HK1102354A

HK1102354A - Tricyclic imidazopyridines and intermediates for the synthesis thereof

Info

Publication number: HK1102354A
Application number: HK07106828.8A
Authority: HK
Inventors: Wilm Buhr; Peter Jan Zimmermann; Christof Brehm; Andreas Palmer; Wolfgang Kromer; Stefan Postius; Wolfgang-Alexander Simon; M. Vittoria Chiesa
Original assignee: Altana Pharma Ag
Priority date: 2004-02-17
Filing date: 2005-02-16
Publication date: 2007-11-16

Description

Tricyclic imidazopyridines and intermediates for their synthesis

Technical Field

The present invention relates to a process for the preparation of tricyclic imidazopyridines, to valuable intermediates used in said process, to novel tricyclic imidazopyridines prepared with this process and to their use in the pharmaceutical industry as active compounds for the preparation of medicaments.

Description of the Prior Art

U.S. Pat. No. 4,468,400 describes tricyclic imidazo [1, 2-a ] pyridines having different ring systems fused to the imidazopyridine skeleton, which compounds are said to be useful in the treatment of peptic ulcer diseases. International patent applications WO 98/42707, WO 98/54188, WO 00/17200, WO00/26217, WO 00/63211, WO 01/72756, WO 01/72754, WO 01/72755, WO 01/72757, WO 02/34749, WO 03/014120, WO 03/016310, WO03/014123, WO 03/068774 and WO 03/091253 disclose tricyclic imidazopyridine derivatives containing very specific substitution patterns, which are said to be equally suitable for the treatment of gastrointestinal diseases.

Description of the invention

It has been found that compounds having X ═ NH, such as disclosed in WO03/014123, can be prepared with a large number of substituents through a general reaction sequence starting from novel intermediates, which compounds are not described in the examples in said patent application.

Thus, in a first aspect, the present invention relates to compounds of formula 1 and salts thereof,

wherein

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, fluoro-1-4C-alkyl or hydroxy-1-4C-alkyl,

r2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or cyanomethyl,

r3 is halogen, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, fluoro-1-4C-alkoxy-1-4C-alkyl or a radical-CO-NR 31R32,

wherein

R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-1-4C-alkyl and

r32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl,

or therein

R31 and R32 form together with the nitrogen atom to which they are attached a pyrrolidinyl, piperidino, or morpholino group.

Arom is a R4-, R5-, R6-and R7-substituted mono-or bicyclic aryl group selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1, 2, 3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl, quinolinyl and isoquinolinyl,

wherein

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, halogen, hydroxy, aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono-or di-1-4C-alkylamino or sulfonyl,

r5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy,

r6 is hydrogen, 1-4C-alkyl or halogen and

r7 is hydrogen, 1-4C-alkyl or halogen,

wherein

Aryl is phenyl or substituted phenyl which contains 1, 2 or 3 identical or different substituents from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, carboxyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano.

1-4C-alkyl means straight-chain or branched alkyl having 1 to 4 carbon atoms. Examples which may be mentioned are butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl.

3-7C-cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.

3-7C-cycloalkyl-1-4C-alkyl means one of the above-mentioned 1-4C-alkyl groups substituted by one of the above-mentioned 3-7C-cycloalkyl groups. Examples which may be mentioned are cyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl.

1-4C-alkoxy means that, in addition to the oxygen atom, it contains a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples which may be mentioned are butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably ethoxy and methoxy.

1-4C-alkoxy-1-4C-alkyl means one of the abovementioned 1-4C-alkyl groups which is substituted by one of the abovementioned 1-4C-alkoxy groups. Examples which may be mentioned are the methoxymethyl, the methoxyethyl and the butoxyethyl radical.

1-4C-alkoxycarbonyl (-CO-1-4C-alkoxy) means a carbonyl group attached to one of the above-mentioned 1-4C-alkoxy groups. Examples which may be mentioned are methoxycarbonyl (CH)₃O-C (O) and ethoxycarbonyl (CH)₃CH₂O-C(O)-)。

2-4C-alkenyl means straight-chain or branched alkenyl having 2 to 4 carbon atoms. Examples which may be mentioned are 2-butenyl, 3-butenyl, 1-propenyl and 2-propenyl (allyl).

2-4C-alkynyl means straight-chain or branched alkynyl having 2 to 4 carbon atoms. Examples which may be mentioned are 2-butynyl, 3-butynyl, 2-propynyl (propargyl) and preferably 1-ethynyl, 1-propynyl and 1-butynyl.

fluoro-1-4C-alkyl means one of the above-mentioned 1-4C-alkyl groups substituted by one or more fluorine atoms. An example which may be mentioned is trifluoromethyl.

hydroxy-1-4C-alkyl means the above-mentioned 1-4C-alkyl group substituted by hydroxy. Examples which may be mentioned are hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl.

For the purposes of the present invention, halogen is bromine, chlorine and fluorine.

