazin-4-one To a solution of 1.80 g of 2-bromo-3- (2-butyn-1- yl) -5-formyl-3H-imidazole-4-carboxylic acid methyl ester in 25 ml of ethanol, 0.31 ml of hydrazine hydrate, dissolved in 1 ml of ethanol, are added dropwise at room temperature. Five minutes later, 1.5 ml of concentrated acetic acid are added and the mixture is refluxed for 30 minutes. After cooling, the precipitated solid is filtered off with suction, washed with 10 ml of ethanol and 20 ml of diethyl ether and dried. Yield: 1.25 g (74% of theory) mass spectrum (ESI ⁺ ): m / z = 267/269 (Br) [M + H] ⁺

Example IV

2-bromo-3- (2-butyn-1-yl) -5-f (4-methyl-quinazolin-2-methyl-3,5-dihydro-imidazo [4,5-dlpyridazin-4-one A mixture of 365 mg 2-bromo-3- (2-butyn-1-yl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one, 265 mg of 2-chloromethyl-4-methyl-quinazoline and 210 mg of potassium carbonate in 6 ml of acetonitrile is stirred at room temperature for 17 h, after which the reaction mixture is filtered through 5 g of aluminum oxide with ethyl acetate and the filtrate is concentrated, the residue is triturated in diisopropyl ether, separated from the ether and dried. Yield: 300 mg (53% theory)

Mass spectrum (ESI ⁺ ): m / z = 423/425 (Br) [M + H] ⁺

The following compounds are obtained analogously to Example IV:

(1) 2-bromo-3- (2-butyn-1-yl) -5 - [(3-methyl-isoquinolin-1-yl) methyl] -3,5-dihydroimidazo [4,5-d] pyridazin-4-one mass spectrum (ESI ⁺ ): m / z = 422/424 (Br) [M + H] ⁺

(2) 2-bromo-3- (2-butyn-1-yl) -5- (2-cyanophenylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

Mass spectrum (ESI ⁺ ): m / z = 382/384 (Br) [M + H] ⁺ (3) 2-bromo-3- (2-butyn-1-yl) -5- (4-cyano-isoquinolin-3-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4 -one

Mass spectrum (ESI ⁺ ): m / z = 463/465 (Br) [M + Hj ⁺

Example V

^ S) -2-r (2-aminopropyl) amino1-3- (2-butyn-1-yl) -5- (2-cvanphenylmethyl) -3.5-dihvdro-imidazor4.5-d1pyridazin-4-one

A mixture of 0.36 g of 2-bromo-3- (2-butyn-1-yl) -5- (2-cyanophenylmethyl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one , 0.42 g of (S) -1, 2-diaminopropane dihydrochloride and 0.52 g of potassium carbonate in 6 ml of N-methylpyrrolidone is stirred at 120 ° C. for 2.5 h. Saturated aqueous sodium chloride solution is then added and the precipitate which has separated out is separated off. The aqueous phase is extracted with ethyl acetate, the combined organic phases are dried over sodium sulfate and concentrated. Yield: 580 mg (approx. 60% pure) R _f value: 0.30 (silica gel, methylene chloride / methanol / ammonium hydroxide = 90: 10: 0.1)

The following connection is obtained analogously to Example V:

(1) 2 - [(2-amino-2-methyl-propyl) amino] -3- (2-butyn-1-yl) -5- (2-cyanophenylmethyl) -3,5-dihydro-imidazo [4, 5-d] pyridazin-4-one

R _f value: 0.25 (silica gel, methylene chloride / methanol / ammonium hydroxide = 90: 10: 0.1)

(2) fS 2 - [(2-benzyloxycarbonylamino-prop-1-yl) amino] -3- (2-butyn-1-yl) -5 - [(4-methyl-quinazolin-2-yl) methyl] - 3,5-dihydro-imidazo [4,5-d] pyridazin-4-one product (2) was obtained by reacting 2-bromo-3- (2-butyn-1-yl) -5 - [(4-methyl -china- zolin-2-yl) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one with (S) -N- (2-benzyloxycarbonylamino-prop-1-yl ) -N-methyl-amine obtained. Mass spectrum (ESI ⁺ ): m / z = 565 [M + H] ⁺

(3) (S) -2 - [(2-aminopropyl) amino] -3- (2-butyn-1-yl) -5- (4-cyano-isoquinolin-3-ylmethyl) - 3,5-dihydro- imidazo [4,5-dpyridazin-4-one R _f value: 0.30 (silica gel, methylene chloride / methanol / ammonium hydroxide = 90: 10: 0.1) Example VI t ^" S) -2-r ( ^, 2-tert-Butyloxycarbonylamino-propyπamino1-3- (2-butyn-1-vπ-5- (2-cvanphenyl-methvD-3,5-dihvdro-imidazor4,5- d1pyridazin-4-one To a solution of 1, 04 g S) -2 - [(2-aminopropyl) amino] -3- (2-butyn-1-yl) -5- (2-cyanophenylmethyl) -3 , 5-dihydro-imidazo [4,5-d] pyridazin-4-one and 0.54 ml of triethylamine in 200 ml of dichloromethane are added at room temperature to 0.73 g of di-tert-butyl pyrocarbonate The residue is taken up in ethyl acetate and washed once each with water, dilute citric acid, water and saturated aqueous sodium chloride solution. The organic phase is then dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel (petroleum ether / Ethyl acetate 1: 1) Yield: 0.40 g (30% of theory) Mass spectrum (ESI ⁺ ): m / z = 476 [M + H] ⁺

