DE10309927A1 - New trisubstituted dihydro-imidazo-pyridazinone or imidazo-pyridinone derivatives, useful as dipeptidylpeptidase-IV inhibitors for e.g. treating diabetes mellitus type I or II, arthritis or obesity - Google Patents

Abstract

2,3,5-Trisubstituted 3,5-dihydro-imidazol-(4,5-d)-pyridazin-4-one or 3,5-dihydro-imidazo-(4,5-c)-pyridin-4-one derivatives (I) and their tautomers, enantiomers, diastereomers (or mixtures) and salts are new. 2,3,5-Trisubstituted 3,5-dihydro-imidazol-(4,5-d)-pyridazin-4-one or 3,5-dihydro-imidazo-(4,5-c)-pyridin-4-one derivatives of formula (I) and their tautomers, enantiomers, diastereomers (or mixtures) and salts are new: [Image] X : N or CR 5>; R 5>H or Me; R 1>5-7 membered cycloalkyleneimino (C-substituted by amino and optionally substituted (os) by alkyl), 6- or 7-membered cycloalkyleneimino (with CH 2 in the 4-position replaced by NH), or 5-7C cycloalkylamino (where the cycloalkyl is substituted by amino or the CH 2 in the 3-position is replaced by NH); R 2>benzyl (os in the ring by 1 or 2 F, Cl or Br or by CN), 3-8C alkenyl, 3-5C alkynyl, (3-7C) cycloalkylmethyl, (5-7C) cycloalkenylmethyl, furylmethyl, thienylmethyl, pyrrolylmethyl, thiazolylmethyl, imidazolylmethyl, pyridinylmethyl, pyrimidinylmethyl, pyridazinylmethyl or pyrazinylmethyl; R 3>1-6C alkyl, phenylalkyl or naphthylalkyl (both os in the ring by halo, CN, alkyl or OMe), 2-phenyl-2-hydroxyethyl, phenylcarbonylmethyl (os in the ring by OH, alkoxy, aminocarbonyl-alkoxy, N-alkyl- or N,N-dialkylaminocarbonyl-alkoxy, NH 2, alkylcarbonylamino, 3-6C cycloalkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino or CONH 2), (3-methyl-2-oxo-2,3-dihydro-benzoxazolyl)-carbonylmethyl, thienylcarbonylmethyl, Het-alkyl, imidazo-(1,2-a)-pyridin-2-yl-methyl, 5-methylimidazo-(1,2-a)-pyridin-2-yl-methyl, 1,5-naphthyridin-2-ylmethyl, 1,2,4-triazolo-(4,3-a)-pyridin-3-ylmethyl, (Z)-3-(pentafluorophenyl)-prop-2-enyl, 1-(R 6>)-2-oxo-1,2-dihydroquinolin-4-ylmethyl, 1-(R 6>)-2-oxo-1,2-dihydroquinolin-6-ylmethyl or 2-(R 6>)-1-oxo-1,2-dihydroisoquinolin-4-ylmethyl; Het : 5- or 6-membered monocyclic heteroaryl (os by 1 or 2 alkyl or by morpholino, pyridyl or phenyl), where 6-membered heteroaryl contains 1-3 N, 5-membered heteroaryl contains one N, N(alkyl), N(phenylalkyl), O or S (optionally together with 1-3 further N) and the heteroaryl rings are optionally fused with a benzo ring (os by one halo, 1 or 2 alkyl, one CF 3 or one OMe), the benzoheterocyclic groups being bonded via the heterocycle or the benzo ring; R 6>H or Me; and R 4>H or alkyl. Alkyl moieties have 1-3C unless specified otherwise, and (m)ethyl are os by F. An independent claim is also included for the preparation of (I). ACTIVITY : Antidiabetic; Antiarthritic; Anorectic; Immunosuppressive; Osteopathic; Antilipemic; Antiarteriosclerotic; Tranquilizer; Cardiant; Diuretic; Hypotensive; Nephrotropic; Antiinflammatory; Antiinfertility. MECHANISM OF ACTION : Dipeptidylpeptidase-IV (DPP-IV) inhibitor; B-cell degeneration inhibitor; Glucagon-like peptide (GLP) action modulator. 2-(3-Amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(quinoxalin-6-ylmethyl)-3,5-dihydro-imidazol-(4,5-d)-pyridazin-4-one (Ia) had IC 5 0 1.2 nM for inhibition of DPP-IV.

Description

deren Tautomere, deren Enantiomere, deren Diastereomere, deren Gemische und deren Salze, insbesonders deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren, welche wertvolle pharmakologische Eigenschaften aufweisen, insbesondere eine Hemmwirkung auf die Aktivität des Enzyms Dipeptidylpeptidase-IV (DPP-IV), deren Herstellung, deren Verwendung zur Prävention oder Behandlung von Krankheiten oder Zuständen, die in Zusammenhang mit einer erhöhten DPP-IV Aktivität stehen oder die durch Reduktion der DPP-IV Aktivität verhindert oder gemildert werden können, insbesondere von Diabetes mellitus Typ I oder Typ II, die eine Verbindung der allgemeinen Formel (I) oder ein physiologisch verträgliches Salz davon enthaltenden Arzneimittel sowie Verfahren zu deren Herstellung.The present invention relates to new substituted imidazopyridinones and imidazopyridazinones of the general formula

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

Object of the present invention are thus the above compounds of general formula I, which have valuable pharmacological properties that pharmacologically active compounds containing drugs, their use and methods of making them.

oder eine Gruppe der Formel

in der R⁶ ein Wasserstoffatom oder eine Methylgruppe bedeutet,
und R⁴ ein Wasserstoffatom oder eine C_1–3-Alkylgruppe,
wobei die in den Definitionen enthaltenen Alkyl- und Alkoxygruppen, die mehr als zwei Kohlenstoffatome aufweisen, soweit nichts anderes erwähnt wurde, geradkettig oder verzweigt sein können,
und wobei die Wasserstoffatome der in den Definitionen enthaltenen Methyl- oder Ethylgruppen ganz oder teilweise durch Fluoratome ersetzt sein können.In the above general formula I mean
X is a nitrogen atom or a group of the formula CR ⁵ ,
where R ^{5 represents} a hydrogen atom or a methyl group,
R ^{1 is} a 5- to 7-membered cycloalkyleneimino group which is substituted in the carbon skeleton by an amino group and which may be substituted by a C _{1 -3} -alkyl group,
a 6- to 7-membered cycloalkyleneimino group in which the methylene group in the 4-position is replaced by an -NH group,
or an amino group substituted by a C _5-7 cycloalkyl group, the C _5-7 cycloalkyl group being substituted by an amino group or a carbon atom in the 3-position of the C _5-7 cycloalkyl group being replaced by an -NH group,
R ^{2 is} a benzyl group in which the phenyl radical can be substituted by one or two fluorine, chlorine or bromine atoms or by a cyano group,
a linear or branched C _3-8 alkenyl group,
a C _3-5 alkynyl group,
a C _3-7 cycloalkylmethyl group,
a C _5-7 cycloalkenylmethyl group,
or a furylmethyl, thienylmethyl, pyrrolylmethyl, thiazolylmethyl, imidazolylmethyl, pyridinylmethyl, pyrimidinylmethyl, pyridazinylmethyl or pyrazinylmethyl group,
R ³ is a linear or branched C _1-6 alkyl group, an optionally alkyl- or in the aryl moiety by a cyano group, a C _1-3 alkyl or a methoxy substituted phenyl-C _1-3 naphthyl-C _1-3 alkyl group,
a 2-phenyl-2-hydroxyethyl group,
a phenylcarbonylmethyl group,
in which the phenyl group is replaced by a hydroxy, C _1-3 alkyloxy, aminocarbonyl C _1-3 alkoxy, (C _1-3 alkylamino) carbonyl C _1-3 alkoxy, [di ( C _1-3 alkyl) amino] carbonyl C _1-3 alkoxy, amino, C _1-3 alkyl carbonylamino, C _3-6 cycloalkyl carbonylamino, C _1-3 alkoxy carbonylamino, C _1-3 alkylsulfonylamino or aminocarbonyl group may be substituted,
a thienylcarbonylmethyl group,
a heteroaryl-C _1-3 alkyl group,
where the expression “heteroaryl group” is to be understood as meaning a monocyclic 5- or 6-membered heteroaryl group optionally substituted by one or two C _1-3 alkyl groups or by a phenyl group in the carbon skeleton, where
the 6-membered heteroaryl group has one, two or three nitrogen atoms and
the 5-membered heteroaryl group is an imino group which is optionally substituted by a C _1-3 alkyl or phenylC _1-3 alkyl group, an oxygen or sulfur atom or
an imino group optionally substituted by a C _1-3 alkyl or phenyl C _1-3 alkyl group or an oxygen or sulfur atom and additionally a nitrogen atom or
contains an imino group optionally substituted by a C _1-3 alkyl or phenyl C _1-3 alkyl group and two or three nitrogen atoms,
and wherein, in addition, a phenyl ring may be fused to the aforementioned monocyclic heteroaryl groups via two adjacent carbon atoms
and the bond can take place via an atom of the heterocyclic part or of the fused-on phenyl ring,
a bicyclic heteroarylmethyl group according to one of the formulas

or a group of the formula

in which R ^{6 represents} a hydrogen atom or a methyl group,
and R ^{4 represents} a hydrogen atom or a C _1-3 alkyl group,
where the alkyl and alkoxy groups contained in the definitions and which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched,
and the hydrogen atoms of the methyl or ethyl groups contained in the definitions can be replaced in whole or in part by fluorine atoms.

eine 1,2,4-Triazolo[4,3-a]pyridin-3-yl-gruppe der Formel

oder eine Gruppe der FormelPreferred compounds of the general formula I are those in which
X is a nitrogen atom or a group of the formula CR ⁵ ,
where R ^{5 represents} a hydrogen atom or a methyl group,
R ^{1 is} piperazin-1-yl-, 3-amino-piperidin-1-yl-, 3-amino-3-methyl-piperidin-1-yl-, 3-amino-pyrrolindin-1-yl-, 1,4 Diazepan-1-yl, (2-amino-cyclohexyl) -amino or piperidin-3-yl-amino group,
R ^{2 is} a benzyl group in which the phenyl radical can be substituted by one or two fluorine atoms or by a cyano group,
a linear or branched C _3-8 alkenyl group,
a propin-3-yl or but-2-yn-4-yl group,
a cyclopropylmethyl group,
a C _5-7 cycloalkenylmethyl group,
or a furylmethyl or thienylmethyl group,
R ^{3 is} a linear or branched C _1-6 alkyl group,
a phenyl-C _1-2 -alkyl or naphthyl-C _1-2 alkyl group optionally substituted in the aryl part by a cyano, a C _1-3 alkyl or a methoxy group,
a 2-phenyl-2-hydroxyethyl group,
a phenylcarbonylmethyl group,
in which the phenyl group is replaced by a hydroxy, C _1-3 alkyloxy, aminocarbonyl C _1-3 alkoxy, (C _1-3 alkylamino) carbonyl C _1-3 alkoxy, [di ( C _1-3 alkyl) amino] carbonyl C _1-3 alkoxy, amino, C _1-3 alkyl carbonylamino, C _3-6 cycloalkyl carbonylamino, C _1-3 alkoxy carbonylamino, C _1-3 alkylsulfonylamino or aminocarbonyl group may be substituted,
a thienylcarbonylmethyl group,
a thienylethyl group,
a heteroaryl methyl group,
where under the expression “heteroaryl group” a pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl or thienyl group optionally substituted in the carbon skeleton by one or two methyl groups or by a phenyl group understand is
and wherein, in addition, a phenyl ring may be fused to the aforementioned monocyclic heteroaryl groups via two adjacent carbon atoms
and the bond can take place via an atom of the heterocyclic part or of the fused-on phenyl ring,
an imidazo [1,2-a] pyridin-2-yl-methyl group of the formula