1-4C-alkoxy-1-4C-alkoxy means one of the above-mentioned 1-4C-alkoxy groups substituted by a further 1-4C-alkoxy group. Examples which may be mentioned are 2- (methoxy) ethoxy (CH)₃-O-CH₂-CH₂-O-) and 2- (ethoxy) ethoxy (CH)₃-CH₂-O-CH₂-CH₂-O-)。

1-4C-alkoxy-1-4C-alkyl means one of the abovementioned 1-4C-alkoxy-1-4C-alkyl groups which is substituted by one of the abovementioned 1-4C-alkoxy groups. One example which may be mentioned is 2- (methoxy) ethoxymethyl (CH)₃-O-CH₂-CH₂-O-CH₂-)。

fluoro-1-4C-alkoxy-1-4C-alkyl means one of the abovementioned 1-4C-alkyl groups which is substituted by fluoro-1-4C-alkoxy. Here, fluoro-1-4C-alkoxy means one of the abovementioned 1-4C-alkoxy groups which is completely or predominantly substituted by fluorine. Examples of 1-4C-alkoxy which may be mentioned, completely or predominantly, by fluorine are 1, 1, 1, 3, 3, 3-hexafluoro-2-propoxy, 2-trifluoromethyl-2-propoxy, 1, 1, 1-trifluoro-2-propoxy, perfluoro-tert-butoxy, 2, 2, 3, 3, 4,4, 4-heptafluoro-1-butoxy, 4,4, 4-trifluoro-1-butoxy, 2, 2, 3, 3, 3-pentafluoropropoxy, perfluoroethoxy, 1, 2, 2-trifluoroethoxy, especially 1, 1, 2, 2-tetrafluoroethoxy, 2, 2, 2-trifluoroethoxy, trifluoromethoxy and preferably difluoromethoxy.

1-7C-alkyl means straight-chain or branched alkyl having 1 to 7 carbon atoms. Examples which may be mentioned are heptyl, isoheptyl- (5-methylhexyl), hexyl, isohexyl- (4-methylpentyl), neohexyl- (3, 3-dimethylbutyl), pentyl, isopentyl- (3-methylbutyl), neopentyl- (2, 2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl.

carboxy-1-4C-alkyl means, for example, carboxymethyl (-CH)₂COOH) or carboxyethyl (-CH)₂CH₂COOH) group.

Di-1-4C-alkylamino means amino which is substituted by two identical or different abovementioned 1-4C-alkyl radicals. Examples which may be mentioned are dimethylamino, diethylamino and diisopropylamino.

2-4C-alkenyloxy means a group which, in addition to an oxygen atom, also contains a 2-4C-alkenyl group. An example which may be mentioned is allyloxy.

aryl-1-4C-alkyl means aryl-substituted 1-4C-alkyl. An example which may be mentioned is benzyl.

aryl-1-4C-alkoxy means aryl-substituted 1-4C-alkoxy. An example which may be mentioned is benzyloxy.

In addition to the nitrogen atom, the mono-or di-1-4C-alkylamino radical contains one or two of the abovementioned 1-4C-alkyl radicals. Preference is given to di-1-4C-alkylamino and particular preference to dimethyl-, diethyl-or diisopropylamino.

Arom groups which may be mentioned are, for example, the following substituents: 4-acetoxyphenyl, 4-acetylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl, 3-benzyloxy-4-methoxyphenyl, 4-benzyloxy-3-methoxyphenyl, 3, 5-bis- (trifluoromethyl) phenyl, 4-butoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-5-nitrophenyl, 4-chloro-3-nitrophenyl, 3- (4-chloro-phenoxy) phenyl, 2, 4-dichlorophenyl group, 3, 4-difluorophenyl group, 2, 4-dihydroxyphenyl group, 2, 6-dimethoxyphenyl group, 3, 4-dimethoxy-5-hydroxyphenyl group, 2, 5-dimethylphenyl group, 3-ethoxy-4-hydroxyphenyl group, 2-fluorophenyl group, 4-hydroxyphenyl group, 2-hydroxy-5-nitrophenyl group, 3-methoxy-2-nitrophenyl group, 3-nitrophenyl group, 2, 3, 5-trichlorophenyl group, 2, 4, 6-trihydroxyphenyl group, 2, 3, 4-trimethoxyphenyl group, 2-hydroxy-1-naphthyl group, 2-methoxy-1-naphthyl group, 4-methoxy-1-naphthyl group, 2-hydroxy-1-naphthyl group, 1-methyl-2-pyrrolyl, 3, 4-dimethyl-2-pyrrolyl, 5-ethoxycarbonyl-2, 4-dimethyl-3-pyrrolyl, 3, 4-dibromo-5-methyl-2-pyrrolyl, 2, 5-dimethyl-1-phenyl-3-pyrrolyl, 5-carboxy-3-ethyl-4-methyl-2-pyrrolyl, 3, 5-dimethyl-2-pyrrolyl, 2, 5-dimethyl-1- (4-trifluoromethylphenyl) -3-pyrrolyl, 1- (2, 6-dichloro-4-trifluoromethylphenyl) -2-pyrrolyl, and mixtures thereof, 1- (2-nitrobenzyl) -2-pyrrolyl, 1- (2-fluorophenyl) -2-pyrrolyl, 1- (4-trifluoromethoxyphenyl) -2-pyrrolyl, 1- (4-ethoxycarbonyl) -2, 5-dimethyl-3-pyrrolyl, 5-chloro-1, 3-dimethyl-4-pyrazolyl, 5-chloro-1-methyl-3-trifluoromethyl-4-pyrazolyl, 1- (4-chlorobenzyl) -5-pyrazolyl, 1, 3-dimethyl-5- (4-chlorophenoxy) -4-pyrazolyl, 1-methyl-3-trifluoromethyl-5- (3-trifluoromethylphenoxy) -4-pyrazole A group, 5-allyloxy-1-methyl-3-trifluoromethyl-4-pyrazolyl, 5-chloro-1-phenyl-3-trifluoromethyl-4-pyrazolyl, 3, 5-dimethyl-1-phenyl-4-imidazolyl, 4-bromo-1-methyl-5-imidazolyl, 2-butylimidazolyl, 1-phenyl-1, 2, 3-triazol-4-yl, 3-indolyl, 4-indolyl, 7-indolyl, 5-methoxy-3-indolyl, 5-benzyloxy-3-indolyl, 1-benzyl-3-indolyl, 2- (4-chlorophenyl) -3-indolyl, a salt thereof with a carboxylic acid, a salt thereof, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, 7-benzyloxy-3-indolyl, 6-benzyloxy-3-indolyl, 2-methyl-5-nitro-3-indolyl, 4, 5, 6, 7-tetrafluoro-3-indolyl, 1- (3, 5-difluorobenzyl) -3-indolyl, 1-methyl-2- (4-trifluorophenoxy) -3-indolyl, 1-methyl-2-benzimidazolyl, 5-nitro-2-furyl, 5-hydroxymethyl-2-furyl, 3-furyl, 5- (2-nitro-4-trifluoromethylphenyl) -2-furyl, 4-ethoxycarbonyl-5-methyl-2-furyl, 5- (2-trifluoromethoxyphenyl) -2-furyl, 5- (4-methoxy-2-nitrophenyl) -2-furyl, 4-bromo-2-furyl, 5-dimethylamino-2-furyl, 5-bromo-2-furyl, 5-sulfo (sulfo) -2-furyl, 2-benzofuryl, 2-thienyl, 3-methyl-2-thienyl, 4-bromo-2-thienyl, 5-nitro-2-thienyl, 5-methyl-2-thienyl, 5- (4-methoxyphenyl) -2-thienyl, 5- (4-methoxy-2-thienyl), 4-methyl-2-thienyl, 3-phenoxy-2-thienyl, 5-carboxy-2-thienyl, 2, 5-dichloro-3-thienyl, 2-benzothienyl, 3-methyl-2-benzothienyl, 2-bromo-5-chloro-3-benzothienyl, 2-thiazolyl, 2-amino-4-chloro-5-thiazolyl, 2, 4-dichloro-5-thiazolyl, 2-diethylamino-5-thiazolyl, 3-methyl-4-nitro-5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-methyl-2-pyridyl, 2-methoxy-5-thienyl, 2-pyridyl, 3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridyl, 2, 6-dichloro-4-pyridyl, 3-chloro-5-trifluoromethyl-2-pyridyl, 4- (4-chlorophenyl) -3-pyridyl, 2-chloro-5-methoxycarbonyl-6-methyl-4-phenyl-3-pyridyl, 2-chloro-3-pyridyl, 6- (3-trifluoromethylphenoxy) -3-pyridyl, 2- (4-chlorophenoxy) -3-pyridyl, 2, 4-dimethoxy-5-pyrimidine, 2-quinolyl, 3-quinolyl, and pharmaceutically acceptable salts thereof, 4-quinolyl, 2-chloro-3-quinolyl, 2-chloro-6-methoxy-3-quinolyl, 8-hydroxy-2-quinolyl and 4-isoquinolyl.