The following compound is obtained analogously to Example VI:

(1) 2 - [(2-tert-Butyloxycarbonylamino-2-methyl-propyl) amino] -3- (2-butyn-1-yl) -5- (2-cyanophenylmethyl) -3,5-dihydro-imidazo [ 4,5-d] pyridazin-4-one mass spectrum (ESI ⁺ ): m / z = 490 [M + H] ⁺

(2) (S) -2 - [(2-tert-butyloxycarbonylamino-propyl) amino] -3- (2-butyn-1-yl) -5- (4-cyano-isoquinolin-3-ylmethyl) -3, 5-dihydro-imidazo [4,5-d] pyridazin-4-one mass spectrum (ESI ⁺ ): m / z = 557 [M + H] ⁺

Example VII

(S) -2-rN- (2-tert-Butyloxycarbonylamino-propyπ-N-methylamino1-3- (2-butyn-1-vπ-5- (2-cvanphenylmethv0-3,5-dihvdro-imidazor4.5 -d1pyridazin-on-4

To an ice-cooled solution of 0.39 g of (S) -2 - [(2-tert-butyloxycarbonylamino-propyl) amino] -3- (2-butyn-1-yl) -5- (2-cyanophenylmethyl) -3, 5-dihydro-imidazo [4,5-d] pyridazin-4-one in 5 ml of dimethyl sulfoxide are added to 0.96 g of potassium tert-butoxide. The mixture is stirred at room temperature until the solution is clear. Then 53 μl of methyl iodide are added, and the solution is stirred for a further 3.5 h at room temperature. Then water is added to the reaction solution, the precipitate which has separated out is separated off and washed with water. The dried precipitate is purified by chromatography on silica gel (petroleum ether / ethyl acetate 1: 1). Yield: 0.26 g (66% of theory)

Mass spectrum (ESI ⁺ ): m / z = 490 [M + H] ⁺

The following compound is obtained analogously to Example VII:

(1) 2- [N- (2-tert-Butyloxycarbonylamino-2-methyl-propyl) -N-methyl-amino] -3- (2-butyn-1-yl) -5- (2-cyanophenylmethyl) -3 , 5-dihydro-imidazo [4,5-d] pyridazin-4-one mass spectrum (ESI ⁺ ): m / z = 504 [M + H] ⁺

(2) fS) -2- [N- (2-tert-Butyloxycarbonylamino-propyl) -N-methylamino] -3- (2-butyn-1-yl) - 5- (4-cyano-isoquinolin-3 -ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one mass spectrum (ESI ⁺ ): m / z = 571 [M + H] ⁺

Example VIII Methyl 2-bromo-5- (frans-2-methoxy-vinyl) -3H-imidazole-4-carboxylate Under an argon atmosphere, 38 ml of 38 ml of an ice-cooled solution of 6.64 g of methoxy-methyltriphenylphosphonium chloride in 140 ml of tetrahydrofuran a 0.5 M solution of potassium bis (trimethylsilyl) amide in toluene was added dropwise over 10 min. The reaction mixture is stirred for a further 15 min in an ice bath and then cooled to -70 ° C. Then a solution of 4.41 g of 2-bromo-3- (2-butyn-1-yl) -5-formyl-3H-imidazole-4-carboxylic acid methyl ester in 40 ml of tetrahydrofuran is added dropwise over 30 min. After stirring for a further 45 min at -70 ° C., the solution is warmed to room temperature and stirred for a further 1 h at this temperature. Then water is added to the reaction solution and extracted with ethyl acetate. The organic extracts are dried over sodium sulfate, the solvent is removed and the residue is chromatographed on silica gel (cyclohexane / ethyl acetate 9: 1-> 7: 3). Yield: 2.67 g (55% of theory), pure fraπs compound mass spectrum (ESI ⁺ ): m / z = 313/315 (Br) [M + H] ⁺ Example IX

2-bromo-5- (fra / 7s-2-methoxy-vinylV3H-imidazole-4-carboxylic acid To a solution of 3.50 g of 2-bromo-5- (fjans-2-methoxy-vinyl) -3H-imidazole- 4-carboxylic acid methyl ester in 140 ml of tetrahydrofuran is given a solution of 2.20 g of lithium hydroxide in 175 ml of water, the solution is stirred for 4 h at room temperature, then 92 ml of aqueous 1 M hydrochloric acid are added and the solution is dissolved in The precipitate is separated off, washed with water and dried. Yield: 3.30 g (99% of theory)

Mass spectrum (ESI ⁺ ): m / z = 299/301 (Br) [M + H] ⁺

Example X 2-bromo-3- (2-butyn-1-yl) -5- ( ^, fraπs-2-methoxy-vinvπ-3H-imidazole-4-carboxylic acid- (3-methyl-isoquinolin-1-ylmethv0-amide

A solution of 3.50 g of 2-bromo-5- (frans-2-methoxy-vinyl) -3H-imidazole-4-carboxylic acid and 1.30 g of TBTU in 1, 20 ml of triethylamine and 30 ml of dimethylformamide becomes 15 min stirred at room temperature. Then 1.09 g of 3-methyl-isoquinolin-1-yl-methylamine are added, and the resulting suspension is stirred for 4 hours at room temperature. Then ice-cold water is added and the precipitate is separated off. The precipitate is dissolved in dichloromethane, the solution is dried over sodium sulfate and the solvent is removed. Yield: 1.38 g (78% of theory) mass spectrum (ESI ⁺ ): m / z = 453/455 (Br) [M + H] ⁺