a 1,2,4-triazolo [4,3-a] pyridin-3-yl group of the formula

or a group of the formula

in der R⁶ ein Wasserstoffatom oder eine Methylgruppe bedeutet,
und R⁴ ein Wasserstoffatom oder eine C_1–3-Alkylgruppe bedeuten,
wobei die in den Definitionen enthaltenen Alkyl- und Alkoxygruppen, die mehr als zwei Kohlenstoffatome aufweisen, soweit nichts anderes erwähnt wurde, geradkettig oder verzweigt sein können,
und wobei die Wasserstoffatome der in den Definitionen enthaltenen Methyl- oder Ethylgruppen ganz oder teilweise durch Fluoratome ersetzt sein können,
deren Tautomere, deren Enantiomere, deren Diastereomere, deren Gemische und deren Salze,
insbesondere jedoch diejenigen Verbindungen der allgemeinen Formel I, in denen X, R², R³ und R⁴ wie oben erwähnt definiert sind und
R¹ eine 3-Amino-piperidin-1-yl-gruppe bedeutet,
deren Tautomere, deren Enantiomere, deren Diastereomere, deren Gemische und deren Salze.

in which R ^{6 represents} a hydrogen atom or a methyl group,
and R ^{4 represents} a hydrogen atom or a C _1-3 alkyl group,
where the alkyl and alkoxy groups contained in the definitions and which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched,
and the hydrogen atoms of the methyl or ethyl groups contained in the definitions can be replaced in whole or in part by fluorine atoms,
their tautomers, their enantiomers, their diastereomers, their mixtures and their salts,
in particular, however, those compounds of the general formula I in which X, R ² , R ³ and R ⁴ are defined as mentioned above and
R ^{1 represents} a 3-aminopiperidin-1-yl group,
their tautomers, their enantiomers, their diastereomers, their mixtures and their salts.

A second subgroup of the preferred compounds relates to those compounds of the general formula I in which
X, R ¹ , R ³ and R ^{4 are} as defined above and
R ^{2 represents} a 3-methylallyl, a 3,3-dimethylallyl or a but-2-yn-4-yl group,
their tautomers, their enantiomers, their diastereomers, their mixtures and their salts.

• (1) 2-(3-Amino-piperidin-1-yl)-3-but-2-inyl-5-(naphthalin-1-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-on
  
• (2) 2-(3-Amino-piperidin-1-yl)-3-but2-inyl-5-(3-methyl-isochinolin-1-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-on,
  
• (3) 2-(3-Amino-piperidin-1-yl)-3-but-2-inyl-5-(chinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-on
  
  und
• (4) 2-(3-Amino-piperidin-1-yl)-3-but-2-inyl-5-(1-methyl-1H-benzimidazol-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-on
  

sowie deren Enantiomere und deren Salze.The following compounds of the general formula I are particularly preferred:

• (1) 2- (3-Amino-piperidin-1-yl) -3-but-2-ynyl-5- (naphthalen-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazine -4-one
  
• (2) 2- (3-Amino-piperidin-1-yl) -3-but2-ynyl-5- (3-methyl-isoquinolin-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d ] pyridazin-4-one,
  
• (3) 2- (3-amino-piperidin-1-yl) -3-but-2-ynyl-5- (quinazolin-2-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazine -4-one
  
  and
• (4) 2- (3-Amino-piperidin-1-yl) -3-but-2-ynyl-5- (1-methyl-1H-benzimidazol-2-ylmethyl) -3,5-dihydro-imidazo [4 , 5-d] pyridazin-4-one
  

as well as their enantiomers and their salts.

• a) Umsetzung einer Verbindung der allgemeinen Formel
  
  in der X, R², R³ und R⁴ wie eingangs erwähnt definiert sind und Z¹ eine nukleofuge Austrittsgruppe wie beispielsweise ein Chlor- oder Bromatom oder eine C_1–3-Alkylsulfanyl-, C_1–3-Alkylsulfinyl- oder C_1–3-Alkylsulfonylgruppe bedeutet, mit einem Amin der allgemeinen Formel H-R¹ (III),in der R¹ wie eingangs definiert ist.

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

• a) implementation of a compound of the general formula
  
  in which X, R ² , R ³ and R ⁴ are defined as mentioned at the outset and Z ^{1 is} a nucleofugic leaving group such as, for example, a chlorine or bromine atom or a C _1-3 alkylsulfanyl, C _1-3 alkylsulfinyl or C _{1 -3-} Alkylsulfonylgruppe means with an amine of the general formula HR ¹ (III), in which R ^{1 is} as defined at the beginning.

• b) Entschützung einer Verbindung der allgemeinen Formel
  
  in der R², R³ und R⁴ wie eingangs erwähnt definiert sind und R^1' eine der eingangs für R¹ erwähnten Gruppen bedeutet, in der die Imino-, Amino- bzw. Alkylaminogruppe durch eine Schutzgruppe substituiert ist.

The reaction is advantageously carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulfolane, optionally in the presence of an inorganic or tertiary organic base, for example sodium carbonate, potassium carbonate or potassium hydroxide, a tertiary organic base, for example triethylamine, or in the presence of N-ethyl-diisopropylamine (Hünig base), these organic bases can also serve as solvents at the same time, 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, however, preferably carried out at temperatures between -10 and 120 ° C. However, the reaction can also be carried out without a solvent or in an excess of the amine of the general formula R ^{4 '} -H.

• b) deprotection of a compound of the general formula
  
  in which R ² , R ³ and R ⁴ are defined as mentioned at the outset and R ^{1 'is} one of the groups mentioned at the outset for R ¹ in which the imino, amino or alkylamino group is substituted by a protective group.

The release of an amino group from a protected Precursor is a standard reaction in synthetic organic Chemistry. A large number of groups can be considered as protective groups. An overview of the Chemistry of the protecting groups can be found in Theodora W. Greene and Peter G. M. Wuts, Protective Groups in Organic Synthesis, Second Edition, 1991, published by John Wiley and Sons and in Philip J. Kocienski, Protecting Groups, Georg Thieme Verlag, 1994.

Examples of protecting groups include:
the tert-butyloxycarbonyl group, which can be obtained by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment 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. split off,
the 2.2.2-trichloroethoxycarbonyl group, which can be split off by treatment with metals such as zinc or cadmium in a solvent such as acetic acid or a mixture of tetrahydrofuran and a weak aqueous acid at temperatures between 0 ° C. and the boiling point of the solvent used and
the carbobenzyloxycarbonyl group, which can be split off, for example, by hydrogenolysis in the presence of a noble metal catalyst such as, for example, palladium-carbon and a solvent such as, for example, alcohols, ethyl acetate, dioxane, tetrahydrofuran or mixtures of these solvents at temperatures between 0 ° C. and the boiling point of the solvent, by treatment with Boron tribromide in methylene chloride at temperatures between -20 ° C and room temperature, or by treatment with aluminum chloride / anisole at temperatures between 0 ° C and room temperature.

If desired, a protective residue used during the reactions to protect reactive groups is then split off and / or
a compound of the general formula I thus obtained is separated into its stereoisomers and / or
a compound of the general formula I thus obtained is converted into its salts, in particular for pharmaceutical use into its physiologically tolerable salts with an inorganic or organic acid.

In the above Implementations can optionally present reactive groups such as hydroxyl, carboxy, Phosphono, O-alkyl-phosphono, amino, alkylamino or imino groups while the implementation by usual Protected groups protected which are split off after the implementation.

For example, the trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group comes as a protective radical for a hydroxyl group,
as protective residues for a carboxy group, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group,
as protective residues for a phosphono group an alkyl group such as the methyl, ethyl, isopropyl or n-butyl group, the phenyl or benzyl group and
as protective radicals for an amino, alkylamino or imino group, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally for the amino group Phthalyl group into consideration.

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

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

The cleavage of a tert-butyl or tert-butyloxycarbonyl radical is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, if necessary Use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

The cleavage of a trifluoroacetyl residue is preferably carried out, if appropriate, by treatment with an acid such as hydrochloric acid in the presence of a solvent like acetic acid at temperatures between 50 and 120 ° C or by treatment with Sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C.

The cleavage of a phthalyl radical is preferably carried out 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 Temperatures between 20 and 50 ° C.

The cleavage of only one alkyl radical from an O, O'-dialkylphosphono group for example with sodium iodide in a solvent such as acetone, ethyl methyl ketone, acetonitrile or dimethylformamide at temperatures between 40 and 150 ° C, but preferably at temperatures between 60 and 100 ° C.

The elimination of both alkyl residues from an O, O'-dialkylphosphono group takes place, for example, with iodotrimethylsilane, bromotrimethylsilane or chlorotrimethylsilane / sodium iodide in a solvent such as methyl chloride, Chloroform or acetonitrile at temperatures between 0 ° C and Boiling temperature of the reaction mixture, but preferably at Temperatures between 20 and 60 ° C.

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

For example, the obtained cis / trans mixtures by chromatography in their cis and trans isomers, the compounds of the general formula obtained I, which occur in racemates, according to methods known per se (see Allinger N.L. and Eliel E.L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of general Formula I based on at least 2 asymmetric carbon atoms their physico-chemical differences according to known Methods, e.g. by chromatography and / or fractional crystallization, into their diastereomers, which, if in racemic Form, then as mentioned above can be separated into the enantiomers.

The enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optical active solvent or by reaction with a salt with the racemic compound or derivatives such as Esters or amides forming optically active Substance, especially acids and their activated derivatives or alcohols, and separating the diastereomeric salt mixture or derivative obtained in this way, e.g. due to different solubilities, whereby from the pure diastereomeric salts or derivatives the free antipodes can be released by the action of suitable agents. Especially common, optically active acids are e.g. the D and L forms of tartaric acid or dibenzoyl tartaric acid, Di-O-p-toluoyl-tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or China acid. The optically active alcohol is, for example, (+) - or (-) - menthol and as an optically active acyl radical in amides, for example (+) - or (-) - menthyloxycarbonyl into consideration.

Furthermore, the compounds obtained of the formula I in their salts, in particular for pharmaceutical use in their physiologically tolerable Salts with inorganic or organic acids. Come as acids therefor for example hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic into consideration.

In addition, the so obtained new compounds of formula I, if this is a carboxy group included, if desired subsequently in their salts with inorganic or organic bases, in particular for the pharmaceutical application in their physiologically acceptable Salts, transfer. As bases come here, for example, sodium hydroxide, potassium hydroxide, arginine, Cyclohexylamine, ethanolamine, diethanolamine and triethanolamine in Consideration.

The used as raw materials Compounds of the general formulas II to IV are either known from the literature or you get this according to methods known per se, for example through the synthetic routes shown in Schemes 1 to 5.