One aspect of the invention (a aspect) relates to compounds of formula 1, wherein

R3 is hydrogen, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, fluoro-1-4C-alkoxy-1-4C-alkyl or a radical-CO-NR 31R32,

wherein

R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and

r32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

or therein

R31 and R32 form together with the nitrogen atom to which they are attached a pyrrolidinyl, piperidino, or morpholino group,

and R1, R2 and Arom have the meanings as described at the outset.

Another aspect (b aspect) of the present invention relates to compounds of formula 1 and salts thereof, wherein

R3 is a group-CO-NR 31R32,

r31 is 3-7C-cycloalkyl and

r32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl, and R1, R2 and Arom have the meanings indicated at the outset.

The invention also relates to compounds of formula 1 and salts thereof, wherein

wherein

R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and

r32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

or therein

R31 and R32 together with the nitrogen atom to which they are attached form pyrrolidinyl, piperidino, or morpholino

wherein

r6 is hydrogen, 1-4C-alkyl or halogen and

r7 is hydrogen, 1-4C-alkyl or halogen,

wherein

Aryl is phenyl or substituted phenyl with 1, 2 or 3 identical or different substituents from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, carboxyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano.

The compounds to be mentioned are those of formula 1 and their salts,

wherein

R1 is 1-4C-alkyl or 3-7C-cycloalkyl

R2 is hydrogen, 1-4C-alkyl, halogen or fluoro-1-4C-alkyl

R3 is halogen, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl or a radical-CO-NR 31R32,

wherein

R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl and

or therein

arom is R4-, R5-, R6-and R7-substituted phenyl,

wherein

R4 is hydrogen or 1-4C-alkyl,

r5 is hydrogen or 1-4C-alkyl,

r6 is hydrogen or 1-4C-alkyl and

r7 is hydrogen.

Also mentioned are compounds of formula 1 and salts thereof,

wherein

R1 is 1-4C-alkyl or 3-7C-cycloalkyl

R2 is hydrogen, 1-4C-alkyl, halogen or fluoro-1-4C-alkyl

R3 is halogen, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, or a group-CO-NR 31R32,

wherein

R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and

r32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

or therein

R31 and R32 together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, or morpholino group

Arom is R4-, R5-, R6-and R7-substituted phenyl,

wherein

R4 is hydrogen or 1-4C-alkyl,

r5 is hydrogen or 1-4C-alkyl,

r6 is hydrogen or 1-4C-alkyl and

r7 is hydrogen.

Compounds to be mentioned in particular are those of the formula 1 and their salts,

wherein

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl,

r3 is halogen, hydroxy-1-4C-alkyl, 1-4C-alkoxycarbonyl or a radical-CO-NR 31R32, wherein

or therein

arom is phenyl.

Compounds which may also be mentioned in particular are those of the formula 1 and their salts,

wherein

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl,

r3 is halogen, hydroxy-1-4C-alkyl, 1-4C-alkoxycarbonyl or a radical-CO-NR 31R32,

wherein

R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and

r32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

or therein

arom is phenyl.