Example XI

2-Brorn-3- (2-butyn-1-vπ-5-r (3-methyl-isoquinolin-1-yl) methvn-3.5-dihvdro-imidazor4.5-clpyridin-4-one in a 1: 1 mixture with 2-chloro-3- (2-butyn-1-yl) -5-r (3-methyl-isoquinolin-1-Vl) methvn-3,5-dihvdro-imidazor4,5-c1pyridin-4-one 0, 74 g of 2-bromo-3- (2-butyn-1-yl) -5 - (- τaπs-2-methoxy-vinyl) -3H-imidazol-4-carboxylic acid- (3-methyl-isoquinolin-1-ylmethyl) -amide are stirred in 35 ml of aqueous 4 M hydrochloric acid for 3 h at 85 ° C. After cooling to room temperature, dichloromethane is added give and make the solution alkaline with sodium hydroxide solution. The organic phase is separated off and the aqueous phase is extracted twice with dichloromethane. The combined organic phases are dried over sodium sulfate, the solvent is removed and the residue is purified on silica gel (dichloromethane / methanol 99: 1-

> 95: 5).

Yield: 0.39 g (1: 1 mixture of the two title compounds)

Mass spectrum (ESI ⁺ ): m / z = 421/423 (Br) [M + H] ⁺ and m / z = 377/379 (Cl) [M + H] ⁺

Making the end connections:

example 1

2-rN- (2-aminoethvπ-N-methylamino1-3- (2-butyne-1-vπ-5-rf4-methyl-quinazolin-2-vi) methvπ-3,5-dihvdro-imidazor4.5- d1pyridazin-4-onl

A mixture of 300 mg of 2-bromo-3- (2-butyn-1-yl) -5 - [(4-methyl-quinazolin-2-yl) - methyl] -3,5-dihydro-imidazo [4.5 -d] pyridazin-4-one, 400 mg of N-methylethylenediamine and 210 mg of potassium carbonate in 6 ml of dimethyl sulfoxide is stirred at 60 ° C. for 8 h. Saturated aqueous sodium chloride solution is then added and the aqueous phase extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The crude product is purified by chromatography on a silica gel column using methylene chloride / methanol (3: 2) as the eluent. Yield: 85 mg (29% of theory) mass spectrum (ESI ⁺ ): m / z = 417 [M + H] ⁺

The following compound is obtained analogously to Example 1:

(1) 2- [N- (2-aminoethyl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(3-methyl-isoquinolin-1-yl) methyl] - 3,5-dihydro-imidazo [4,5-d] pyridazin-4-ONJ

Mass spectrum (ESI ⁺ ): m / z = 416 [M + H] ⁴ (2) 2- [N- (2-aminoethyl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(3-methyl-isoquinolin-1-yl) methyl] - 3,5-dihydro-imidazo [4,5-c] pyridine-4-one |

Product (2) was obtained by reacting a 1: 1 mixture of 2-bromo-3- (2-butyn-1-yl) -5 - [(3-methyl-isoquinolin-1-yl) methyl] -3.5 -dihydro-imidazo [4,5-c] pyridin-4-one and 2-

Chloro-3- (2-butyn-1-yl) -5 - [(3-methyl-isoquinolin-1-yl) methyl] -3,5-dihydro-imidazo [4,5-c] pyridin-4-one mit_N-methyl-ethy! endiamine obtained according to the described procedure.

Mass spectrum (ESI ⁺ ): m / z = 415 [M + H] ⁺

Example 2 t ^" S) -2- [N- (2-Amino-propyπ-N-methylaminol-3- (2-butyn-1-yl) -5- (2-cvanphenylmethvπ-

3,5-dihydro-imidazof4.5-dlpyridazin-4-one |

To a solution of 250 mg of S -2- [N- (2-tert-butyloxycarbonylamino-propyl) -N-methylamino] -3- (2-butyn-1-yl) -5- (2-cyanophenylmethyl) - 3,5-dihydro-imidazo [4,5-d] pyridazin-4-one in 5 ml dichloromethane, 1.4 ml trifluoroacetic acid are added dropwise. The solution is stirred for 4 h at room temperature, then diluted with dichloromethane and made alkaline with saturated aqueous sodium carbonate solution. The organic phase is separated off, washed with water, dried over magnesium sulfate and concentrated. The residue is stirred with tert-butyl methyl ether and, after separating off the ether, dried in vacuo at 40-50 ° C. Yield: 161 mg (81% of theory) mass spectrum (ESI ⁺ ): m / z = 390 [M + H] ⁺ The following compound is obtained analogously to Example 2:

(1) 2- [N- (2-Amino-2-methyl-propyl) -N-methyl-amino] -3- (2-butyn-1-yl) -5- (2-cyanophenyl-methyl) -3 , 5-dihydro-imidazo [4,5-d] pyridazin-4-one |

Mass spectrum (ESI ⁺ ): m / z = 404 [M + H] ⁺

(2) (S) -2- [N- (2-aminopropyl) -N-methylamino] -3- (2-butyn-1-yl) -5- (4-cyano-isoquinoline-3- ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one |