Scheme 1: Possible synthetic route to the substituted 3,5-dihydro-imidazo [4,5-c] pyridin-4-ones

Scheme 2: Possible alternative synthetic route to the substituted 3,5-dihydro-imidazo [4,5-c] pyridin-4-ones

Scheme 3: Possible synthetic route to the substituted 3,5-dihydro-imidazo [4,5-d] pyridazin-4-ones

Scheme 4: Possible alternative synthetic route to the substituted 3,5-dihydro-imidazo [4,5-d] pyridazin-4-ones

Scheme 5: Another possible synthetic route to the substituted 3,5-dihydro-imidazo [4,5-d] pyridazin-4-ones

As already mentioned at the beginning, point the compounds of the invention of the general formula I and its physiologically compatible Salts valuable pharmacological properties, in particular an inhibitory effect on the enzyme DPP-IV.

The biological properties of the new compounds were tested as follows:
The ability of the substances and their corresponding salts to inhibit DPP-IV activity can be demonstrated in an experimental setup in which an extract of the human colon carcinoma cell line Caco-2 is used as the DPP IV source. The differentiation of the cells to induce the DPP-IV expression was carried out according to the description by Reiher et al. in an article entitled "Increased expression of intestinal cell line Caco-2", published in Proc. Natl. Acad. Sci. Vol. 90, pages 5757-5761 (1993). The cell extract was obtained from cells solubilized in a buffer (10mM Tris HCl, 0.15M NaCl, 0.04 tiu 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 μl substrate solution (AFC; AFC is amido-4-trifluoromethylcoumarin), final concentration 100 μM, were placed in black microtiter plates. 20 μl assay buffer (final concentrations 50 mM Tris HCl pH 7.8, 50 mM NaCl, 1% DMSO) were pipetted in. The reaction was started by adding 30 μl solubilized Caco-2 protein (final concentration 0.14 μg protein per well). The test substances to be checked were typically added prediluted in 20 μl, the assay buffer volume then being reduced accordingly. The reaction was carried out at room temperature, the incubation period was 60 minutes. The fluorescence was then measured in a Victor 1420 multilabel counter, the excitation wavelength being 405 nm and the emission wavelength 535 nm. Blank values (corresponding to 0% activity) were obtained in batches without Caco-2 protein (volume replaced by assay buffer), control values (corresponding to 100% activity) were obtained in batches without added substance. The potency of the respective test substances, expressed as IC ₅₀ values, were calculated from dose-response curves, each of which consisted of 11 measuring points. Here, for example, the compounds of Examples 1 and 2 showed IC ₅₀ values which were less than 2 μmol / L.

The compounds produced according to the invention are well tolerated for example after oral administration of 10 mg / kg of the compound of Example 2 in rats no changes could be observed in the behavior of the animals.

In terms of the ability the DPP-IV activity To inhibit the compounds of the general Formula I and its corresponding pharmaceutically acceptable salts capable of all those states or affect diseases caused by inhibition of DPP-IV activity can be influenced. It can therefore be expected that the compounds of the invention for prevention or Treatment of diseases or conditions such as diabetes mellitus Type I and Type II, diabetic complications, metabolic acidosis or ketosis, insulin resistance, dyslipidemia of various origins, Arthritis, atherosclerosis and related diseases, obesity, Allograft transplantation and osteoporosis caused by calcitonin are suitable. Furthermore are these substances suitable, the B-cell degeneration such as To prevent apoptosis or necrosis of pancreatic B cells. The substances are further suitable, the functionality of pancreatic Cells to improve or restore, next to the number and size of pancreatic To increase B cells. additionally and justified through the role of glucagon-like peptides, e.g. GLP-1 and GLP-2 and linking them with DPP-IV inhibition, it is expected that the compounds of the invention are suitable, among other things, for a sedative or anxiolytic effect to achieve, furthermore catabolic states after surgery or hormonal stress responses affect or mortality and morbidity after myocardial infarction. They are also suitable for the treatment of all conditions, which are related to and through the above effects GLP-1 or GLP-2 are mediated. The compounds of the invention are also can be used as diuretics or antihypertensives and for prevention and treatment of acute kidney failure. Likewise are them for prevention and therapy of chronic inflammatory bowel diseases. Furthermore it is expected that DPP-IV Inhibitors and thus also the compounds according to the invention for treatment infertility or to improve fertility in Humans or in the mammalian organism can be used especially when infertility is related insulin resistance or polycystic ovarian syndrome stands. The substances are also suitable for deficiency states of Influence growth hormone associated with short stature.

The compounds of the invention can also can be used in combination with other active ingredients. To the Therapeutics suitable for such a combination include e.g. Antidiabetic agents such as metformin, sulfonylureas (e.g. glibenclamide, Tolbutamide, Glimepiride), Nateglinide, Repaglinide, Thiazolidindione (e.g. Rosiglitazone, Pioglitazone), PPAR-gamma agonists (e.g. GI 262570), alpha-glucosidase inhibitors (e.g. acarbose, Voglibose), alpha2-antagonists, Insulin and insulin analogs, GLP-1 and GLP-1 analogs (e.g. Exendin-4) or amylin. In addition, inhibitors of protein tyrosine phosphatase 1, Substances that have deregulated glucose production in the liver influence, such as Inhibitors of glucose-6-phosphatase, or the fructose-1,6-bisphosphatase, the glycogen phosphorylase, glucagon receptor Antagonists and inhibitors of phosphoenolpyruvate 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, cholesterol absorption inhibitors such as ezetimibe, bile acid binding substances such as for example colestyramine, HDL-increasing compounds such as Example inhibitors of CETP or regulators of ABC1 or active substances to treat obesity, such as sibutramine or tetrahydrolipstatin or β3 agonists like SB-418790 or AD-9677. Next to it is a combination with medication to influence high blood pressure such as All antagonists or ACE Inhibitors, diuretics, β-blockers and others or combinations thereof.

To achieve a corresponding The required dose is expediently effective when administered intravenously 1 to 100 mg, preferably 1 to 30 mg, and in the case of oral administration 1 to 1000 mg, preferably 1 to 100 mg, each 1 to 4 times a day. For this can be produced according to the invention Compounds of formula I, optionally in combination with others Active substances, together with one or more inert usual excipients and / or diluents, e.g. with cornstarch, Milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, Polyvinyl pyrrolidone, citric acid, Tartaric acid, water, Water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, Propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures, in usual pharmaceutical preparations such as tablets, coated tablets, capsules, powders, Suspensions or suppositories incorporated.

The following examples are intended the invention closer explain:

example 1

2- (3-Amino-piperid in-1-yl) -3-benzyl-5- (naphthalin-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

1a) 4,5-dichloro-2-naphthalen-1-ylmethyl-2H-pyridazin-3-one

9.0 g (65 mmol) of potassium carbonate were added to a solution of 10.0 g (60.61 mmol) of 4,5-dichloro-3-hydroxy-pyridazine in 50 ml of dimethyl sulfoxide, then 9.42 g (63 mmol) of 1- (chloromethyl) naphthalene were added and stirred at 50 ° C for 17 hours. After cooling, the dark solution was distilled with 300 ml of dist. Water was added, then 300 ml of dichloromethane were stirred in, suction filtered through Celite, the aqueous phase was separated off and extracted three times with 50 ml of dichloromethane each time. The combined organic phases were washed with water, dried over sodium sulfate and concentrated. The crude product thus obtained was dissolved in 250 ml of dichloromethane, the solution was filtered through silica gel and then concentrated. The residue was triturated with petroleum ether, suction filtered and dried.
Yield: 67.6% of theory.
C ₁₅ H ₁₀ Cl ₂ N ₂ O (305.17)
Rf value: 0.71 (silica gel, dichloromethane)
Mass spectrum: (M + H) ⁺ = 305/7 (CI)

1b) 4-Hydroxy-2-naphthalen-1-ylmethyl-5-nitro-2H-pyridazin-3-one

A solution of 11.04 g (160 mmol) of sodium nitrite in 40 ml of water was added to a solution of 12 g (39.3 mmol) of 4,5-dichloro-2-naphthalin-1-ylmethyl-2H-pyridazin-3-one in 120 ml of dimethylformamide added and the mixture stirred at 85 ° C for 24 hours. The mixture was then concentrated in vacuo and the residue was stirred with a mixture of 30 ml of semi-concentrated hydrochloric acid and 30 ml of ethanol, the product crystallizing. It was filtered off, washed with ethanol and dried.
Yield: 81.7% of theory
C ₁₅ H ₁₁ N ₃ O ₄ (297.27)
Rf value: 0.32 (silica gel, dichloromethane / ethanol 19: 1)

1e) 4-amino-2-naphthalen-1-ylmethyl-5-nitro-2H-pyridazin-3-one

9.4 g (31.6 mmol) of 4-hydroxy-2-naphthalin-1-ylmethyl-5-nitro-2H-pyridazin-3-one were mixed with 150 ml of saturated methanolic ammonia solution and heated to 130 ° C. in the red bomb for 24 hours. The mixture was concentrated on a rotary evaporator to a volume of about 40 ml, the precipitated product removed sucks and recrystallized from tetrahydrofuran.
Yield: 53.4% of theory
C ₁₅ H ₁₂ N ₄ O ₃ (296.29)
Rf value: 0.68 (silica gel, dichloromethane / ethanol 50: 1)
Mass spectrum: (M + H) ⁺ = 297
(M-H) ^- = 295

1d) 4,5-diamino-2-naphthalen-1-ylmethyl-2H-gyridazin-3-one

5 g (16.88 mmol) of 4-amino-2-naphthalin-1-ylmethyl-5-nitro-2H-pyridazin-3-one, dissolved in 150 ml of tetrahydrofuran, were added with the addition of 250 mg of platinum oxide in a Parr apparatus at room temperature and 2 atm H ₂ reduced. The catalyst was filtered off, the filtrate was concentrated and the crude product thus obtained was processed without further purification.
Yield: 99% of theory
C ₁₅ H ₁₄ N ₄ O (266.3)
Rf value: 0.14 (silica gel, dichloromethane / ethanol 19: 1)

1e) 2-mercapto-5- (naphthalin-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

4.99 g (28.0 mmol) of N, N'-thiocarbonyldiimidazole were added to a solution of 4.4 g (16.5 mmol) of 4,5-diamino-2-naphthalen-1-ylmethyl-2H-pyridazin-3-one in 100 ml of tetrahydrofuran and stirred overnight at room temperature. Then it was evaporated in vacuo, the residue was mixed with about 30 ml of water, weakly acidified with hydrochloric acid, the precipitated product was filtered off with suction, washed with water and dried.
Yield: 98% of theory
C ₁₆ H ₁₂ N ₄ OS (308.36)
Rf value: 0.22 (silica gel, dichloromethane / ethanol 19: 1)
Mass spectrum: (M - H) ^- = 307

1f) 2-methylsulfanyl-5- (naphthalen-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

To a suspension of 5.3 g (17.19 mmol) of 2-mercapto-5- (naphthalin-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one in 100 ml dichloromethane and 100 ml Methanol was added to 2.38 g (17.2 mmol) of potassium carbonate and 1.07 ml (17.20 mmol) of iodomethane and stirred overnight at room temperature. The solvent was then evaporated off, about 30 ml of water were added to the residue, acidified with 2N hydrochloric acid, and the product thus obtained was filtered off with suction, washed with water and dried.
Yield: 54.1% of theory
C ₁₇ H ₁₄ N ₄ OS (322.39)
Rf value: 0.70 (silica gel, dichloromethane / ethanol 50: 1)
Mass spectrum: (M + H) ⁺ = 323
¹ H NMR Spectrum (d ₆ -DMSO): δ = 2.70 (s, 3H); 5.81 (s, 2H); 7.20 (dd, 1H); 7.43 (t, 1H); 7.57 (m. 2H); 7.86 (dd, 1H); 7.95 (dd, 1H); 8.29 (dd, 1H); 8.38 (s, 1H), 13.85 (broad s, 1H) ppm.