Compounds which may also be mentioned in particular are those of the formula 1 and salts thereof,

wherein

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl,

r3 is halogen, 1-4C-alkoxycarbonyl or a radical-CO-NR 31R32,

wherein

R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl and

r32 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl,

or therein

arom is phenyl.

Further compounds to be mentioned in particular are those of formula 1 and salts thereof,

wherein

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl,

r3 is halogen, 1-4C-alkoxycarbonyl or a radical-CO-NR 31R32,

wherein

R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and

r32 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

or therein

arom is phenyl.

The compounds to be emphasized are those of formula 1 and salts thereof,

wherein

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl,

r3 is halogen, 1-4C-alkoxycarbonyl or a radical-CO-NR 31R32,

wherein

or therein

R31 and R32 form together with the nitrogen atom to which they are attached a pyrrolidinyl group,

arom is phenyl.

Compounds to be emphasized are also those of formula 1 and salts thereof,

wherein

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl,

r3 is halogen, 1-4C-alkoxycarbonyl or a radical-CO-NR 31R32,

wherein

R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and

r32 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

or therein

arom is phenyl.

Compounds which are also to be emphasized are those of formula 1 and salts thereof,

wherein

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl,

r3 is halogen or 1-4C-alkoxycarbonyl,

arom is phenyl.

The invention also relates to the use of compounds of formula 1, in which R1, R2, R3 and Arom have the meanings indicated in the subgroups, for preparing compounds of formula 2

And salts thereof, wherein R1, R2, R3 and Arom have the meanings as indicated in the subgroups, are considered suitable for the treatment of gastrointestinal disorders.

The following exemplary compounds of formula 2 (table 1) can be synthesized from the compounds of formula 1 according to the general procedures described in more detail below. Other compounds of formula 2 not listed in table 1 can also be prepared from the corresponding compounds of formula 1.

Table 1:

R1	R2	R3	Arom
R1	R2	R3	Arom
CH₃	CH₃	CH₃OCH₂CH₂N(H)C(O)-	phenyl radical
CH₃	CH₃	CH₃OCH₂CH₂N(H)C(O)-	phenyl radical	CH₃	CH₃	CH₃CH₂OC(O)-	Phenyl radical
CH₃	CH₃	CH₃N(H)C(O)-	Phenyl radical	CH₃	CH₃	CH₃CH₂OC(O)-	Phenyl radical
CH₃	CH₃	CH₃N(H)C(O)-	Phenyl radical	CH₃	CH₃	HOCH₂CH₂N(H)C(O)-	Phenyl radical
CH₃	CH₃	(CH₃)₂N-C(O)-	Phenyl radical	CH₃	CH₃	HOCH₂CH₂N(H)C(O)-	Phenyl radical
CH₃	CH₃	(CH₃)₂N-C(O)-	Phenyl radical	CH₃	CH₃	H₂N-C(O)-	Phenyl radical
CH₃	CH₃	morpholino-C (O) -alpha	Phenyl radical	CH₃	CH₃	H₂N-C(O)-	Phenyl radical
CH₃	CH₃	morpholino-C (O) -alpha	Phenyl radical	CH₃	CH₃	pyrrolidinyl-C (O) -substituted	Phenyl radical
CH₃	CH₃	HO-CH₂-	Phenyl radical	CH₃	CH₃	pyrrolidinyl-C (O) -substituted	Phenyl radical
CH₃	CH₃	HO-CH₂-	Phenyl radical	CH₃	CH₃	cyclopropyl-N (H) -C (O) -substituted	Phenyl radical

Accordingly, the present invention also relates to the compounds of formula 2 and salts thereof listed in table 1 above.

Suitable salts-according to substitution-of the compounds of formula 1 and formula 2 are especially the acid addition salts. Particularly mentioned are the salts of pharmaceutically acceptable inorganic and organic acids commonly used in the pharmaceutical industry. Suitable are the water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, pamoic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where, depending on whether the acid is a mono-or polybasic acid and the desired salt, the salts are prepared with the acids in equimolar or differing molar ratios.

The pharmacologically unacceptable salts initially obtained are converted into pharmaceutically acceptable salts by methods known to the person skilled in the art, for example as process products for the preparation of the compounds of formula 1 or 2 according to the invention on an industrial scale.

It is known to those skilled in the art that the compounds of formula 1 or formula 2 and salts thereof according to the present invention may contain different amounts of solvent, for example when they are isolated in crystalline form. Accordingly, the present invention also includes all solvates and especially all hydrates of the compounds of formula 1 or formula 2, and all solvates and especially all hydrates of the salts of the compounds of formula 1 or formula 2.

The preparation of the compound of formula 2 is carried out, for example, as shown in scheme 1, so that the compound of formula 1, wherein R1, R2, R3 and Arom have the meanings as indicated in the subgroups, is subjected to a cyclization reaction under, for example, acidic conditions with, for example, sulfuric acid.

Scheme 1

The compound of formula 2 obtained according to scheme 1 can be subjected to further derivatization, if desired. For example, if a compound of formula 2 with R3 ═ Br is obtained, various other compounds of formula 2 can be synthesized by further chemical transformations known in the art via reactions known to the expert. If, for example, a compound is desired in which R3 ═ CO-1-4C-alkoxy or R3 ═ CO-NR31R32, appropriate derivatization can be carried out using methods known in the art (e.g., metal-catalyzed carbonylation of the corresponding brominated compound or conversion of the ester to an amide).

For example, compounds of formula 1 of the present invention wherein R1, R2, R3 and Arom have the meanings as set forth in the subgroups can be prepared under standard reaction conditions following the reaction sequence outlined in scheme 2, for example, as described in more detail in the examples.