Mass spectrum (ESI ⁺ ): m / z = 441 [M + H] ⁺

Example 3 rS) -2-rN- (2-aminopropylVN-methylamino1-3- (2-butyne-1-vn-5- 4-methyl-quinazoline-2-vπmethvn-3.5-dihvdro-imidazor4.5-d1pyridazine -4-onl

H,

To a solution of 130 mg S ^^ - ^ - Benzyloxycarbonylamino-prop-ly aminoj-S- (2-butin-1-yl) -5 - [(4-methyl-quinazolin-2-yl) methyl] -3, 5-dihydro-imidazo [4,5-d] pyridazin-4-one in 3 ml dichloromethane are added 40 ul iodotrimethylsilane. After 1 and For 3 h stirring at room temperature, 100 ul of iodotrimethylsilane are added again. The solution is stirred for a further 4 h at room temperature and then mixed with 5 ml of methanol and concentrated. Then 1 M hydrochloric acid is added and the aqueous phase is washed twice with dichloromethane. The aqueous phase is made alkaline with sodium carbonate and extracted three times with dichloromethane. The organic extracts are dried over sodium sulfate, the solvent is removed and the residue is purified on silica gel (dichloromethane / methanol 1: 0-> 3: 1).

Yield: 30 mg (30% of theory) mass spectrum (ESI ⁺ ): m / z = 431 [M + H] ⁺

The following compounds can also be obtained analogously to the above examples and other processes known from the literature:

(1) 2- [N- (2-aminoethyl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(4-cyano-naphth-1-yl) methyl] - 3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(2) 2- [N- (2-aminoethyl) -N-methylamino] -3- (2-butyn-1-yl) -5- (2-cyanophenylmethyl) -

3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(3) 2- [N- (2-Amino-prop-1-yl) -N-methyl-amino] -3- (2-butyn-1-yl) -5- (quinoxalin-6-ylmethyl) -3 , 5-dihydro-imidazo [4,5-d] pyridazin-4-one

(4) 2- [N- (2-aminocyclopropyl) amino] -3- (2-butyn-1-yl) -5- (2-cyanophenylmethyl) -3,5-dihydro-imidazo [4,5- d] pyridazin-4-one

(5) 2- [N- (2-Amino-prop-1-yl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(4-cyano-naphth-1 - yl) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one (6) 2- [N- (2-amino-2-methyl-prop-1-yl) -N -methylamino] -3- (2-butyn-1-yl) -5 - [(4-methyl-quinazolin-2-yl) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazine -4-one

(7) 2- [N- (2-Amino-2-methyl-prop-1-yl) -N-methyl-amino] -3- (2-butyn-1-yl) -5- (phenylcarbonylmethylJ-S. δ-dihydro-imidazo ^ .δ-djpyridazin ^ -one

(8) 2- [N- (2-Amino-prop-1-yl) -N-methyl-amino] -3- (2-butyn-1-yI) -5- [3- (2-nitrophenyl) prop -2-en-1-yl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(9) 2- [N- (1-Aminocycloprop-1-methyl) -N-methyl-amino] -3- (2-butyn-1-yl) -5 - [(4-methyl-quinazolin-2-yl ) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one (10) 2- [N- (2-aminoethyl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(3-chloro-2-cyanophenyl) methyl] - 3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(11) 2- [N- (2-aminoethyl) -N-methylamino] -3- (2-butyn-1-yl) -5 - ([1, 5] naphthyridin-2-ylmethyl) -3, 5-dihydro-imidazo [4,5-d] pyridazin-4-one (12) 2- [N- (2-aminoprop-1-yl) -N-methylamino] -3- (2-butyn-1 -yl) -5- (quinoxalin-6-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(13) 2- [N- (2-Aminoethyl) -N-methylamino] -3- (2-butyn-1-yl) -5- (quinazolin-7-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(14) 2- [N- (2-aminoprop-1-yl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(1 -cyano-isoquinolin-3-yl ) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(15) 2- [N- (2-Aminoethyl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(4-morpholin-4-ylquinazolin-2-yl) methyl ] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(16) 2- [N- (2-aminoprop-1-yl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(4-phenyl-pyrimidin-2-yl ) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one (17) 2- [N- (2-aminoethyl) -N-methylamino] -3- (2-butyne -1 -yl) -5- (2,3-dimethyl-quinoxaline)

6-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(18) 2- [N- (2-aminoethyl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(1-cyano-isoquinolin-3-yl) methyl] - 3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(19) 2- [N- (2-aminoethyl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(3-methoxyphenyl) carbonylmethyl] -3, 5-dihydro-imidazo [4,5-d] pyridazin-4-one