1g) 3-Benzyl-2-methylsulfanyl-5- (naphthalin-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

A solution of 1.0 g (3.10 mmol) of 2-methylsulfanyl-5- (naphthalin-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one in 15 ml of dimethylformamide was treated with 547 mg (3.20 mmol) benzyl bromide and then mixed with 442 mg (3.20 mmol) potassium carbonate and stirred overnight at room temperature. The mixture was then diluted with about 40 ml of water and extracted three times with 15 ml of ethyl acetate each time. The organic extracts were washed with water, dried over sodium sulfate and concentrated. The crude product thus obtained was purified by column chromatography (silica gel; eluent: petroleum ether with 10-20% ethyl acetate).
Yield: 54.7% of theory
C ₂₄ H ₂₀ N ₄ OS (412.52)
Rf value: 0.77 (silica gel, petroleum ether / ethyl acetate 1: 1)
Mass spectrum: (M + H) ⁺ = 413

1h) 3-benzyl-2-methylsulfonyl-5- (naphthalen-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

A solution of 700 mg (1.70 mmol) of 3-benzyl-2-methylsulfanyl-5- (naphthalin-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one concentrated in 30 ml A solution of 395 mg (2.50 mmol) of potassium permanganate was added dropwise to acetic acid with stirring at room temperature and the mixture was stirred for a further two hours. Since the oxidation was not yet complete, a further 150 mg of potassium permanganate, dissolved in 5 ml of water, were added and the mixture was stirred for another two hours. The reaction solution was then mixed with 0.5 g of sodium bisulfite, then diluted with about 40 ml of water and extracted three times with 20 ml of dichloromethane. The organic extracts were washed with 5% sodium hydrogen sulfite solution, then with water and dried over sodium sulfate. The crude product obtained after the concentration was purified by column chromatography (silica gel; eluent: dichloromethane with 1% ethanol).
Yield: 55.7% of theory
C ₂₄ H ₂₀ N ₄ O ₃ S (444.52)
Rf value: 0.41 (silica gel, petroleum ether / ethyl acetate 7: 3)
Mass spectrum: (M + H) ⁺ = 445

1i) [1- (1-Benzyl-6-naphthalen-1-ylmethyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperidin-3-yl ] -carbamic acid tert-butyl ester

200 mg (0.45 mmol) 3-benzyl-2-methylsulfonyl-5- (naphthalin-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one and 600 mg (3.0 mmol) Piperidin-3-yl-carbamic acid tert-butyl ester were stirred together under nitrogen at 150 ° C. for 16 hours. The reaction mixture was then dissolved in 30 ml of dichloromethane, the solution was washed with 1N sodium hydroxide solution and dried over sodium sulfate. The crude product obtained after the concentration was purified by column chromatography (silica gel; eluent: dichloromethane with 1–2% ethanol).
Yield: 26.6% of theory
C ₃₃ H ₃₆ N ₆ O ₃ (564.69)
Rf value: 0.59 (silica gel, dichloromethane / ethanol 19: 1)
Mass spectrum: (M + H) ⁺ = 565

1j) 2- (3-aminopiperidin-1-yl) -3-benzyl-5- (naphthalen-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one- hydrochloride

A solution of 60 mg (0.106 mmol) [1- (1-benzyl-6-naphthalin-1-ylmethyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl ) -piperidin-3-yl] -carbamic acid tert-butyl ester in 5 ml dichloromethane was mixed with 0.5 ml trifluoroacetic acid and stirred for two hours at room temperature. The mixture was evaporated to dryness, the residue was dissolved in 5 ml of dichloromethane and the solution was washed with 1N sodium hydroxide solution and water and then dried over sodium sulfate. It was evaporated again, the residue was dissolved in a mixture of 3 ml of diethyl ether and acetone, and the hydrochloride of the product was precipitated by the dropwise addition of ethereal hydrochloric acid. This was suctioned off and dried.
Yield: 37.7% of theory
C ₂₈ H ₂₈ N ₆ O × HCl (501.04)
Rf value: 0.22 (silica gel, dichloromethane / ethanol 19: 1)
Mass spectrum: (M + H) ⁺ = 465

Example 2

2- (3-Amino-piperidin-1-yl) -3-but-2-ynyl-5- (naphthalen-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4- on

2a) 3-But-2-ynyl-2-methylsulfanyl-5- (naphthalen-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

A solution of 900 mg (2.79 mmol) of 2-methylsulfanyl-5- (naphthalin-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one (Example 1f) in 15 ml of dimethylformamide 415 mg (3.0 mmol) of potassium carbonate and 399 mg (3.0 mmol) of 1-bromo-2-butyne were added and the mixture was stirred at room temperature for eight hours. The mixture was then diluted with about 30 ml of water and saturated with sodium chloride, the reaction product crystallizing out. It was suction filtered and purified by column chromatography (silica gel, eluent: petroleum ether with 10-50% ethyl acetate).
Yield: 71.7% of theory
C ₂₁ H ₁₈ N ₄ OS (374.47)
Rf value: 0.69 (silica gel, petroleum ether / ethyl acetate 1: 1)
Mass spectrum: (M + H) ⁺ = 375

2b) 3-But-2-ynyl-2-methylsulfonyl-5- (naphthalen-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

A solution of 600 mg (1.60 mmol) of 3-but-2-ynyl-2-methylsulfanyl-5- (naphthalen-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one In 30 ml of glacial acetic acid, a solution of 500 mg of potassium permanganate in 20 ml of water was added dropwise while stirring at room temperature. After three hours at room temperature, a sodium bisulfite solution was added dropwise until the reaction mixture was almost completely decolorized. The mixture was then diluted with about 50 ml of water and saturated with sodium chloride. The crude product which precipitated out was filtered off with suction and purified by column chromatography (aluminum oxide; eluent: dichloromethane).
Yield: 43.0% of theory
C ₂₁ H ₁₈ N ₄ O ₃ S (406.47)
Rf value: 0.70 (silica gel, dichloromethane / ethanol 19: 1)
Mass spectrum: (M + H) ⁺ = 407
¹ H NMR Spectrum (d ₆ -DMSO): δ = 1.80 (s, 3H); 3.60 (s, 3H); 5.61 (s, 2H); 5.85 (s, 2H); 7.30 (dd, 1H); 7.45 (t, 1H); 7.58 (m. 2H); 7.90 (dd, 1H); 7.96 (dd, 1H); 8.30 (dd, 1H); 8.64 (s, 1H) ppm.

2c) [1- (1-But-2-ynyl-6-naphthalen-1-ylmethyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperidine -3-yl] -carbamic acid tert-butyl ester

A mixture of 260 mg (0.64 mmol) of 3-but-2-ynyl-2-methylsulfonyl-5- (naphthalen-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one and 800 mg (3.99 mmol) of piperidin-3-yl-carbamic acid tert-butyl ester was stirred under nitrogen at 150 ° C. for two hours. After cooling, the mixture was dissolved in about 15 ml of dichloromethane, washed with dilute ammonia solution and dried over sodium sulfate. The crude product obtained after the concentration was purified by column chromatography (silica gel; eluent: dichloromethane with 1-5% ethanol)
Yield: 35.6% of theory
C ₃₀ H ₃₄ N ₆ O ₃ (526.64)
Rf value: 0.53 (silica gel, dichloromethane / ethanol 19: 1)
Mass spectrum: (M + H) ⁺ = 527

2d) 2- (3-aminopiperidin-1-yl) -3-but-2-ynyl-5- (naphthalen-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazine- 4-one hydrochloride

A solution of 120 mg (0.23 mmol) [1- (1-but-2-ynyl-6-naphthalen-1-ylmethyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazine T-butyl ester of -2-yl) -piperidin-3-yl] carbamate and 1.0 ml of trifluoroacetic acid in 10 ml of dichloromethane were stirred at room temperature for three hours and then evaporated to dryness. The residue was dissolved in 15 ml of dichloromethane, the solution was washed with 1N sodium hydroxide solution, dried over sodium sulfate and concentrated. The crude product thus obtained was purified by column chromatography (silica gel; eluent: dichloromethane with 2–5% ethanol). The product was dissolved in 8 ml of ethyl acetate, and the hydrochloride was precipitated by dropwise addition of ethereal hydrochloric acid, filtered off with suction and dried.
Yield: 66.3% of theory
C ₂₅ H ₂₆ N ₆ O × HCl (462.99)
Rf value: 0.22 (silica gel, dichloromethane / ethanol 9: 1)
Mass spectrum: (M + H) ⁺ = 427
¹ H NMR Spectrum (d ₆ -DMSO): δ = 1.69 (m, 2H); 1.80 (s, 3H); 1.93 (m, 1H); 2.07 (m, 1H); 3.20 (m, 2H); 3.40 (m, 1H); 3.52 (m, 1H); 3.73 (m, 1H); 5.19 (m, 2H); 5.80 (s, 2H); 7.22 (d, 1H); 7.45 (t, 1H); 7.57 (m. 2H); 7.88 (dd, 1H); 7.96 (d. 1H); 8.29 (d, 1H); 8.31 (s, 1H); 8.40 (broad s, 3H) ppm.

