DE19602855A1 - New ((acyl-amino-phenyl)methyl-oxy- or -imino)imidazo:pyridine compounds - Google Patents

Abstract

Imidazopyridine compounds of formula (I) and their salts and oxides of the pyridine are new. R0 = 1-4C alkyl, CH2OH or CF3; R1 = 1-4C alkyl; R2, R4 = H, 1-4C alkyl, 1-4C alkoxy, halo or CF3; R3 = SO2R6, CO-R7, COO-R8 or CON(R9)R1-0; R5 = H, 1-4C alkyl, 1-4C alkoxy or halo; A = O or NH; R6 = 1-4C alkyl (optionally substituted by S(O)n-R19 or Ar or partly or completely substituted by F), Ar, CqH(2q-2)-aryl, or optionally OH-substituted thiolane (or its oxide or dioxide); Ar = aryl (optionally substituted by R16, R17 and R18); R7 = Ar or 1-4C alkyl substituted by Ar; R8 = Me (optionally substituted by R12), 2-4 C alkyl (optionally substituted by R11, R12 or R15), -N=C(R13)R14, Ar or -CqH(2q+1); R9 = H or 1-4C alkyl; R10 = R11-substituted 2-4C alkyl 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 Ar; R13, R14 = 1-4C alkyl, phenyl or phenyl-(1-4C alkyl); or R13+R14 = 4-6C alkylene; R15 = phthalimidyl or S(O)a-R19; 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)a-R19; 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.

Description

Field of application of the invention

The invention relates to new 3-methylimidazopyridines which are used in pharmazeu tical industry as active ingredients for the manufacture of pharmaceuticals should be used.

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 denotes 1-4C-alkyl, hydroxymethyl or trifluoromethyl,
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 wherein
R13 and R14 together represent a 4-6C-alkylene group,
R15 represents phthalimidyl or -S (O) _n -R19, where
Aryl means 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 butylsulfonyl radicals .

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 denotes 1-4C-alkyl, hydroxymethyl or trifluoromethyl,
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 means phthalimidyl or S (O) _n -R19, where
Aryl means 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 denotes 1-4C-alkyl,
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 is SO₂-R6, CO-R7 or COO-R8,
R4 means hydrogen,
R5 means hydrogen
A NH means
R6 means 1-4C-alkyl,
R7 denotes aryl substituted by R16,
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,
R11 denotes 1-4C-alkoxy 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 represents phthalimidyl or -S (O) _n -R19, where
Aryl means phenyl and
R16 means hydroxy or benzoyl,
R19 denotes 1-4C-alkyl,
n represents 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, wherein R0, R1, R2, R4, R5 and A the above have the meanings given and the radical R3 is a sulfide group (-S-) contains, oxidized, or that one
• d) 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 after a), b), c) or d) he holding 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.

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 Ver driving variant b) is also carried out on a ver the expert familiar way, for example using such methods, as in the European patent applications EP-A-0 268 989 or EP-A-0 308 917.

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 oxidation of the sulfides to the sulfoxides or sulfones analogously to Ver driving variant c) is carried out under the conditions as the specialist for oxidation of sulfides to sulfoxides and sulfones is 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 for the oxidation of sulfides to sulfoxides and sulfones commonly used reagents in question, especially peroxy acids, such as B. peroxyacetic acid, trifluoroperoxyacetic acid, 3,5-dinitroperoxy benzoic 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 chlo hydrocarbons such as benzene, toluene, dichloromethane or chloro roform, preferably in esters or ethers, such as ethyl acetate, Es isopropyl acetate or dioxane, or in alcohols, preferably Isopro panol, 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. WO92 / 08716).

The ether cleavage in the case of compounds of the formula I according to variant d) takes place also in a manner known to the person skilled in the art.

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 are from the European patent application EP-A-0 299 470 known or can be prepared in an analogous manner.

The starting compounds IV can be used in a manner analogous to that in the euro European patent application EP-A-0 308 917. 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 following examples serve to explain the preparation of the compounds of the invention. In particular, the examples also serve there to, the implementations according to process variants a), b), c) and d), and the example of 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 and bp for boiling point.  