Scheme 2

For example, compounds of formula 3 wherein R3 is 1-4C-alkoxycarbonyl or-CONR 31R32 are known from WO 02/20523 or WO 99/55706, or such compounds may be prepared using the same or other substituents R3 (e.g. R3 is halogen) in a manner known to the expert, e.g. analogously to the synthesis disclosed in j.med.chem.1985, 28, 876-perone 892.

The compound of formula 1 obtained according to scheme 2 may be subjected to further derivatization reactions, if desired. If a compound of formula 1 is obtained, for example R3 ═ 1-4C-alkoxycarbonyl, further chemical transformations known in the art can be carried out by reactions known to the expert, in order to synthesize various other compounds of formula 1. If, for example, a compound of formula 1 is desired in which R3 ═ CO-NR31R32, appropriate derivatization can be carried out by methods known to the expert (for example conversion of the ester to a carboxylic acid and further to an amide), so that during the derivatization reaction the amino function in the 8-position may need to be protected with a suitable protecting group, for example in the form of di-tert-butoxycarbonyl-amino.

Alternatively, compounds of formula (1), for example, wherein R3 ═ CO-NR31R32, can be prepared according to scheme 3 by derivatization of the substituent R3 at the stage of compounds of formula 5. If compounds of formula 1 are obtained, for example R3 ═ 1-4C-alkoxycarbonyl, further chemical transformations known per se can be carried out by reactions known to the expert in order to synthesize various other compounds of formula 1.

Scheme 3

The compounds of formula 2 have at least one chiral center in the backbone. The present invention therefore provides all possible enantiomers, including the pure enantiomers, of the compound of formula 2 in any mixing ratio, which is a preferred subject of the present invention.

The compounds of formula 2a can be isolated from the corresponding racemic mixtures of formula 2, which are preferred subjects of the present invention, by isolating the compounds of formula 2a from their optical enantiomers using techniques known to the expert.

The separation can be achieved, for example, by crystallization of diastereomeric salts after reaction of the racemic mixture of the free acid compound of formula 2 with a suitable, optically pure acid, or by preparative chromatography using a chiral column, as described by way of example in the examples, or by other methods known to the expert.

Among the compounds of formula 2a, preference is given to those in which R1, R2, R3 and Arom have the meanings indicated above for the compounds of formula 1.

Although enantiomerically pure tricyclic imidazo [1, 2-a ] pyridine derivatives are known, for example from international patent application WO 95/27714, compounds of formula 2a which are more active than their optical enantiomers were also not expected. So far, for any combination of substituents R1, R2, R3 and Arom, the preferred enantiomer of formula 2a, due to its more pronounced activity in inhibiting gastric acid secretion than its optical enantiomer, has not been described.

It has also been unexpectedly found that the enantiomer of formula 2a is significantly more active than its optical enantiomer in inhibiting gastric acid secretion.

Preferred exemplary compounds of formula 2a are those wherein R1, R2, R3 and Arom have the meanings listed in table 2.

Table 2:

R1	R2	R3	Arom
R1	R2	R3	Arom	CH₃	CH₃	CH₃OCH₂CH₂N(H)C(O)-	phenyl radical
CH₃	CH₃	CH₃CH₂OC(O)-	Phenyl radical	CH₃	CH₃	CH₃OCH₂CH₂N(H)C(O)-	phenyl radical
CH₃	CH₃	CH₃CH₂OC(O)-	Phenyl radical	CH₃	CH₃	CH₃N(H)C(O)-	Phenyl radical
CH₃	CH₃	HOCH₂CH₂N(H)C(O)-	Phenyl radical	CH₃	CH₃	CH₃N(H)C(O)-	Phenyl radical
CH₃	CH₃	HOCH₂CH₂N(H)C(O)-	Phenyl radical	CH₃	CH₃	(CH₃)₂N-C(O)-	Phenyl radical
CH₃	CH₃	H₂N-C(O)-	Phenyl radical	CH₃	CH₃	(CH₃)₂N-C(O)-	Phenyl radical
CH₃	CH₃	H₂N-C(O)-	Phenyl radical	CH₃	CH₃	morpholino-C (O) -alpha	Phenyl radical
CH₃	CH₃	pyrrolidinyl-C (O) -substituted	Phenyl radical	CH₃	CH₃	morpholino-C (O) -alpha	Phenyl radical
CH₃	CH₃	pyrrolidinyl-C (O) -substituted	Phenyl radical	CH₃	CH₃	HO-CH₂-	Phenyl radical
CH₃	CH₃	cyclopropyl-N (H) -C (O) -substituted	Phenyl radical	CH₃	CH₃	HO-CH₂-	Phenyl radical

The present invention therefore also relates to compounds of the formula 2a in which R1, R2, R3 and Arom have the meanings as indicated in the subgroups for the compounds of the formula 1 according to the invention.

The invention also relates to those compounds of formula 2a listed in table 2 above and salts thereof.

The following examples serve to illustrate the invention in more detail, without limiting it. Likewise, other compounds of formula 1, formula 2 and formula 2a, the preparation of which is not described in detail, can be prepared analogously or in a manner familiar to those skilled in the art, using conventional process techniques, per se. The abbreviation min stands for minutes, h for hours and m.p. for melting point.

Examples

I. Compounds of formula 1

1.6-bromo-2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridin-8-ylamine

40g (105mmol) of (6-bromo-2, 3-dimethyl-imidazo [1, 2-a ] pyridin-8-yl) - (1-phenyl-allyl) -amine were melted at 220 ℃. After 4 hours, the reaction was cooled to room temperature and the residue was crystallized from diisopropyl ether to give 20.8g (56%) of the title compound as a beige solid, m.p.128 ℃.

