CA2559444A1 - Imidazopyridazine diones, the production thereof, and the use of the same as a medicament - Google Patents

Imidazopyridazine diones, the production thereof, and the use of the same as a medicament Download PDF

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CA2559444A1
CA2559444A1 CA002559444A CA2559444A CA2559444A1 CA 2559444 A1 CA2559444 A1 CA 2559444A1 CA 002559444 A CA002559444 A CA 002559444A CA 2559444 A CA2559444 A CA 2559444A CA 2559444 A1 CA2559444 A1 CA 2559444A1
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amino
ylmethyl
piperidin
dihydro
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Matthias Eckhardt
Frank Himmelsbach
Elke Langkopf
Iris Kauffmann-Hefner
Mohammad Tadayyon
Leo Thomas
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Boehringer Ingelheim International GmbH
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Abstract

The invention relates to substituted imidazopyridazine diones of general formula (I) wherein R1 to R4 have the designation defined in patent claim 1.
The invention also relates to the tautomers, enantiomers, diastereomers, mixtures and salts of said diones, comprising valuable pharmacological properties, especially an inhibitive effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).

Description

,.

86520fft Boehringer Ingelheim Case 1/1658 Foreign filing text Imidazopyridazinediones, their preparation and their use as pharmaceutical compositions The present invention relates to substituted imidazopyridazinediones of general formula R~\N /N
/~ R4 R2/ ' N
O
the tautomers, the stereoisomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV), the preparation thereof, the use thereof for preventing or treating illnesses or conditions connected with an increased DPP-IV activity or capable of being prevented or alleviated by reducing the DPP-IV activity, particularly type I or type II
diabetes mellitus, the pharmaceutical compositions containing a compound of general formula (I) or a physiologically acceptable salt thereof and processes for the preparation thereof.
In the above formula I
R~ denotes an arylmethyl group, a heteroarylmethyl group, Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text 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~_3-alkyloxy-carbonyl or nitro group, R2 denotes a C~_6-alkyl group, an aryl or heteroaryl group, a C~_6-alkyl group substituted by a group Ra, where Ra denotes a fluorine, chlorine or bromine atom, a C3_~-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~_3-alkyl)- group, or by a carbonyl, sulphinyl or sulphonyl group, or a trifluoromethyl, aryl, heteroaryl, cyano, carboxy, C~_3-alkoxy-carbonyl, aminocarbonyl, C~_3-alkylamino-carbonyl or di-(C~_3-alkyl)-amino-carbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C~_3-alkyl)-piperazin-1-ylcarbonyl, arylcarbonyl, heteroarylcarbonyl, C~_3-alkylsulphinyl or C~_3-alkylsulphonyl group, a C2_6-alkyl group substituted by a group Rb, where Rb is isolated from the cyclic nitrogen atom by at least two carbon atoms and Rb denotes a hydroxy, C~_3-alkoxy, C~_3-alkylsulphanyl, amino, C~_3-alkylamino or di-(C~_3-alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl or 4-(C~_3-alkyl)-piperazin-1-yl group, Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text a C3_6-cycloalkyl group or a C3_6-alkenyl or C3_6-alkynyl group, while the multiple bond is isolated from the cyclic nitrogen atom by at least one carbon atom, R3 denotes a C5_~-cycloalkenylmethyl group optionally substituted by a C~_3-alkyl group, an arylmethyl or heteroarylmethyl group, a straight-chain or branched C2_$-alkenyl group which may be substituted by 1 to 15 fluorine atoms or by a cyano, nitro or C~_3-alkoxy-carbonyl group, or a straight-chain or branched C3_6-alkynyl group which may be substituted by 1 to 9 fluorine atoms or by a cyano, nitro or C2_$-alkoxy-carbonyl group, and R4 denotes a pyrrolidin-1-yl or azetedin-1-yl group which is substituted in the 3 position by an amino or C~_3-alkylamino group and may additionally be substituted by one or two C~_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~_3-alkylamino group and may additionally be substituted by one or two C~_3-alkyl groups, a piperazin-1-yl or homopiperazin-1-yl group which may be substituted by one or two C~_3-alkyl groups, an amino group substituted by the groups R~5 and R~6 wherein Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text R'5 denotes a hydrogen atom, a C~_6-alkyl, C3_6-cycloalkyl, C3_6-cycloalkyl-C~_3-alkyl, aryl or aryl-C~_3-alkyl group and R~6 denotes a R~'-C2_3-alkyl group, while the C2_3-alkyl moiety is straight-chain and may be substituted by 1 to 4 C~_3-alkyl groups, which may be identical or different, and R" denotes an amino or C~_3-alkylamino group, an amino group substituted by the groups R'S and R'$, wherein R~5 is as hereinbefore defined and R'$ denotes a C3_6-cycloalkyl-methyl group substituted by R'9 in the 1 position of the cycloalkyl group or a C3_6-cycloalkyl group substituted by a R'9-CH2- group in the 1 position, while R'9 denotes an amino or C~_3-alkylamino group, an amino group substituted by the groups R'S and R2° wherein R~5 is as hereinbefore defined and R2° 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 R2° may each be substituted by one or two C~_3-alkyl groups, an amino group substituted by the groups R'5 and RZ' wherein R~5 is as hereinbefore defined and R2~ denotes a C3_~-cycloalkyl group substituted in the 2 or 3 position by an amino or C~_3-alkylamino group, which may additionally be substituted by one or two C~_3-alkyl groups, while by the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups, which may be mono-, di- or trisubstituted by Rh independently of one another, while the substituents may be identical or different Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text and Rh denotes a fluorine, chlorine, bromine or iodine atom, a trifluoromethyl, cyano, nitro, amino, aminocarbonyl, C~_3-alkoxy-carbonyl, aminosulphonyl, methylsulphonyl, acetylamino, methylsulphonylamino, C~_3-alkyl, cyclopropyl, ethenyl, ethynyl, morpholinyl, hydroxy, C~_3-alkyloxy, difluoromethoxy or trifluoromethoxy group, and 5 wherein additionally each hydrogen atom may be replaced by a fluorine atom, by the heteroaryl groups mentioned in the definition of the above groups are meant a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, phenanthridinyl, quinolinyl or isoquinolinyl group, or a pyrrolyl, furanyl, thienyl or pyridyl group is meant, wherein one or two methyne groups are replaced by nitrogen atoms, or a indolyl, benzofuranyl, benzothiophenyl, phenanthridinyl, quinolinyl or isoquinolinyl group is meant, wherein one to three methyne groups are replaced by nitrogen atoms, or a 1,2-dihydro-2-oxo-pyridinyl, 1,4-dihydro-4-oxo-pyridinyl, 2,3-dihydro-3-oxo-pyridazinyl, 1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl, 1,2-dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-oxo-pyrimidinyl, 1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl, 1,2-dihydro-2-oxo-pyrazinyl, 1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl, 2,3-dihydro-2-oxo-indolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxo-1H-benzimidazolyl, 2,3-dihydro-2-oxo-benzoxazolyl, 1,2-dihydro-2-oxo-quinolinyl, 1,4-dihydro-4-oxo-quinolinyl, 1,2-dihydro-1-oxo-isoquinolinyl, 1,4-dihydro-4-oxo-cinnolinyl, 1,2-dihydro-2-oxo-quinazolinyl, 3,4-dihydro-4-oxo-quinazolinyl, 1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl, 1,2-dihydro-2-oxoquinoxalinyl, 1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl, 1,2-dihydro-1-oxo-phthalazinyl, 1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl, cumarinyl, 2,3-dihydro-benzo[1,4]dioxinyl or 3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl group is meant, Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text and the above-mentioned heteroaryl groups may be mono- or disubstituted by Rh, while the substituents may be identical or different and Rh is as hereinbefore defined, 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, the prodrugs thereof and the salts thereof.
The carboxy groups mentioned in the definition of the abovementioned groups may 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 furthermore the amino and imino groups mentioned in the definition of the abovementioned groups may be substituted by a group which can be cleaved 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).
By a group which can be converted in vivo into a carboxy group is meant, for example, a hydroxymethyl group, a carboxy group esterified with an alcohol wherein the alcohol moiety is preferably a C~_6-alkanol, a phenyl-C~_3-alkanol, a C3_9-cycloalkanol, while a C5_$-cycloalkanol may additionally be substituted by one or two C~_3-alkyl groups, a C5_$-cycloalkanol wherein a methylene group in the 3 or 4 position is replaced by an oxygen atom or by an imino group optionally substituted by a C~_3-alkyl, phenyl-C~_3-alkyl, phenyl-C~_3-alkoxycarbonyl or C2_6-alkanoyl group and the cycloalkanol moiety may additionally be substituted by one or two C~_3-alkyl groups, a C4_~-cycloalkenol, a C3_5-alkenol, a phenyl-C3_5-alkenol, a C3_5-alkynol or phenyl-C3_5-alkynol, with the proviso that no bonds to the oxygen atom start from a carbon atom which carries a double or triple bond, a C3_$-cycloalkyl-C~_3-alkanol, a bicycloalkanol with a total of 8 to 10 carbon atoms which may additionally be Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text substituted in the bicycloalkyl moiety by one or two C~_3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula RP-CO-O-(RqCR~)-OH, wherein Rp denotes a C~_$-alkyl, C5_~-cycloalkyl, C~_$-alkyloxy, C5_~-cycloalkyloxy, phenyl or phenyl- C~_3-alkyl group, Rq denotes a hydrogen atom, a C~_3-alkyl, C5_~-cycloalkyl or phenyl group and R~ denotes a hydrogen atom or a C~_3-alkyl group, by a group which is negatively charged under physiological conditions is meant, for example, a tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C~_6-alkylsulphonylamino, phenylsulphonylamino, benzylsulphonylamino, trifluoromethylsulphonylamino, C~_6-alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl