DE19602853A1 - New halo-substituted imidazo-pyridine compounds - Google Patents

Abstract

Halo-substituted imidazopyridine compounds of formula (I) and their salts and N-oxides are new: R0= halo or thiocyanate; R1 = 1-4C alkyl; R2, R4 = H, 1-4C alkyl, 1-4C alkoxy, halo or CF3; R3 = SO2R6, COR7, COOR8 or CON(R9)(R10); R5 = H, 1-4C alkyl, 1-4C alkoxy or halo; A = O or NH; R6 = 1-4C alkyl (optionally substituted by F or S(O)nR19); aryl or aryl-(1-4C) alkyl) (both optionally aryl-substituted by R16, R17 or R18), CqH2q-2-aryl or an optionally OH substituted thiolan, thiolanoxide or thiolandioxide; R7 = aryl or aryl-(1-4C alkyl) (both optionally aryl-substituted by R16-R18); R8 =2-4C alkyl (substituted by R11 or R15), 1-4C alkyl (substituted by R12), N=C(R13)(R14), aryl (optionally substituted by R16-R18) or CqH2q+1; R9 = H or 1-4C alkyl; R10 = 2-4C alkyl (substituted by R11) or 1-4C alkyl (optionally substituted by R12); R11 = 1-4C alkoxy, 1-4C alkylcarbonyloxy, OH, hydroxy-(2-4C alkoxy) or 1-4C alkoxy-(1-4C alkoxy); R12 = 1-4C alkoxycarbonyl, 1-4C alkylcarbonyl, COOH, mono- or di(1-4C alkyl)aminocarbonyl, thienyl, pyridyl or aryl (optionally substituted by R16-R18); R13, R14 = 1-4C alkyl, phenyl or phenyl-(1-4C alkyl); or R13+R14 = 4-6C alkylene; R15 = phthalimidyl or S(O)nR19; R16 = H, halo, NO2, 1-4C alkyl, 1-4C alkoxy (optionally fully or partially substituted by F), CF3, OH, COOH, 1-4C alkoxycarbonyl, CN, phenyl, benzoyl, mono- or di-(1-4C alkyl)amino, NH2, 1-4C alkylcarbonylamino or S(O)nR19; R17 = H, halo, 1-4C alkoxy, NO2, COOH, 1-4C alkyl or OH; R18 = H or halo; R19 = 1-4C alkyl; n = 0-2; q = 2 or 3; and aryl = phenyl or naphthyl

Description

Field of application of the invention

The invention relates to new halogenimidazopyridines which are used in pharmazeu tical industry as active ingredients for the manufacture of pharmaceuticals should be applied.

Known technical background

In European patent application EP-A-0 033 094 Imidazo [1,2-a] py ridine described, which carry an aryl substituent in the 8-position, the preferably a phenyl, thienyl, pyridyl or by chlorine, fluorine, Me thyl, tert-butyl, trifluoromethyl, methoxy or cyano substituted phenyl rest is. Aryl residues are particularly interesting in EP-A-0 033 094 the residues phenyl, o- or p-fluorophenyl, p-chlorophenyl and 2,4,6-trimethyl called phenyl, of which the residues phenyl, o- or p-fluorophenyl and 2,4,6- Trimethylphenyl are particularly preferred. - In European patent applications reports EP-A-0 204 285, EP-A-0 228 006, EP-A-0 268 989 and EP-A-0 308 917 Imidazo [1,2-a] pyridines are described which have a 3-position unsaturated saturated aliphatic radical, in particular a (substituted) alkynyl radical carry. - In the European patent application EP-A-0 266 890 Imida zo [1,2-a] pyridines described in the 8-position by an alkenyl, Al alkyl or cycloalkylalkyl are substituted.

Description of the invention

It has now been found that the compounds described in more detail below gene, which differ from the compounds of the prior art in particular differentiate by substitution in the 3- or 8-position de and have particularly advantageous properties.  

The invention relates to compounds of the formula I (see attached formula sheet), in which
R0 means halogen or thiocyanate,
R1 is 1-4C-alkyl,
R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,
R3 is SO₂-R6, CO-R7, COO-R8 or CON (R9) R10,
R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,
R5 denotes hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,
AO (oxygen) or NH means
R6 1-4C-alkyl, aryl, aryl substituted by R16, R17 and R18, aryl-1-4C-alkyl, aryl-1-4C-alkyl substituted by R16, R17 and R18 in the aryl part, completely or partially substituted by fluorine 1 -4C-alkyl, 1-4C-alkyl substituted by -S (O) _n -R19 or the radical -C _q H _2q-2- aryl, or represents an unsubstituted or hydroxy-substituted cycle which is selected from the group Thiolan, thiolan oxide or thiolan dioxide,
R7 is aryl, aryl-1-4C-alkyl, aryl substituted by R16, R17 and R18, or aryl-1-4C-alkyl substituted by R16, R17 and R18 in the aryl radical,
R8 substituted by R11 2-4C-alkyl, substituted by R12 1-4C-alkyl, -N = C (R13) R14, substituted by R15 2-4C-alkyl, aryl, the radical -C _q H _{2q + 1} or by R16, R17 and R18 are substituted aryl,
R9 represents hydrogen or 1-4C-alkyl,
R10 denotes 2-4C-alkyl substituted by R11, 1-4C-alkyl substituted by R12 or 1-4C-alkyl,
R11 denotes 1-4C-alkoxy, 1-4C-alkylcarbonyloxy, hydroxy, hydroxy-2-4C-alkoxy or 1-4C-alkoxy-1-4C-alkoxy,
R12 denotes 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, carboxy, mono-1-4C-alkylaminocarbonyl, di-1-4C-alkylaminocarbonyl, thienyl, pyridyl, aryl or aryl substituted by R16, R17 and R18,
R13 1-4C-alkyl, phenyl or phenyl-1-4C-alkyl and
R14 is 1-4C-alkyl, phenyl or phenyl-1-4C-alkyl, or in which R13 and R14 together represent a 4-6C-alkylene group,
R15 is phthalimidyl or -S (O) _n -R19, where aryl is phenyl or naphthyl and
R16 is hydrogen, halogen, nitro, 1-4C-alkyl, 1-4C-alkoxy, trifluoromethyl, hydroxy, carboxy, 1-4C-alkoxycarbonyl, cyano, completely or partially substituted by fluorine-substituted 1-4C-alkoxy, phenyl, benzoyl, mono - and di-1-4C-alkylamino, amino, 1-4C-alkylcarbonylamino or S (O) _n -R19,
R17 is hydrogen, halogen, 1-4C-alkoxy, nitro, carboxy, 1-4C-alkyl or hydroxy and
R18 represents hydrogen or halogen,
R19 denotes 1-4C-alkyl,
n denotes the numbers 0, 1 or 2,
q means the numbers 2 or 3,
and their salts and the N-oxides of pyridines and their salts.

Halogen in the sense of the invention is bromine, chlorine and fluorine.

1-4C-alkyl represents straight-chain or branched alkyl radicals with 1 to 4 Carbon atoms. Examples include butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and especially the Methyl residue.

1-4C-alkoxy represents an oxygen atom to which one of the above ge called 1-4C-alkyl radicals is bound. Examples include Methoxy, the ethoxy, the propoxy and the butoxy radical.

Aryl-1-4C-alkyl represents one of the above-mentioned 1-4C-alkyl radicals, the is substituted by phenyl or naphthyl.

As wholly or partially substituted by fluorine 1-4C-alkyl are included for example, the 1,2,2-trifluoroethyl, the 2,2,3,3,3-pentafluoropropyl, the Perfluoroethyl, 1,1,2,2-tetrafluoroethyl, trifluoromethyl, di called fluoromethyl and 2,2,2-trifluoroethyl.

Phenyl-1-4C-alkyl stands for one of the above, substituted by phenyl tuiert 1-4C-alkyl residues. For example, the phenethyl and the Ben called cylrest.  

Examples are phenyl radicals substituted by R16, R17 and R18 the residues 2-bromophenyl, 4-bromophenyl, 4-benzoylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 2,3-dichlorophenyl, 2,4-dichloro phenyl, 2-chloro-5-nitrophenyl, 4-chloro-3-nitrophenyl, 2,6-dichlorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2-fluoro-5-nitrophenyl, 2,3-dimethoxy phenyl, 2,4-dimethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methyl phenyl, 4-methyl-3-nitrophenyl, 2,4-dimethylphenyl, 2-nitrophenyl, 3-nitro phenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 3,4-dinitrophenyl, 3,5-dinitro phenyl, 2,6-dinitrophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 4-ethoxy phenyl, 3-trifluoromethylphenyl and 4-trifluoromethylphenyl.

2-4C-alkyl represents an alkyl radical with 2 to 4 carbon atoms. At the ethyl, propyl and butyl radicals may be mentioned as examples.

1-4C-Alkoxycarbonyl stands for a radical next to the carbonyl group contains one of the aforementioned 1-4C alkoxy radicals. For example the methoxycarbonyl and the ethoxycarbonyl radical may be mentioned.

1-4C-alkylcarbonyl stands for a radical which, in addition to the carbonyl group contains the above-mentioned 1-4C-alkyl radicals. For example, the Called acetyl radical.

1-4C-Alkylcarbonyloxy stands for a radical next to the carbonyloxy radical contains one of the above 1-4C-alkyl radicals. For example, the Called acetyloxy residue.

In addition to the nitrogen atom, mono- and di-1-4C-alkylamino contain one or two of the above 1-4C alkyl radicals. Di-1-4C-al is preferred kylamino and here in particular dimethyl, diethyl or diisopropylamino.

Mono- and di-1-4C-alkylaminocarbonyl contain in addition to the carbonyl group one of the abovementioned mono- or di-1-4C-alkylamino residues. At the N-methyl, the N, N-dimethyl, the N-ethyl, the N-propyl, the N, N-diethyl and the N-isopropylcarbamoyl radical.

Hydroxy-2-4C-alkoxy stands for one of the above-mentioned 2-4C-alkoxy residues, which is substituted by a hydroxy group. For example called the 2-hydroxyethoxy radical (-O-CH₂-CH₂-OH).  

1-4C-Alkoxy-1-4C-alkoxy stands for one of the above-mentioned 1-4C- Alkoxy radicals, which is substituted by a further 1-4C alkoxy radical. Examples are the residues 2- (methoxy) ethoxy (-O-CH₂-CH₂-O-CH₃) and 2- (ethoxy) ethoxy (-O-CH₂-CH₂-O-CH₂-CH₃).