2.8-amino-2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid methyl ester

18g (53.7mmol) of methyl 2, 3-dimethyl-8- (1-phenyl-allylamino) -imidazo [1, 2-a ] pyridine-6-carboxylate in 80ml of N, N-dimethylaniline are heated at 220 ℃ for 22 h. After cooling to room temperature, the reaction was concentrated in vacuo and the residue was crystallized from diisopropyl ether to yield 94g (52%) of the title compound as a brown solid m.p.118-120 ℃.

3.8-amino-2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] -pyridine-6-carboxylic acid carboxamide

A solution of 0.23g (0.43mmol)8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid formamide in 10ml dichloromethane is treated with 0.025g (0.22mmol) trifluoroacetic acid and the reaction mixture is stirred at room temperature for 16 h. The solution was adjusted to pH 6 by addition of 6N sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/methanol 9: 1) and crystallized from acetone to give 0.15g (100%) of the title compound as a white solid m.p.204-208 ℃.

4.8-amino-2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

A solution of 04g (0.54mmol)8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide in 10ml dichloromethane is treated with 0.04g (0.28mmol) trifluoroacetic acid and the reaction mixture is stirred at room temperature for 16 h. The solution was poured into water, neutralized with saturated sodium bicarbonate solution and extracted with dichloromethane (3 × 20 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/methanol 9: 1) to give 0.16g (84%) of the title compound as a brown solid, m.p.163-167 ℃.

5.8-amino-2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid (2-hydroxy-ethyl) -amide

A solution of 0.2g (0.53mmol)8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid (2-hydroxy-ethyl) -amide in 10ml dichloromethane is treated with 0.03g (0.27mmol) trifluoroacetic acid and the reaction mixture is stirred at room temperature for 16 h. The solution was adjusted to pH 6 by the addition of 6N sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/methanol 9: 1) and crystallized from diethyl ether to give 0.15g (75%) of the title compound as a yellow solid, m.p.113-115 ℃.

6.1- [ 8-amino-2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridin-6-yl ] -1-pyrrolidin-1-yl-methanone hydrochloride

A solution of 0.5(0.89mmol)1- [8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridin-6-yl ] -1-pyrrolidin-1-yl-methanone in 15ml dichloromethane is treated with 0.05g (0.4mmol) trifluoroacetic acid and the reaction mixture is stirred at room temperature for 16 h. The solution was adjusted to pH 6 by the addition of 6N sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/methanol 9: 1) and treated with ethereal HCl in acetone to give 0.18g (58%) of the title compound as a white solid m.p.229-231 ℃.

7.8-amino-2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid (2-methoxy-ethyl) -amide

A solution of 0.5g (0.86mmol)8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid (2-methoxy-ethyl) -amide in 15ml dichloromethane is treated with 0.05g (0.43mmol) trifluoroacetic acid and the reaction mixture is stirred at room temperature for 16 h. The solution was adjusted to pH 6 by the addition of 6N sodium hydroxide solution, extracted with dichloromethane, the organic layer dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/methanol 9: 1) and crystallized from ether-isopropanol to give 0.22g (70%) of the title compound as a yellow solid m.p.204-208 ℃.

8.8-amino-2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid amide

A solution of 0.27g (0.52mmol)8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid amide in 10ml dichloromethane is treated with 0.03g (0.28mmol) trifluoroacetic acid and the reaction mixture is stirred at room temperature for 16 h. The solution was adjusted to pH 6 by the addition of 6N sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/methanol 9: 1) and crystallized from ether to yield 0.16g (100%) of the title compound as a brown solid m.p.83-87 ℃.

II. Compounds of formula 2

2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid- (2-methoxy-ethyl) -amide

To a suspension of 0.2g (0.64mmol)2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid in dichloromethane (12ml) were added 0.2g (0.64mmol) O- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and the reaction was stirred at room temperature for 30 min. Mu.l (3.2mmol) of 2-methoxy-ethylamine were added and the reaction mixture was stirred at room temperature for 4 h. The solution was poured into water (15ml) and extracted with dichloromethane (4X 20 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/methanol 15: 1) to yield 0.1g (44%) of the title compound as a yellow solid, m.p.178-180 ℃.

2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid ethyl ester

To a solution of 6.8g (19.1mmol) 5-bromo-2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene in 300ml ethanol were added 2.0g (7.6mmol) triphenylphosphine, 16ml (124.1mmol) triethylamine and 0.64g (2.9mmol) palladium (II) acetate. The mixture was transferred to an autoclave and carbonylated (6 bar carbon monoxide pressure, 100 ℃) for 20 h. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether 2: 1) to give 6.1g (91%) of the title compound as a yellow solid, m.p.96-101 ℃.

2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid methylamide

To a suspension of 1.0g (3.1mmol)2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] -naphthalene-5-carboxylic acid in dichloromethane (30ml) was added 1.1g (3.4mmol) O- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and the reaction was stirred at room temperature for 2H. 6.2ml (12.4mmol) of methylamine (2M in THF) are added and the reaction mixture is stirred at room temperature for 42 h. The solution was poured into water (30ml) and extracted with dichloromethane (3X 15 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/methanol 10: 1) and crystallized from diisopropyl ether/ethyl acetate (3: 1) to give 0.3g (31%) of the title compound as a yellow solid m.p.245-248 ℃.