Examples Output connections A1. (2-chloromethyl-3-methylphenyl) carbamic acid 2- (N-phthalimido-2-ethyl-l) ester

A suspension of 2-chloromethyl-1-isocyanato-3-methylbenzene (1 g) and N- (2-Hydroxyethyl) phthalimide (1.07 g) in petroleum ether (b.p. 100-140 ° C) (100 ml) is heated under reflux for 8 h and then nachge for a further 16 h at RT stirs. The precipitate is filtered off and with a little dichloromethane and Washed diethyl ether. 1.06 g (52%) of the title compound are obtained as a solid of mp. 176-178 ° C.

A2. 8- (2-tert-Butoxycarbonylamino-6-methyl-benzylamino) -2,3-dimethyl imidazo [1,2-a] pyridine

To a solution of 8-amino-2,3-dimethylimidazo [1,2-a] pyridine (4.8 g) and 2-tert-Butoxycarbonylamino-6-methylbenzyl chloride (9.2 g) in acetone (250 ml) 5.5 g of sodium iodide and 8.0 g of sodium carbonate are added at RT then heated to boiling under reflux for 6 h. After cooling the Solution to RT and concentration, the residue in a mixture of 200 ml Ethyl acetate and 200 ml of water dissolved and the organic phase is removed separates. After three further extractions, each with 100 ml of ethyl acetate which the combined organic phases dried over magnesium sulfate and then concentrated. The title compound crystallizes as weak yellow solid. After chromatographic purification on silica gel (flow with tel: toluene / dioxane = 20: 1) and recrystallization from diisopropyl ether hold 7.1 g (62%) of the title compound of mp. 149-152 ° C.

A3. 8- (2-Amino-6-methyl-benzylamino) -2,3-dimethyl-imidazo [1,2-a] pyridine Method A

A solution of 8- (6-methyl-2-nitrobenzylamino) -2,3-dimethylimidazo [1,2-a]  pyridine (61 g) in methanol (5.5 l) is dissolved in the presence of 15 g palladium Activated carbon (5%) as a catalyst at RT and under atmospheric pressure for Hydrogenated for 1.5 h. After filtering off the catalyst and concentrating the Residue dissolved in boiling ethyl acetate (2.7 l). After cooling to RT 51 g (82%) of the title compound of mp. 206-208 ° C. are isolated.

Method B

6.7 g of 8- (2-tert-butoxycarbonylamino-6-methylbenzylamino) -2,3-dimethylimi dazo [1,2-a] pyridine are added in portions at 25-30 ° C to a mixture Trifluoroacetic acid (30 ml) and anisole (3 ml) added. After 30 minutes Stirring at RT, the solution is poured into 100 ml of ice water and then mixed with 75 ml of 6 N sodium hydroxide solution. The precipitate is filtered off and purified chromatographically on silica gel (solvent: toluene / dioxane 8: 1). After recrystallization from ethyl acetate, 3.1 g (62%) are obtained. the title compound of mp. 206-208 ° C.

B1. (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.

B2. (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.  

C1. 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.

C2. 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.

C3. (2-Chloromethyl-3-methylphenyl) carbamic acid 2- (2-methoxyethoxy) eth-yl ester

A solution of 2-chloromethyl-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.

C4. (2-chloromethyl-3-methylphenyl) carbamic acid (2-thienylmethyl) 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.

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

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 / methanol 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.

C6. (2-chloromethyl-3-methylphenyl) carbamic acid (3-hydroxybenzyl) ester -

A mixture of 2-chloromethyl-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 / methanol 19: 1). 1 g (30%) of the title compound is obtained as a crude product in the form of an amorphous solid.

C7. (2-chloromethyl-3-methyl-phenyl) -carbamic acid- (2-N-phthalimidoethyl) - ester

A suspension of 2-chloromethyl-1-isocyanato-3-methylbenzene (1.0 g) and 2-Hydroxyethyl-N-phthalimide (1.07 g) in petroleum ether 100/140 (100 ml) becomes 8 h heated at reflux. The mixture is then stirred at RT for a further 16 h. The never the mixture is filtered off, with a little dichloromethane and with diethyl ether washed and dried in a high vacuum. 1.06 g (52%) of the title compound are isolated as a light beige solid. Mp 176-178 ° C.  