4-6C-alkylene stands for straight-chain or branched alkylene radicals with 4 to 6 carbon atoms. For example, the residues are tetramethylene (-CH₂-CH₂-CH₂-CH₂-), pentamethylene (-CH₂-CH₂-CH₂-CH₂-CH₂-) and hexamethylene [-CH₂- (CH₂) ₄-CH₂-] called.

As wholly or partly substituted by fluorine 1-4C-alkoxy be in for example the 1,2,2-trifluoroethoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,1,2,2-tetrafluoroethoxy, the trifluoromethoxy, the difluoromethoxy and the 2,2,2-trifluoroethoxy radical called.

1-4C-Alkylcarbonylamino stands for an amino group which is replaced by one of the 1-4C-alkylcarbonyl radicals mentioned above is substituted. Example the acetamido residue (H₃C-CO-NH-) may be mentioned.

The group -C _q H _{2q + 1} is, for example, the isopropenyl radical. The group -C _q H _2q-2- aryl preferably represents the 2-phenylvinyl radical.

Exemplary radicals -S (O) _n -R¹⁹ are the methylthio, ethylthio, propylthio, butylthio, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl and the butylsulfonyl radical .

Exemplary 2-4C-alkyl radicals substituted by R11 are 2- (methoxy) ethyl, 2- (ethoxy) ethyl, 2- (propoxy) ethyl, 2- (butoxy) ethyl, 3- (methoxy) propyl, 3- (ethoxy) propyl, 3- (propoxy) propyl, 3- (butoxy) propyl, 2- (Ace tyloxy) ethyl, 2- (ethylcarbonyloxy) ethyl, 2- (propylcarbonyloxy) ethyl, 3- (acetyloxy) propyl, 3- (ethylcarbonyloxy) propyl, 3- (propylcarbonyl oxy) propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2- (2-hydroxyethoxy) ethyl, 2- (3-hydroxypropoxy) ethyl, 3- (2-hydroxyethoxy) propyl, 2- [2- (methoxy) ethoxy)] ethyl, 2- [2- (ethoxy) ethoxy] ethyl and 4-hydroxybutyl.  

Exemplary 1-4C-alkyl radicals substituted by R12 are (methoxy carbonyl) methyl, (ethoxycarbonyl) methyl, (propoxycarbonyl) methyl, 2- (Me thoxycarbonyl) ethyl, 2- (ethoxycarbonyl) ethyl, 2- (propoxycarbonyl) ethyl, 3- (methoxycarbonyl) propyl, 2-oxopropyl, 2-oxobutyl, 2-oxopentyl, 3-oxo butyl, 3-oxopentyl, 3-oxohexyl, 4-oxopentyl, 4-oxohexyl, 4-oxoheptyl, Carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, (N-methyl carbamoyl) methyl, (N-ethylcarbamoyl) methyl, (N-propylcarbamoyl) methyl, 2- (N-methylcarbamoyl) ethyl, 2- (N-ethylcarbamoyl) ethyl, 2- (N-propylcarba moyl) ethyl, 3- (N-methylcarbamoyl) propyl, 3- (N-ethylcarbamoyl) propyl, 3- (N-propylcarbamoyl) propyl, (N, N-dimethylcarbamoyl) methyl, 2- (N, N-Di methylcarbamoyl) ethyl, 3- (N) N-dimethylcarbamoyl) propyl, (N-ethyl-N- methylcarbamoyl) methyl, 2- (N-ethyl-N-methylcarbamoyl) ethyl, 3- (N-ethyl- N-methylcarbamoyl) propyl, (N, N-diethylcarbamoyl) methyl, 2- (N, N-diethyl carbamoyl) ethyl, 2-thienylmethyl, 2- (2-thienyl) ethyl, 3-thienylmethyl, 2- (3-thienyl) ethyl, 3- (2-thienyl) propyl, 3- (3-thienyl) propyl, (3-hydroxy phenyl) methyl, 2- (3-hydroxyphenyl) ethyl, 3- (3-hydroxyphenyl) propyl, 2-pyridylmethyl, (4-nitrophenyl) methyl, (2-nitro-4,5-dimethoxyphenyl) methyl, 3-pyridylmethyl, 4-pyridylmethyl, 2- (2-pyridyl) ethyl, 3- (2- Pyridyl) propyl and 2- (1-pyridyl) ethyl.

Exemplary 2-4C-alkyl radicals substituted by R15 may be mentioned 2- (phthalimidyl) ethyl, 3- (phthalimidyl) propyl, 2- (methylthio) ethyl, 2- (Ethylthio) ethyl, 2- (propylthio) ethyl, 3- (methylthio) propyl, 3- (ethyl thio) propyl, 2- (methylsulfinyl) ethyl, 2- (ethylsulfinyl) ethyl, 2- (Pro pylsulfinyl) ethyl, 2- (methylsulfonyl) ethyl, 2- (ethylsulfonyl) ethyl and 2- (propylsulfonyl) ethyl.

Exemplary radicals -SO₂-R6 are naphthyl-1-, 5- (dimethyl amino) naphthyl-1, naphthyl-2, phenyl-1, 2,5-dichlorophenyl-1-, 2-nitro phenyl-1-, 3,5-dichloro-2-hydroxyphenyl-1-, 3-nitrophenyl-1-, 4-bromo phenyl-1-, 4-fluorophenyl-1-, 4-chlorophenyl-1-, 4-chloro-3-nitrophenyl-1-, 4-acetamidophenyl-1-, 4-nitrophenyl-1-, 4-methoxyphenyl-1-, 4-carboxy phenyl-1-, 4-methylphenyl-1-, 2- (methoxycarbonyl) phenyl-1-, 3-trifluoro methylphenyl-1-, 2,5-dimethoxyphenyl-1-, 2-methylphenyl-1-, 2,5-dimethyl phenyl-1-, 4- (dimethylamino) -3-nitrophenyl-1-, 3-carboxyphenyl-1-, 5-carb oxy-2-methoxyphenyl-1-, 5-carboxy-2-chloro-3-nitrophenyl-1-, 3,4-dichlor phenyl-1-, 3-chloro-4-fluorophenyl-1-, 4-ethylphenyl-1-, 4-propylphenyl-1-,  4-isopropylphenyl-1-, 2-fluorophenyl-1-, 3-fluorophenyl-1-, 4-trifluoro methoxyphenyl-1-, 4-trifluoromethylphenyl-1-, 2,4-difluorophenyl-1-, 5- (diethylamino) naphthyl-1-, 2-chlorophenyl-1-, 2-methyl-5-nitrophenyl-1-, 2-trifluoromethylphenyl-1-, 3-chlorophenyl-1-, 3,5-dichlorophenyl-1-, 3-methylphenyl-1-, 2-chloro-6-methylphenyl-1-, 5-bromo-2-methoxyphenyl-1-, 3,4-dimethoxyphenyl-1-, 2,3-dichlorophenyl-1-, 2-bromophenyl-1-, 3-chloro 2-methylphenyl-1-, 2-chloro-5-trifluoromethylphenyl-1-, 2,6-dichlorophenyl-1-, 3-bromophenyl-1-, 2-trifluoromethoxyphenyl-1-, 4-cyanophenyl-1-, 2-cyan phenyl-1-, 4-butoxyphenyl-1-, 4-acetamido-3-chlorophenyl-1-, 2,4-dichloro phenyl-1-, 2-chloro-4-trifluoromethylphenyl-1-, 2-chloro-4-fluorophenyl-1-, 5-fluoro-2-methylphenyl-1-, 5-chloro-2-methoxyphenyl-1-, 3-carboxy-4-hydroxy phenyl-1-, 2-methoxy-5-methylphenyl-1-, 2,5-dibromophenyl-1, biphenyl-4-, 2,6-difluorophenyl-1-, 2-methyl-5- (methylsulfonyl) phenyl-1-, 3,5-dicarb oxyphenyl-1-, 3-nitro-4-methylphenyl-1-, 2-nitro-4-methoxyphenyl-1-, 3,4-difluorophenyl-1-, 4-butylphenyl-1-, 2-chloro-4-cyanophenyl-1-, 2,3-di methylphenyl-1-, 4-bromo-2-trifluoromethoxyphenyl-1-, 3-cyanophenyl-1-, 3-chloro-4-methylphenyl-1-, 4-bromo-2-ethylphenyl-1-, 4- (methylsulfonyl) phenyl-1-, 2- (methylsulfonyl) phenyl-1, isopropyl, methyl, benzyl, Propyl, ethyl, 2,2,2-trifluoroethyl, butyl, methylsulfonylmethyl, (2-nitrophenyl) methyl-, 2- (naphthyl-1-) ethyl-, 2-phenylvinyl-, (thiolan dioxide) -3-yl- and (4-hydroxythiolane dioxide) -3-yl-sulfonyl.

Exemplary residues COO-R8 are propenyl-2-oxycarbonyl-, (4-nitro phenyl-1-) oxycarbonyl-, (4-nitrophenyl-1-) methoxycarbonyl-, (4-methyl phenyl) oxycarbonyl-, (4-bromophenyl-1-) oxycarbonyl-, (4-fluorophenyl-1-) oxycarbonyl-, (4-methoxyphenyl-1-) oxycarbonyl, (2-nitrophenyl-1-) oxy carbonyl-, (4-methoxycarbonylphenyl-1-) oxycarbonyl-, isopropyloxycarbonyl-, (4,5-dimethoxy-2-nitrophenyl-1-) methoxycarbonyl, 2-methoxyethoxycarbonyl, 2- (methylthio) ethoxycarbonyl-, 2- (ethylthio) ethoxycarbonyl-, 2- (methyl sulfinyl) ethoxycarbonyl-, 2- (ethylsulfinyl) ethoxycarbonyl-, 2- (methyl sulfonyl) ethoxycarbonyl-, 2- (ethylsulfonyl) ethoxycarbonyl-, 2- (phthali midyl) ethoxycarbonyl and the 1-methylpropoxycarbonyl radical.

The salts for compounds of the formula I - depending on the substitution - all acid addition salts or in particular all salts with bases in Be dress. The pharmacologically acceptable salts of Inorganic and organic acid commonly used in galenics  bases and bases. On the one hand, water-soluble and water-insoluble acid addition salts with acids such as salt acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, Acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxyben zoyl) -benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, laurin acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embon acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy 2-naphthoic acid, the acids used in salt production - depending on whether it is a single or polybasic acid and whichever Salt is desired - in an equimolar or a different amount ratio can be used.