2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] -naphthalene-5-carboxylic acid (2-hydroxy-ethyl) -amide

To a suspension of 1.0g (3.1mmol)2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] -naphthalene-5-carboxylic acid in dichloromethane (50ml) was added 1.5g (4.7mmol) O- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and the reaction was stirred at room temperature for 2H. 943. mu.l (4.7mmol) ethanolamine was added and the reaction stirred at room temperature overnight. The solution was poured into water (50ml) and extracted with dichloromethane (3X 30 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue is crystallized from ethyl acetate/diisopropyl ether (5: 1) to give 0.8g (69%) of the title compound as a yellow solid m.p.242-244 ℃.

2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid dimethylamide

To a suspension of 0.6g (1.9mmol)2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] -naphthalene-5-carboxylic acid in dichloromethane (30ml) were added 0.6g (2.1mmol) O- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and the suspension was stirred at room temperature for 2H. 3.7ml (7.5mmol) dimethylamine (2M in THF) was added and the reaction mixture was stirred at room temperature overnight. The solution was poured into water (30ml) and extracted with dichloromethane (2X 20 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/methanol 14: 1) to yield 0.5g (74%) of the title compound as a beige solid, m.p.185-187 ℃.

2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid amide

To a suspension of 0.6g (1.9mmol)2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid in dichloromethane (30ml) were added 0.6g (2.1mmol) O- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and the suspension was stirred at room temperature for 2H. 22.8ml (11.4mmol) ammonia (0.5M in dioxane) was added and the solution stirred at room temperature overnight. The reaction mixture was poured into water (30ml) and extracted with dichloromethane (3X 15 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/methanol 10: 1) to give 0.33g (55%) of the title compound as a beige solid, m.p.331-332 ℃.

1- (2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalen-5-yl) -1-morpholin-4-yl-methanone

To a suspension of 0.3g (0.9mmol)2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] -naphthalene-5-carboxylic acid in dichloromethane (10ml) were added 0.3g (1.0mmol) O- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and the suspension was stirred at room temperature overnight. 431. mu.l (4.9mmol) of morpholine were added and the solution was stirred at room temperature for 5 h. The reaction mixture was poured into water (30ml) and extracted with dichloromethane (3X 20 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/methanol 20: 1) and crystallized from diethyl ether to yield 0.18g (50%) of the title compound as a white solid, m.p.155-156 ℃.

h.1- (2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalen-5-yl) -1-pyrrolidin-1-yl-methanone

To a suspension of 0.32g (1.0mmol)2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] -naphthalene-5-carboxylic acid in dichloromethane (10ml) were added 0.34g (1.1mmol) O- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and the suspension was stirred at room temperature overnight. 413 μ l (4.9mmol) of pyrrolidine were added and the solution was stirred at room temperature for 5 h. The reaction mixture was poured into water (30ml) and extracted with dichloromethane (3X 20 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/methanol 20: 1) and crystallized from diethyl ether to yield 0.12g (32%) of the title compound as a yellow solid, m.p.201-203 ℃.

(2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalen-5-yl) -methanone

413mg (1.2mmol) of ethyl 2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylate are dissolved in 8ml of tetrahydrofuran and the solution is cooled to 0 ℃. The reaction mixture was stirred for 2h, poured into water (5ml) and extracted with dichloromethane (4X 50 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/methanol 25: 1) to yield 220mg (61%) of the title compound as a yellow solid, m.p.226-230 ℃.

(8S) -2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid dimethylamide

By using 250 × 50mm CHIRALPAK^®Preparative chromatography on AD 20 μm column for resolution of racemic 2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a]Naphthalene-5-carboxylic acid dimethylamide (1.7g, 4.9 mmol). The mobile phase consists of an n-heptane/isopropanol mixture [85/15(v/v)]And (4) forming. Separation was achieved at room temperature at a flow rate of 120 ml/min. The product was detected at a wavelength of 280 nm. The isolation provided 0.73g (50%; about 100%) of the title compound ((8S) -enantiomer) as a yellow solid. m.p.185 ℃.

The optical purity was determined by optical rotation. The title compound ((8S) -enantiomer) was found to have an [ α ] D20 value of-72 ° (c ═ 0.1, dichloromethane).

(8R) -2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid dimethylamide

Isolation of the title compound ((8R) -enantiomer) was performed as described in example j, yielding 0.75g (50%; about 99.7%) of the title compound as a yellow solid. m.p.183 ℃. The [ alpha ] -of the title compound ((8R) -enantiomer) was determined]^D ₂₀The value was +72 ° (c ═ 0.1, dichloromethane).

(8R) -2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid carboxamide

By using 250 × 20mm CHIRALCEL^®Preparative chromatography on OD-H5 μm column for resolution of racemic 2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a]Naphthalene-5-carboxylic acid formamide (426mg, 1.3 mmol). The mobile phase consists of an acetonitrile/diethylamine mixture [100/0.1(v/v)]And (4) forming. Separation was achieved at room temperature at a flow rate of 20 ml/min. The product was detected at a wavelength of 350 nm. The isolation provided 0.20g (50%; about > 99.5%) of the title compound ((8R) -enantiomer) as a yellow solid. m.p.263-264 ℃.

The optical purity was determined by optical rotation. The [ alpha ] -of the title compound ((8R) -enantiomer) was determined]^D ₂₀The value was +82 ° (c ═ 1.16, chloroform).

(8S) -2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid carboxamide

The isolation of the title compound ((8S) -enantiomer) was carried out as described in example 1 to yield 0.20g (50%; > 99.5% excess) of the title compound as a yellow solid. m.p.263-264 ℃.

The [ alpha ] of the title compound ((8S) -enantiomer) was determined]^D ₂₀The value was-94 ° (c ═ 1.16, chloroform).