End products 1. Ethanesulfonic acid- [2- (2,3-dimethyl-imidazo [1,2-alpyridin-8yl-amino methyl) -3-methylphenyl] amide

A solution of 8- (2-amino-6-methyl-benzylamino) -2,3-dimethyl-imidazo [1,2-a] pyridine (1.86 g), pyridine (1.1 ml) and ethanesulfonic acid chloride (1.18 ml) in dichloromethane (40 ml) is stirred at RT for 48 h. After that dilute the reaction mixture with dichloromethane (60 ml) on water (100 ml) added and extracted. The organic phase is made with sodium hydrogen carbonate solution (60 ml) and washed with water (60 ml), over sodium sul fat dried and concentrated. By crystallizing the residue Acetone and subsequent filtration give 0.8 g (32%) of the title compound binding of mp. 240-242 ° C.

2. n-Propanesulfonic acid- [2- (2,3-dimethyl-imidazo [1,2-alpyridin-8ylamino methyl) -3-methylphenyl] amide

A solution of 8- (2-amino-6-methyl-benzylamino) -2,3-dimethyl-imidazo [1,2-a] pyridine (2.5 g), pyridine (1.4 ml) and n-propanesulfonic acid chloride (2nd ml) in dichloromethane (50 ml) is stirred at RT for 5 days. After that the Reaction mixture diluted with dichloromethane (50 ml), added to water and extracted. The organic phase is treated with sodium hydrogen carbonate Solution (50 ml) and washed with water (50 ml), over sodium sulfate dries and evaporates. By crystallizing the residue from acetone and subsequent filtration gives 1.8 g (52%) of the title compound of Mp 245-248 ° C.

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

A suspension of 8-amino-2,3-dimethyl-imidazo [1,2-a] pyridine (0.48 g), (2-Chloromethyl-3-methylphenyl) carbamic acid 2- (2-methoxyethoxy) ethyl ester (0.9 g), sodium carbonate (0.8 g) and sodium iodide (0.15 g) in acetone (20 ml) is stirred at RT for 16 h. Then the precipitate is filtered off with Washed acetone and the filtrate was concentrated on a rotary evaporator. Of the  Residue is taken up in sodium hydrogen carbonate solution (50 ml) and extracted with dichloromethane (3 × 50 ml). The united organic ex tracts are washed with water (100 ml), dried over sodium sulfate and constricted. The residue is purified by chromatography twice Silica gel (eluent A: dichloromethane / methanol 13: 1, eluent B: Ethyl acetate) cleaned. The main fraction is with ethereal hydrochloric acid spiked and concentrated. 0.7 g (50%) of the title compound are obtained as amorphous solid that sinters at 70-80 ° C.

4. 8- {2- [O- (carbamoyl) acetone oxime] -6-methyl-benzylamino} -2,3-dimethyl imidazo [1,2-a] pyridine

A suspension of 8-amino-2,3-dimethyl-imidazo [1,2-a] pyridine (0.63 g), O- (2-chloromethyl-3-methylphenylcarbonyl) acetone oxime (1 g), sodium carbonate (1.04 g) and sodium iodide (0.2 g) in acetone (20 ml) is ge for 16 h at RT stirs. The precipitate is filtered off, washed with acetone and that The filtrate was concentrated on a rotary evaporator. The residue is in sodium Hydrogen carbonate solution (50 ml) was taken up and dichloromethane (3 × 50 ml) extracted. The combined organic extracts are washed with water (50 ml) washed, dried over sodium sulfate and concentrated. The residue is by chromatography on silica gel (eluent: dichloromethane / Methanol 13: 1) cleaned. After concentration of the main fraction and crystal lization from diethyl ether gives 0.92 g (62%) of the title compound of Mp 138 ° C.

5. 8- {2 - [(2-pyridinyl-methoxy) carbonylamino] -6-methyl-benzyloxy} - 2,3-dimethyl-imidazo [1,2-a] pyridine

A suspension of 8-amino-2,3-dimethyl-imidazo [1,2-a] pyridine (0.58 g), (2-chloromethyl-3-methylphenyl) carbamic acid (2-pyridinylmethyl) est-er (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 with acetone washed and the filtrate concentrated on a rotary evaporator. Of the Residue is taken up in sodium hydrogen carbonate solution (40 ml) and extracted with dichloromethane (3 × 40 ml). The united organic Extracts are washed with water (70 ml), dried over sodium sulfate and constricted. The residue is purified by chromatography on silica gel  (Eluent: ethyl acetate) cleaned. After concentration of the main fraction and Crystallization from acetone gives 0.4 g (27%) of the title compound of 163-165 ° C.