Example 3

3,5-dibenzyl-2- (piperazin-1-yl) -3,5-dihydro-imidazo [4,5-c] pyridin-4-one

3a) 2,4-dichloro-3-nitropyridine

A solution of 30.0 g (0.192 mol) of 2,4-dihydroxy-3-nitropyridine in 300 ml of phosphorus oxychloride was heated to reflux for 50 hours, then about 200 ml of phosphorus oxychloride were distilled off and the residue was decomposed with ice water (about 300 ml). The dark solution obtained in this way was extracted twice with 150 ml of ethyl acetate each time, the organic phases were washed with saturated sodium chloride solution, dried and concentrated. The crude product thus obtained was purified by column chromatography (silica gel, eluent: dichloromethane).
Yield: 75% of theory.
Rf value: 0.88 (silica gel, dichloromethane / ethanol = 9: 1)
Mass spectrum: M ⁺ = 192/4/6

3b) 4-amino-2-chloro-3-nitropyridine

A solution of 28.0 g (0.193 mol) of 2,4-dichloro-3-nitropyridine in 300 ml of ethanol saturated with ammonia was stirred at room temperature for four days, then evaporated to dryness and the crude product thus obtained was purified by column chromatography (silica gel, eluent: Dichloromethane with 0-5% ethanol).
Yield: 71% of theory.
C ₅ H ₄ ClN ₃ O ₂ (173.56)
Mass spectrum: (M + H) ⁺ = 174/6

3e) 4-amino-2-hydroxy-3-nitropyridine

A solution of 18.0 g (104 mmol) of 4-amino-2-chloro-3-nitropyridine in 120 ml of dimethyl sulfoxide and 30 ml of water was stirred at 130 ° C. for four hours. The solution was then cooled and left overnight with ice cooling. The product which crystallized out was filtered off with suction, washed with a little water and dried at 50.degree.
Yield: 69% of theory.
C ₅ H ₅ N ₃ O ₃ (155.11)
Mass spectrum: (M + H) ⁺ = 156
(M-H) ^- = 154

3d) 3,4-diamino-2-hydroxypyridine

11.0 g (71 mmol) of 4-amino-2-hydroxy-3-nitropyridine were dissolved in 150 ml of dimethylformamide and reduced at room temperature by catalytic hydrogenation (Pd / C 10%).
Yield: 83% of theory.
C ₅ H ₇ N ₃ O (125.13)
Mass spectrum: (M + H) ⁺ = 126

3e) 2-mercapto-3,5-dihydro-imidazo [4,5-c] pyridin-4-one

A suspension of 5.0 g (39.96 mmol) of 3,4-diamino-2-hydroxypyridine and 12.82 g (80.0 mmol) of potassium ethyl xanthate in 100 ml of ethanol was heated under reflux for three hours. The mixture was then cooled to room temperature and about 20 ml of diethyl ether were added. The precipitated product was filtered off, washed with about 10 ml of diethyl ether, dried, dissolved in about 30 ml of water and this solution acidified with concentrated hydrochloric acid. The product which precipitated was filtered off with suction, washed with 15 ml of water and dried at 50.degree.
Yield: 82% of theory.
C ₆ H ₅ N ₃ OS (167.19)
Mass spectrum: (M + H) ⁺ = 168
(M-H) ^- = 166

3f) 2-methylmercapto-3,5-dihydro-imidazo [4,5-c] pyridin-4-one

To a suspension of 5.30 g (31.7 mmol) of 2-mercapto-3,5-dihydro-imidazo [4,5-c] pyridin-4-one in 100 ml of dichloromethane and 50 ml of methanol was added 4.38 g (31.7 mmol) of potassium carbonate and 1.97 ml (31.7 mmol) of methyl iodide were added and the mixture was stirred at room temperature overnight. Then a further 15 ml of methanol were added and undissolved constituents were filtered off. The filtrate was evaporated and the crude product thus obtained was purified by column chromatography (silica gel, eluent: dichloromethane with 5-25% Ethanol).
Yield: 96% of theory.
C ₇ H ₇ N ₃ OS (181.22)
Rf value: 0.53 (silica gel, dichloromethane / ethanol 9: 1)
Mass spectrum: (M + H) ⁺ = 182
¹ H NMR Spectrum (d ₆ -DMSO): δ = 2.62 (s, 3H); 6.40 (broad s, 1H); 7.03 (d, 1H); 11.12 (broad s, 1H); 12.95 (broad d, 1H) ppm.

3g) 3,5-dibenzyl-2-methylmercapto-3,5-dihydro-imidazo [4,5-c] pyridin-4-one

To a solution of 362 mg (2.0 mmol) of 2-methylmercapto-3,5-dihydro-imidazo [4,5-c] pyridin-4-one in 5.0 ml of dimethylformamide were added 553 mg (4.0 mmol) of potassium carbonate and 0.48 ml ( 4.0 mmol) of benzyl bromide and this mixture was stirred for three hours at room temperature. The mixture was then diluted with 10 ml of water and extracted three times with 10 ml of ethyl acetate each time. The organic extracts were dried and concentrated, the crude product thus obtained was purified by column chromatography (silica gel, eluent: dichloromethane with 0-3% ethanol).
Yield: 26% of theory.
C ₂₁ H ₁₉ N ₃ OS (361.47)
Rf value: 0.62 (silica gel, dichloromethane / ethanol 19: 1)
Mass spectrum: (M + H) ⁺ = 362
¹ H NMR Spectrum (d ₆ -DMSO): δ = 2.67 (s, 3H); 5.21 (s, 2H); 5.62 (s, 2H); 6.63 (d. 1H); 7.20-7.37 (m, 10H); 7.56 (d, 1H) ppm.

3h) 3,5-dibenzyl-2-methanesulfonyl-3,5-dihydro-imidazo [4,5-c] pyridin-4-one

A solution was added to a solution of 181 mg (0.50 mmol) of 3,5-dibenzyl-2-methylmercapto-3,5-dihydro-imidazo [4,5-c] pyridin-4-one in 10 ml of dichloromethane at room temperature with stirring of 190 mg (1.10 mmol) of 3-chloro-peroxybenzoic acid in 5 ml of dichloromethane was added dropwise. After the addition had ended, the mixture was stirred for a further 30 minutes, then the reaction mixture was shaken out with about 25 ml of 5% sodium hydrogen carbonate solution, the organic phase was separated off, dried over sodium sulfate and evaporated. The crude product thus obtained, which contained about 20% of the methanesulfinyl compound, was processed without further purification.
Yield: approx. 75% of theory
C ₂₁ H ₁₉ N ₃ O ₃ S (393.47)
Rf value: 0.66 (silica gel, dichloromethane / ethanol 19: 1)
Mass spectrum: (M + H) ⁺ = 394

3i) 3,5-dibenzyl-2- (piperazin-1-yl) -3,5-dihydro-imidazo [4,5-c] pyridin-4-one

860 mg (10 mmol) of piperazine was added dropwise with cooling with 660 mg (11 mmol) of glacial acetic acid, then 180 mg of 3,5-dibenzyl-2-methanesulfonyl-3,5-dihydro- [imidazo4,5-c] pyridine-4 -one (crude product from Example 3 h) was added and the mixture was stirred at 150 ° C. for 24 hours. After cooling, approx. 10 ml of water are added, the mixture is made alkaline with concentrated ammonia solution and the mixture is extracted three times with 5 ml of dichloromethane each time. The extracts were dried over sodium sulfate and evaporated. The crude product thus obtained was purified by column chromatography (silica gel; eluent: petroleum ether with 20-60% ethyl acetate).
Yield: 5.5% of theory
C ₂₄ H ₂₅ N ₅ O (399.50)
Rf value: 0.28 (silica gel, petroleum ether / ethyl acetate 7: 3)
Mass spectrum: (M + H) ⁺ = 400

Example 4

2- (3-Amino-piperidin-1-yl) -5-benzyl-3-but-2-iny1-3,5-dihydro-imidazo [4,5-c] pyridin-4-one

4a) 1-benzyl-4-benzyloxy-3-nitro-pyridin-2-one

A solution of 4.68 g (30 mmol) of 2,4-dihydroxy-3-nitro-pyridine in 100 ml of dimethylformamide was mixed in portions with 2.88 g (60 mmol) of a 50% suspension of sodium hydride in paraffin oil and stirred for 15 minutes. Then 8.91 ml (75 mmol) of benzyl bromide were added and the mixture was stirred at 80 ° C. for 24 hours. The solution was then carefully stirred into about 250 ml of water and extracted three times with 70 ml of ethyl acetate. The extracts were washed with saturated sodium chloride solution, dried and concentrated in vacuo. The residue was triturated with diethyl ether, suction filtered and dried. The product thus obtained was processed without purification.
Yield: 59% of theory.
C ₁₉ H ₁₆ N ₂ O ₄ (336.35)
Mass spectrum: (M + H) ⁺ = 337

4b) 4-amino-1-benzyl-3-nitro-pyridin-2-one

20 ml of a saturated ethanolic ammonia solution were added to a solution of 5.5 g (16.3 mmol) of 1-benzyl-4-benzyloxy-3-nitro-pyridin-2-one in 50 ml of dichloromethane and the mixture was stirred in a closed flask at room temperature for 3 days. The solution was evaporated to dryness, the residue was triturated with diethyl ether, suction filtered and dried.
Yield: 97% of theory.
C ₁₂ H ₁₁ N ₃ O ₃ (245.24)
Rf value: 0.31 (silica gel; dichloromethane / ethanol 19: 1)

4e) 1-benzyl-3,4-diamino-pyridin-2-one

3.9 g (15.9 mmol) of 4-amino-1-benzyl-3-nitro-pyridin-2-one, dissolved in 250 ml of tetrahydrofuran, were hydrogenated over platinum oxide at 50 psi H ₂ pressure and room temperature. After filtering off the catalyst, the filtrate was evaporated and the residue was further processed raw.
Yield: 99% of theory.
C ₁₂ H ₁₃ N ₃ O (215.26)

4d) 5-Benzyl-2-mercapto-3,5-dihydro-imidazo [4,5-c] pyridin-4-one

A solution of 3.40 g (15.8 mmol) of 1-benzyl-3,4-diamino-pyridin-2-one and 4.99 g (28.0 mmol) of N, N'-thiocarbonyl-diimidazole in 200 ml of tetrahydrofuran was stirred overnight at room temperature. then evaporated, the residue mixed with about 50 ml of water, adjusted to pH 7 with 2N hydrochloric acid and this solution stirred for about 30 minutes at room temperature. The product which precipitated was filtered off with suction, washed with about 50 ml of water and dried at 50.degree.
Yield: 98% of theory.
C ₁₃ H ₁₁ N ₃ OS (257.32)
Rf value :: 0.45 (silica gel; dichloromethane / ethanol 9: 1)

5-benzyl-2-methylsulfanyl-3,5-dihydro-imidazo [4,5-c] pyridin-4-one

4.0 g (15.55 mmol) of 5-benzyl-2-mercapto-3,5-dihydro-imidazo [4,5-c] pyridin-4-one were suspended in a mixture of 100 ml of dichloromethane and 50 ml of methanol, then 2.15 g (15.55 mmol) potassium carbonate and 0.97 ml (15.55 mmol) iodomethane were added and the mixture was stirred at room temperature for 1 hour. The mixture was then filtered, the filtrate was concentrated and the residue was further reacted raw.
Yield: 94% of theory.
C ₁₄ H ₁₃ N ₃ OS (271.34)
Rf value :: 0.49 (silica gel; dichloromethane / ethanol 9: 1)
Mass spectrum: (M + H) ⁺ = 272

4f) 5-Benzyl-3-but-2-ynyl-2-methylsulfanyl-3,5-dihydro-imidazo [4,5-c] pyridin-4-one

To a solution of 4.0 g (14.7 mmol) of 5-benzyl-2-methylsulfanyl-3,5-dihydro-imidazo [4,5-c] pyridin-4-one and 1.31 ml (15.0 mmol) of 1-bromo-2- 2.07 g (15.0 mmol) of potassium carbonate were added to butyne in 100 ml of dimethylformamide and the mixture was stirred at room temperature for one hour. Then about 200 ml of saturated sodium chloride solution were added and extracted three times with 50 ml of ethyl acetate each time. The extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The crude product thus obtained was purified by column chromatography (silica gel; eluent: dichloromethane with 0-2% ethanol).
Yield: 48% of theory.
C ₁₈ H ₁₇ N ₃ OS (323.42)
Rf value :: 0.71 (silica gel; dichloromethane / ethanol 9: 1)
¹ H NMR Spectrum (d ₆ -DMSO): δ = 1.78 (s, 3H); 2.70 (s, 3H); 5.18 (s, 2H); 5.23 (s, 2H); 6.61 (d, 1H); 7.23-7.38 (m, 5H); 7.53 (d, 1H) ppm.
Mass spectrum: (M + H) ⁺ = 324

4g) 5-Benzyl-3-but-2-ynyl-2-methylsulfonyl-3,5-dihydro-imidazo [4,5-c] pyridin-4-one