On the other hand, salts with bases are also particularly suitable. As with games for salts with bases are alkali (lithium, sodium, potassium) or Calcium, aluminum, magnesium, titanium, ammonium, meglumin or guani dinium salts mentioned, the bases in salt production also here equimolar or a divergent ratio used the.

Pharmacologically incompatible salts, which are used, for example, in the manufacture development of the compounds of the invention on an industrial scale as Ver Driving products that may initially arise are known to the person skilled in the art Process converted into pharmacologically acceptable salts.

Preferred compounds of formula I are those in which
R0 means halogen,
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl or halogen,
R3 is SO₂-R6, CO-R7, COO-R8 or CON (R9) R10,
R4 means hydrogen,
R5 means hydrogen
AO (oxygen) or NH means
R6 1-4C-alkyl, aryl, aryl substituted by R16, aryl-1-4C-alkyl, aryl-1-4C-alkyl substituted by R16 in the aryl part or 1-4C-alkyl substituted by -S (O) _n -R19 means
R7 denotes aryl, aryl-1-4C-alkyl, aryl substituted by R16 or aryl-1-4C-alkyl substituted by R16 in the aryl radical,
R8 denotes 2-4C-alkyl substituted by R11, 1-4C-alkyl substituted by R12, -N = C (R13) R14 or 2-4C-alkyl substituted by R15, aryl or aryl substituted by R16,
R9 means hydrogen,
R10 denotes 2-4C-alkyl substituted by R11 or 1-4C-alkyl substituted by R12,
R11 denotes 1-4C-alkoxy, 1-4C-alkylcarbonyloxy, hydroxy or 1-4C-alkoxy-1-4C-alkoxy,
R12 denotes 1-4C-alkoxycarbonyl, carboxy, mono-1-4C-alkylaminocarbonyl, di-1-4C-alkylaminocarbonyl, thienyl, pyridyl, aryl or aryl substituted by R16,
R13 1-4C alkyl and
R14 is 1-4C-alkyl,
R15 is phthalimidyl or -S (O) _n -R19, where aryl is phenyl and
R16 is hydrogen, halogen, nitro, 1-4C-alkyl, 1-4C-alkoxy, hydroxy, carboxy, 1-4C-alkoxycarbonyl, benzoyl, mono- and di-1-4C-alkylamino, amino, 1-4C-alkylcarbonylamino or S (O) _n -R19 means
R19 denotes 1-4C-alkyl,
n denotes the numbers 0, 1 or 2,
and their salts.

Particularly preferred compounds of the formula I are those in which
R0 means halogen,
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl or halogen,
R3 is SO₂-R6, COO-R8 or CON (R9) R10,
R4 means hydrogen,
R5 means hydrogen
AO (oxygen) or NH means
R6 denotes 1-4C-alkyl or aryl-1-4C-alkyl,
R8 is 2-4C-alkyl substituted by R11, 1-4C-alkyl substituted by R12, -N = C (R13) R14 or 2-4C-alkyl substituted by R15,
R9 means hydrogen,
R10 denotes 1-4C-alkyl substituted by R12,
R11 denotes 1-4C-alkoxy, hydroxy or 1-4C-alkoxy-1-4C-alkoxy,
R12 denotes 1-4C-alkoxycarbonyl, carboxy, thienyl, pyridyl or aryl substituted by R16,
R13 1-4C alkyl and
R14 is 1-4C-alkyl,
R15 is phthalimidyl or -S (O) _n -R19, where aryl is phenyl and
R16 means hydroxy
R19 denotes 1-4C-alkyl,
n denotes the numbers 0, 1 or 2,
and their salts.

Another object of the invention is a method for producing the Compounds of formula I and their salts. The procedure is ge indicates that one

• a) compounds of the formula II (see attached formula sheet), in which R0, R1, R2, R4, R5 and A have the meanings given above, with Ver bonds of the formula R3-X, wherein R3 has the meaning given above and X represents a suitable leaving group, or that
• b) compounds of the formula III (see attached formula sheet), in which R0, R1 and A have the meanings given above, with compounds of Formula IV (see attached formula sheet), wherein R2, R3, R4 and R5 the have the meanings given above and X is a suitable leaving group represents, implements, or that one
• c) Compounds of formula I, in which R0 is hydrogen, with ge suitable halogenating agents, or that
• d) Compounds of formula I, wherein R0, R1, R2, R4, R5 and A to the above have given meanings and the radical R3 has a sulfide group (-S-) contains, oxidized, or that one
• e) Compounds of formula I, wherein R0, R1, R2, R4, R5 and A the above have the meanings given and the radical R3 is an ether group (-O-) contains, on the ether group to the corresponding terminal hydroxide (-OH) splits,

and that, if desired, then those according to a), b), c), d) or e) obtained compounds I converted into their salts, or that one desired if necessary, then the verbin from the salts of the compounds I obtained releases I releases.

The introduction of the rest R3 into the compounds II according to the process variant a) takes place in a manner familiar to the person skilled in the art, for example in this way as described in the examples below. Exemplary fiction corresponding compounds of formula R3-X, wherein X is a suitable leaving group means are corresponding sulfonic acid chlorides, chloroformic acid esters or acid chlorides.

Which reaction conditions for carrying out the process in detail NEN are necessary to the expert due to his specialist knowledge common.

The reaction of the compounds III with the compounds IV according to the process variant b) also takes place in a manner familiar to the person skilled in the art se, for example, using methods analogous to those described in European patent applications EP-A-0 268 989 or EP-A-0 308 917 are written.

A suitable leaving group X in compounds of the formula IV is in for example a halogen atom (preferably chlorine or bromine) or a methane sulfonyloxy group. The reaction is advantageously carried out in the presence a base (e.g. an inorganic hydroxide such as sodium hydroxide, or an inorganic carbonate, such as sodium carbonate, or an organic Nitrogen base, such as triethylamine, pyridine, collidine or 4-dimethylaminopy ridin), with the addition of catalysts such as alkali metal or tetrabu tylammonium bromide, the reaction can be favored.

The halogenation of compounds of the formula I according to process variant c), in which R0 is hydrogen takes place in a manner known per se preferably as described in the examples. As a suitable means of Introduction of chlorine can be used, for example, by N-chlorosuccinimide the.  

Which reaction conditions for carrying out the process in detail NEN are required, the specialist is familiar due to his specialist knowledge fig.

The oxidation of the sulfides to the sulfoxides or sulfones analogously to the procedure rensvariants d) takes place under the conditions as the expert for Oxidation of sulfides to sulfoxides and sulfones are common [see this z. B. J. Drabowicz and M. Mikolajczyk, Organic preparations and procedures int. 14 (1-2), 45-89 (1982) or E. Block in S. Patai, The Chemistry of Functional Groups, Supplement E. Part 1, pp. 539-608, John Wiley and Sons (Interscience Publication), 1980]. Com. As an oxidizing agent All of them are common for the oxidation of sulfides to sulfoxides and sulfones Usually used reagents in question, especially peroxyacids such as e.g. B. peroxyacetic acid, trifluoroperoxyacetic acid, 3,5-dinitroperoxybenzoe acid, peroxymaleic acid, magnesium monoperoxiphthalate or preferred m-chloroperoxybenzoic acid.

The reaction temperature is (depending on the reactivity of the oxidizing agent and degree of dilution) between -70 ° C and the boiling point of the used Solvent, but preferably between -30 ° and + 20 ° C. As beneficial has the oxidation with halogens or with hypohalites (e.g. with aqueous sodium hypochlorite solution), which conveniently at Temperatures between 0 ° and 50 ° C is carried out. The reaction will for example in inert solvents, e.g. B. aromatic or chlorinated ten hydrocarbons, such as benzene, toluene, dichloromethane or chloroform, preferably in esters or ethers, such as ethyl acetate, acetic acid isopropyl ester or dioxane, or in alcohols, preferably isopropanol, carried out.

The sulfoxides according to the invention are optically active compounds. Depending on The type of substituent can also have other chiral centers in the molecule be. The invention therefore encompasses both the enantiomers and diastereomers as well as their mixtures and racemates. The enantiomers can in themselves known way (for example, by production and separation corresponding diastereoisomeric compounds) can be separated (see e.g. WO 92/08716).  

The ether cleavage in the case of compounds of the formula I according to variant e) takes place also in a manner known to the person skilled in the art, for example as in described the examples.

The substances according to the invention are isolated and purified in known way z. B. such that the solvent is removed in vacuo distilled and the residue obtained from a suitable solvent recrystallized or one of the usual cleaning methods, such as as the column chromatography on a suitable support, subject.

Acid addition salts are obtained by dissolving the free base in a ge suitable solvents, e.g. B. in water, in a chlorinated hydrocarbon substance such as methylene chloride or chloroform, a lower aliphatic Alcohol (ethanol, isopropanol), a ketone, such as acetone, or an ether, such as THF or diisopropyl ether, which contains the desired acid, or the the desired acid is then added.

The salts are removed by filtration, reprecipitation, precipitation with a non-solution solvent for the addition salt or by evaporating the solvent won. Salts obtained can by alkalization, e.g. B. with aq ammonia solution, are converted into the free bases, which in turn can be converted into acid addition salts. Let it this way pharmacologically unacceptable acid addition salts in pharmacolo Convert compatible acid addition salts.

The compounds of formula R3-X, wherein X is a suitable leaving group, be preferably chlorine means are either known or can be known Way. For example, required chlor ants acid esters from the corresponding alcohols by reaction with phosgene be preserved.

The starting compounds III can be as in the examples below described, are produced, for example by halogenation of such Compounds III (with intermediate protection of the residue -AH) in which R0 means a hydrogen atom. Alternatively, the compounds III can also from suitable starting compounds using such Ver  drive are produced as they are in EP-A-0 268 989 or in EP-A-0 308 917 (Process 1 or Process A) are described.

The starting compounds IV can in an analogous manner as in the European described patent application EP-A-0 308 917. Al Alternatively, the preparation can also start from compounds of the formula IV, in which R3 is hydrogen. To do this Compounds first converted into the corresponding isocyanate and through subsequent reaction with an appropriate amine, oxime or alcohol desired compound of formula IV implemented.

The starting compounds I, in which R0 is hydrogen, can be from known starting compounds and / or using analog known Methods (see EP-A-0 033 094, EP-A-0 268 989 and EP-A-0 308 917) in an be made in a known manner.