(20) 2- [N- (2-aminoprop-1-yl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(2-methoxyphenyl) carbonylmethyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(21) 2- [N- (2-Aminoethyl) -N-methylamino] -3- (2-buten-1-yl) -5 - [(3-methyl-isoquinolin-1-yl) methyl] - 3,5-dihydro-imidazo [4,5-d] pyridazin-4-one (22) 2- [N- (2-amino-prop-1-yl) -N-methylamino] -3- (3rd -methyl-but-2-en-1-yl) -5 - [(3-methyl-isoquinolin-1-yl) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(23) 2- [N- (2-Aminoethyl) -N-methylamino] -3- (1-cyclopenten-1-yl) -5 - [(3-methyl-isoquinolin-1-yl) methyl ] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(24) 2- [N- (2-Amino-2-methyl-prop-1-yl) -N-methyl-amino] -3- (1-buten-1-yl) -5 - [(3-methyl isoquinolin-1-yl) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(25) 2- [N- (2-aminoethyl) -N-methylamino] -3 - [(2-chlorophenyl) methyl] -5 - [(4-methylquinazolin-2-yl) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one (26) 2- [N- (2-aminoethyl) -N-methylamino] -3 - [(2-bromophenyl) methyl] -5 - [(4-methyl-quinazolin-2-yl) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one (27) 2- [N- (2-amino-2-methyl-prop-1-yl) -N-methylamino] -3 - [(2-iodophenyl) methyl] -5- [(4-methyl-quinazolin-2-yl) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one (28) 2- [N- (2-Amino-prop-1-yl) -N-methylamino] -3 - [(2-cyanophenyl) methyl] -5 - [(4-methyl-quinazoline- 2-yl) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one (29) 2- [N- (2-amino-prop-1-yl) -N-methyl- amino] -3- (furan-2-ylmethyl) -5 - [(4-methyl-quinazolin-2-yl) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one ( 30) 2- [N- (2-Aminoethyl) -N-methylamino] -3- (thien-3-ylmethyl) -5 - [(4-methyl-quinazoline-2-yl) methyl] -3 , 5-dihydro-imidazo [4,5-d] pyridazin-4-one

(31) 2- [N- (2-Amino-prop-1-yl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(4-methoxy-naphth-

1-yl) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(32) 2- [N- (2-Amino-prop-1-yl) -N-methyl-amino] -3- (2-butyn-1-yl) -5- [3- (pentafluorophenyl) prop -2-en-1-yl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one (33) 2 - [(azetidin-3-yl) amino] -3- (2- butyn-1-yl) -5 - [(4-methyl-quinazolin-2-yl) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(34) 2- [N- (Azetidin-3-yl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(4-methyl-quinazolin-2-yl) methyl ] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one (35) 2- [N- (2-amino-1, 1, 2-trimethylprop-1-yl) -N-methyl -amino] -3- (2-butyn-1-yl) -5 - [(3-methyl-isoquinolin-1-yl) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4 -one

(36) 2 - [(3-methyl-azetidin-3-yl) amino] -3- (2-butyn-1-yl) -5 - [(4-methyl-quinazolin-2-yl) - methyl] - 3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(37) 2- [N- (2-Amino-prop-1-yl) -N-methyl-amino] -3- (2-butyn-1-yl) -5 - [(3-methyl-isoquinoline -1-yl) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one (38) 2- [N- (2-amino-1-methyl-prop-1-yl) -N-methyl-amino] -3- (2-butyn-1-yl) -5 - [(3-methyl-isoquinolin-1-yl) methyl] -3,5-dihydro-imidazo [4,5-d ] pyridazin-4-one

(39) 2- [N- (2-Amino-prop-1-yl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(3-cyanopyridine-2 - yl) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(40) 2- [N- (2-Amino-prop-1-yl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(3-cyanopyridine-2 - yl) methyl] -3,5-dihydro-imidazo [4,5-c] pyridin-4-one

(41) 2- [N- (2-aminoethyl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(4-methyl-quinazolin-2-yl) methyl] - 3,5-dihydro-imidazo [4,5-c] pyridin-4-one (42) 2- [N- (2-Amino-prop-1-yl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(4-methyl-quinazoline -2-yl) methyl] -3,5-dihydro-imidazo [4,5-c] pyridin-4-one

(43) 2- [N- (2-Amino-prop-1-yl) -N-methyl-amino] -3- (2-butyn-1-yl) -5 - ([1, 5] naphthyridine-2 - ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

(44) 2- [N- (2-Amino-prop-1-yl) -N-methyl-amino] -3- (2-butyn-1-yl) -5- (4,6-dimethylpyrimidine) 2-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

Example 3

Draαees with 75 mq of active substance

1 coated tablet contains: active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethyl cellulose 15.0 mg magnesium stearate 1.5 mα 230.0 mg

production:

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and half of the stated amount of magnesium stearate. Pressings with a diameter of approx. 13 mm are produced on a tabletting machine, these are rubbed on a suitable machine through a sieve with a 1.5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tablet machine into tablets of the desired shape. Core weight: 230 mg stamp: 9 mm, curved The dragee cores thus produced are coated with a film consisting essentially of hydroxypropylmethyl cellulose. The finished film coated tablets are polished with beeswax. Drage weight: 245 mg.

Example 4

Tablets with 100 mα of active substance

Composition: 1 tablet contains: Active substance 100.0 mg milk sugar 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg

Herstellunqverfahren:

Active ingredient, milk sugar and starch are mixed and moistened evenly with an aqueous solution of the polyvinylpyrrolidone. After sieving the moist mass (2.0 mm mesh size) and drying in a rack drying cabinet at 50 ° C., sieving is carried out again (1.5 mm mesh size) and the lubricant is added. The ready-to-press mixture is processed into tablets. Tablet weight: 220 mg diameter: 10 mm, biplane with double-sided facet and one-sided partial notch. Example 5

Tablets with 150 mg of active substance

Composition:

1 tablet contains: active substance 150.0 mg milk sugar powder 89.0 mg corn starch 40.0 mg colloids silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg

Production: The active substance mixed with milk sugar, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a sieve with a 1.5 mm mesh size.