6. 8- {2 - [(2-thienyl-methoxy) carbonylamino] -6-methyl-benzyloxy} -2,3- dimethyl-imidazo [1,2-a] pyridine

A suspension of 8-amino-2,3-dimethyl-imidazo [1,2-a] pyridine (0.68 g), (2-chloromethyl-3-methyl-phenyl) carbamic acid 2- (2-thienyl-methyl) ester (1.25 g), sodium carbonate (1.12 g) and sodium iodide (0.16 g) in acetone (40 ml) is stirred at RT for 16 h. The precipitate is filtered off with acetone washed and the filtrate concentrated on a rotary evaporator. The back Stand is taken up in sodium bicarbonate solution and with dichlor extracted methane (3 x 50 ml). The combined organic extracts are washed with water (50 ml), dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: vinegar ester) cleaned. After concentration of the main fraction and crystallization Ethyl acetate / diisopropyl ether gives 0.61 g (34%) of the title compound from mp. 146-147 ° C.

7. 8- {2 - [(3-hydroxybenzyloxy) carbonylamino] -6-methyl-benzyloxy} -2,3-di methyl imidazo [1,2-a] pyridine

A suspension of 8-amino-2,3-dimethyl-imidazo [1,2-a] pyridine (0.63 g), (2-chloromethyl-3-methylphenyl) carbamic acid 3-hydroxybenzyl ester (1.2 g), Sodium carbonate (1 g) and sodium iodide (0.14 g) in acetone (20 ml) are stirred for 16 h stirred at RT. The precipitate is filtered off and washed with acetone and constricted. The residue is dissolved in sodium bicarbonate solution (40 ml) was added and extracted with dichloromethane (3 × 40 ml). The United organic extracts are washed with water, over sodium sulfate dries and evaporates. The residue is indicated by flash chromatography Silica gel (eluent: dichloromethane / methanol 13: 1) cleaned. After one The main fraction and crystallization from acetone give 0.4 g (22 %) of the title compound of mp. 190-193 ° C.  

8. 8- {2 - [(Hydroxycarbonylmethyloxy) carbonylamino] -6-methyl-benzyl amino} -2,3-dimethyl-imidazo [1,2-a] pyridine hydrochloride A) 8- {2 - [(Methoxycarbonyl-methoxycarbonylamino] -6-methyl-benzyl amino} -2,3-dimethyl-imidazo [1,2-a] pyridine

A suspension of 8-amino-2,3-dimethyl-imidazo [1,2-a] pyridine (2.05 g), (2-chloromethyl-3-methylphenyl) carbamic acid (methoxycarbonyl methyl) ester (3.45 g), sodium carbonate (3.42 g) and sodium iodide (0.59 g) in acetone (60 ml) is stirred at RT for 20 h. The precipitate is filtered off with acetone washed and the filtrate concentrated on a rotary evaporator. The back Stand is taken up in sodium bicarbonate solution and with dichlor extracted methane (3 x 70 ml). The combined organic extracts are washed with water (100 ml), dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: Di chloromethane / methanol 13: 1). After concentration of the main fraction 1 g of a foamy product is obtained. This raw product is an approx. 1: 1 Mixture of substances from 3- [2- (2,3-dimethyl-imidazo [1,2-a] pyridin-8-ylami no-methyl) -3-methylphenyl] -oxazolidin-2,4-dione and the title compound A, (Plasticizer for quality control: dichloromethane / methanol / ammonia 13: 1: 0.5). This raw product was directly implemented further.

B) 8 - {(2 - [(Hydroxycarbonylmethyloxy) carbonylamino] -6-methyl-benzyl amino} -2,3-dimethyl-imidazo [1,2-a] pyridine hydrochloride

The approx. 50% crude product from A) (0.9 g) is dissolved in ethanol (10 ml), a solution of potassium hydroxide (0.15 g) in ethanol (10 ml) was added and stirred at RT for 21h. The reaction solution is then concentrated. Of the The residue is taken up in 1 N hydrochloric acid (25 ml) and with dichloromethane (7 x 20 ml) extracted. The combined organic extracts become one concentrated and chromatographed on silica gel (eluent: dichloromethane / Methanol 13: 1 as a gradient up to 1: 1). The fraction with Rf = 0.05-0.1 (flow medium: dichloromethane / methanol = 13: 1) is concentrated and in a high vacuum 60 ° C dried 16 h. 0.2 g (21%) of the title compound of Mp 114 ° C (sinters).  