The following examples serve to explain the preparation of the compounds of the invention. In particular, the examples also serve there to implementations according to process variants a), b), c), d) and e), as well as the preparation of selected starting compounds write. Likewise, other compounds of formula I and others Starting compounds, the production of which is not explicitly described, in analogously or in a manner familiar to the person skilled in the art under applications be made using conventional process technologies. The abbreviation RT stands for room temperature, h stands for hour (s), min for minute (s), mp. for melting point, dec. for decomposition.  

Examples Output connections A1. 3-chloro-2-methyl-8-pivaloylamino-imidazo [1,2-a] pyridine

5.0 g (18.6 mmol) of 2-methyl-8-pivaloylamino-imidazo [1,2-a] pyridine are dissolved hydrochloride made from 8-amino-2-methyl-imidazo [1,2-a] pyridine and Pivaloyl chloride, mp. 229-230 ° C, in glacial acetic acid (20 ml) and conducts at 15 ° C slowly add chlorine gas until the reaction is complete after DC control (approx. 20 min). Then the solvent is distilled off, the residue in vinegar ester / water (30 ml each) added, with saturated sodium hydrogen made basic and extracted carbonate solution. Then again extracted with ethyl acetate (3 × 30 ml). The combined organic extracts are washed with water (50 ml), dried over magnesium sulfate and constricted. The residue is purified by chromatography on silica gel (flow medium: toluene / dioxane = 9: 1) cleaned. After narrowing the fractions with Rf = 0.2, the title compound (4.1 g, 83%) is obtained as a colorless solid material. Mp 117-118 ° C.

A2. 8-amino-3-chloro-2-methylimidazo [1,2-a] pyridine

A suspension of 3-chloro-2-methyl-8-pivaloylamino-imidazo [1,2-a] pyridine (4.0 g, 15 mmol) in 60% sulfuric acid (25 ml) is ge at 100 ° C for 1 h stirs. After cooling to RT, water (100 ml) is added and 10 N Sodium hydroxide solution adjusted to pH 10. Then with ethyl acetate (3 × 50 ml) extra here. The combined organic extracts are washed with water (50 ml) wash, dried over magnesium sulfate and concentrated. The backlog will taken up in boiling toluene, clarified with silica gel and crystallized. The title compound is isolated as a beige solid. Educ. 1.9 g (70%), M.p. 126-127 ° C.

A3. 3-chloro-2-methyl-8- (6-methyl-2-nitro-benzy] amino) -imidazo [1,2-a] pyridine

To a solution of 8-amino-3-chloro-2-methylimidazo [1,2-a] pyridine (9.26 g) and 6-methyl-2-nitrobenzyl chloride (10.5 g) in acetone (380 ml) are added  RT 8.55 g sodium iodide and 13.7 g sodium carbonate and then heated 7 hours under reflux to boiling. After cooling the mixture to RT and on the residue is concentrated in a mixture of 250 ml of ethyl acetate and 250 ml Water is taken up and the organic phase is separated off. After three white tter extractions, each with 250 ml of ethyl acetate, the combined organic extracts dried over magnesium sulfate and then a narrowed. The residue is purified by chromatography on silica gel (eluent: Toluene / dioxane = 20: 1) cleaned. After concentration of the fractions with Rf = 0.25 and crystallization from ethyl acetate / cyclohexane is the title compound as light yellow solid isolated. Educ. 63%, mp 142-144 ° C.

A4. 8- (2-amino-6-methyl-benzylamino) -3-chloro-2-methyl-imidazo [1,2-a] pyridine hydrochloride

A solution of 3-chloro-2-methyl-8- (6-methyl-2-nitro-benzylamino) imida zo [1,2-a] pyridine (2.0 g, 6 mmol) in methanol (175 ml) and dioxane (175 ml) is mixed with platinum-on-carbon catalyst (5%) and 2 h at RT and Atmospheric pressure hydrogenated. After 2 h, 2N hydrochloric acid (5 ml) is added and hydrogenated again for 1 h under the same conditions. Then the Kataly filtered off, the filtrate was adjusted to pH 8.5 with 2 N sodium hydroxide solution and the solvent was distilled off on a rotary evaporator. The backlog will dissolved in boiling ethyl acetate (400 ml). After cooling to RT, Diiso propyl ether (250 ml) added and to complete the crystallisa tion stirred at 4 ° C for 30 min. Then the precipitate is suctioned off with Washed diisopropyl ether and dried in vacuo. The title link (1.66 g, 92%) is isolated as a beige solid. Mp 243-246 ° C.

B1. 3-chloro-8- (2-chloro-6-nitro-benzylamino) -2-methyl-imidazo [1,2-a] pyrid-in

Starting from 8-amino-3-chloro-2-methylimidazo [1,2-a] pyridine (20.0 g), 2-chloro-6-nitro-benzyl bromide (30.06 g), sodium carbonate (30.6 g) and natri Umiodide (20.0 g) in acetone (500 ml) is obtained according to that in Example A3 given procedure after chromatography on silica gel (eluent: To toluene / dioxane = 20: 1) and crystallization from ethyl acetate / diisopropyl ether 27.0 g (67%) of the title compound, mp. 133-135 ° C.  

B2. 8- (2-Amino-6-chloro-benzylamino) -3-chloro-2-methylimidazo [1,2-a] pyridine

Starting from 3-chloro-8- (2-chloro-6-nitro-benzylamino) -2-methyl-imidazo- [1,2-a] pyridine (3.51 g) and platinum on carbon catalyst (0.5 g) in ice vinegar (250 ml) is obtained according to the procedure given in Example A4 after precipitation at pH 10 and subsequent stirring from hot methanol 2.17 g (68%) of the title compound, mp 223-226 ° C.

C1. [2- (hydroxymethyl) -3-methylphenyl] carbamic acid (2-methoxyethyl) ester -

To a solution of 33 g (0.24 mol) of 2-amino-6-methylbenzyl alcohol and 19.4 ml (0.24 mol) of pyridine in 600 ml of isopropyl alcohol are added dropwise at 10 ° C. with stirring and cooling, 33.2 g (0.24 mol) of chloroformic acid (2-methoxy ethyl) ester. The mixture is stirred for a further 2 h at 0 ° C., water and Isopro are added pylacetate and extracted several times with isopropyl acetate. The organic phase is dried with magnesium sulfate and concentrated at 50 ° C in a Rotavapor. The residue is chromato on a silica gel column using ethyl acetate graphed. After concentrating in vacuo, 36 g (68%) of the title compound are obtained binding as oil.

C2. [2- (chloromethyl) -3-methylphenyl] carbamic acid (2-methoxyethyl) ester

To a solution of 18.0 g (0.075 mol) of the above compound in 80 ml of toluene are added dropwise with stirring and cooling 9.4 g (0.079 mol) of thionyl chloride at 17-20 ° C and left overnight at RT. You cool in the ice bath, rubs in and receives 11.2 g (57.7%) of the title compound from the Schmp. 100-102 ° C. By concentrating the mother liquor and crystallizing from toluene / - Petroleum ether (bp 40 ° C) gives a second precipitation of 4.8 g (24.7%) with a similar melting point.

C3. 8- {2 - [(2-methoxyethoxy) carbonylamino] -6-methyl-benzyloxy} -2-methyl imidazo [1,2-a] pyridine

A solution of 8-hydroxy-2-methyl-imidazo [1,2-a] pyridine (10.0 g) in what serfree tetrahydrofuran (250 ml) with sodium hydride (2.2 g 80% Dispersion in mineral oil) was added and the mixture was stirred at RT for 1 h. Then one Solution of [2-chloromethyl) -3-methylphenyl] carbamic acid- (2-methoxyethyl)  ester (17.4 g) in anhydrous tetrahydrofuran (150 ml) was added dropwise and added finally stirred at RT for 3 h. Then the suspension is reduced to approx. 100 ml concentrated, mixed with water (500 ml) and with ethyl acetate (3 × 300 ml) extracted. The combined organic extracts are over Magne dried sodium sulfate and concentrated. The residue is on silica gel (Eluent: toluene / dioxane = 9: 1) chromatographed. After narrowing the Fractions with Rf = 0.15-0.25 are isolated as 7.5 g of the title compound pale yellow oil, which still contains about 5% of a non-separable side pro product is contaminated. In this form, the raw product was used directly for the Implementation used in Example 9.

C4. (2-hydroxymethyl-3-methylphenyl) carbamic acid (methoxycarbonylmethyl-) ester

Starting from methoxycarbonylmethyl chloroformate (11.7 g), 2-amino-6-me ethyl benzyl alcohol (10.5 g) and pyridine (6.2 ml) in dichloromethane (230 ml) is obtained according to the procedure given in Example C1, according to Chroma topography on silica gel (eluent: ethyl acetate / petroleum ether 50/70 = 1: 1) and crystallization from diisopropyl ether 6.8 g (20%) of the title compound, 70-74 ° C.

C5. (2-chloromethyl-3-methylphenyl) carbamic acid (methoxycarbonylme thyl) ester

(2-hydroxymethyl-3-methylphenyl) carbamic acid (methoxycarbonylmethyl) ester (6.8 g) is placed in dichloromethane (60 ml) and added dropwise with thio nyl chloride (3.4 ml) was added. The mixture is then stirred at RT for 1 h. Then the solvent is distilled off and the residue twice with dichlorme than (50 ml each) and turned on again on the rotary evaporator tight. 7 g (96%) of the title compound of mp 114-116 ° C. are obtained.

D1. 3-bromo-2-methyl-8-pivaloylamino-imidazo [1,2-a] pyridine

To a solution of 2-methyl-8-pivaloylamino-imidazo [1,2-a] pyridine-hydro chloride (10 g, 37.3 mmol) in glacial acetic acid (100 ml) becomes a solution of at 4 ° C Bromine (1.91 ml, 37.3 mmol) in glacial acetic acid (10 ml) while stirring vigorously drips. The mixture is then stirred for a further 30 min at 4 ° C. and then the ice distilled off vinegar. The remaining oil is sown in a mixture of  saturated sodium bicarbonate solution and ethyl acetate (100 ml each) taken and extracted with ethyl acetate (3 × 100 ml). The organic extracts are dried over magnesium sulfate and concentrated. The backlog will by chromatography on silica gel (eluent: toluene / dioxane = 20: 1) cleans. After crystallization from diisopropyl ether, the title is obtained compound as a beige solid. Educ. 89%; Mp 144-146 ° C.