or perfluoro-C~_6-alkylsulphonylaminocarbonyl group and by a group which can be cleaved in vivo from an imino or amino group is meant, for example, a hydroxy group, an acyl group such as a phenylcarbonyl group optionally mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C~_3-alkyl or C~_3-alkoxy groups, while the substituents may be identical or different, a pyridinoyl group or a C~_~6-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl or allyloxycarbonyl group, a C~_~6-alkoxycarbonyl or C~_~6-alkylcarbonyloxy group, wherein hydrogen atoms may be wholly or partially replaced by fluorine or chlorine atoms such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text ., dodecyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy, 2,2,2-trichloroethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, tert.butylcarbonyloxy, pentylcarbonyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy, decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy or hexadecylcarbonyloxy group, a phenyl-C~_6-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a 3-amino-propionyl group wherein the amino group may be mono- or disubstituted by C~_6-alkyl or C3_~-cycloalkyl groups and the substituents may be identical or different, a C~_3-alkylsulphonyl-C2_4-alkoxycarbonyl, C~_3-alkoxy-C2_4-alkoxy-C2_4-alkoxycarbonyl, RP-CO-O-(RqCR~)-O-CO, C~_6-alkyl-CO-NH-(RSCRt)-O-CO- or C~_6-alkyl-CO-O-(RSCRt)-(RSCRt)-O-CO- group, wherein Rp to R~ are as hereinbefore defined, RS and Rt, which may be identical or different, denote hydrogen atoms or C~_3-alkyl groups.
Moreover, unless otherwise stated, the saturated alkyl and alkoxy moieties containing more than 2 carbon atoms mentioned in the definitions above also include the branched isomers thereof such as the isopropyl, tert.butyl, isobutyl group, etc.
R' may denote, for example, a 2-cyanobenzyl, 3-fluorobenzyl, 3-methoxybenzyl, bromo-2-cyanobenzyl, 3-chloro-2-cyanobenzyl, 2-cyano-4-fluorobenzyl, 2-cyano-6-fluorobenzyl, 3,5-dimethoxybenzyl, 2,6-dicyanobenzyl, 5-cyanofuranylmethyl, oxazolylmethyl, isoxazolylmethyl, 5-methoxycarbonylthienylmethyl, pyridinylmethyl, 3-cyanopyridin-2-ylmethyl, 3-cyanopyridin-4-ylmethyl, 4-cyanopyridin-3-ylmethyl, 6-cyanopyridin-2-ylmethyl, 6-fluoropyridin-2-ylmethyl, pyrimidin-2-ylmethyl, 4-methyl-pyrimidin-2-ylmethyl, 4,6-dimethyl-pyrimidin-2-ylmethyl, 3-(2-cyanophenyl)-prop-2-enyl, 3-(pyridin-2-yl)-prop-2-enyl, 3-(pentafluorophenyl)-prop-2-enyl, phenyl-carbonylmethyl, 3-methoxyphenylcarbonylmethyl, naphth-1-ylmethyl, naphth-2-ylmethyl, 4-cyanonaphth-1-ylmethyl, quinolin-1-ylmethyl, quinolin-2-ylmethyl, quinolin-6-ylmethyl, 4-cyanoquinolin-1-ylmethyl, isoquinolin-1-ylmethyl, 4-cyano-isoquinolin-1-ylmethyl, 4-cyano-isoquinolin-3-ylmethyl, 3-methylisoquinolin-1-Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text ylmethyl, quinazolin-2-ylmethyl, 4-methylquinazolin-2-ylmethyl, [1,5]naphthiridin-2-yl, [1,5]naphthiridin-3-yl, 1-methyl-benzotriazol-5-ylmethyl, phenanthridin-6-ylmethyl, quinoxalin-6-ylmethyl or 2,3-dimethyl-quinoxalin-6-ylmethyl group.
R2 may denote, for example, a methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, methylpropyl, 2-propen-1-yl, 2-propyn-1-yl, cyclopropylmethyl, benzyl, 2-phenylethyl, phenylcarbonylmethyl, 3-phenylpropyl, 2-hydroxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, 2-(pyrrolidino)ethyl, 2-(piperidino)ethyl, 2-(morpholino)ethyl, 2-(piperazino)ethyl, 2-(4-methylpiperazino)ethyl, 3-hydroxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-(dimethylamino)propyl, 3-(diethylamino)propyl, 3-(pyrrolidino)propyl, 3-(piperi-dino)propyl, 3-(morpholino)propyl-,3-(piperazino)propyl, 3-(4-methylpiperazino)-propyl, carboxymethyl, (methoxycarbonyl)methyl, (ethoxycarbonyl)methyl, 2-carboxyethyl, 2-(methoxycarbonyl)ethyl, 2-(ethoxycarbonyl)ethyl, 3-carboxypropyl, 3-(methoxycarbonyl)propyl, 3-(ethoxycarbonyl)propyl, (aminocarbonyl)methyl, (methylaminocarbonyl)methyl, (dimethylaminocarbonyl)methyl, (pyrroli-dinocarbonyl)methyl, (piperidinocarbonyl)methyl, (morpholinocarbonyl)methyl, 2-(aminocarbonyl)ethyl, 2-(methylaminocarbonyl)ethyl, 2-(dimethylaminocarbo-nyl)ethyl, 2-(pyrrolidinocarbonyl)ethyl, 2-(piperidinocarbonyl)ethyl, 2-(morpholino-carbonyl)ethyl, cyanomethyl, 2-cyanoethyl, 2-fluoroethyl, pyridin-3-ylmethyl or pyridin-4-ylmethyl group.
R3 may denote, for example, a 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-propyn-1-yl, 2-butyn-1-yl, 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.
R4 may denote, for example, a 3-aminopyrrolidin-1-yl, 3-aminopiperidin-1-yl, 3-(methylamino)-piperidin-1-yl, 3-(ethylamino)-piperidin-1-yl, 3-amino-2-methyl-piperi-Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text din-1-yl, 3-amino-3-methyl-piperidin-1-yl, 3-amino-4-methyl-piperidin-1-yl, 3-amino-5-methyl-piperidin-1-yl, 3-amino-6-methyl-piperidin-1-yl, 4-aminopiperidin-1-yl, 3-amino-hexahydroazepin-1-yl, 4-amino-hexahydroazepin-1-yl, (2-aminocyclo-propyl)amino, (2-aminocyclobutyl)amino, (3-aminocyclobutyl)amino, 5 (2-aminocyclopentyl)amino, (3-aminocyclopentyl)amino, (2-aminocyclohexyl)amino, (3-aminocyclohexyl)amino, piperazin-1-yl, homopiperazin-1-yl, N-(2-aminoethyl)-N-methylamino, N-(2-aminopropyl)-N-methylamino or N-(2-amino-2-methyl-propyl)-N-methylamino group.
10 Preferred compounds of the above general formula I are those wherein R~ and R2 are as hereinbefore defined, R3 denotes a 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enyl-methyl, furanylmethyl, thienylmethyl, chlorobenzyl, bromobenzyl, iodobenzyl, methoxybenzyl or cyanobenzyl group, and R4 denotes an N-(2-aminoethyl)-N-methyl-amino group which may be substituted in the ethyl moiety by one or two C~_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~_3-alkyl groups, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.
Particularly preferred compounds of the above general formula I are those wherein R' denotes a phenylmethyl, phenylcarbonylmethyl, phenylprop-2-enyl, pyridinylmethyl, pyrimidinylmethyl, naphthylmethyl, quinolinylmethyl, isoquinolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl, phenanthridinylmethyl, naphthyridinylmethyl or benzotriazolylmethyl group, while all the above-mentioned Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text aryl and heteroaryl groups may be substituted by one or two fluorine, chlorine, bromine atoms or one or two cyano, nitro, amino, C~_3-alkyl, C~_3-alkyloxy and morpholinyl groups, while the substituents are identical or different, Rz denotes a C~_6-alkyl group which may be substituted by a fluorine atom or a cyano, carboxy, C~_3-alkyloxy-carbonyl, aminocarbonyl, C~_3-alkylaminocarbonyl, C~_3-alkylsulphonyl, aryl or heteroaryl group, while the aryl or heteroaryl group is as hereinbefore defined, C2_6-alkyl group a substituted by a group Rb, where Rb is isolated from the cyclic nitrogen atom by at least two carbon atoms and Rb denotes a hydroxy or C~_3-alkyloxy group, or a C3_6-alkenyl or C3_6-alkynyl group, while the multiple bond is isolated from the cyclic nitrogen atom by at least one carbon atom, R3 denotes a 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enyl-methyl, furanylmethyl, thienylmethyl, chlorobenzyl, bromobenzyl, iodobenzyl or cyanobenzyl group and R4 denotes 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.
Most particularly preferred compounds of the above general formula I are those wherein R~ denotes a cyanobenzyl, phenylcarbonylmethyl, methylquinazolinylmethyl, methyl-isoquinolinylmethyl, naphthylmethyl or quinolinylmethyl group, Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text R2 denotes a methyl, prop-2-enyl, prop-2-ynyl, 2-fluoroethyl, cyanomethyl, carboxy-methyl, aminocarbonylmethyl, pyridinylmethyl or phenylmethyl group, R3 denotes a 2-butyn-1-yl group and R4 denotes a 3-aminopiperidin-1-yl or piperazin-1-yl group, the enantiomers, the diastereomers, the mixtures thereof and salts.
The following preferred compounds may be mentioned by way of example:
(1) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-(quinolin-2-yl-methyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, (2) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, (3) (R)-1-(1-but-2-ynyl )-2-(3-amino-piperidin-1-yl)-5-(prop-2-enyl)-6-(quinolin-2-yl-methyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, (4) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(phenylmethyl)-6-(quinolin-2-yl-methyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, (5) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, (6) 1-(but-2-ynyl)-2-(piperazin-1-yl)-5-methyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, (7) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-hydroxycarbonylmethyl-6-(naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text (8) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-aminocarbonylmethyl-6-(naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, (9) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(pyridin-3-ylmethyl)-6-(naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, (10) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(prop-2-ynyl)-6-(naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, (11) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(pyridin-4-ylmethyl)-6-(naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, (12) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(3-methyl-isoquinolin-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, (13) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(phenylcarbonylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, (14) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(4-methyl-quinazolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, (15) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(2-cyano-benzyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, (16) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-fluoro-ethyl)-6-(4-methyl-quinazolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, and the salts thereof.

Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text According to the invention the compounds of general formula I are obtained by methods known per se, for example by the following methods:
a) reacting a compound of general formula R1\N N
/~Z' ( II ), R2/ ' N
O
wherein R' to R3 are as hereinbefore defined and Z' denotes a leaving group such as a halogen atom, a substituted hydroxy, mercapto, sulphinyl, sulphonyl or sulphonyloxy group such as for example a chlorine or bromine atom, a methanesulphonyl or methanesulphonyloxy group, with a compound of general formula H - R4 ,(III) wherein R4 is as hereinbefore defined.
The reaction is expediently carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethylsulphoxide, methylene chloride, ethyleneglycolmonomethylether, ethyleneglycoldiethylether or sulpholane, optionally in the presence of an inorganic or tertiary organic base, e.g. sodium carbonate or potassium hydroxide, a tertiary organic base, e.g. triethylamine, or in the presence of N-ethyl-diisopropylamine (Hunig base), while these organic bases may simultaneously also serve as solvent, and optionally 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 Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text preferably at temperatures between -10 and 120°C. However, the reaction may also be carried out without a solvent or in an excess of the compound of general formula IV used.
5 b) In order to prepare a compound of general formula I wherein R4 according to the definition provided hereinbefore contains an amino group or an alkylamino group optionally substituted in the alkyl moiety:
deprotecting a compound of general formula R \N N
/~R4 ( IV ), R2/ ' N
O
wherein R', R2 and R3 are as hereinbefore defined and R4' contains an N-tert.-butyloxycarbonylamino group or an N-tert.-butyloxycarbonyl-N-alkylamino group, while the alkyl moiety of the N-tert.-butyloxycarbonyl-N-alkyl-amino group may be substituted as mentioned hereinbefore.
The tert.-butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with bromotrimethylsilane or iodotrimethylsilane, optionally using a solvent such as methylene chloride, ethyl acetate, dioxane, methanol, isopropanol or diethyl ether at temperatures between 0 and 80°C.
If according to the invention a compound of general formula I is obtained which contains an amino, alkylamino or imino group, this may be converted by acylation or sulphonylation into a corresponding acyl or sulphonyl compound of general formula I
or Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text if a compound of general formula I is obtained which contains an amino, alkylamino or imino group, this may be converted by alkylation or reductive alkylation into a corresponding alkyl compound of general formula I or if a compound of general formula I is obtained which contains a carboxy group, this may be converted by esterification into a corresponding ester of general formula I or if a compound of general formula I is obtained which contains a carboxy or ester group, this may be converted by reaction with an amine into a corresponding amide of general formula I.
The subsequent esterification is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane or most advantageously in a corresponding alcohol, optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionylchloride, trimethylchlorosilane, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole and optionally additionally in the presence of 4-dimethylamino-pyridine, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, conveniently at temperatures between 0 and 150°C, preferably at temperatures between 0 and 80°C.
The subsequent ester formation may also be carried out by reacting a compound which contains a carboxy group with a corresponding alkyl halide.
The subsequent acylation or sulphonylation is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane with a corresponding acyl or sulphonyl derivative, optionally in the presence of a tertiary organic base or in the presence of an inorganic base or in the presence of a Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole and optionally also in the presence of 4-dimethylamino-pyridine, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, expediently at temperatures between 0 and 150°C, preferably at temperatures between 0 and 80°C.
The subsequent alkylation is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane with an alkylating agent such as a corresponding halide or sulphonic acid ester, e.g. with methyl iodide, ethyl bromide, dimethyl sulphate or benzyl chloride, optionally in the presence of a tertiary organic base or in the presence of an inorganic base, expediently at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C.
The subsequent reductive alkylation is carried out with a corresponding carbonyl compound such as formaldehyde, acetaldehyde, propionaldehyde, acetone or butyraldehyde in the presence of a complex metal hydride such as sodium borohydride, lithium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride, expediently at a pH of 6-7 and at ambient temperature or in the presence of a hydrogenation catalyst, e.g. with hydrogen in the presence of palladium/charcoal, at a hydrogen pressure of 1 to 5 bar. The methylation can also be carried out in the presence of formic acid as reduction agent at elevated temperatures, e.g. at temperatures between 60 and 120°C.
The subsequent amide formation is carried out by reacting a corresponding reactive carboxylic acid derivative with a corresponding amine, optionally in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, whilst the amine used may simultaneously serve as solvent, optionally in the presence of a Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text tertiary organic base or in the presence of an inorganic base or with a corresponding carboxylic acid in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole and optionally also in the presence of 4-dimethylamino-pyridine, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, expediently at temperatures between 0 and 150°C, preferably at temperatures between 0 and 80°C.

In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group, protecting groups for a carboxy group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group, protecting groups for an amino, alkylamino or imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis 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 sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120°C, preferably at temperatures between 10 and 100°C.

Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal 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 ambient 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 group is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethylether.
A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120°C or by treating with sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran, at temperatures between 0 and 50°C.
A phthalyl group 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.
Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
Thus, for example, the cisltrans mixtures obtained may be separated by chromatography into their cis and trans isomers, the compounds of general formula I
obtained which occur as racemates may be separated by methods known per se (cf.
Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text Interscience, 1971) into their optical enantiomers and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g.
by chromatography and/or fractional crystallisation, and, if these compounds are 5 obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically 10 active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of 15 suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be, for example, (+) or (-)-menthol and an optically active acyl group in amides, for example, may be a (+)- or (-)-menthyloxycarbonyl.
Furthermore, the compounds of formula I obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or malefic acid.
Moreover, if the new compounds of formula I thus obtained contain a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text The compounds of general formulae II and IV used as starting compounds are either known from the literature or may be prepared by methods known from the literature (see Examples I to VII).
As already mentioned hereinbefore, the compounds of general formula I
according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibiting effect on the enzyme DPP-IV.
The biological properties of the new compounds were investigated as follows:
The ability of the substances and their corresponding salts to inhibit the DPP-IV
activity can be demonstrated in an experiment 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 in order to induce the DPP-IV expression was carried out in accordance with the description by Reiher et al. in an article entitled "Increased expression of intestinal cell line Caco-2" , which appeared in Proc. Natl. Acad. Sci. Vol.
90, pp.
5757-5761 (1993). The cell extract was obtained from cells solubilised in a buffer (10mM Tris HCI, 0.15 M NaCI, 0.04 t.i.u. aprotinin, 0.5% Nonidet-P40, pH 8.0) by centrifugation at 35,000 g for 30 minutes at 4°C (to remove cell debris).
The DPP-IV assay was carried out as follows:
50 NI of substrate solution (AFC; AFC is amido-4-trifluoromethylcoumarin), final concentration 100 uM, were placed in black microtitre plates. 20 pl of assay buffer (final concentrations 50 mM Tris HCI pH 7.8, 50 mM NaCI, 1 % DMSO) was pipetted in. The reaction was started by the addition of 30 pl of solubilised Caco-2 protein (final concentration 0.14 pg of protein per well). The test substances under investigation were typically added prediluted to 20 pl, while the volume of assay buffer was then reduced accordingly. The reaction was carried out at ambient temperature, the incubation period was 60 minutes. Then the fluorescence was measured in a Victor 1420 Multilabel Counter, with the excitation wavelength at 405 nm and the emission wavelength at 535 nm. Dummy values (corresponding to 0 activity) were obtained in mixtures with no Caco-2 protein (volume replaced by assay buffer), control values (corresponding to 100 % activity) were obtained in mixtures without any added substance. The potency of the test substances in question, Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text expressed as IC5o values, were calculated from dosage/activity curves consisting of 11 measured points in each case. The following results were obtained:
Compound DPP IV inhibition (Example no.) ICSO [nM]