9. 2,3-Dimethyl-8- {2 - [(2-methylsulfanylethoxy) carbonylamino] -6-methyl-ben zylamino} imidazo [1,2-a] pyridine hemifumarate

A 20% solution of phosgene in toluene (2.8 ml) is washed with anhydrous Diluted dichloromethane (15 ml) and cooled to 0 ° C. Then there will be a solution of 2-methylsulfanylethanol (0.46 ml) and N-methylmorpholine (0.59 ml) in anhydrous dichloromethane (10 ml) was added dropwise. The mix turns 15 min at 0 ° C, then warmed to RT and ge for another 30 min stirs. A suspension of 8- (2-amino-6- methyl-benzylamino) -2,3-dimethyl-imidazo [1,2-a] pyridine (1.0 g) and tri added ethylamine (0.49 ml) in anhydrous dichloromethane (30 ml) and stirred for 1 h at RT. Then aqueous sodium bicarbonate solution (70 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 × 50 ml). The combined organic phases are washed with water (50 ml), dried over magnesium sulfate and concentrated. The backlog is in a hot solution of fumaric acid (400 mg) in acetone (30 ml) and added Cooled to 4 ° C. The precipitate is filtered off and from little hot Acetone stirred. After drying in a high vacuum, 0.65 g (47%) of the Title compound isolated as light beige crystals. Mp 174-176 ° C.

10. 2,3-Dimethyl-8- {2 - [(2-methylsulfinylethoxy) carbonylamino] -6-methyl-ben zylamino} imidazo [1,2-a] pyridine hemifumarate

A solution of 2,3-dimethyl-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 / ammonia = 19: 1: 0.1) chromatographed. The fractions with Rf = 0.15 are collected and concentrated. The residue in a hot solution of fumaric acid (150 mg) in acetone (20 ml) recorded and then cooled to 4 ° C. After filtration and  Drying under high vacuum isolates 0.54 g (46%) of the title compound as light beige crystals. Mp 137-138 ° C.

11. 2,3-Dimethyl-8- {2 - [(2-methylsulfonylethoxy) carbonylamino] -6-methyl-ben zylamino} imidazo [1,2-a] pyridine

A solution of 2,3-dimethyl-8- {2 - [(2-methylsulfanylethoxy) carbonyl amino] -6-methyl-benzylamino} -imidazo [1,2-a] pyridine (500 mg) in anhydrous Dichloromethane (10 ml) is cooled to 0 ° C and in portions with m-chlorine peroxibenzoic acid (0.87 g) was added and the mixture was then stirred at 0 ° C. for a further 45 min. Then aqueous sodium bicarbonate solution (15 ml) is added Stirred for 10 min, the organic phase separated and the aqueous phase with Dichloromethane (3 x 10 ml) extracted. The combined organic phases are washed with water (25 ml), dried over magnesium sulfate and constricted. To separate by-products, the residue is on silica gel (eluent: ethyl acetate / methanol = 10: 1) chromatographed. The Fractions with Rf = 0.3 are collected and concentrated. The backlog will crystallized from ethyl acetate / diisopropyl ether. After filtration and Drying under high vacuum is isolated as 250 mg (22%) of the title compound light beige crystals. M.p. 161-162 ° 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; ⌀ = 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 denotes 1-4C-alkyl, hydroxymethyl or trifluoromethyl,
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. 2. Compounds of formula I according to claim 1, in which
R0 denotes 1-4C-alkyl, hydroxymethyl or trifluoromethyl,
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 denotes 1-4C-alkyl,
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 is SO₂-R6, CO-R7 or COO-R8,
R4 means hydrogen,
R5 means hydrogen
A NH means
R6 means 1-4C-alkyl,
R7 denotes aryl substituted by R16,
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,
R11 denotes 1-4C-alkoxy 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 or benzoyl,
R19 denotes 1-4C-alkyl,
n represents 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 formula I, wherein 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
• 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 an ether group (-O-) on the ether group to the corresponding terminal hydroxide (-OH) splits,

and that, if desired, then after a), b), c) or d) he holding compounds I converted into their salts, or that one desired if the verbin is then obtained from salts of the compounds I obtained releases 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.