D2. 8-amino-3-bromo-2-methylimidazo [1,2-a] pyridine

The procedure given for example A2 gives, starting from 3-bromo-2-methyl-8-pivaloylamino-imidazo [1,2-a] pyridine the title compound after crystallization from toluene as a beige solid. Educ. 45%; Mp 156-157 ° C.

E1. 2-chloromethyl-1-isocyanato-3-methylbenzene

2-Amino-6-methyl-benzyl alcohol (10.0 g) is abs. Toluene (200 ml) 50 ° C solved. At this temperature, 45 ml of approximately 3.5 M ethereal are added dropwise Hydrochloric acid for 0.5 h. The resulting suspension is 2 h at RT stirred. Then 5.3 ml of thionyl chloride are added at this temperature drips (gas evolution). The suspension is stirred for a further 16 h and then then concentrated on a rotary evaporator (bath temperature 40 ° C). The back is taken up 3 times in 200 ml of toluene and turned on again and again narrowed. The crystalline residue is suspended in 400 ml of anhydrous toluene pendulum and heated to 50 ° C in an oil bath. Then Trichloromethylchlorofor mat (11.3 ml) was added dropwise. After the addition is complete, the mixture is refluxed for 5 hours heated until gas evolution ceases. Then the toluene stripped off in vacuo and the residue distilled under high vacuum. You get 6.55 g (49%) of the title compound as a colorless liquid bp 0.25 mbar 92-93 ° C.

E2. O- (2-chloromethyl-3-methylphenylaminocarbonyl) acetone oxime

A solution of 2-chloromethyl-1-isocyanato-3-methylbenzene (2 g) and aceto noxime (0.85 g) in n-hexane (20 ml) is stirred at RT for 16 h, during which time an incidence occurs Precipitation from. After filtration and washing with n-hexane and diethyl ether 2.4 g (86%) of the title compound are obtained as a solid of mp. 76-78 ° C.  

E3. (2-Chloromethyl-3-methylphenyl) carbamic acid 2- (2-methoxyethoxy) eth-yl ester

A solution of 2-chloro-methyl-1-isocyanato-3-methylbenzene (2 g) and Di ethylene glycol monomethyl ether (1.32 g) in n-hexane (50 ml) on the back for 5 h river heated. After cooling to RT, a suspension is obtained. By fil tration and washing with n-hexane and diethyl ether is isolated 1.3 g (39%) of the title compound as a solid, mp. 78-83 ° C.

E4. (2-chloromethyl-3-methylpheny]) carbamic acid (2-thieny] methyl) ester

2-chloromethyl-1-isocyanato-3-methylbenzene (2.5 g) and thiophene methanol (1.57 g) are combined and stirred at RT. When crystallisa begins tion, petroleum ether 50/70 (20 ml) is added and the suspension is stirred for 16 h at RT. After filtration and washing with diethyl ether, 2.57 g are obtained (63%) of the title compound as a solid, mp. 111-114 ° C.

E5. (2-Chloromethyl-3-methylphenyl) carbamic acid (2-pyridinylmethyl) esters

A solution of 2-chloromethyl-1-isocyanato-3-methylbenzene (2.5 g) and 2-Hy Droxymethylpyridine (1.5 g) in dichloromethane (25 ml) is ge for 16 h at RT stirs. By concentration on the rotary evaporator (bath temperature 22 ° C) and subsequent chromatography on silica gel (eluent: dichlorme than / Methano] 13: 1) a solution of the title compound is obtained, which on Rotary evaporator (bath temperature 22 ° C) is concentrated (not Crystallize, otherwise decomposition). The crude product obtained the title connection will be implemented immediately.

E6. (2-chloromethyl-3-methylphenyl) carbamic acid (3-hydroxybenzyl) ester -

A mixture of 2-chloro-methyl-1-isocyanato-3-methylbenzene (2 g) and 3-hydroxybenzyl alcohol (1.6 g) is heated in an oil bath at 75 ° C and then by chromatography on silica gel (eluent: dichlorme than / Methano] 19: 1). 1 g (30%) of the title compound is obtained as a crude product in the form of an amorphous solid.  

E7. [3- (2-chloromethyl-3-methylphenyl) ureido] acetic acid methyl ester

To a solution of glycine methyl ester hydrochloride in 2N sodium hydroxide solution (30 ml) becomes 2-chloromethyl-1-isocyanato-3-methylbenzene (1.4 g) with strong Stir given and stirred at RT for 1 h. After filtering the suspension 1.5 g (75%) of the title compound of mp. 146-149 ° C. are isolated.  

End products 1. 3-Chloro-2-methyl-8- {2 - [(2-methylsulfanylethoxy) carbonylamino] -6-methyl benzylamino} imidazo [1,2-a] pyridine hemifumarate

A 20% solution of phosgene in toluene (10.1 ml) is washed with anhydrous Diluted dichloromethane (30 ml) and cooled to 0 ° C. Then there will be a solution of 2-methylsulfanylethanol (1.83 ml) and N-methylmorpholine (2.3 ml) in anhydrous dichloromethane (25 ml) was added dropwise. The mix turns 15 min at 0 ° C, then warmed to RT and ge another h stirs. A suspension of 8- (2-amino-6- methyl-benzy] amino) -3-chloro-2-methyl-imidazo [1,2-a] pyridine (2.1 g) and Triethylamine (1 ml) in anhydrous dichloromethane (120 ml) was added dropwise and stirred for 1 h at RT. Then aqueous sodium bicarbonate solution (200 ml) was added and the mixture was stirred for a further 30 min. The organic phase is off separated and the aqueous phase extracted with dichloromethane (3 × 100 ml). The combined organic phases are washed with water (150 ml), dried over magnesium sulfate and concentrated. The backlog is in a hot solution of fumaric acid (820 mg) in acetone (100 ml) and cooled to 4 ° C. The precipitate is filtered off and still little hot acetone. After drying in a high vacuum, 2.5 g (76%) the title compound isolated as light beige crystals. Mp 180-182 ° C.

2. 3-chloro-2-methyl-8- {2 - [(2-methylsulfinylethoxy) carbonylamino] -6-methyl benzylamino} imidazo [1,2-a] pyridine hemifumarate

A solution of 3-chloro-2-methyl-8- (2 - [(2-methylsulfanylethoxy) carbonyl amino] -6-methyl-benzylamino} imidazo [1,2-a] pyridine (1.0 g) in anhydrous Dichloromethane (25 ml) is cooled to 0 ° C and in portions with m-chlorine peroxibenzoic acid (800 mg) was added and the mixture was then stirred at 0 ° C. for a further 15 min. Then aqueous sodium bicarbonate solution (25 ml) is added Stirred for 10 min, the organic phase separated and the aqueous phase with Dichloromethane (3 x 20 ml) extracted. The combined organic phases are washed with water (50 ml), dried over magnesium sulfate and constricted. To remove the sulfone, the residue on silica gel (Eluent: ethyl acetate / methanol = 10: 1) chromatographed. The factions with Rf = 0.16 are collected and concentrated. The backlog is in a  hot solution of fumaric acid (280 mg) in acetone (40 ml) and then cooled to 4 ° C. After filtration and drying in a high vacuum 0.9 g (79%) of the title compound are isolated as light beige crystals. M.p. 162-164 ° C.

3. 3-chloro-2-methyl-8- {2 - [(2-methylsulfonylethoxy) carbonylamino] -6-methyl benzylamino} imidazo [1,2-a] pyridine Method A

A solution of 3-chloro-2-methyl-8- (2 - [(2-methylsulfanylethoxy) carbonyl amino] -6-methyl-benzylamino} -imidazo [1,2-a] pyridine (700 mg) in anhydrous Dichloromethane (25 ml) is cooled to 0 ° C and in portions with m-chlorine peroxibenzoic acid (1.3 g) were added and the mixture was then stirred at 0 ° C. for a further 45 min. Then aqueous sodium bicarbonate solution (25 ml) is added Stirred for 10 min, the organic phase separated and the aqueous phase with Dichloromethane (3 x 20 ml) extracted. The combined organic phases are washed with water (50 ml), dried over magnesium sulfate and constricted. To separate by-products, the residue is on silica gel (eluent: toluene / dioxane = 2: 1) chromatographed. The factions with Rf = 0.33 are collected and concentrated. The residue is made from vinegar ester / diisopropyl ether crystallized. After filtration and drying in High vacuum isolates 270 mg (37%) of the title compound as a light beige Crystals. Mp 174-175 ° C.

Method B

The title compound was also starting from 8- (2-amino-6-methylbenzyl amino) -3-chloro-2-methylimidazo [1,2-a] pyridine, chloroformic acid (2-me thylsulfony] ethyl) ester and N-methylmorpholine according to that in Example 4 described working method. (Education 71%).

4. 3-chloro-8- {2-chloro-6 - [(2-methylsulfonylethoxy) carbonylamino] benzyl amino} -2-methyl-imidazo [1,2-a] pyridine

To a suspension of 8- (2-amino-6-chloro-benzylamino) -3-chloro-2-methyl imidazo [1,2-a] pyridine (970 mg) and chloroformic acid (2-methyl-sulfonyl  ethyl ester (1.12 g) in anhydrous dichloromethane (30 ml) is at RT a solution of N-methylmorpholine (607 mg) in anhydrous dichloromethane (5 ml) slowly added dropwise. The mixture is stirred at RT for a further 1 h and then extracted with aqueous sodium bicarbonate solution (3 × 25 ml). The organi cal phase is washed with water (30 ml), dried over magnesium sulfate net and constricted. The residue is purified by chromatography on silica gel (Eluent: toluene / dioxane = 3: 1) cleaned. The fractions with Rf = 0.2 are restricted. The residue is kri from ethyl acetate / diisopropyl ether installed. After filtration and drying under high vacuum, the mixture is isolated 870 mg (62%) of the title compound as a light beige solid. Mp 164-166 ° C.

5. 3-chloro-8- {2 - [- 2-methoxyethoxy) carbonylaminol-6-methyl-benzylamino} -2- methyl imidazo [1,2-a] pyridine hemifumarate

Starting from 8-amino-3-chloro-2-methyl-imidazo [1,2-a] pyridine (910 mg), [2- (chloromethyl) -3-methylphenyl] carbamic acid (2-methoxyethyl) ester (1.42 g), sodium carbonate (1.34 g) and sodium iodide (835 mg) in acetone (65 ml) is obtained according to the procedure described in Example A3 Chromatography on silica gel (eluent: toluene / dioxane = 9: 1) and Kri stallisation with fumaric acid (450 mg) from hot acetone (35 ml) 1.4 g (44%) the title compound of mp. 181-182 ° C.