The granules dried at 45 ° C are rubbed through the same sieve again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture. Tablet weight: 300 mg stamp: 10 mm, flat

Example 6

Hard gelatin capsules with 150 mg of active substance

1 capsule contains: Active ingredient 150.0 mg corn starch dr. approx. 180.0 mg powdered milk sugar approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg

production:

The active ingredient is mixed with the excipients, passed through a sieve with a mesh size of 0.75 mm and mixed homogeneously in a suitable device. The final mix is filled into size 1 hard gelatin capsules. Capsule filling: approx. 320 mg capsule shell: hard gelatin capsule size 1.

Example 7 Suppositories with 150 mg of Active Substance

1 suppository contains: Active ingredient 150.0 mg polyethylene glycol 1500 550.0 mg polyethylene glycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2000.0 mg

Production: After the suppository mass has melted, the active ingredient is homogeneously distributed therein and the melt is poured into pre-cooled molds. Example 8

Suspension with 50 mg of active substance

100 ml suspension contain: Active ingredient 1.00 g carboxymethyl cellulose Na salt 0.10 g p-hydroxybenzoic acid methyl ester 0.05 g p-hydroxybenzoic acid propyl ester 0.01 g cane sugar 10.00 g glycerin 5.00 g sorbitol solution 70% 20.00 g aroma 0.30 g water dist. ad 100 ml

production:

Dest. Water is heated to 70 ° C. P-Hydroxybenzoic acid methyl ester and propyl ester as well as glycerol and carboxymethyl cellulose sodium salt are dissolved therein with stirring. It is cooled to room temperature and the active ingredient is added with stirring and dispersed homogeneously. After adding and dissolving the sugar, the sorbitol solution and the aroma, the suspension is evacuated with stirring for deaeration. 5 ml of suspension contain 50 mg of active ingredient.

Example 9

Ampoules with 10 mg of active substance

Composition: active ingredient 10.0 mg 0.01 n hydrochloric acid s.q. Aqua bidest ad 2.0 ml

Production: The active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 2 ml ampoules.

Example 10 ampoules with 50 mg of active substance

Composition: active ingredient 50.0 mg 0.01 N hydrochloric acid s.q. Aqua bidest to 10.0 ml

production:

The active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 10 ml ampoules.

Claims

claims

1. Compounds of the general formula

in the

R ^{1 is} an arylmethyl or arylethyl group,

a heteroarylmethyl or heteroarylethyl group,

an arylcarbonylmethyl group,

a heteroarylcarbonylmethyl group or

an arylprop-2-enyl or heteroarylprop-2-enyl group, in which the propenyl chain can be substituted by 1 to 4 fluorine atoms or a cyano, Cι_ ₃ alkyloxy-carbonyl or nitro group,

X is a nitrogen atom or a CR ⁵ group, wherein R ^{5 is} a hydrogen atom or a Cι. ₃ alkyl group,

R ^{2 is} a hydrogen atom,

a Cι. ₆ -alkyl group, an aryl or heteroaryl group,

a substituted by a group R _a Cι_ ₆ alkyl group, wherein R _{a is} a C ₃ -7-cycloalkyl group in which one or two methylene groups independently of one another each by an oxygen or sulfur atom, by a -NH- or -N (Cι_ _3rd Alkyl) group or can be replaced by a carbonyl, sulfinyl or sulfonyl group, or a trifluoromethyl, aryl, heteroaryl, cyano, carboxy, C- |. ₃ -alkoxy- carbonyl-, aminocarbonyl-, Cι- ₃ -alkylamino-carbonyl-, di- (Cι- ₃ -alkyl) -amino- carbonyl-, pyrrolidin-1 -ylcarbonyl-, piperidin-1-ylcarbonyl-, morpholine- 4-ylcar bonyl-, piperazin-1 -ylcarbonyl-, 4- (Cι. ₃ -alkyl) -piperazin-1 -ylcarbonyl-, arylcarbonyl-, heteroarylcarbonyl-, Cι_ ₃ -alkylsulfinyl-, Cι- ₃ -alkylsulfonyl-, Hydroxy-, C-ι- ₃ -alkoxy-, Cι- ₃ -AlkylsulfanyI-, amino-, Cι. ₃ alkylamino, di- (C _{1 3} alkyl.) - amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl or 4- ( Cι. ₃ -Alkyl) -piperazin-1 -yl group means

a trifluoromethyl, carboxy, Cι. -Alkoxy-carbonyl-, aminocarbonyl-, Cι- ₃ -alkyl-amino-carbonyl-, di- (Cι. ₃ -alkyl) -amino-carbonyl-, pyrrolidin-1 -ylcarbonyl-, piperidin-1-ylcarbonyl-, morpholine -4-ylcarbonyl-, piperazin-1 -ylcarbonyl-, 4- (Cι. ₃ -alkyl) -piperazin- 1 -ylcarbonyl-, arylcarbonyl-, heteroarylcarbonyl-, Cι- ₃ -alkylsulfinyl-, Cι. ₃ -Alkylsulfonyl-, Cι- ₄ -alkoxy-, Cι- ₄ -Alkylsulfanyl-, Amino-, Cι. ₃ -alkylamino- or di- (Cι_ ₃ -alkyl) - amino-, pyrrolidin-1-yl-, piperidin-1-yl-, morpholin-4-yl-, piperazin-1-yl- or 4- (Cι- ₃ - alkyl) piperazin-1 -yl group,