To a solution of 400 mg (1.24 mmol) of 5-benzyl-3-but-2-ynyl-2-methylsulfanyl-3,5-dihydro-imidazo [4,5-c] pyridin-4-one in 10 ml of concentrated acetic acid a solution of 316 mg (2.0 mmol) of potassium permanganate in 10 ml of water was slowly added dropwise with stirring. After three hours at room temperature, 400 mg of sodium bisulfite (Na ₂ S ₂ O ₅ ) were added and diluted with about 30 ml of water. It was extracted five times with 30 ml of dichloromethane each time, the extracts dried over sodium sulfate and concentrated. The product thus obtained was reacted further without purification.
Yield: 50% of theory.
C ₁₈ H ₁₇ N ₃ O ₃ S (355.42)
Rf value :: 0.40 (silica gel; dichloromethane / ethanol 19: 1)
Mass spectrum: (M + H) ⁺ = 356

4h) [1- (5-Benzyl-3-but-2-ynyl-4-oxo-4,5-dihydro-3H-imidazo [4,5-c] pyridin-2-yl) piperidin-3-yl ] -carbamic acid tert-butyl ester

A mixture of 220 mg (0.62 mmol) of 5-benzyl-3-but-2-ynyl-2-methylsulfonyl-3,5-dihydro-imidazo [4,5-c] pyridin-4-one and 781.1 mg (3.90 mmol ) Piperidin-3-yl-carbamic acid tert-butyl ester was heated at 170 ° C. for 5 hours under nitrogen. After cooling to room temperature, the crude product thus obtained was purified by column chromatography (silica gel; eluent: dichloromethane with 0-3% ethanol).
Yield: 23% of theory
C ₂₇ H ₃₃ N ₅ O ₃ (475.60)
Rf value :: 0.32 (silica gel; dichloromethane / ethanol 19: 1)
Mass spectrum: M ⁺ = 475
(M + H) ⁺ = 476

4i) 2- (3-aminopiperidin-1-yl) -5-benzyl-3-but-2-yny1-3,5-dihydro-imidazo [4,5-c] pyridin-4-one

A solution of 70.0 mg (0.147 mmol) [1- (5-benzyl-3-but-2-ynyl-4-oxo-4,5-dihydro-3H-imidazo [4,5-c] pyridin-2-yl ) -piperidin-3-yl] -carbamic acid tert-butyl ester and 0.5 ml trifluoroacetic acid in 3.0 ml dichloromethane was stirred for one hour at room temperature. The mixture was then evaporated in vacuo and the residue was dissolved in about 5 ml of dichloromethane. This solution was washed with about 5 ml of 1N sodium hydroxide solution, then dried over sodium sulfate and evaporated. The residue was dissolved in about 3 ml of ethyl acetate, and the product was precipitated as hydrochloride by dropwise addition of ethereal hydrochloric acid and dried.
Yield: 41% of theory.
C ₂₂ H ₂₅ N ₅ O × HCl (411.94)
Rf value: 0.22 (silica gel; dichloromethane / ethanol 9: 1)
Mass spectrum: M ⁺ = 375
(M + H) ⁺ = 376

Example 7

2- (3-Amino-piperidin-1-yl) -3-but-2-ynyl-5- (3-methyl-isoquinolin-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-on-4

Prepared analogously to Example 1j from {1- [1-but-2-ynyl-6- (3-methyl-isocholin-1-ylmethyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d ] pyridazin-2-yl] piperidin-3-yl} carbamic acid tert-bulyl ester and tifluoroacetic acid in dichloromethane.
Yield: 57% of theory.
C ₂₅ H ₂₇ N ₇ O × HCl (477.99)
Rf value: 0.13 (silica gel; dichloromethane / ethanol 9: 1)
Mass spectrum: (M + H) ⁺ = 442

Example 86

2- (3-Amino-piperidin-1-yl) -3- (3-methyl-but-2-enyl) -5- (3-methyl-isoquinolin-1-ylmethyl) -3,5-dihydro-imidazo [ 4,5-c] pyridin-4-one

Prepared analogously to Example 1j by splitting off the Boc protective group with tifluoroacetic acid in dichloromethane.
Yield: 84% of theory.
C ₂₇ H ₃₂ N ₆ O (456.59)
Mass spectrum: (M + H) ⁺ = 457
¹ H NMR Spectrum (d ₆ -DMSO): δ = 1.11-1.25 (m, 1H); 1.57-1.90 (m, 9H); 2.50 -2.65 (m, 1H); 2.75-2.88 (m, 2H); 3.25-3.45 (m, 2H); 4.81 (d. 2H); 5.33 (t, 1H); 5.78 (s, 2H); 6.48 (d. 1H); 7.40 (d. 1H); 7.58-7.65 (m, 2H); 7.72 (t, 1H); 7.89 (d. 1H); 8.40 (d, 1H) ppm.

Example 136

2- (3-amino-pigeridin-1-yl) -3-but-2-ynyl-5- (4-methyl-quinazolin-2-ylmethyl) -3,5-dihydro [4,5-d] pyridazine 4-one

136a) 2-bromo-1-but-2-ynyl-1H-imidazole-4,5-dicarboxylic acid dimethyl ester

A solution of 15.0 g (57.0 mmol) of dimethyl 2-bromo-imidazole-4,5-dicarboxylate, 5.15 ml (57.0 mmol) of 1-bromo-2-butyne and 50 ml of N, N-diisopropylethylamine in 280 ml of tetrahydrofuran became one Heated to reflux for one hour. The mixture was evaporated, the residue was mixed with about 100 ml of water and extracted three times with 70 ml of ethyl acetate. The extracts were washed with 50 ml of water, dried and concentrated. The crude product thus obtained was purified by column chromatography (silica gel; eluent: dichloromethane with 0-2% ethanol).
Yield: 75% of theory.
C ₁₁ H ₁₁ BrN ₂ O ₄ (315.13)
Rf value :: 0.82 (silica gel; dichloromethane / ethanol 9: 1)
Mass spectrum: (M + H) ⁺ = 315/317

136b) 2-Bromo-3-but-2-ynyl-5-formyl-3H-imidazole-4-carboxylic acid, methyl ester

To a solution of 13.5 g (42.84 mmol) of dimethyl 2-bromo-1-but-2-ynyl-1H-imidazole-4,5-dicarboxylate in 220 ml of tetrahydrofuran was added 43 ml (at -70 ° C under an argon atmosphere) 43 mmol) of a 1 molar solution of diisobutylaluminum hydride in tetrahydrofuran were added dropwise within 20 minutes. The mixture was stirred at -70 ° C. for a further 4 hours, then 20 ml of a mixture of 1M hydrochloric acid and tetrahydrofuran were added dropwise. After warming to room temperature, about 200 ml of water were added and extracted three times with 70 ml of ethyl acetate. The extracts were dried and concentrated, and the crude product thus obtained was purified by column chromatography (silica gel; eluent: petroleum ether with 20-50% ethyl acetate).
Yield: 52% of theory.
C ₁₀ H ₉ BrN ₂ O ₃ (285.10)
Mass spectrum: (M + H) ⁺ = 285/287
¹ H NMR Spectrum (d ₆ -DMSO): δ = 1.80 (s, 3H); 3.93 (s, 3H); 5.11 (s, 2H); 10.12 (s, 1H) ppm.

136e) 2-bromo-3-but-2-ynyl-3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

To a solution of 1.80 g (6.31 mmol) of 2-bromo-3-but-2-ynyl-5-formyl-3H-imidazole-4-carboxylic acid methyl ester in 25 ml of ethanol was added 0.31 ml of hydrazine hydrate (99%, 6.31 mmol), dissolved in 1 ml of ethanol, was added dropwise. Five minutes later, 1.5 ml of concentrated acetic acid was added and refluxed for 30 minutes. After cooling, the precipitated solid was filtered off, washed with 10 ml of ethanol and 20 ml of diethyl ether and dried.
Yield: 74% of theory.
C ₉ H ₇ BrN ₄ O (267.09)
Mass spectrum: (M + H) ⁺ = 267/269
¹ H NMR Spectrum (d ₆ -DMSO): δ = 1.80 (s, 3H); 5.28 (s, 2H); 8.38 (s, 1H); 12.99 (s, 1H) ppm.

136 d) 2-bromo-3-but-2-ynyl-5- (4-methyl-quinazolin-2-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one

To a solution of 300 mg (1.12 mmol) of 2-bromo-3-but-2-yny1-3,5-dihydro-imidazo [4,5-d] pyridazin-4-one and 260.1 mg (1.35 mmol) of 2- Chloromethyl-4-methyl-quinazoline in 4.0 ml of dimethylformamide were added to 489 mg (1.5 mmol) of cesium carbonate and this mixture was stirred at 80 ° C. in an argon atmosphere for 2 hours. The mixture was then diluted with 10 ml of water and stirred at room temperature for 30 minutes. The crude product which precipitated out was filtered off with suction and purified by column chromatography (silica gel; eluent: petroleum ether with 20-50% ethyl acetate).
Yield: 51% of theory.
C ₁₉ H ₁₅ BrN ₆ O (423.28)

136e) {1- [1-but-2-ynyl-6- (4-methyl-quinazolin-2-ylmethyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin- 2-yl] -piperidine-3-yl} -carbamic acid tert-butyl ester

A solution of 240 mg (0.567 mmol) of 2-bromo-3-but-2-ynyl-5- (4-methyl-quinazolin-2-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazine -4-one and 140.2 mg (0.70 mmol) of tert-butyl piperidin-3-yl-carbamate in 4 ml of dimethyl sulfoxide were mixed with 95 mg (0.9 mmol) of sodium carbonate and stirred at 80 ° C. for 3 hours. Then another 50 mg of tert-butyl piperidin-3-yl-carbamic acid were added and the mixture was stirred at 80 ° C. for a further 2 hours. After cooling to room temperature, 10 ml of water were added and the mixture was stirred for 30 minutes. The product which precipitated was filtered off with suction, washed with 5 ml of water and dried.
Yield: 81% of theory.
C ₂₉ H ₃₄ N ₈ O ₃ (542.65)

136f) 2- (3-aminopperidin-1-yl) -3-but-2-ynyl-5- (4-methyl-quinazolin-2-ylmethyl) -3,5-dihydro [4,5-d] pyridazin-on-4

Prepared analogously 1j from 240 mg (0.442 mmol) {1- [1-but-2-ynyl-6- (4-methyl-quinazolin-2-ylmethyl) -7-oxo-6,7-dihydro-1H-imidazo [ 4,5-d] pyridazin-2-yl] - piperidin-3-yl} -carbamic acid tert-butyl ester with trifluoroacetic acid in dichloromethane.
Yield: 56% of theory.
C ₂₄ H ₂₆ N ₈ O (442.53)
Rf value :: 0.42 (silica gel; dichloromethane / ethanol 9: 1 with the addition of 1 drop of concentrated ammonia solution)
Mass spectrum: (M + H) ⁺ = 443
¹ H NMR Spectrum (d ₆ -DMSO): δ = 1.23-1.37 (m, 1H); 1.60-1.95 (m, 6H); 2.75 3.10 (m, 6H); 3.58-3.72 (m, 2H); 5.10 (s, 2H); 5.61 (s, 2H); 7.70 (t, 1H); 7.82 (d. 1H); 7.93 (t, 1H); 8.28 (d, 1H); 8.30 (s, 1H); ppm (exchangeable protons not visible).