6. 3-bromo-8- {2 - [(2-methoxyethoxy) carbonylamino] -6-methyl-benzylamino} -2- methyl imidazo [1,2-a] pyridine hemifumarate

Starting from 8-amino-3-bromo-2-methylimidazo [1,2-a] pyridine (7.0 g), [2- (chloromethyl) -3-methylphenyl] carbamic acid (2-methoxyethyl) ester (10.9 g), sodium carbonate (10.0 g) and sodium iodide (6.4 g) in acetone (500 ml) is obtained according to the procedure described in Example A3 Chromatography on silica gel (eluent: toluene / dioxane = 9: 1) and Kri stallization with fumaric acid (3.35 g) from hot acetone (400 ml) 8.2 g (42%) of the title compound of mp 179-181 ° C.  

7. 3-chloro-8- {2 - [(2-hydroxyethoxy) carbonylamino] -6-methyl-benzylamino} -2- methyl imidazo [1,2-a] pyridine

Potassium iodide (2.0 g) becomes a solution of [18] crown-6 (4.0 g) in water added free dichloromethane and stirred at RT until almost clear solution is formed (approx. 30 min). Then 3-chloro-8- {2 - [(2-methoxy ethoxy-carbonylamino] -6-methyl-benzylamino} -2-methyl-imidazo [1-2-a] pyridine (1.0 g) added and the solution cooled to -30 ° C. With vigorous stirring becomes a 1M solution of boron tribromide in dichloromethane at this temperature (7.6 ml) slowly added dropwise and then stirred at -30 ° C for 3 h. Then it is warmed to approx. 0 ° C and aqueous sodium bicarbonate solution (50 ml) admitted. The organic phase is separated off and the aqueous phase is extracted with dichloromethane (3 × 50 ml). The united organic Phases are washed with water (50 ml), dried over magnesium sulfate and constricted. The residue is purified by chromatography on silica gel (Eluent: toluene / dioxane = 2: 1) cleaned. The fractions with Rf = 0.3 are concentrated and the residue is crystallized from ethyl acetate. The Ti telverbindung is isolated as a beige solid. Mp 178 ° C (dec.).

8. 3-bromo-8- {2- [2-hydroxyethoxy) carbonylamino] -6-methyl-benzylamino} -2- methyl imidazo [1,2-a] pyridine

Starting from 3-bromo-8- {2 - [(2-methoxyethoxy) carbonylamino] -6-methylbenzyl amino} -2-methyl-imidazo [1,2-a] pyridine (3.0 g), [18] crown-6 (10.6 g), potash Umiodide (5.3 g) and boron tribromide (20.1 ml of a 1M solution) in anhydrous Dichloromethane (200 ml) is obtained according to the Ar described in Example 7 sometimes after chromatography on silica gel (eluent: toluene / dioxane 2: 1) and crystallization from ethyl acetate, the title compound of mp. 180 ° C (dec.).

9. 3-chloro-8- {2 - [(2-methoxyethoxy) carbonylamino] -6-methyl-benzyloxy} -2- methyl imidazo [1,2-a] pyridine

To a solution of 8- {2 - [(2-methoxyethoxy) carbonylamino] -6-methylbenzyl oxy) -2-methyl-imidazo [1,2-a] pyridine (4.0 g) in ethanol (75 ml) is at RT While stirring vigorously, add N-chlorosuccinimide (1.9 g). The Suspension is stirred at RT for a further 30 min. Then saturated table salt  solution added (500 ml) and extracted with ethyl acetate (3 × 200 ml). The combined organic extracts are washed with water (100 ml), over Magnesium sulfate dried and concentrated. The residue is on silica gel (Eluent: toluene / dioxane = 9: 1) chromatographed. The fractions with Rf = 0.24 are concentrated and the residue is ethyl acetate / diisopropyl ether crystallized. The title compound is iso as a beige solid liert. Mp 153-154 ° C.

10. O- {2 - [(3-chloro-2-methylimidazo [1,2-alpyridin-8-yl) aminomethyl] -3- methylphenylaminocarbonyl} acetone oxime

A suspension of 8-amino-3-chloro-2-methyl-imidazo [1,2-a] pyridine (0.71 g), O- (2-chloromethyl-3-methylphenylaminocarbonyl) acetone oxime (1 g), Sodium carbonate (1.04 g) and sodium iodide (0.2 g) in acetone (20 ml) Stirred at RT for 16 h. The precipitate is filtered off and added with acetone washed. The filtrate is concentrated on a rotary evaporator. The residue is taken up in sodium bicarbonate solution and 3 × with dichlorme than extracted. The combined organic extracts are with water washed, dried over sodium sulfate and concentrated. The backlog will purified by chromatography on silica gel (eluent: ethyl acetate). After concentrating the main fraction on a rotary evaporator (bath temperature 25 ° C) and crystallization from diethyl ether 0.28 g (18%) of the title compound isolated. Mp 131-132 ° C.

11. 3-Chloro-8- {2 - [(2-methoxyethoxy-2-ethoxy) carbonylamino] -6-methyl benzylamino} -2-methyl-imidazo [1,2-a] pyridine hydrochloride

A suspension of 8-amino-3-chloro-2-methyl-imidazo [1,2-a] pyridine (0.78 g), (2-chloromethyl-3-methylpheny]) carbamic acid 2- (2-methoxyethoxy) ethyl ester (1.3 g), sodium carbonate (1.14 g) and sodium iodide (0.16 g) in Acetone (20 ml) is stirred at RT for 4 days. The precipitate is filtered off and washed with acetone. The filtrate is concentrated in vacuo. The residue is taken up in sodium hydrogen carbonate solution and 3 times extracted with dichloromethane. The organic extracts are made with water washed, dried over sodium sulfate and concentrated. The backlog will by double chromatography on silica gel (eluent A: ethyl acetate, Solvent B: dichloromethane / methanol 13: 1) cleaned. The main fraction  is mixed with ethereal hydrochloric acid and concentrated. 0.6 g is obtained (29%) of the title compound of mp 70-75 ° C.

12. 3-chloro-8- {2 - [(2-thienylmethoxy) carbonylamino] -6-methyl-benzylamino} -2- methyl imidazo [1,2-a] pyridine

A suspension of 8-amino-3-chloro-2-methyl-imidazo [1,2-a] pyridine (0.76 g), (2-chloromethyl-3-methylphenyl) carbamic acid 2- (2-thienylmethyl) ester (1.25 g), sodium carbonate (1.12 g) and sodium iodide (0.16 g) in Ace clay (40 ml) is stirred at RT for 7 days. The precipitate is filtered off, washed with acetone and the filtrate concentrated in vacuo. The residue is taken up in sodium bicarbonate solution and 3 times with dichlorme than extracted. The organic phases are washed with water, over Dried sodium sulfate and concentrated. The residue is removed by Chromato graphie on silica gel (eluent: dichloromethane / methanol 13: 1) cleaned. After concentration of the main fraction and crystallization from diethyl ether 0.42 g (22%) of the title compound, mp. 136-139 ° C.

13. 3-Chloro-8- {2 - [(2-pyridinyl-methoxy) carbonylaminol-6-methyl-benzylami no} -2-methyl-imidazo [1,2-a] pyridine

A suspension of 8-amino-3-chloro-2-methyl-imidazo [1,2-a] pyridine (0.65 g), (2-chloromethyl-3-methylphenyl) carbamic acid (2-pyridinyl) me ethyl ester (1.04 g), sodium carbonate (0.95 g) and sodium iodide (0.2 g) in Acetone (25 ml) is stirred at RT for 16 h. The precipitate is filtered off, washed with acetone and concentrated in vacuo. The residue is in Na trium hydrogen carbonate solution and 3 times with dichloromethane extra here. The organic extracts are washed with water, over sodium dried sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: ethyl acetate). After constricting the main Fraction and crystallization from acetone gives the title compound of 166-169 ° C.

14. 3-Chloro-8- {2 - [(3-hydroxybenzyloxy) carbonylamino] -6-methyl-benzylamino} - 2-methyl-imidazo [1,2-a] pyridine

A suspension of 8-amino-3-chloro-2-methyl-imidazo [1,2-a] pyridine (0.48 g), (2-Chloromethyl-3-methylphenyl) carbamic acid 3-hydroxybenzyl ester  (0.8 g), sodium carbonate (0.7 g) and sodium iodide (0.1 g) in acetone (20 ml) is stirred at RT for 2 days. The precipitate is filtered off with acetone washed and the filtrate concentrated on a rotary evaporator. The back is taken up in sodium bicarbonate solution and 3 times with Di extracted chloromethane. The organic extracts are washed with water , dried over sodium sulfate and concentrated. The backlog will by double chromatography on silica gel (eluent A: ethyl acetate, Solvent B: dichloromethane / methanol 13: 1) cleaned. The main fraction is concentrated and crystallized from acetone. 0.25 g (21%) of Title compound as a colorless solid, mp. 70-75 ° C.

15. 3-Chloro-8- {2 - [(methoxycarbonylmethyloxy) carbony] amino] -6-methylbenzyl amino} -2-methyl-imidazo [1,2-a] pyridine

A suspension of 8-amino-3-chloro-2-methylimidazo [1,2-a] pyridine (2.3 g), (2-chloromethyl-3-methylphenyl) carbamic acid methoxycarbonylmethyl ester (3.45 g), sodium carbonate (3.42 g) and sodium iodide (0.59 g) in acetone (60 ml) is stirred at RT for 16 h. The precipitate is filtered off with Washed acetone and the filtrate concentrated in vacuo. The residue is taken up in sodium bicarbonate solution and 3 times with dichlorme than extracted. The organic extracts are washed with water, over Dried sodium sulfate and concentrated. The backlog is replaced by two Chromatography on silica gel (eluent A: ethyl acetate / petroleum ether 50/70 1: 1, eluent B: dichloromethane / methanol 13: 1) cleaned. After constriction the main fraction gives 3 g of the title compound as a glassy solidification tes oil (yield 57%).