a C ₃ . _7- cycloalkyl group, in which one or two methylene groups independently of one another are each replaced by an oxygen or sulfur atom, by an -NH or -N (Cι_ ₃ alkyl) group, or by a carbonyl, sulfinyl or sulfonyl group can be, or

a C ₃ - ₆ alkenyl or C ₃ .6 alkynyl group, R ^3, optionally by a Cι. ₃ alkyl group substituted C ₅ . _7- cycloalkenylmethyl group,

an arylmethyl or heteroarylmethyl group,

a straight-chain or branched C ₂ . _8- alkenyl group, which can be substituted by 1 to 15 fluorine atoms or a cyano, nitro or Cι- ₃ alkoxycarbonyl group,

or a straight-chain or branched C ₃ . ₈ -alkynyl group, which has 1 to 9 fluorine atoms or a cyan, nitro or Cι. ₃ -alkoxy-carbonyl group can be substituted,

and

R ^{4 is} an amino group substituted by the radicals R ¹⁵ and R ¹⁶ , in which

R ^{15 is} a hydrogen atom, a Cι. ₆ alkyl, C ₃ - ₆ cycloalkyl, C3. _6- Cycloalkyl-C1.3- alkyl, aryl or aryl -CC. ₃ -alkyl group and

R ^{16 represents} an R ¹⁷ -C ₂ - ₃ alkyl group, the C ₂ - ₃ alkyl part being straight-chain and being substituted by 1 to 4 Cι_ ₃ alkyl groups, which may be the same or different, and wherein the C ₂ - ₃ -alkyl group from position 2 can be linked to R ¹⁷ , and

R ^{17 represents} an amino or C ₃ alkylamino group,

an amino group substituted by the radicals R ¹⁵ and R ¹⁸ , in which R ^{15 is} as defined above and R ^{18 is} a C ₃ -o-cycloalkyl-Cι_ ₂ -alkyl group substituted by R ¹⁹ in the 1 position of the cycloalkyl radical or one in 1- or 2-position by an R ¹⁹ -Cι- ₂ alkyl group substituted C ₃ .ι ₀ cycloalkyl group, where R ^{19 is} an amino or Cι. ₃ -alkylamino group,

an amino group substituted by the radicals R ¹⁵ and R ²⁰ , in which

R ^{15 is} as defined above and R ^{20 is} a C ₄ - or C ₈ .ι ₀ -cycloalkyl group in which a methylene group from position 3 of the C ₄ or C ₈ -ιo-cycloalkyl group by a -NH- Group is replaced represents

or an amino group substituted by the radicals R ¹⁵ and R ²¹ , in which

R ¹⁵ is defined as mentioned above and R ^{21 is} a C ₃ - ₄ - or C ₈ substituted in the 2- or 3-position by an amino or C ₃ alkyl alkyl group. _{10 represents} cycloalkyl group,

mean,

wherein the above-mentioned radicals R, R ²⁰ and R may be mono- or disubstituted by R _b , where the substituents may be the same or different and R _{b is} a fluorine atom, a Ct- _3- alkyl-, trifluoromethyl-, cyano-, amino -, Cι_ ₃ - alkylamino, hydroxy or Cι. _{3 represents} alkyloxy group, and in which one or two methylene groups of the cycloalkyl radical independently of one another in each case by an oxygen or sulfur atom or by an -NH or -N (Ct. ₃ -alkyl) group, or by a carbonyl or sulfinyl group or sulfonyl group can be replaced,

whereby the aryl groups mentioned in the definition of the abovementioned radicals are to be understood as meaning phenyl or naphthyl groups which can be mono-, di- or tri-substituted independently of one another by R _h , where the substituents can be identical or different and R _{h is} one Fluorine, chlorine, bromine or iodine atom, a trifluoromethyl, cyano, nitro, amino, aminocarbonyl, Cι_ ₃ alkoxycarbonyl, aminosulfonyl, methyl sulfonyl, acetylamino, methylsulfonylamino, C1-3 Alkyl, cyclopropyl, ethenyl, ethinyl, morpholinyl, hydroxy, Ct_ ₃ alkyloxy, Represents difluoromethoxy or trifluoromethoxy group, and in which each hydrogen atom can additionally be replaced by a fluorine atom,

the heteroaryl groups mentioned in the definition of the abovementioned radicals are to be understood as a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group,

or a pyrrolyl, furanyl, thienyl or pyridyl group in which one or two methine groups are replaced by nitrogen atoms,

or an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group in which one to three methine groups are replaced by nitrogen atoms and the above-mentioned heteroaryl groups can be mono- or disubstituted by R _h , where the substituents can be the same or different and R _h is defined as mentioned above,

the monocyclic and polycyclic ring systems in the definition of the cycloalkyl radicals mentioned above are to be understood, the multiple cycles being fused, spiro-linked or bridged,

unless stated otherwise, the alkyl, alkenyl and alkynyl groups mentioned above can be straight-chain or branched,

the carboxy groups mentioned in the definition of the abovementioned radicals can be replaced by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions,

and wherein the amino and imino groups mentioned in the definition of the abovementioned radicals can be substituted by a radical which can be split off in vivo, their tautomers, enantiomers, diastereomers, their mixtures, their prodrugs and their salts.