1(1) 4 1(2) 6 1 (3) 14 1 (4) 52 The compounds prepared according to the invention are well tolerated as no toxic side effects could be detected in rats after the oral administration of 10 mg/kg of the compound of Example 1 (1 ), for example.
In view of their ability to inhibit DPP-IV activity, the compounds of general formula I
according to the invention and the corresponding pharmaceutically acceptable salts thereof are suitable for influencing any conditions or diseases which can be affected by the inhibition of the DPP-IV activity. It is therefore to be expected that the compounds according to the invention will be suitable for the prevention or treatment of diseases or conditions such as type I and type II diabetes mellitus, diabetic complications (e.g. retinopathy, nephropathy or neuropathies), metabolic acidosis or ketosis, reactive hypoglycaemia, insulin resistance, metabolic syndrome, dyslipidaemias of various origins, arthritis, atherosclerosis and related diseases, obesity, allograft transplantation and osteoporosis caused by calcitonin. In addition, these substances are suitable for preventing B-cell degeneration such as e.g.
apoptosis or necrosis of pancreatic B-cells. The substances are also suitable for improving or restoring the function of pancreatic cells and additionally increasing the size and number of pancreatic B-cells. Additionally, on the basis of the role of the glucagon-like peptides such as e.g. GLP-1 and GLP-2 and their link with DPP-IV
inhibition, it is expected that the compounds according to the invention will be suitable for achieving, inter alia, a sedative or tranquillising effect, as well as having a favourable effect on catabolic states after operations or hormonal stress responses or possibly reducing mortality and morbidity after myocardial infarct.
Moreover, they Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text are suitable for treating any conditions connected with the effects mentioned above and mediated by GLP-1 or GLP-2. The compounds according to the invention may also be used as diuretics or antihypertensives and are suitable for preventing and treating acute kidney failure. The compounds according to the invention may also be used to treat inflammatory complaints of the respiratory tract. They are also suitable for preventing and treating chronic inflammatory bowel diseases such as e.g.
irritable bowel syndrome (IBS), Crohn's disease or ulcerative colitis and also pancreatitis. It is also expected that they can be used for all kinds of injury or damage to the gastrointestinal tract such as may occur in colitis and enteritis, for example.
Moreover, it is expected that DPP-IV inhibitors and hence the compounds according to the invention can be used to treat infertility or to improve fertility in humans or mammals, particularly if the infertility is connected with insulin resistance or with polycystic ovary syndrome. On the other hand these substances are suitable for influencing sperm motility and are thus suitable for use as male contraceptives. In addition, the substances are suitable for treating growth hormone deficiencies connected with restricted growth, and may reasonably be used for all indications for which growth hormone may be used. The compounds according to the invention are also suitable, on the basis of their inhibitory effect on DPP-IV, for treating various autoimmune diseases such as e.g. rheumatoid arthritis, multiple sclerosis, thyroiditis and Basedow's disease, etc. They may also be used to treat viral diseases and also, for example, in HIV infections, for stimulating blood production, in benign prostatic hyperplasia, gingivitis, as well as for the treatment of neuronal defects and neurodegenerative diseases such as Alzheimer's disease, for example. The compounds described may also be used for the treatment of tumours, particularly for modifying tumour invasion and also metastasisation; examples here are their use in treating T-cell lymphomas, acute lymphoblastic leukaemia, cell-based pancreatic carcinomas, basal cell carcinomas or breast cancers. Other indications are stroke, ischaemia of various origins, Parkinson's disease and migraine. In addition, further indications include follicular and epidermal hyperkeratoses, increased keratinocyte proliferation, psoriasis, encephalomyelitis, glomerulonephritis, lipodystrophies, as well as psychosomatic, depressive and neuropsychiatric diseases of all kinds.
The compounds according to the invention may also be used in conjunction with other active substances. Suitable therapeutic agents for such combinations include for example antidiabetic agents such as metformin, sulphonylureas (e.g.
glibenclamid, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone, pioglitazone), PPAR-gamma agonists (e.g. GI 262570) and Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297), alpha-glucosidase inhibitors (e.g. acarbose, voglibose), other DPPIV inhibitors, alpha2 antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin. Also, 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 e.g. inhibitors of glucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents, such as HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and its derivatives, PPAR-alpha agonists, PPAR-delta agonists, ACAT
inhibitors (e.g. avasimibe) or cholesterol absorption inhibitors such as for example ezetimibe, bile acid-binding substances such as for example cholestyramine, inhibitors of ileac bile acid transport, HDL-raising compounds such as for example inhibitors of CETP or regulators of ABC1 or active substances for the treatment of obesity, such as e.g. sibutramine or tetrahydrolipostatin, dexfenfluramine, axokine, antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or f33-agonists such as SB-418790 or AD-9677 as well as agonists of the 5HT2c receptor.
It is also possible to combine the compounds with drugs for treating high blood pressure such as e.g. All antagonists or ACE inhibitors, diuretics, f3-blockers, Ca-antagonists, etc., or combinations thereof.
The dosage required to achieve such an effect is expediently, by intravenous route, 1 to 100 mg, preferably 1 to 30 mg, and by oral route 1 to 1000 mg, preferably 1 to 100 mg, in each case 1 to 4 times a day. For this purpose, the compounds of formula I prepared according to the invention, optionally combined with other active substances, may be incorporated together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The Examples that follow are intended to illustrate the invention:

Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text Preparation of the starting compounds:
Example I
4-methyl 2-bromo-1-(but-2-ynyl)-1 H-imidazole-4,5-dicarboxylate a dimethyl 2-bromo-1 H-imidazole-4,5-dicarboxylate 9.50 g bromine in 100 ml dichloromethane are added dropwise to a mixture of 9.90 g methyl 1 H-imidazole-4,5-dicarboxylate and 7.46 g potassium carbonate in 200 ml dichloromethane and 80 ml acetonitrile. The mixture is stirred for 12 h at ambient 10 temperature in the dark and then added to a saturated aqueous solution of sodium thiosulphate and sodium chloride. The organic phase is separated off and the aqueous phase is extracted several times with ethyl acetate. The combined organic phases are dried over sodium sulphate and the solvent is removed.
Yield: 12.31 g (87% of theory) 15 Mass spectrum (ESI+): m/z = 263/265 (Br) [M+H]+
b) dimethyl 2-bromo-1-(but-2-ynyl)-1 H-imidazole-4,5-dicarbox I~~ ate 3.06 g 1-bromo-2-butyne are added dropwise to a mixture of 6.00 g of dimethyl bromo-1 H-imidazole-4,5-dicarboxylate and 3.80 g of potassium carbonate in 40 ml of 20 dimethylformamide. The mixture is stirred for 12 h at ambient temperature and then added to an aqueous saturated solution of sodium thiosulphate. The organic phase is separated off and the aqueous phase is extracted three times with ethyl acetate.
The combined organic phases are dried over sodium sulphate, the solvent is removed and the residue is chromatographed over silica gel (cyclohexane/ethyl 25 acetate 4:1 > 1:1 ).
Yield: 5.28 g (74% of theory) Mass spectrum (ESI+): m/z = 315/317 (Br) [M+H]+
c) 4-methyl 2-bromo-1~but-2-ynyl)-1 H-imidazole-4,5-dicarbox ly ate 65 ml 1 M sodium hydroxide solution are added to a solution of 22.00 g dimethyl 2-bromo-1-(but-2-ynyl)-1 H-imidazole-4,5-dicarboxylate in 120 ml of a mixture of water, tetrahydrofuran and methanol (1:1:1). After 15 min stirring at ambient temperature Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text the organic solvents are removed and the residue is adjusted to pH 1 with 1 M
hydrochloric acid. The aqueous phase is extracted four times with ethyl acetate, the combined organic phases are dried over sodium sulphate, and the solvent is removed. The residue is triturated with diisopropylether, separated off by means of a paper filter and dried.
Yield: 15.00 g (71 % of theory) Mass spectrum (ESI+): m/z = 301/303 (Br) [M+H]+
Example II
Tert-butyl N'-(auinolin-2-yl)methylene-hydrazine carboxylate A solution of 10.70 g 2-quinolinecarboxaldehyde and 9.00 g tert-butyl hydrazinecarboxylate in 200 ml of ethanol is refluxed for 2 h with stirring.
Then the solution is evaporated to dryness and the residue is triturated with diisopropylether, separated off and dried at 50°C .
Yield: 16.00 g (87% of theory) Mass spectrum (ESI+): m/z = 272 [M+H]+
The following compound is obtained analogously to Example II:
(1) tert-butyl N'-(naphth-1-yl)methylene-hydrazinecarboxylate Mass spectrum (ESI+): m/z = 293 [M+Na]+
Example III
Tert-but I~quinolin-2-ylmethyl)-hydrazinecarboxylate 0.5 g 10% Pd/C are added to a solution of 15.00 g tert-butyl N'-(quinolin-2-yl)methylene-hydrazinecarboxylate in 200 ml of methanol. The resulting mixture is then shaken for 6 h at ambient temperature under 1 atm H2 pressure. Then the precipitate and the catalyst are separated from the solvent, the precipitate is dissolved in tetrahydrofuran, filtered again and in this way the catalyst is separated off. The THF solution is evaporated down and the residue is triturated with tert-butylmethylether, separated off and dried at 50°C . The tert-butylmethylether phase is evaporated down again and the residue is triturated this time with diethyl ether, Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text separated off and dried at 50°C. The two solid fractions from the purification with tert-butylmethylether and diethyl ether are combined.
Yield: 9.00 g (60% of theory) Mass spectrum (ESI+): m/z = 274 [M+H]+
The following compound is obtained analogously to Example III:
(1) tert-butyl N'-(naphth-1-ylmethyl)-hydrazinecarboxylate Mass spectrum (ESI+): m/z = 273 [M+H]+
Example IV
Tert-butyl N'-(2-phenylsulphonyl-ethyl-hydrazinecarboxylate A solution of 0.79 g tent-butyl hydrazinecarboxylate and 1.00 g phenylvinylsulphone in 8 ml of ethanol is refluxed for 5 h with stirring. Then the solvent is removed completely and the residue is chromatographed over silica gel (cyclohexane/ethyl acetate).
Yield: 1.00 g (56% of theory) Mass spectrum (ESI+): m/z = 301 [M+H]+
Example V
Methyl 5-[N'-tert-butoxycarbonyl-N-(quinolin-2-ylmethyl)-hydrazinocarbonyl]-1-(but-2-ynyl)- 2-chloro-1 H-imidazol-4-carboxylate 1.2 ml of thionyl chloride and lastly 0.2 ml of dimethylformamide are added to a solution of 4.50 g of 4-methyl 2-bromo-1-(but-2-ynyl)-1 H-imidazole-4,5-dicarboxylate in 20 ml dichloromethane. The solution is stirred for 17 h at ambient temperature.
Then 30 ml of toluene are added and the solution is evaporated to dryness. The residue is dissolved in 10 ml of dimethylformamide, then 4.02 g of tert-butyl N'-(quinolin-2-ylmethyl)-hydrazinecarboxylate and 4 ml Hunig base are added. The solution is stirred for 0.5 h at ambient temperature and then evaporated down.
The residue is chromatographed over silica gel (cyclohexane/ethyl acetate 3:2).
Yield: 2.00 g (26% of theory) Mass spectrum (ESI+): m/z = 512/514 (CI) [M+H]+

Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text The following compounds are obtained analogously to Example V:
(1) methyl 5-[N'-tert-butoxycarbonyl-N-(naphth-1-ylmethyl)-hydrazinocarbonyl]-(but-2-ynyl)-2-chloro-1 H-imidazole-4-carboxylate mixed with methyl 2-bromo-5-[N'-tert-butoxycarbonyl-N-(naphth-1-ylmethyl)-hydrazinocarbonyl]-1-(but-2-ynyl)-1 H-imidazole-4-carboxylate Mass spectrum (ESI+): m/z = 555/557 (Br); m/z = 512/514 (CI) [M+H]+
(2) methyl 5-[N'-tert-butoxycarbonyl-N-(2-phenylsulphonyl-ethyl)-hydrazinocarbonyl]-1-(but-2-ynyl)-2-chloro-1 H-imidazole-4-carboxylate Mass spectrum (ESI+): m/z = 539/541 (CI) [M+H]+
Example VI
1-(but-2-ynyl)-2-chloro-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]=
pyridazine-4,7-dione 2.80 g methyl 2-chloro-5-[N'-tert-butoxycarbonyl-N-(quinolin-2-ylmethyl)-hydrazinocarbonyl]-1-(but-2-ynyl)-1 H-imidazol-4-carboxylate are dissolved in 50 ml of ethyl acetate. Then 1.5 ml of 4 M hydrochloric acid in dioxane are added, and the solution is stirred for 2 h at 50°C. Then the solution is cooled to ambient temperature, the precipitate formed is separated off, washed with ethyl acetate and diethyl ether and dried in the drying cupboard at 50°C.
Yield: 1.60 g (77% of theory) Mass spectrum (ESI+): m/z = 380/382 (CI) [M+H]+
The following compounds are obtained analogously to Example VI:
(1) 1-(but-2-ynyl)-2-chloro-6-(naphth-1-ylmethyl)-5,6-dihydro-1H-imidazo[4.5d]-pyridazine-4,7-dione mixed with 2-bromo-1-(but-2-ynyl)-6-naphth-1-ylmethyl-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 423/425 (Br); m/z = 379/381 (CI) [M+H]+

Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text (2) 1-(but-2-ynyl)-2-chloro-6-(2-phenylsulphonyl-ethyl)-5,6-dihydro-1 H-imidazo[4,5-d]-pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 407/409 (CI) [M+H]+
Example VII
1-(but-2-ynyl)-2-chloro-5-cyanomethyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazof4,5-dlp.,hridazine-4,7-dione 0.20 g 1-(but-2-ynyl)-2-chloro-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]-pyridazine-4,7-dione and 0.25 g potassium carbonate are placed in 4 ml of dimethylformamide. Then 53 pl of bromoacetonitrile are added and the mixture is stirred for 2 h at 40°C. After the addition of aqueous saturated sodium chloride solution the mixture is extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulphate, and then the solvent is removed. The residue is purified over silica gel (cyclohexane/ethyl acetate 1:1 ).
Yield: 0,14 g (42% of theory) Mass spectrum (ESI+): m/z = 419/421 (CI) [M+H]+
The following compounds are obtained analogously to Example VII:
(1) 1-(but-2-ynyl)-2-chloro-5-methyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 394/396 (CI) [M+H]+
(2) 1-(but-2-ynyl)-2-chloro-5-(prop-2-enyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 420/422 (CI) [M+H]+
(3) 1-(but-2-ynyl)-2-chloro-5-(phenylmethyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 470/472 (CI) [M+H]+

Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text (4) 1-(but-2-ynyl)-2-chloro-5-methyl-6-(naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione mixed with 1-(but-2-ynyl)-2-bromo-5-methyl-(naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 437/439 (Br); m/z = 393/395 (CI) [M+H]+

(5) 1-(but-2-ynyl)-2-chloro-5-(tert-butoxycarbonylmethyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 494/496 (CI) [M+H]+
10 (6) 1-(but-2-ynyl)-2-chloro-5-aminocarbonylmethyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 437/439 (CI) [M+H]+
(7) 1-(but-2-ynyl)-2-chloro-5-(pyridin-3-ylmethyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-15 1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 471/473 (CI) [M+H]+
(8) 1-(but-2-ynyl)-2-chloro-5-(prop-2-ynyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione 20 Mass spectrum (ESI+): m/z = 418/420 (CI) [M+H]+
(9) 1-(but-2-ynyl)-2-chloro-5-(pyridin-4-ylmethyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 471/473 (CI) [M+H]+
(10) 1-(but-2-ynyl)-2-chloro-5-methyl-6-(2-phenylsulphonyl-ethyl)-5,6-dihydro-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 421/423 [M+H]+
The starting materials used are 1-(but-2-ynyl)-2-chloro-6-(2-phenylsulphonyl-ethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione and methyl iodide.

Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text (11) 1-(but-2-ynyl)-2-chloro-5-(2-fluoro-ethyl)-6-(2-phenylsulphonyl-ethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 453/455 [M+H]+
The starting materials used are 1-(but-2-ynyl)-2-chloro-6-(2-phenylsulphonyl-ethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione and 2-methylsulphonyloxyethyl fluoride.
Example VIII
(R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperid in-1-yl)-5-cyanomethyl-6-(auinolin-2-ylmethyl -5) 6-dihydro-1 H-imidazof4,5-dlpyridazine-4,7-dione A solution of 0.14 g 1-(but-2-ynyl)-2-chloro-5-cyanomethyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, 0.15 g potassium carbonate and 0.07 g (R)-3-tert-butoxycarbonylaminopiperidine in 2 ml dimethylsulphoxide is stirred for 5 h at 60°C. Then water is added and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate, and then the solvent is removed. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:1 ).
Yield: 0.13 g (75% of theory) Mass spectrum (ESI+): m/z = 583 [M+H]+
The following compounds are obtained analogously to Example VIII:
(1) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-methyl-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 558 [M+H]+
(2) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(prop-2-enyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 584 [M+H]+
(3) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(phenylmethyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text Mass spectrum (ESI+): m/z = 634 [M+H]+
(4) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-methyl-(naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 557 [M+H]+
(5) (R)-1-(but-2-ynyl)-2-(3-tent-butoxycarbonylamino-piperidin-1-yl)-5-(tent-butoxy-carbonylmethyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 658 [M+H]+
(6) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-aminocarbonyl-methyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 601 [M+H]+
(7) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(pyridin-3-ylmethyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 635 [M+H]+
(8) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(prop-2-ynyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 582 [M+H]+
(9) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(pyridin-4-ylmethyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 635 [M+H]+
(10) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-methyl-6-(2-phenylsulphonyl-ethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 585 [M+H]+

Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text (11) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(2-fluoro-ethyl)-6-(2-phenylsulphonyl-ethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 617 [M+H]+
Example IX
(R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-methyl-5,6-dihydro-1 H-imidazof4,5-dlpyridazine-4,7-dione 0.11 g potassium-tent-butoxide are added to a solution of 0.52 g of (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-methyl-6-(2-phenylsulphonyl-ethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione in 5 ml of tetrahydrofuran.
The solution is stirred for 10 min at ambient temperature and then diluted with water. It is extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulphate, and the solvent is then removed. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate).
Yield: 0.31 g (85% of theory) Mass spectrum (ESI+): m/z = 417 [M+H]+
The following compound is obtained analogously to Example IX:
(1) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(2-fluoro-ethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 449 [M+H]+
Example X
(R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-methyl-6-(3-methyl-isoauinolin-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione 0.20 g of (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-methyl-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione and 0.10 g potassium carbonate are placed in 2 ml of dimethylformamide. Then 0.10 g of 3-methyl-isoquinolin-1-yl-methylchloride are added and the mixture is stirred for 5 h at 50°C.
After the addition of water the mixture is extracted three times with ethyl acetate, the combined organic Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text phases are dried over sodium sulphate, and the solvent is removed. The residue is purified over silica gel (cyclohexane/ethyl acetate 1:1 ).
Yield: 0.06 g (22% of theory) Mass spectrum (ESI+): m/z = 572 [M+H]+
The following compounds are obtained analogously to Example X:
(1) (R)-1-(but-2-ynyl)-2-(3-tent-butoxycarbonylamino-piperidin-1-yl)-5-methyl-(phenylcarbonylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 535 [M+H]+
(2) (R)-1-(but-2-ynyl)-2-(3-tent-butoxycarbonylamino-piperidin-1-yl)-5-methyl-6-(4-methyl-quinazolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 573 [M+H]+
(3) (R)-1-(but-2-ynyl)-2-(3-tent-butoxycarbonylamino-piperidin-1-yl)-5-methyl-6-(2-cyano-benzyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 532 [M+H]+
(4) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(2-fluoro-ethyl)-6-(4-methyl-quinazolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 605 [M+H]+

Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text Preparation of the end compounds:
Example 1 (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-(quinolin-2-ylmethyl)-5 5 6-dihydro-1 H-imidazof4 5-dlpVridazine-4,7-dione x 2 trifluoroacetic acid I
N / O i N
N ~N I ~~--N
N
O NHz 1 ml of trifluoroacetic acid is added to a solution of 0.13 g of (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-cyanomethyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione in 2 ml dichloromethane. The solution 10 is stirred for 4 h at ambient temperature, then diluted with 5 ml of toluene and evaporated to dryness. The residue is stirred with diethyl ether, separated off using a filter paper and dried at 50°C .
Yield: 100 mg (63% of theory) Mass spectrum (ESI+): m/z = 483 [M+H]+
The following compounds are obtained analogously to Example 1:
(1) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x 2 trifluoroacetic acid Mass spectrum (ESI+): m/z = 458 [M+H]+
I
N / O i N
N ~ /~- N
/N N
O NHz Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text (2) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)- 5-(prop-2-enyl)-6-(quinolin-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x 2 trifluoroacetic acid Mass spectrum (ESI+): m/z = 484 [M+H]+
I \
N / O i N
I /~---N
~N N
O NHz (3) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(phenylmethyl)-6-(quinolin-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x 2 trifluoroacetic acid Mass spectrum (ESI+): m/z = 534 [M+H]+
N
O i N
I /~N
'N
O NHz (4) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x 1 trifluoroacetic acid Mass spectrum (ESI+): m/z = 457 [M+H]+
I
/ / o N N
I I /~ N
/N N
O NHz (5) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-hydroxycarbonylmethyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x 2 trifluoroacetic acid Mass spectrum (ESI+): m/z = 502 [M+H]+

Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text I
N / O i N
/~- N
HO~ N
O NHz (6) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-aminocarbonylmethyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 501 [M+H]+
(reaction solution was worked up under aqueous conditions with potassium carbonate solution) I~
I
N / O i N
/~ N
H N 'N
O NHz (7) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(pyridin-3-ylmethyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 535 [M+H]+
(reaction solution was worked up under aqueous conditions with potassium carbonate solution) I I
N / O i N
N \ N I /~-- N
'N

Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text (8) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(prop-2-ynyl)-6-(quinolin-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 482 [M+H]+
(reaction solution was worked up under aqueous conditions with potassium carbonate solution) I~
I \
N / O i N
/~-N
'N
O NHz (9) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(pyridin-4-ylmethyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x 3 trifluoroacetic acid Mass spectrum (ESI+): m/z = 535 [M+H]+
I
I
N / O %
N~ N N
I /~--N
'N
O NHz (10) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(3-methyl-isoquinolin-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x trifluoroacetic acid Mass spectrum (ESI+): m/z = 472 [M+H]+
I~
/ ~N O i N N
I I /~ N
/N N
O NHz Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text (11) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(phenylcarbonylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x trifluoroacetic acid Mass spectrum (ESI+): m/z = 435 [M+H]+
i o0 N
/~ N
/N N

(12) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(4-methyl-quinazolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 473 [M+H]+
(reaction solution was worked up under aqueous conditions with potassium carbonate solution and the product was purified over silica gel with dichloromethane/methanol) I\
N' / N O i N
/~ N
/N N
O NHz (13) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(2-cyano-benzyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Mass spectrum (ESI+): m/z = 432 [M+H]+
(reaction solution was worked up under aqueous conditions with potassium carbonate solution and the product was purified over silica gel with dichloromethane/methanol) Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text O i N
N
/~ N
/N N
O NHz (14) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-fluoro-ethyl)-6-(4-methyl-5 quinazolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x trifluoroacetic acid Mass spectrum (ESI+): m/z = 505 [M+H]+
I\
N' //N O i N
N ~ ~~-N
F~/N N
O NHz Example 2 1-(but-2-ynyl)-2-(piperazin-1-yl)-5-methyl-6-(quinolin-4-ylmethyl)-5,6-dihydro-imidazof4,5-dlpyridazine-4,7-dione I
N ~ O i N
/~--N NH
/N N
A mixture of 80 mg of 1-(but-2-ynyl)-2-chloro-5-methyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione and 85 mg of 1,4-piperazine in 2 ml of dimethylformamide is stirred for 18 h at 65°C. The reaction mixture is diluted with Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate, the solvent is evaporated and the residue is chromatographed over silica gel (cyclohexane/ethyl acetate 1:1 ).
Yield: 30 mg (33% of theory) Mass spectrum (ESI+): m/z = 444 [M+H]+
The following compounds may also be obtained analogously to the foregoing Examples and other methods known from the literature:
(1) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-cyanoethyl-6-(4-cyano-naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (2) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-(4-fluoro-naphth-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (3) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-(3-methyl-isoquinolin-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (4) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-carboxymethyl-6-(2-cyano-benzyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (5)1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(2-fluoro-benzyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (6) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(methylaminocarbonylmethyl)-6-(4-methyl-quinazolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (7) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-(phenylcarbonylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (8) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(2-nitrophenyl-prop-2-enyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (9) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(methoxycarbonylmethyl)-6-(3-methoxy-phenylcarbonylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (10) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-carboxy-ethyl)-6-(3-cyano-pyridin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (11) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-methoxy-ethyl)-6-([1.5]naphthyridin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text (12) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-hydroxy-ethyl)-6-(quinoxalin-6-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (13) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(1-methyl-1 H-benzotriazol-5-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (14) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(pyridin-3-yl)-6-(quinazolin-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (15) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(4-cyano-quinazolin-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (16) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-fluoro-ethyl)-6-(1-cyano-isoquinolin-3-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (17) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(4-phenyl-pyrimidin-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (18) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-hydroxy-ethyl)-6-(4-cyano-isoquinolin-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (19) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-[4-(morpholin-4-yl)quinazolin-2-ylmethyl]-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (20) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-cyano-ethyl)-6-([1.5]naphthyridin-3-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (21) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-methoxy-ethyl)-6-(2,3-dimethyl-quinoxalin-6-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (22) 1-(3,3-dimethylprop-2-enyl)-2-(3-amino-piperidin-1-yl)-5-(2-methylsulphonyl-ethyl)-6-(4-cyano-naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (23) 1-(but-1-enyl)-2-(3-amino-piperidin-1-yl)-5-(prop-2-enyl)-6-(4-fluoro-naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (24) 1-(cyclopent-1-enylmethyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-(3-methyl-isoquinolin-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (25) 1-(2-chloro-phenylmethyl)-2-(3-amino-piperidin-1-yl)-5-ethyl-6-(2-cyano-phenylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (26) 1-(2-bromo-phenylmethyl)-2-(3-amino-piperidin-1-yl)-5-(prop-2-ynyl)-6-(2-fluoro-phenylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text (27) 1-(but-2-enyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-(4-methyl-quinazolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (28) 1-(thien-3-ylmethyl)-2-(3-amino-piperidin-1-yl)-5-(prop-2-enyl)-6-(phenylcarbonylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (29) 1-(thien-2-ylmethyl)-2-(3-amino-piperidin-1-yl)-5-(2-phenylethyl)-6-[3-(2,3,4,5,6-pentafluorophenyl)-prop-2-enyl]-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (30) 1-(furan-3-ylmethyl)-2-(3-amino-piperidin-1-yl)-5-(2-methoxyethyl)-6-[(3-methoxy-phenyl)carbonylmethyl]-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (31) 1-(cyclopent-1-enylmethyl)-2-(3-amino-piperidin-1-yl)-5-(2-cyano-ethyl)-6-(4-cyano-naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (32) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(methoxycarbonylmethyl)-6-(4 methoxy-naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (33) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(cyclopropylmethyl)-6-(3-methyl-isoquinolin-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (34) 1-( but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(aminomethylcarbonylmethyl)-6-(4-bromo-2-cyano-phenylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (35) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-fluoroethyl)-6-(3,5-dimethoxyphenylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (36) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-[2-(methylaminocarbonyl)-ethyl]-6 (4,5-dimethylquinazolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7 dione (37) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-methylsulphonyl-ethyl)-6-(3-isopropoxy-phenylcarbonylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (38) 1-(3,3-dimethylprop-2-enyl)-2-(3-amino-piperidin-1-yl)-5-(2-hydroxethyl)-6-[3-(pyridin-2-yl)-prop-2-enyl]-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (39) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(3-methylbutyl)-6-(2-aminophenylcarbonylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (40) 1-(but-2-ynyl)-2-(2-aminoethyl-methylamino)-5-cyanomethyl-6-[4-(morpholin-yl)-quinazolin-2-ylmethyl]-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (41) 1-(but-2-ynyl)-2-(piperazin-1-yl)-5-propyl-6-([1.5]naphthyridin-3-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text (42) 1-(but-2-ynyl)-2-[N-(2-aminopropyl)-N-methyl-amino]-5-methyl-6-(2,3-dimethyl-quinoxalin-6-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (43) 1-(3,3-dimethylprop-2-enyl)-2-(homopiperazin-1-yl)-5-cyanomethyl-6-(4-cyano-naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (44) 1-(but-1-enyl)-2-[N-(2-aminoethyl]-N-methyl-amino]-5-(methoxycarbonylmethyl)-6-(2-cyano-4-fluoro-phenylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7 dione (45) 1-(cyclopent-1-enylmethyl)-2-(piperazin-1-yl)-5-(prop-2-ynyl)-6-(3-methyl-isoquinolin-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (46) 1-(2-iodo-phenylmethyl)-2-(3-amino-piperidin-1-yl)-5-hexyl-6-(3-chloro-4-cyano-phenylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (47) 1-(2-cyano-phenylmethyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(6-cyano-pyridin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (48) 1-(but-2-ynyl)-2-(piperazin-1-yl)-5-(2-hydroxy-ethyl)-6-(3-methyl-isoquinolin-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (49) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(pyridin-4-ylmethyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (50) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(tetrahydrofuran-3-ylmethyl)-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (51) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(carboxymethyl)-6-(4-cyano-quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (52) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(4,6-dimethyl-pyrimidin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (53) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(cyanomethyl)-6-(4,6-dimethyl-pyrimidin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (54) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(4-methyl-pyrimidin-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (55) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(6-cyano-pyridin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione (56) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(carboxymethyl)-6-(3-cyano-pyridin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text Ex. Structure Ex. Structure (1) li (2) F
I \ \
I \ \ / / o / / o N
N N N\ N ~ /~N
I I /~ N ~ N
N ~N N O NHz O NHz (3) \ \~ (4) \
/ iN O i i I / p i N ~
N ~N I N~N ~N I N~N
HO
O NHz O NHz (5) ~ \ (6) I \
F / O i ~ \
N I N~N N~N O i / N O N N
O NHz W ~N I /~N~
N 'N
O NHz (7) / ~ (8) ( \
\ O O ~ O N~ /
N O \ p i N ~ N ~ N' N N N
I ~ ~~ N, O NHz /N NN
O NHz (9) o/ (10) I \
i ~N O i _ N~
N
\ O O HO N I /~N
N N
N~-N ~ O NHz O
O NHZ

Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text (11) I ~N (12) ~N
I w N w N
/ O i / O i /~ N N I /~ N
\O~/ ~N HO~/ ~N
IOI NHz ~O~ NHz (13) ~N_N~ (14) ~N~
N INI
I~ I
/ O i / O i N N
I N~-N ~ I N I /~-N
/ ~N ~N
O NH2 O ~NHz (15) I w ~ N (16) I w N
i ~ ~i N iN O ~ I ~N O i /~N N I /~N
/N N F~/N N
O NH2 O NHz (17) / I (18) N
II
I
N\/N O ~ I
/ ~N O i N
N
/N I N~N N I /~--N
O NH2 HO~ N
O NHz (19) I w ~ (20) NI w I y I sN
N\ /'N O ~ / O i N\ N I N N I /~'N
y ~ ~N
O ~NHz N O NHz Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text (21) (22) II
~N
N \ \ \
I / ~ I / / o I
O ~N N
N N O I I /~ N
I /~N ~~S~/N ~/\N
~O~/ N ~--~ I I NH
Q NHz O O z (23) F (24) \ \
\ \ I / ~NO /
I ~ /
0 ~ 'N N
N~ N ~ I I N~ N
N I / N w N
~N N ~ NH2 NHZ
(25) \ cl (26) \ Br I ~ I
N ~ / O ~ I F / O
/~--N N I /~-N
~N~N ~N~N
O NHz O NHz (27) I \ (2$) / I s \ \ o0 NI ~ N N
O I N /
I I /~- N
N N ~N N
N ~N I /~N~ O NHz 'N
O NHz (29) F F F (30) o~
/
I\
w F / F \ I O / O
g ~ O /
\ O N N
I I /~- N
N I /~N ~O~/N N
\ N II N O NHz / O NHz Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text (31 ) INI (32) o ~
\ \ \ \
I
I / / o ~ / / o N
N
/~ N N I /~ N
~N~ N
N / O N NH2 \ ~\ O NHz O O
(33) I \ \ (34) Br iN O ~ I \
N N N i, / O i /~-N o N N
N ~--~ I I /~--N
O NHz \N~N~N
O NHz (35) ~ (36) I \
I \ °\
_ \
/ O / NI ~N O i N N
FAN I N~N~ O N I N~N
O NHz ~ N
/NI H ~ NHz (37) ~ (38) I \
O i IV
\ I o O i O
N N
N~ I I /~ N
O N I / N HON N
\\S~\/N N O NHz O O NHz (39) / I NHz (4p) I \ o \ O i 0 ~ I \
I N~N N~N O i N
" N NH N~ N I / N/
O z ~N N

Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text (41 ) I \ (42) N I ~N I ~N
N
/ O i I
N / O i ~NH N N
/~ N
O N N
O NHz (43) II (44) F
I~
I \ \
/ o / / o / N~
\O N N
N ~ ~~ I / N
N~~N I /~N~ H O N N
,N ~ O NHz O
(45) I \ \ (46) ci I \ i / ~N ~ /
O ~ Ni / O
N N ~ \N N
I /~N NH N I /~N~
N ~--~ / NN
O O NHZ
(47) I ~ ~iN N~\ (48) I \ \
iN O / / / ~N O i N
N N I />-N~NH
I N N HON N
NHZ O
(49) I \ (50) I \
I \ I \
N / O i N /
O i N\ININN O NI/~--N
N
p NHz ~ NHZ

Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text (5~ ) ~ \ ~ N (52) \ ~ N~N O i NI / O j N N
I I /~ N
N /N N
/~-N\ > o NHZ
HO 'N
O NHz (53) ~ (54) I
N /N O i N\ /N O i N N N
N
N ~ I I />--N I I />---N~
N N /N N
O NHz O NHz (55) \ ~~N (56) I \
I / ~N O i ~N O i N
N N
N
N I /~ N / I fV~---N
/ N O NHz 0 NHz Example 3 Coated tablets containing 75 mq of active substance 1 tablet core contains:
active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg 10 polyvinylpyrrolidone 10.0 mg hydroxypropylmethylcellulose 15.0 mg magnesium stearate 1.5 ma 230.0 mg 15 Preparation:
The active substance is mixed with calcium phosphate, corn starch, polyvin-ylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate. Blanks about 13 mm in diameter are produced in a tablet-Boehringer Ingeihelll'1 CA 02559444 2006-09-11 Case 1/1658 foreign filing text making machine and these are then rubbed through a screen with a mesh size of 1.5 mm using a suitable machine and mixed with the rest of the magnesium stearate.
This granulate is compressed in a tablet-making machine to form tablets of the desired shape.
weight of core: 230 mg die: 9 mm, convex The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are polished with beeswax.
Weight of coated tablet: 245 mg.
Example 4 Tablets containin 1q 00 mg of active substance Composition:
1 tablet contains:
active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 ma 220.0 mg Method of Preparation:
The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50°C it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets.
Weight of tablet: 220 mg Diameter: 10 mm, biplanar, facetted on both sides and notched on one side.

Boehringer Ingelheim Case 1/1658 ~. CA 02559444 2006-09-11 foreign filing text Example 5 Tablets containingi 150 mg of active substance Composition:

1 tablet contains:

active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg Preparation:
The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granules, dried at 45°C, are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.
Weight of tablet: 300 mg die: 10 mm, flat Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text Example 6 Hard gelatine capsules containing 150 mg of active substance 1 capsule contains:

active substance 150.0 mg corn starch (dried) approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg Preparation:
The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packed into size 1 hard gelatine capsules.
Capsule filling: approx. 320 mg Capsule shell: size 1 hard gelatine capsule.
Example 7 Suppositories containing 150 mg of active substance 1 suppository contains:

active substance 150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2,000.0 mg Preparation:
After the suppository mass has been melted the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.

Boehringer Ingelheim Case 1/1658 CA 02559444 2006-09-11 foreign filing text Example 8 Suspension containing 50 mg of active substance 100 ml of suspension contain:

active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g 70% sorbitol solution 20.00 g flavouring 0.30 g dist. water ad 100 ml Preparation:
The distilled water is heated to 70°C. The methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring. After the sugar, the sorbitol solution and the flavouring have been added and dissolved, the suspension is evacuated with stirring to eliminate air.
5 ml of suspension contain 50 mg of active substance.
Example 9 Ampoules containing 10 mg active substance Composition:
active substance 10.0 mg 0.01 N hydrochloric acid q.s.
double-distilled water ad 2.0 ml Boehringer Ingelheim Case 1/1658 . CA 02559444 2006-09-11 foreign filing text Preparation:
The active substance is dissolved in the necessary amount of 0.01 N HCI, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.

Example 10 Ampoules containing 50 ma of active substance 10 Composition:
active substance 50.0 mg 0.01 N hydrochloric acid q.s.
double-distilled water ad 10.0 ml Preparation:
The active substance is dissolved in the necessary amount of 0.01 N HCI, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.