Example 178

2- (3-Amino-piperidin-1-yl) -3-but-2-ynyl-5- (2-oxo-2-phenyl-ethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-on-4

Prepared analogously to Example 1j by splitting off the Boc protective group with trifluoroacetic acid in dichloromethane.
Yield: 79% of theory.
C ₂₃ H ₂₈ N ₆ O ₂ (420.51)
Mass spectrum: (M + H) ⁺ = 421
¹ H NMR Spectrum (d ₆ -DMSO): δ = 1.16-1.27 (m, 1H); 1.60-1.95 (m, 9H); 2.65 (dd, 1H); 2.88 (m, 2H); 3.35-3.54 (m, 2H); 4.87 (d, 2H); 5.33 (t, 1H); 5.70 (s, 2H); 7.60 (t, 2H); 7.72 (t, 1H); 8.07 (d, 2H); 8.30 (s, 1H) ppm.

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

Example 182

2- (3-Amino-piperidin-1-yl) -3-but-2-ynyl-5- (quinoxalin-6-ylmethyl) -3,5-dihydro [4,5-d] pyridazin-4-one

Prepared analogously to Example 1j by splitting off the Boc protective group with trifluoroacetic acid in dichloromethane.
Yield: 69% of theory.
C ₂₃ H ₂₄ NaO (428.50)
Mass spectrum: (M + H) ⁺ = 429
1H NMR Spectrum (d ₆ -DMSO): δ = 1.22-1.33 (m, 1H); 1.60-1.94 (m 5H); 2.75-3.08 (m, 3H); 3.53-3.70 (m, 2H); 5.10 (s, 2H); 5.60 (s, 2H); 7.79 (dd, 1H); 7.90 (s, 1H); 8.08 (d, 1H); 8.32 (s, 1H); 8.92 (s, 2H) ppm (exchangeable protons not visible).

Example 183

2- (3-Amino-piperidin-1-yl) -3-but-2-ynyl-5- (4-methyl-pyridin-2-ylmethyl) -3,5-dihydro [4,5-d] pyridazine 4-one

Prepared analogously to Example 1j by splitting off the Boc protective group with trifluoroacetic acid in dichloromethane.
Yield: 90% of theory.
C ₂₁ H ₂₅ N ₇ O × 2 HCl (464.40)
Rf value :: 0.43 (silica gel; dichloromethane / methanol 7: 3) mass spectrum: (M + H) ⁺ = 392
¹ H NMR Spectrum (d ₆ -DMSO): δ = 1.65-1.80 (m, 2H); 1.80 (s, 3H); 1.90-2.10 (m, 2H); 3.15-3.43 (m, 3H); 3.45-3.55 (m, 1H); 3.72-3.82 (m, 1H); 5.18 (q, 2H); 5.70 (s, 2H); 7.58 (s, 1H); 7.79 (d. 1H); 8.39 (s, 1H); 8.60 (broad s; 2H); 8.73 (d, 1H) ppm.

Example 184

2- (3-Amino-piperidin-1-yl) -3-but-2-ynyl-5- (4-phenyl-quinazolin-2-ylmethyl) -3,5-dihydro [4,5-d] pyridazine 4-one

Prepared analogously to Example 1j by splitting off the Boc protective group with trifluoroacetic acid in dichloromethane.
Yield: 63% of theory.
C ₂₉ H ₂₈ N ₈ O (504.60)
Mass spectrum: (M + H) ⁺ = 505
¹ H NMR Spectrum (d ₆ -DMSO): δ = 1.22-1.33 (m, 1H); 1.60-1.95 (m, 5H); 2.78 (dd, 1H); 2.85-3.06 (m, 2H); 3.56-3.72 (m, 2H); 5.11 (s, 2H); 5.72 (s, 2H); 7.56 7.75 (m, 6H); 7.90-8.03 (m, 2H); 8.08 (d, 1H); 8.30 (s, 1H) ppm.

Example 185

2- (3-Amino-piperidin-1-yl) -3-but-2-ynyl (quinoxaline-2-ylmethyl) -3,5-dihydro [4,5-d] pyridazin-4-one

Prepared analogously to Example 1j by splitting off the Boc protective group with trifluoroacetic acid in dichloromethane.
Yield: 88% of theory.
C ₂₃ H ₂₄ N ₈ O × HCl (464.96)
Mass spectrum: (M + H) ⁺ = 429
¹ H NMR Spectrum (d ₆ -DMSO): δ = 1.63-1.75 (m, 2H); 1.77 (s, 3H); 1.88-2.10 (m, 2H); 3.13-3.26 (m, 2H); 3.35-3.56 (m, 2H); 3.75 (dd, 1H); 5.15 (q, 2H); 5.71 (s, 2H); 7.80-7.86 (m, 2H); 7.99 (m, 1H); 8.09 (m, 1H); 8.33 (s, 1H); 8.45 (broad s, 2H); 8.92 (s, 1H) ppm.

Example 186

2- (3-Amino-piperidin-1-yl) -3-but-2-ynyl-5- (2,3-dimethyl-quinoxalin-6-ylmethyl) -3,5-dihydro [4,5-d] pyridazin-on-4

Prepared analogously to Example 1j by splitting off the Boc protective group with trifluoroacetic acid in dichloromethane.
Yield: 52% of theory.
C ₂₅ H ₂₈ N ₈ O (456.56)
Mass spectrum: (M + H) ⁺ = 457
¹ H NMR Spectrum (d ₆ -DMSO): δ = 1.18-1.31 (m, 1H); 1.58-1.72 (m, 1H); 1.73-1.93 (m, 5H); 2.66 (s, 3H); 2.68 (s, 3H); 2.75 (dd, 1H); 2.83-3.05 (m, 1H); 3.55-3.68 (m, 2H); 5.10 (s, 2H); 5.53 (s, 2H); 7.62 (dd, 1H); 7.70 (s, 1H); 7.92 (d. 1H); 8.31 (s, 1H) ppm.

Example 187

2- (3-Amino-piperidin-1-yl) -3-but-2-ynyl-5- (4-cyano-naphthalen-1-ylmethyl) -3,5-dihydro [4,5-d] pyridazine 4-one

Prepared analogously to Example 1j by splitting off the Boc protective group with trifluoroacetic acid in dichloromethane.
Yield: 62% of theory.
C ₂₆ H ₂₅ N ₇ O (451.53)
Mass spectrum: (M + H) ⁺ = 452
¹ H NMR Spectrum (d ₆ -DMSO): δ = 1.22-1.32 (m, 1H); 1.58-1.71 (m, 1H); 1.75-1.93 (m, 5H); 2.77 (dd, 1H); 2.83-3.05 (m, 2H); 3.55-3.70 (m, 2H); 5.60 (s, 2H); 5.88 (s, 2H); 7.28 (d, 1H); 7.76 - 7.88 (m, 2H); 8.10 (d, 1H); 8.17 (d, 1H); 8.30 (s, 1H); 8.47 (d, 1H) ppm.

Example 188

2- (3-Amino-piperidin-1-yl) -3- (3-methyl-but-2-enyl) -5- (2-oxo-2-phenyl-ethyl) -3,5-dihydro-imidazo [ 4,5-c] pyridin-4-one

Prepared analogously to Example 1j by splitting off the Boc protective group with trifluoroacetic acid in dichloromethane.
Yield: 69% of theory.
C ₂₄ H ₂₉ NO ₂ (419.53)
Mass spectrum: (M + H) ⁺ = 420
¹ H NMR Spectrum (d ₆ -DMSO): δ = 1.15-1.27 (m, 1H); 1.57-1.92 (m, 9H); 2.55 -2.70 (m, 2H); 2.76-2.92 (m, 2H); 3.41 (dt, 1H); 4.80 (d. 2H); 5.32 (t, 1H); 5.04 (s, 2H); 6.51 (d, 1H); 7.34 (d, 1H); 7.60 (t, 2H); 7.70 (t, 1H); 8.08 (d, 2H) ppm.

Example 189

2- (3-aminopiperidin-1-yl) -3- (3-methyl-but-2-enyl) -5- (2-oxo-2-phenyl-ethyl dihydro-imidazo [4,5-d] pyridazin-on-4

Prepared analogously to Example 1j by splitting off the Boc protective group with trifluoroacetic acid in dichloromethane.
Yield: 88% of theory.
C ₂₂ H ₂₄ N ₆ O ₂ (404.47)
Mass spectrum: (M + H) ⁺ = 405
¹ H NMR Spectrum (d ₆ -DMSO): δ = 1.55 (m, 1H); 1.70 (m, 1H); 1.88 (m, 1H); 1.99 (m, 1H); 3.05-3.22 (m, 3H); 3.57 (m, 1H); 3.71 (dt, 1H); 5.11 (s, 2H); 5.70 (s, 2H); 7.60 (t, 2H); 7.72 (t, 1H); 8.08 (d, 2H); 8.32 (s, 1H) ppm.

Example 190

2- (3-Amino-piperidin-1-yl) -3- (3-methyl-but-2-enyl) -5- (naphthalen-1-ylmethyl) -3,5-dihydro-imidazo [4,5- c] pyridin-4-one

Prepared analogously to Example 1j by splitting off the Boc protective group with trifluoroacetic acid in dichloromethane.
Yield: 86% of theory.
C ₇₂ H ₃₁ N ₅ O (441.58)
Mass spectrum: (M + H) ⁺ = 442
¹ H NMR Spectrum (d ₆ -DMSO): δ = 1.13-1.75 (m, 1H); 1.57-1.95 (m, 9H); 2.57 (dd, 1H); 2.83 (m, 2H); 3.30-3.47 (m, 2H); 4.87 (d, 2H); 5.39 (t, 1H); 5.68 (s, 2H); 6.50 (d. 1H); 7.09 (d, 1H); 7.32 (d, 1H); 7.42 (t, 1H); 7.58 (m. 2H); 7.89 (d. 1H); 7.98 (d. 1H); 8.21 (d, 1H) ppm.

Example 191

Dragées with 75 mg of active substance

1 tablet core contains: active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropyl methylcellulose 15.0 mg magnesium stearate 1.5 mg 230.0 mg

production:

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and half of the stated amount of magnesium stearate. Pressings with a diameter of approx. 13 mm are produced on a tableting machine, these are rubbed on a suitable machine through a sieve with a 1.5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tablet machine into tablets of the desired shape. Weight of core: 230 mg Stamp: 9 mm, curved

The dragee cores thus produced are coated with a film which essentially consists of hydroxypropylmethyl cellulose. The finished film coated tablets are polished with beeswax.
Sugar weight: 245 mg.

Example 192

Tablets with 100 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 mg 220.0 mg

Production process:

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

Example 193

Tablets with 150 mg of active substance

Composition:

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

production:

The ones with milk sugar, cornstarch and silica mixed active substance is moistened with a 20% aqueous solution of polyvinylpyrrolidone and passed through a sieve with a mesh size of 1.5 mm.

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

Example 194

Hard gelatin capsules with 150 mg of active substance

1 capsule contains: active substance 150.0 mg Cornstarch dr. approximately 180.0 mg Milk sugar powder. approx. 87.0 mg magnesium stearate 3.0 mg approximately 420.0 mg

production:

The active ingredient comes with the excipients blended, passed through a sieve of 0.75 mm mesh size and in a suitable device homogeneously mixed.