2. Compounds of general formula I according to claim 1, in which

R ¹ and R ^{4 are defined} as mentioned in claim 1,

X is a nitrogen atom or a -CH group,

R ^{2 is} a hydrogen atom, a C ^ alkyl, C ₃ - ₆ cycloalkyl or phenyl group and

R ^{3 is} a 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enylmethyl, furanylmethyl, thienylmethyl, chlorobenzyl, Bromobenzyl, iodobenzyl, methoxybenzyl or cyano benzyl group,

their enantiomers, their diastereomers, their mixtures and their salts.

3. Compounds of general formula I according to claim 2, in which

R ^{1 is} phenylmethyl, phenylcarbonylmethyl, phenylprop-2-enyl, pyridinylmethyl, pyrimidinylmethyl, naphthylmethyl, quinolinylmethyl, isoquinolinylmethyl, chinazolinylmethyl, quinoxalinylmethyl, naphthyridinylmethyl, or benzotriazole or two fluorine, chlorine, bromine atoms or one or two cyan, nitro, amino, Cι. ₃ -alkyl-, Cι. ₃ -alkyloxy and morpholinyl groups can be substituted, the substituents being identical or different,

X is a nitrogen atom or a -CH group,

R ^{2 is} a hydrogen atom, R ^{3 is} a 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enylmethyl, furanylmethyl, thienylmethyl, chlorobenzyl, Bromobenzyl, iodobenzyl or cyanobenzyl group and

R ^{4 represents} an N- (2-aminoethyl) -N-methyl-amino group in which the ethyl group can be substituted by 1 to 4 methyl groups,

their tautomers, their mixtures and their salts.

4. Compounds of general formula I according to claim 3, in which

R ^{1 is} an isoquinolinylmethyl, quinazolinylmethyl or benzyl group which can be substituted by a methyl or cyano group,

X is a nitrogen atom or a -CH group,

R ^{2 is} a hydrogen atom,

R ^{3 is} a 2-butyn-1-yl group and

R ^{3 is} an N- (2-aminoethyl) -N-methylamino, N- (2-aminopropyl) -N-methylamino or N- (2-amino-2-methylpropyl) -N-methylamino group mean,

their tautomers and their salts.

5. The following compounds of general formula I according to claim 1:

(a) 2- [N- (2-Aminoethyl) -N-methyl-amino] -3- (2-butyn-1-yl) -5 - [(4-methyl-quinazolin-2-yl) methyl] - 3,5-dihydro-imidazo [4,5-d] pyridazin-4-one | (b) 2- [N- (2-Aminoethyl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(3-methyl-isoquinolin-1-yl) methyl] - 3,5-dihydro-imidazo [4,5-d] pyridazin-4-one |

(c) (SJ-2- [N- (2-aminopropyl) -N-methylamino] -3- (2-butyn-1-yl) -5- (2-cyanophenylmethyl) -3,5- dihydro-imidazo [4,5-d] pyridazin-4-one | (d) 2- [N- (2-amino-2-methylpropyl) -N-methylamino] -3- (2-butyn-1 - yl) -5- (2-cyanophenylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one (

(e) ('S) -2- [N- (2-aminopropyl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(4-methyl-quinazoline- 2-yl) methyl] -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one [

(f) 2- [N- (2-Aminoethyl) -N-methylamino] -3- (2-butyn-1-yl) -5 - [(3-methyl-isoquino ^' n-1-yl) methyl ] -3,5-dihydro-imidazo [4,5-c] pyridine-4-one |

(g) (S) -2- [N- (2-aminopropyl) -N-methylamino] -3- (2-butyn-1-yl) -5- (4-cyano-isoquinoline- 3-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one |

as well as their tautomers and their salts.

6. Physiologically acceptable salts of the compounds according to claims 1 to 5 with inorganic or organic acids or bases.

7. Medicament containing a compound according to one of claims 1 to 5 or a physiologically acceptable salt according to claim 6 in addition to optionally one or more inert carriers and / or diluents.

8. Use of a compound according to at least one of claims 1 to 6 for the manufacture of a medicament for the treatment of type I and diabetes mellitus

Type II, arthritis, obesity, allograft transplantation and osteoporosis caused by calcitonin is suitable.

9. A method for producing a medicament according to claim 7, characterized in that a compound according to at least one of claims 1 to 6 is incorporated into one or more inert carriers and / or diluents in a non-chemical way.

10. A process for the preparation of the compounds of general formula I according to claims 1 to 6, characterized in that

a) a compound of the general formula

in the

R ¹ to R ³ and X are defined as mentioned in claim 1 and

Z ^{1 is} a leaving group such as a halogen atom, a substituted hydroxy, mercapto,

Represents sulfinyl, sulfonyl or sulfonyloxy group, with R ⁴ -H or salts thereof, wherein R ^{4 is} as defined in claim 1, is reacted; or

b) a compound of the general formula

in which R ¹ , R ² , R ³ and X are defined as mentioned in claim 1 and

Z ^{2 represents} one of the groups mentioned in claim 1 for R ⁴ , which contain an amino group which is not bonded directly to the imidazopyridazinone backbone and which in Z ^{2 is} Boc-protected, where Boc is a tert-butyloxycarbonyl radical, is deprotected;

and or

protective groups used subsequently during the reaction are then split off and / or

the compounds of general formula I thus obtained are separated into their enantiomers and / or diastereomers and / or

the compounds of the formula I obtained are converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids or bases.