Claims (10)

1. Compounds of general formula wherein R1 denotes 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, C1-3-alkyloxy-carbonyl or nitro group, R2 denotes a C1-6-alkyl group, an aryl or heteroaryl group, a C1-6-alkyl group substituted by a group R a, where R a denotes a fluorine, chlorine or bromine atom, a C3-7-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(C1-3-alkyl)- group, or by a carbonyl, sulphinyl or sulphonyl group, or a trifluoromethyl, aryl, heteroaryl, cyano, carboxy, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkylamino-carbonyl or di-(C1-3-alkyl)-amino-carbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C1-3-alkyl)-piperazin-1-ylcarbonyl, arylcarbonyl, heteroarylcarbonyl, C1-3-alkylsulphinyl or C1-3-alkylsulphonyl group, a C2-6-alkyl group 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 denotes a hydroxy, C1-3-alkoxy, C1-3-alkylsulphanyl, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl or 4-(C1-3-alkyl)-piperazin-1-yl group, a C3-6-cycloalkyl group or a C3-6-alkenyl or C3-6-alkynyl group, while the multiple bond is isolated from the cyclic nitrogen atom by at least one carbon atom, R3 denotes a C5-7-cycloalkenylmethyl group optionally substituted by a C1-3-alkyl group, an arylmethyl or heteroarylmethyl group, a straight-chain or branched C2-6-alkenyl group which may be substituted by 1 to 15 fluorine atoms or by a cyano, nitro or C1-3-alkoxy-carbonyl group, or a straight-chain or branched C3-6-alkynyl group which may be substituted by 1 to 9 fluorine atoms or by a cyano, nitro or C2-8-alkoxy-carbonyl group, and R4 denotes a pyrrolidin-1-yl or azetedin-1-yl group which is substituted in the 3 position by an amino or C1-3-alkylamino group and may additionally be substituted by one or two C1-3-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 C1-3-alkylamino group and may additionally be substituted by one or two C1-3-alkyl groups, a piperazin-1-yl or homopiperazin-1-yl group which may be substituted by one or two C1-3-alkyl groups, an amino group substituted by the groups R15 and R16 wherein R15 denotes a hydrogen atom, a C1-6-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-alkyl, aryl or aryl-C1-3-alkyl group and R16 denotes a R17 -C2-3-alkyl group, while the C2-3-alkyl moiety is straight-chain and may be substituted by 1 to 4 C1-3-alkyl groups, which may be identical or different, and R17 denotes an amino or C1-3-alkylamino group, an amino group substituted by the groups R15 and R18, wherein R15 is as hereinbefore defined and R18 denotes a C3-6-cycloalkyl-methyl group substituted by R19 in the 1 position of the cycloalkyl group or a C3-6-cycloalkyl group substituted by a R19-CH2- group in the 1 position, while R19 denotes an amino or C1-3-alkylamino group, an amino group substituted by the groups R15 and R20 wherein R15 is as hereinbefore defined and R20 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 R20 may each be substituted by one or two C1-3-alkyl groups, an amino group substituted by the groups R15 and R21 wherein R15 is as hereinbefore defined and R21 denotes a C3-7-cycloalkyl group substituted in the 2 or 3 position by an amino or C1-3-alkylamino group, which may additionally be substituted by one or two C1-3-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, the prodrugs thereof and the salts thereof.
2. Compounds of general formula (I) according to claim 1, wherein R1 and R2 are defined as in claim 1, R3 denotes a 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enyl-methyl, furanylmethyl, thienylmethyl, chlorobenzyl, bromobenzyl, iodobenzyl, methoxybenzyl or cyanobenzyl group, and R4 denotes an N-(2-aminoethyl)-N-methyl-amino group which may be substituted in the ethyl moiety by one or two C1-3-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 C1-3-alkyl groups, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.
3. Compounds of general formula (I) according to claim 2, wherein R1 denotes 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, C1-3-alkyl, C1-3-alkyloxy and morpholinyl groups, while the substituents are identical or different, R2 denotes a C1-6-alkyl group which may be substituted by a fluorine atom or a cyano, carboxy, C1-3-alkyloxy-carbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, C1-3-alkylsulphonyl, aryl or heteroaryl group, while the aryl or heteroaryl group is as hereinbefore defined, C2-6-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 denotes a hydroxy or C1-3-alkyloxy group, or a C3-6-alkenyl or C3-6-alkynyl group, while the multiple bond is isolated from the cyclic nitrogen atom by at least one carbon atom, R3 denotes a 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enyl-methyl, furanylmethyl, thienylmethyl, chlorobenzyl, bromobenzyl, iodobenzyl or cyanobenzyl group and R4 denotes 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. Compounds of general formula (I) according to claim 3, wherein R1 denotes a cyanobenzyl, phenylcarbonylmethyl, methylquinazolinylmethyl, methyl-isoquinolinylmethyl, naphthylmethyl or quinolinylmethyl group, R2 denotes a methyl, prop-2-enyl, prop-2-ynyl, 2-fluoroethyl, cyanomethyl, carboxy-methyl, aminocarbonylmethyl, pyridinylmethyl or phenylmethyl group, R3 denotes a 2-butyn-1-yl group and R4 denotes a 3-aminopiperidin-1-yl or piperazin-1-yl group, the enantiomers, the diastereomers, the mixtures and salts thereof.
5. The following compounds of general formula (I) according to claim 1:
(1) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-(quinolin-2-yl-methyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, (2) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, (3) (R)-1-(1-but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(prop-2-enyl)-6-(quinolin-2-yl-methyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, (4) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(phenylmethyl)-6-(quinolin-2-yl-methyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, (5) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(naphth-1-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, (6) 1-(but-2-ynyl)-2-(piperazin-1-yl)-5-methyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, (7) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-hydroxycarbonylmethyl-6-(naphth-1-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, (8) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-aminocarbonylmethyl-6-(naphth-1-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, (9) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(pyridin-3-ylmethyl)-6-(naphth-1-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, (10) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(prop-2-ynyl)-6-(naphth-1-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, (11) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(pyridin-4-ylmethyl)-6-(naphth-1-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, (12) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(3-methyl-isoquinolin-1-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, (13) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(phenylcarbonylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, (14) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(4-methyl-quinazolin-2-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, (15) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(2-cyano-benzyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, (16) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-fluoro-ethyl)-6-(4-methyl-quinazolin-2-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, and the salts thereof.
6. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 5 with inorganic or organic acids.
7. Pharmaceutical compositions containing a compound according to at least one of claims 1 to 5 or a physiologically acceptable salt according to claim 6, optionally together with one or more inert carriers and/or diluents.
8. Use of a compound according to at least one of claims 1 to 6 for preparing a pharmaceutical composition which is suitable for treating type I and II
diabetes mellitus, arthritis, obesity, allograft transplantation and calcitonin-induced osteoporosis.
9. Process for preparing a pharmaceutical composition according to claim 7, characterised in that a compound according to at least one of claims 1 to 6 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
10. Process for preparing the compounds of general formula (I) according to claims 1 to 6, characterised in that a) a compound of general formula wherein R1 to R3 are defined as in claim 1 and Z1 denotes a leaving group such as a halogen atom, a substituted hydroxy, mercapto, sulphinyl, sulphonyl or sulphonyloxy group, is reacted with a compound of general formula H - R4 ,(III) wherein R4 is as hereinbefore defined; or b) in order to prepare a compound of general formula I wherein R4 according to the definition given in claim 1 contains an amino group or an alkylamino group optionally substituted in the alkyl moiety:
a compound of general formula wherein R1, R2 and R3 are defined as in claim 1 and R4' contains an N-tert.-butyloxycarbonylamino group or an N-tert.-butyloxycarbonyl-N-alkylamino group, where the alkyl moiety of the N-tert.-butyloxycarbonyl-N-alkyl-amino group may be substituted as mentioned hereinbefore, is deprotected;
and any protecting groups used during the reaction are then cleaved and/or the compounds of general formula I thus obtained are resolved into their enantiomers and/or diastereomers and/or the compounds of formula I thus obtained are converted into their salts, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids.
CA002559444A 2004-03-13 2005-03-09 Imidazopyridazine diones, the production thereof, and the use of the same as a medicament Abandoned CA2559444A1 (en)

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DE102004012366A DE102004012366A1 (en) 2004-03-13 2004-03-13 Imidazopyridazinediones, their preparation and their use as medicines
PCT/EP2005/002524 WO2005087774A1 (en) 2004-03-13 2005-03-09 Imidazopyridazine diones, the production thereof, and the use of the same as a medicament

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US7906539B2 (en) 2004-06-24 2011-03-15 Boehringer Ingelheim International Gmbh Imidazoles and triazoles, their preparation, and their use as pharmaceutical compositions

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WO2005097798A1 (en) * 2004-04-10 2005-10-20 Boehringer Ingelheim International Gmbh 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
GB0526291D0 (en) 2005-12-23 2006-02-01 Prosidion Ltd Therapeutic method
CA2741672A1 (en) * 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents

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AU2003241960B2 (en) * 2002-06-06 2009-07-30 Eisai R&D Management Co., Ltd. Novel fused imidazole derivative
UY28103A1 (en) * 2002-12-03 2004-06-30 Boehringer Ingelheim Pharma NEW IMIDAZO-PIRIDINONAS REPLACED, ITS PREPARATION AND ITS EMPLOYMENT AS MEDICATIONS
AU2003902828A0 (en) * 2003-06-05 2003-06-26 Fujisawa Pharmaceutical Co., Ltd. Dpp-iv inhibitor
DE10359098A1 (en) * 2003-12-17 2005-07-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel 2- (piperazin-1-yl) and 2 - ([1,4] diazepan-1-yl) imidazo [4,5-d] pyridazin-4-ones, their preparation and their use as pharmaceuticals

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US7906539B2 (en) 2004-06-24 2011-03-15 Boehringer Ingelheim International Gmbh Imidazoles and triazoles, their preparation, and their use as pharmaceutical compositions

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