1H NMR (CDCl3, delta ppm): 7.65 (s, NH), 7.62 (d, 1H), 7.51 (d, 1H), 7.22 (t, 1H), 7.05 (d, 1H), 6.80 (t, 1H), 6.38 (d, 1H), 4.89 (t, NH), 4.60 (s, 2H) , 4.37 (d, 2H), 3.75 (s, 3H), 2.38 (s, 3H), 2.35 (s, 3H)

16. {3- [2- (3-chloro-2-methylimidazo [1,2-a] pyridin-8-y] aminomethyl) - 3-methyl-phenyl] ureido} acetic acid methyl ester

A suspension of 8-amino-3-chloro-2-methylimidazo [1,2-a] pyridine (1 g), [3- (2-chloromethyl-3-methylphenyl) ureido] acetic acid methyl ester (1.5 g), Sodium carbonate (1.46 g) and sodium iodide (0.21 g) in acetone (40 ml) became 4  Stirred at RT for days. The precipitate is filtered off, replenished with acetone wash and the filtrate concentrated in vacuo. The residue is in sodium Hydrogen carbonate solution taken up and extracted 3 times with dichloromethane. The organic extracts are washed with water, over sodium sulfate dried and concentrated. The residue is separated by two chromatographs phie on silica gel (eluent A: ethyl acetate, eluent B: dichloromethane / Methanol 13: 1) cleaned. The main fraction is concentrated and from acetone crystallized. 0.75 g (33%) of the title compound is obtained as a colorless Solid of mp 171-173 ° C.

17. Methanesulfonic acid- [2- (3-chloro-2-methylimidazo [1,2-a] pyridin-8-yl-am-i nomethyl) -3-methylphenyl] amide

8-2-amino-6-methyl-benzylamino) -3-chloro-2-methyl-imidazo [1,2-a] pyrid-in (1 g) is dissolved in pyridine (10 ml) at 80 ° C. In this hot solution there dropwise methanesulfonic acid chloride (0.51 ml) and heated for 3 h Reflux. The pyridine is then distilled off in vacuo. The residue is taken up in water and extracted with chloroform. The organic Phase is washed with water, dried over sodium sulfate and concentrated tight. After chromatography on silica gel (eluent: ethyl acetate / petroleum ether = 50/70 → 1: 1) and crystallization from ethyl acetate gives 0.36 g (29%) of the title compound of mp. 178-80 ° C.

18. Ethanesulfonic acid- [2- (3-chloro-2-methylimidazo [1,2-a] pyridin-8-yl-amino-no methyl) -3-methylphenyl] amide

8- (2-Amino-6-methyl-benzylamino) -3-chloro-2-methyl-imidazo [1,2-a] pyridine (1 g) is dissolved in pyridine (10 ml) at 80 ° C. In this hot solution there ethanesulfonic acid chloride (0.58 ml) is added dropwise and the mixture is heated on the back for 3 h flow. The pyridine is then distilled off in vacuo. The backlog will taken up in water and extracted with chloroform. The organic phase is washed with water, dried over sodium sulfate and concentrated. After chromatography on silica gel (eluent: ethyl acetate / petroleum ether 50/70 → 1: 1) and crystallization from ethyl acetate gives 0.1 g (8%) of Title compound of mp 80-90 ° C.  

19. n-Propanesulfonic acid- [2- (3-chloro-2-methylimidazo [1,2-a] pyridin-8-yl-- aminomethyl) -3-methylphenyl] amide

8- (2-Amino-6-methyl-benzylamino) -3-chloro-2-methyl-imidazo [1,2-a] pyridine (2 g), N-methylmorpholine (1.5 ml) and propanesulfonic acid chloride (1.54 ml) are dissolved in chloroform (100 ml) and heated under reflux for 7 days. After Cooling to RT, further chloroform (100 ml) is added and the solution is washed with natri umhydrogen carbonate solution (150 ml) extracted. The aqueous phase will extracted again with chloroform (2 × 50 ml). The organic extracts are washed with water, dried over sodium sulfate and concentrated. After chromatography on silica gel (eluent: dichloromethane / methanol 13: 1) and concentration of the main fraction, the title compound is obtained from 70-75 ° C.

20. Benzylsulfonic acid- [2- (3-chloro-2-methylimidazo [1,2-a] pyridin-8-yl- aminomethyl) -3-methylphenyl] amide

8- (2-Amino-6-methyl-benzylamino) -3-chloro-2-methyl-imidazo [1,2-a] pyridine (2 g), N-methylmorpholine (1.5 ml) and phenylmethanesulfonic acid chloride (2.6 g) are dissolved in chloroform (100 ml) and refluxed for 6 days. After Cooling to RT, further chloroform (100 ml) is added and the solution is washed with natri umhydrogen carbonate solution (150 ml) extracted. The aqueous phase will extracted again with chloroform (2 × 50 ml). The organic extracts are washed with water, dried over sodium sulfate and concentrated. After chromatography on silica gel (eluent: dichloromethane / methanol 100: 1) and crystallization from diethyl ether gives 0.6 g (20%) of Title compound of mp 136-139 ° C.

21. 3-Chloro-8- {2 [(hydroxycarbony] methyloxy) carbonylamino] -6-methylbenzyl amino} -2-methyl-imidazo [1,2-a] pyridine sodium salt

3-chloro-8- (2 - [(methoxycarbonylmethyloxy) carbonylamino] -6-methyl-benz-yl amino} -2-methyl-imidazo [1,2-a] pyridine (2.2 g) is dissolved in ethanol (30 ml) dissolves and with a solution of potassium hydroxide (0.45 g) in ethanol (10 ml) added and stirred at RT for 16 h. A suspension is obtained which is filtered becomes. The filtrate is concentrated, taken up in water and 3 times with Di extracted chloromethane. The organic phases are concentrated and transferred to Kie  self-chromatographed (eluent: dichloromethane / methanol 13: 1 as Gradient up to 1: 1). Filtration from diethyl ether gives 0.1 g (4%). the title compound of mp. 180-185 ° C.

22. 3-Chloro-8- {2 - [(N-phthalimido-2-ethoxy) carbonylamino] -6-methylbenzyl amino} -2-methyl-imidazo [1,2-a] pyridine

To a suspension of 8- (2-amino-6-chloro-benzylamino) -3-chloro-2-methyl- imidazo [1,2-a] pyridine (2 g) and N-methylmorpholine (1.5 ml) in anhydrous Chloroform (50 ml) becomes a solution of N- (2-chlorocarbonyloxy at 0-5 ° C ethyl) phthalimide (3.37 g) in chloroform (10 ml) was added dropwise. Then turns 30 Stirred at RT for days. Then the precipitate (educt) is filtered off and the filtrate was concentrated. The residue is chromatographed twice on silica gel (eluent A: dichloromethane / methanol = 13: 1, eluent B: Ethyl acetate / petroleum ether = 50/70 → 1: 1) cleaned. After crystallization of the Main fraction from isopropanol (200 ml) gives the title compound as Solid of mp 180-181 ° C.  

Industrial applicability

The compounds of formula I and their salts have valuable pharmacolo properties that make them commercially viable. They point to in particular a pronounced inhibition of gastric acid secretion and an excellent Protect stomach and intestines in warm-blooded animals. Draw here the compounds of the invention are highly selective activity, a comparatively long duration of action, good enteral activity speed, the lack of significant side effects and a great therapeutic Spread out.

In this context, prevention and Treatment of gastrointestinal diseases, especially gastrointestinal inflammatory diseases and lesions (such as ulcer ventriculi, ulcer duodenum, gastritis, hyperacid or drug-induced irritable stomach) ver stood, for example, by microorganisms (e.g. Helicobacter pylo ri), bacterial toxins, medications (e.g. certain anti-inflammatory drugs and anti rheumatics), chemicals (e.g. ethanol), stomach acid or stressful situations can be caused. The compounds according to the invention have here also an intrinsic effect against the Helicobacter pylori germ.

The inventive properties are found to have excellent properties Compounds on different models in which the antiulcerogenic and the antisecretory properties are surprisingly determined clearly superior to the compounds known from the prior art. Because of these properties, the compounds of formula I and their pharmacologically acceptable salts for use in human and vete ideally suited for clinical medicine, especially for treatment and / or prophylaxis of diseases of the stomach and / or intestine will.

Another object of the invention are therefore the Ver bindings for use in the treatment and / or prophylaxis of the former diseases mentioned.  

The invention also includes the use of the compounds according to the invention gene for the production of medicinal products for the treatment and / or prophy laxe of the aforementioned diseases can be used.

Furthermore, the invention comprises the use of the verb according to the invention Treatments for the treatment and / or prophylaxis of the aforementioned sick units.

Another object of the invention are drugs that one or more rere compounds of formula I and / or their pharmacologically acceptable Contain salts.

The pharmaceuticals are made according to the known and known to the expert Process manufactured. The pharmaceuticals according to the invention are phar macologically active compounds (= active ingredients) either as such, or preferably in combination with suitable pharmaceutical auxiliaries or Carriers in the form of tablets, coated tablets, capsules, suppositories, Pfla asterisk (e.g. as TTS), emulsions, suspensions or solutions, the active substance content advantageously being between 0.1 and 95% and one by the appropriate choice of auxiliaries and carriers the active ingredient and / or precisely adapted to the desired onset of action pharmaceutical dosage form (e.g. a slow-release form or an enteric stent form) can be achieved.

Which auxiliaries or carriers for the desired pharmaceutical formulation are suitable due to his specialist knowledge fig. In addition to solvents, gel formers, suppository bases, tablets Excipients and other active ingredients can, for example, antioxidant tien, dispersing agents, emulsifiers, defoamers, flavoring agents, Preservatives, solubilizers, dyes or especially per meation promoters and complexing agents (e.g. cyclodextrins) are used the.

The active ingredients can be administered orally, parenterally or percutaneously.

In general, it has proven advantageous in human medicine the active ingredient (s) when administered orally in a daily dose of approximately 0.01  up to about 20, preferably 0.05 to 5, in particular 0.1 to 1.5 mg / kg body perweight, optionally in the form of several, preferably 1 to 4 individual gave to achieve the desired result. At a Parenteral treatment can be similar or (especially with intrave administration of the active substances) usually lower doses Application come. The determination of the optimal Do required Any specialist can determine the type and application of the active ingredients easy to do due to his specialist knowledge.

Should the compounds and / or salts according to the invention for the treatment of diseases mentioned above can be used, the pharmaceutical preparations also include one or more pharmacologically active stocks parts of other groups of drugs, such as antacids, for example aluminum hydroxide, magnesium aluminate; Tranquilizers, such as benzodiazepines, for example wise diazepam; Antispasmodics, such as B. Bietamiverin, Camylofin, Anticholi nergica, such as B. oxyphencyclimine, phencarbamide; Local anesthetics, such as e.g. B. Tetracaine, Procaine; if necessary, also ferments, vitamins or amino contain acids.