The final mix is filled into size 1 hard gelatin capsules. Capsule filling: approx. 320 mg Capsule shell: Hard gelatin capsule size 1.

Example 195

Suppositories with 150 mg of active substance

1 suppository contains: active substance 150.0 mg Polyethylene glycol 1500 550.0 mg Polyethylene glycol 6000 460.0 mg polyoxyethylene 840.0 mg 2000.0 mg

production:

After the suppository mass has melted the active ingredient is distributed homogeneously and the melt in pre-cooled forms cast.

Example 196

Suspension with 50 mg of active substance

100 ml suspension contain: active substance 1.00 g Carboxymethylcellulose-Na-salt 0.10 g p-hydroxybenzoate 0.05 g p-hydroxybenzoate 0.01 g cane sugar 10.00 g glycerin 5.00 g Sorbitol solution 70% 20.00 g Aroma 0.30 g Distilled water ad 100 ml

production:

Dest. Water is heated to 70 ° C. This is while stirring p-hydroxybenzoate and propyl ester and glycerol and carboxymethyl cellulose sodium salt dissolved. It will cooled to room temperature and with stirring the active ingredient is added and dispersed homogeneously. After encore and Loosening the sugar, the sorbitol solution and of the aroma the suspension is evacuated with stirring.

5 ml of suspension contain 50 mg of active ingredient.

Example 197

Ampoules with 10 mg of active substance

Composition: Active ingredient 10.0 mg 0.01 N hydrochloric acid sq Aqua bidest ad 2.0 ml

production:

The active substance is required in the Amount of 0.01 N HCl dissolved, made isotonic with sodium chloride, sterile filtered and in 2 ml ampoules bottled.

Example 198

Ampoules with 50 mg of active substance

Composition: Active ingredient 50.0 mg 0.01 N hydrochloric acid sq Aqua bidest ad 10.0 ml

production:

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

Claims (10)

Compounds of the general formula

in which X is a nitrogen atom or a group of the formula CR ⁵ , where R ^{5 is} a hydrogen atom or a methyl group, R ^{1 is} a 5- to 7-membered cycloalkyleneimino group which is substituted in the carbon skeleton by an amino group and by a C _1-3 - Alkyl group, a 6- to 7-membered cycloalkyleneimino group in which the methylene group in the 4-position is replaced by an -NH group, or an amino group substituted by a C _5-7 cycloalkyl group, the C _5-7 cycloalkyl group being substituted by an amino group or a carbon atom in the 3-position of the C _5-7 cycloalkyl group being replaced by an -NH group, R ² a benzyl group in which the phenyl radical can be substituted by one or two fluorine, chlorine or bromine atoms or by a cyano group, a linear or branched C _3-8 alkenyl group, a C _3-5 alkynyl group, a C _{3- 7} -Cylcloalkylmethylgruppe, a C _5-7 -Cycloalkenylmethylgruppe, or a furylmethyl, thienylmethyl, Pyrrolylmethyl-, thiazolylmethyl, imidazolylmethyl, Pyridinylmethyl-, Pyrimidinylmethyl-, Pyridazinylmethyl- or pyrazinylmethyl group, R ³ is a linear or branched C _1-6 alkyl group, an optionally substituted in the aryl moiety by a cyano group, a C _1-3 alkyl or a methoxy group phenyl-C _{1 -3} alkyl or naphthyl-C _1-3 alkyl group, a 2-phenyl-2- hydroxy-ethylgrupp e, a phenylcarbonylmethyl group in which the phenyl group is replaced by a hydroxy, C _1-3 alkyloxy, amino carbonyl C _1-3 alkoxy, (C _1-3 alkylamino) carbonyl C _1-3 alkoxy, [di (C _1-3 alkyl) amino] carbonylC _1-3 alkoxy, amino, C _1-3 alkylcarbonylamino, C _3-6 cycloalkylcarbonylamino , C _1-3 alkoxy-carbonylamino, C _1-3 alkylsulfonylamino or aminocarbonyl group may be substituted, a thienylcarbonylmethyl group, a heteroaryl-C _1-3 alkyl group, where under the expression "heteroaryl group" one in the carbon skeleton optionally by one or two C _1-3 alkyl groups or monocyclic 5- or 6-membered heteroaryl groups substituted by a phenyl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group one optionally having a C _{1- 3-} alkyl or phenyl-C _1-3 alkyl group substituted imino group, an oxygen or sulfur atom or a an imino group optionally substituted by a C _1-3 alkyl or phenylC _1-3 alkyl group or an oxygen or sulfur atom and additionally a nitrogen atom or an optionally substituted by a C _1-3 alkyl or phenylC _1-3 alkyl group substituted imino group and two or three nitrogen atoms, and wherein in addition to the above-mentioned monocyclic heteroaryl groups, a phenyl ring can be fused via two adjacent carbon atoms and the binding can take place via an atom of the heterocyclic part or the fused phenyl ring, a bicyclic heteroarylmethyl group according to one of the formulas

or a group of the formula

in which R ^{6 represents} a hydrogen atom or a methyl group, and R ^{4 represents} a hydrogen atom or a C _1-3 alkyl group, the alkyl and alkoxy groups contained in the definitions having more than two carbon atoms, unless stated otherwise, may be straight-chain or branched, and the hydrogen atoms of the methyl or ethyl groups contained in the definitions in whole or in part may be replaced by fluorine atoms, their tautomers, their enantiomers, their diastereomers, their mixtures, and their salts. Compounds of the general formula I according to claim 1, in which X is a nitrogen atom or a group of the formula CR ⁵ , where R ^{5 is} a hydrogen atom or a methyl group, R ^{1 is} a piperazin-1-yl-, 3-amino-piperidin-1- yl-, 3-amino-3-methyl-piperidin-1-yl-, 3-amino-pyrrolindin-1-yl-, 1,4-diazepan-1-yl-, (2-amino-cyclohexyl) -amino- or piperidin-3-yl-amino group, R ^{2 is} a benzyl group in which the phenyl radical can be substituted by one or two fluorine atoms or by a cyano group, a linear or branched C _3-8 alkenyl group, a propin-3-yl or But-2-yn-4-yl group, a cyclopropylmethyl group, a C _5-7 cycloalkenylmethyl group, or a furylmethyl or thienylmethyl group, R ^{3 is} a linear or branched C _1-6 alkyl group, one optionally in the aryl part by a cyano, a C _1-3 alkyl or a methoxy group substituted phenylC _1-2 alkyl or naphthylC _1-2 alkyl group, a 2-phenyl-2-hydroxyethyl group, a phenylcarbon ylmethyl group in which the phenyl group is replaced by a hydroxy, C _1-3 alkyloxy, amino carbonyl C _1-3 alkoxy, (C _1-3 alkylamino) carbonyl C _1-3 alkoxy, [Di- (C _1-3 alkyl) amino] carbonyl C _1-3 alkoxy, amino, C _1-3 alkyl carbonylamino, C _3-6 cycloalkyl carbonylamino, C _{1 -3} alkoxy-carbonylamino, C _1-3 alkylsulfonylamino or aminocarbonyl group may be substituted, a thienylcarbonylmethyl group, a thienylethyl group, a heteroaryl-methyl group, where under the expression “heteroaryl group” one in the carbon skeleton optionally by one or two methyl groups or by a phenyl group substituted pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl or thienyl group and in addition to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms is a phenyl ring can be condensed and the bond over a Atom of the heterocyclic part or of the fused phenyl ring can take place, an imidazo [1,2-a] pyridin-2-yl-methyl group of the formula

a 1,2,4-triazolo [4,3-a] pyridin-3-yl group of the formula

or a group of the formula

in which R ^{6 represents} a hydrogen atom or a methyl group, and R ^{4 represents} a hydrogen atom or a C _1-3 alkyl group, it being possible for the alkyl and alkoxy groups contained in the definitions, which have more than two carbon atoms, unless stated otherwise, to be straight-chain or branched, and the hydrogen atoms being the The methyl or ethyl groups contained in the definitions can be replaced in whole or in part by fluorine atoms, their tautomers, their enantiomers, their diastereomers, their mixtures and their salts. Compounds of the general formula I according to Claim 1, in which X, R ² , R ³ and R ^{4 are defined} as mentioned in Claim 2 and R ¹ denotes a 3-amino-piperidin-1-yl group, their tautomers and their enantiomers , their diastereomers, their mixtures and their salts. Compounds of the general formula I according to Claim 1, in which X, R ¹ , R ³ and R ^{4 are defined} as mentioned in Claim 2 and R ^{2 is} a 3-methylallyl, a 3,3-dimethylallyl or a but-2- in-4-yl group means their tautomers, their enantiomers, their diastereomers, their mixtures and their salts. The following compounds of general formula I according to claim 1: (1) 2- (3-aminopiperidin-1-yl) -3-but-2-ynyl-5- (naphthalen-1-ylmethyl) -3,5-dihydro imidazo [4,5-d] pyridazin-4-one

(2) 2- (3-Amino-piperidin-1-yl) -3-but2-ynyl-5- (3-methyl-isoquinolin-1-ylmethyl) -3,5-dihydro-imidazo [4,5-d ] pyridazin-4-one

(3) 2- (3-amino-piperidin-1-yl) -3-but-2-ynyl-5- (quinazolin-2-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazine -4-one

(4) 2- (3-Amino-piperidin-1-yl) -3-but-2-ynyl-5- (1-methyl-1H-benzimidazol-2-ylmethyl) -3,5-dihydro-imidazo [4 , 5-d] pyridazin-4-one

as well as their enantiomers and their salts. Physiologically acceptable salts of the compounds according to claims 1 to 5 with inorganic or organic acids. Medicament containing a compound according to at least one of the claims 1 to 5 or a salt according to claim 6 in addition to optionally one or more inert carriers and / or diluents. Use a connection after at least one of claims 1 to 5 or a salt according to claim 6 to manufacture a drug used to treat diabetes Type I and Type II mellitus, arthritis, obesity, allograft transplantation and osteoporosis caused by calcitonin is suitable. A method of manufacturing a medicament according to claim 7, characterized in that on non-chemical Ways a connection according to at least one of claims 1 to 5 or a salt according to claim 6 in one or more inert carriers and / or diluents is incorporated. Process for the preparation of the compounds of formula I according to claims 1 to 6, characterized in that a) a compound of the general formula

in which X, R ² , R ³ and R ^{4 are defined} as mentioned in claims 1 to 5 and Z ^{1 is} a nucleofugic leaving group such as a chlorine or bromine atom or a C _1-3 alkylsulfanyl, C _1-3 - Alkylsulfinyl- or C _1-3 alkylsulfonyl group means with an amine of the general formula HR ¹ (III), in which R ^{1 is} as defined in claims 1 to 5, is reacted or b) a compound of the general formula

in which R ² , R ³ and R ^{4 are defined} as mentioned in claims 1 to 5 and R ^{1 'is} one of the groups mentioned for R ¹ in which the imino, amino or alkylamino group is substituted by a protective group is deprotected and, if desired, a protective residue used during the reactions to protect reactive groups is then split off and / or a compound of the general formula I thus obtained is separated into its stereoisomers and / or a compound of the general formula I thus obtained is converted into its salts, in particular for pharmaceutical use is converted into its physiologically tolerable salts with an inorganic or organic acid.