In this context, the combination of compounds according to the invention with pharmaceuticals which inhibit acid secretion, such as H₂ blockers (e.g. cimetidine, ranitidine), H⁺ / K⁺ ATPase Inhibitors (e.g. omeprazole, pantoprazole), or further with so-called pe peripheral anticholinergics (e.g. pirenzepin, telenzepin) and with gastrin Antagonists with the aim of the main effect in additive or superadditive Reinforcing meaning and / or eliminating or verifying the side effects wrestle, or further the combination with antibacterial substance zen (such as cephalosporins, tetracyclines, nalidixic acid, penicillins or bismuth salts) to combat Helicobacter pylori.  

pharmacology

The excellent gastric protective effect and the gastric acid secretion inhibiting Effect of the compounds of the invention can be found in studies on animals experimental models can be demonstrated. The one listed below Compounds tested according to the invention are numbered provided that ent the numbers of these compounds in the examples speak.

Testing the secretion-inhibiting effect on the perfused rat stomach

Table A below shows the influence of the compounds of the invention after intravenous administration to the acid stimulation stimulated by pentagastrin cretion of the perfused rat stomach shown in vivo.

Table A

methodology

Anesthetized rats (CD rat, female, 200-250 g; 1.5 g / kg im Ure than) the abdomen became after a tracheotomy through a median upper abdomen opened and a PVC catheter transorally in the esophagus and a white fixed via the pylorus in such a way that the ends of the hose were just in the Gastric lumens protruded. The catheter leading out of the pylorus led over a side opening in the right abdominal wall to the outside.  

After thorough rinsing (approx. 50-100 ml) the stomach warmed to 37 ° C physiological NaCl solution continuously flowed through (0.5 ml / min, pH 6.8-6.9; Braun Unita I). In each case caught every 15 minutes Effluat was the pH value (pH meter 632, glass electrode EA 147; ø = 5 mm, Metrohm) and by titration with a freshly prepared 0.01 N NaOH up to pH 7 (Dosimat 665 Metrohm) determines the secreted HCl.

Gastric secretion was stimulated by continuous infusion of 1 µg / kg (= 1.65 ml / h) IV Pentagastrin (V. fem. Sin.) Approx. 30 min after operations end (i.e. after determining 2 pre-fractions). The substances to be checked Zen were administered intravenously in 1 ml / kg liquid volume 60 min after the start of the Pentagastrin continuous infusion administered.

The body temperature of the animals was determined by infrared radiation and heating cushion (automatic, stepless regulation via rectal temperature sensor) kept at a constant 37.8-38 ° C.

Claims (8)

1. Compounds of the formula I wherein
R0 means halogen or thiocyanate,
R1 is 1-4C-alkyl,
R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,
R3 is SO₂-R6, CO-R7, COO-R8 or CON (R9) R10,
R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,
R5 denotes hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,
AO (oxygen) or NH means
R6 1-4C-alkyl, aryl, aryl substituted by R16, R17 and R18, aryl-1-4C-alkyl, aryl-1-4C-alkyl substituted by R16, R17 and R18 in the aryl part, completely or partially substituted by fluorine 1 -4C-alkyl, 1-4C-alkyl substituted by -S (O) _n -R¹⁹ or the radical C _q H _2q-2- aryl, or an unsubstituted or hydroxy-substituted cycle which is selected from the group thiolane , Thiolan oxide or thiolan dioxide,
R7 is aryl, aryl-1-4C-alkyl, aryl substituted by R16, R17 and R18, or aryl-1-4C-alkyl substituted by R16, R17 and R18 in the aryl radical,
R8 substituted by R11 2-4C-alkyl, substituted by R12 1-4C-alkyl, -N = C (R13) R14, substituted by R15 2-4C-alkyl, aryl, the radical -C _q H _{2q + 1} or by R16, R17 and R18 are substituted aryl,
R9 represents hydrogen or 1-4C-alkyl,
R10 denotes 2-4C-alkyl substituted by R11, 1-4C-alkyl substituted by R12 or 1-4C-alkyl,
R11 denotes 1-4C-alkoxy, 1-4C-alkylcarbonyloxy, hydroxy, hydroxy-2-4C-alkoxy or 1-4C-alkoxy-1-4C-alkoxy,
R12 denotes 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, carboxy, mono-1-4C-alkylaminocarbonyl, di-1-4C-alkylaminocarbonyl, thienyl, pyridyl, aryl or aryl substituted by R16, R17 and R18,
R13 1-4C-alkyl, phenyl or phenyl-1-4C-alkyl and
R14 is 1-4C-alkyl, phenyl or phenyl-1-4C-alkyl, or in which R13 and R14 together represent a 4-6C-alkylene group,
R15 is phthalimidyl or S (O) _n -R19, where aryl is phenyl or naphthyl and
R16 is hydrogen, halogen, nitro, 1-4C-alkyl, 1-4C-alkoxy, trifluoromethyl, hydroxy, carboxy, 1-4C-alkoxycarbonyl, cyano, completely or partially substituted by fluorine-substituted 1-4C-alkoxy, phenyl, benzoyl, mono - and di-1-4C-alkylamino, amino, 1-4C-alkylcarbonylamino or S (O) _n -R19,
R17 is hydrogen, halogen, 1-4C-alkoxy, nitro, carboxy, 1-4C-alkyl or hydroxy and
R18 represents hydrogen or halogen,
R19 denotes 1-4C-alkyl,
n denotes the numbers 0, 1 or 2,
q means the numbers 2 or 3,
and their salts and the N-oxides of pyridines and their salts. 2. Compounds of formula I according to claim 1, in which
R0 means halogen,
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl or halogen,
R3 is SO₂-R6, CO-R7, COO-R8 or CON (R9) R10,
R4 means hydrogen,
R5 means hydrogen
AO (oxygen) or NH means
R6 1-4C-alkyl, aryl, aryl substituted by R16, aryl-1-4C-alkyl, aryl-1-4C-alkyl substituted by R16 in the aryl part or 1-4C-alkyl substituted by -S (O) _n -R19 means
R7 denotes aryl, aryl-1-4C-alkyl, aryl substituted by R16 or aryl-1-4C-alkyl substituted by R16 in the aryl radical,
R8 denotes 2-4C-alkyl substituted by R11, 1-4C-alkyl substituted by R12, -N = C (R13) R14 or 2-4C-alkyl substituted by R15, aryl or aryl substituted by R16,
R9 means hydrogen,
R10 denotes 2-4C-alkyl substituted by R11 or 1-4C-alkyl substituted by R12,
R11 denotes 1-4C-alkoxy, 1-4C-alkylcarbonyloxy, hydroxy or 1-4C-alkoxy-1-4C-alkoxy,
R12 denotes 1-4C-alkoxycarbonyl, carboxy, mono-1-4C-alkylaminocarbonyl, di-1-4C-alkylaminocarbonyl, thienyl, pyridyl, aryl or aryl substituted by R16,
R13 1-4C alkyl and
R14 is 1-4C-alkyl,
R15 is phthalimidyl or -S (O) _n -R19, where aryl is phenyl and
R16 is hydrogen, halogen, nitro, 1-4C-alkyl, 1-4C-alkoxy, hydroxy, carboxy, 1-4C-alkoxycarbonyl, benzoyl, mono- and di-1-4C-alkylamino, amino, 1-4C-alkylcarbonylamino or S (O) _n -R19 means
R19 denotes 1-4C-alkyl,
n denotes the numbers 0, 1 or 2,
and their salts. 3. Compounds of formula I according to claim 1, in which
R0 means halogen,
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl or halogen,
R3 is SO₂-R6, COO-R8 or CON (R9) R10,
R4 means hydrogen,
R5 means hydrogen
AO (oxygen) or NH means
R6 denotes 1-4C-alkyl or aryl-1-4C-alkyl,
R8 is 2-4C-alkyl substituted by R11, 1-4C-alkyl substituted by R12, -N = C (R13) R14 or 2-4C-alkyl substituted by R15,
R9 means hydrogen,
R10 denotes 1-4C-alkyl substituted by R12,
R11 denotes 1-4C-alkoxy, hydroxy or 1-4C-alkoxy-1-4C-alkoxy,
R12 denotes 1-4C-alkoxycarbonyl, carboxy, thienyl, pyridyl or aryl substituted by R16,
R13 1-4C alkyl and
R14 is 1-4C-alkyl,
R15 is phthalimidyl or -S (O) _n -R19, where aryl is phenyl and
R16 means hydroxy
R19 denotes 1-4C-alkyl,
n denotes the numbers 0, 1 or 2,
and their salts. 4. A process for the preparation of the compounds of formula I according to claim 1 and their salts, characterized in that

• a) compounds of the formula II, wherein R0, R1, R2, R4, R5 and A have the meanings given according to claim 1, with compounds of the formula R3-X, wherein R3 has the meanings given according to claim 1 and X represents a suitable leaving group, or that one
• b) compounds of the formula III, in which R0, R1 and A have the meanings given according to Claim 1, with compounds of the formula IV, wherein R2, R3, R4 and R5 have the meanings given according to claim 1 and X represents a suitable leaving group, or that
• c) compounds of the formula I in which R1, R2, R3, R4, R5 and A have the meanings given according to claim 1 and R0 is hydrogen, are reacted with suitable halogenating agents, or in that
• d) Compounds of the formula I in which R0, R1, R2, R4, R5 and A have the meanings given according to claim 1 and the radical R3 contains a sulfide group (-S-), or is oxidized
• e) Compounds of the formula I in which R0, R1, R2, R4, R5 and A have the meanings given according to claim 1 and the radical R3 contains an ether group (-O-) on the ether group to the corresponding terminal hydroxide (-OH) splits,

and that, if desired, then those according to a), b), c), d) or e) obtained compounds I converted into their salts, or that one desired if necessary, the ver. from the salts of the compounds I obtained bonds I releases. 5. Medicament containing a compound according to claim 1 and / or pharmacologically acceptable salt thereof together with conventional pharma Zeutische auxiliaries and / or carriers. 6. Compounds according to claim 1 and their pharmacologically acceptable Salts for use in the prevention and treatment of gastrointestinal Diseases. 7. Use of compounds according to claim 1 and their pharmacological compatible salts for the manufacture of medicines for contraception treatment and treatment of gastrointestinal diseases.