(8R) -2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid cyclopropylamide

By using 250 × 20mm CHIRALCEL^®Preparative chromatography on OD-H5 μm column for resolution of racemic 2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a]-naphthalene-5-carboxylic acid cyclopropylamide (163mg, 0.4 mmol). The mobile phase consists of an acetonitrile/diethylamine mixture [100/0.1(v/v)]And (4) forming. Separation was achieved at room temperature at a flow rate of 20 ml/min. The product was detected at a wavelength of 350 nm. The isolation provided 45mg (31%; 99.5% excess) of the title compound ((8R) -enantiomer) as a yellow solid. m.p.249-251 ℃.

The optical purity was determined by optical rotation. The [ alpha ] -of the title compound ((8R) -enantiomer) was determined]^D ₂₀The value was +55 ° (c ═ 1.22, chloroform).

o. (8S) -2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid cyclopropylamide

Isolation of the title compound ((8S) -enantiomer) was carried out as described in example n, yielding 69mg (48%; 99.5% excess) of the title compound as a yellow solid. m.p.252-253 ℃.

The [ alpha ] of the title compound ((8S) -enantiomer) was determined]^D ₂₀The value was-71 ° (c ═ 0.98, chloroform).

(8R) -2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid amide

By using 250 × 20mm CHIRALCEL^®Preparative chromatography on OD-H5 μm column for resolution of racemic 2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a]Naphthalene-5-carboxylic acid amide (80mg, 0.25 mmol). The mobile phase consists of an acetonitrile/ethanol/diethylamine mixture [95/5/0.1(v/v/v)]And (4) forming. Separation was achieved at room temperature at a flow rate of 20 ml/min. The product was detected at a wavelength of 340 nm. The isolation provided 35mg (44%; 97% excess) of the title compound ((8R) -enantiomer) as a yellow solid. m.p. > 300 ℃.

The optical purity was determined by optical rotation. The [ alpha ] -of the title compound ((8R) -enantiomer) was determined]^D ₂₀The value was +73 ° (c ═ 0.4, chloroform).

(8S) -2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid amide

Isolation of the title compound ((8S) -enantiomer) was performed as described in example p to give 34mg (44%; 90% excess) of the title compound as a yellow solid. m.p. > 300 ℃.

The [ alpha ] of the title compound ((8S) -enantiomer) was determined]^D ₂₀The value was-133 ° (c ═ 0.4, chloroform).

r.2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid cyclopropylamide

To a suspension of 0.30g (0.93mmol)2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] -naphthalene-5-carboxylic acid in dichloromethane (10ml) were added 0.33g (1.0mmol) O- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and the suspension was stirred at room temperature overnight. 65 μ l (3.8mmol) of cyclopropylamine were added and the solution was stirred at room temperature for 16 h. The reaction mixture was poured into water (10ml) and extracted with dichloromethane (3X 10 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/methanol 20: 1) to give 0.2g (60%) of the title compound as an ochre solid, m.p.267-269 ℃.

Starting compounds and intermediates

6-bromo-2, 3-dimethyl-imidazo [1, 2-a ] pyridin-8-ylamine

To a solution of 50g (266mmol) 5-bromo-pyridine-2, 3-diamine in 1L dioxane was added 56ml (532mmol) 3-bromo-butan-2-one and the reaction was refluxed for 6 h. The precipitate was filtered off and washed with methanol to give 52.3g of the title compound as its hydrobromide salt. The product was suspended in 500ml of water, neutralized with sodium bicarbonate and extracted with ethyl acetate (3X 200). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue afforded 36.8g (58%) of the title compound as a beige solid. m.p.160-163 ℃.

B. Benzylidene- (6-bromo-2, 3-dimethyl-imidazo [1, 2-a ] pyridin-8-yl) -amine

To a solution of 20.6g (85.8mmol) 6-bromo-2, 3-dimethyl-imidazo [1, 2-a ] pyridin-8-ylamine in 1L toluene was added 13.1ml (128.7mmol) benzaldehyde and the reaction mixture was refluxed (Dean-Stark apparatus) under azeotropic dehydration for 60 h. The solution was concentrated in vacuo and the residue was crystallized from diisopropyl ether to give 20.8g (74%) of the title compound as a yellow solid. m.p.121-126 ℃.

(6-bromo-2, 3-dimethyl-imidazo [1, 2-a ] pyridin-8-yl) - (1-phenyl-allyl) -amine

A solution of 34.7g (105.7mmol) of benzylidene- (6-bromo-2, 3-dimethyl-imidazo [1, 2-a ] pyridin-8-yl) -amine in 1L of dichloromethane is cooled to-60 ℃ and 317ml (317mmol) of vinylmagnesium bromide (1M in THF) are added dropwise. After 2h, the solution was poured into 400ml of saturated aqueous ammonium chloride and extracted with dichloromethane (3X 200 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue afforded 40g (100%) of the title compound as a green oil.

5-bromo-2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene

20.8g (58.3mmol) 6-bromo-2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridin-8-ylamine are suspended in 500ml 70% sulfuric acid and the reaction is heated at 100 ℃ for 2 h. The solution was adjusted to pH 7 with 10M sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel (ethyl acetate/petroleum ether ═ 3: 1) to give 7.8g (38%) of the title compound as a beige solid. m.p.125-129 ℃.

2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid

To a solution of 6.0g (17.2mmol) of 2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid ethyl ester in 290ml of tetrahydrofuran was added a solution of 2.5g (103mmol) of lithium hydroxide in 85ml of water and the mixture was refluxed for 12 h. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (100ml) and the solution pH was adjusted to 4-5 with 2M HCl. The precipitate was filtered off and dried in vacuo at 40 ℃ to yield 4.8g (87%) of the title compound as a yellow solid. m.p.264-268 ℃.

F.8- (benzylidene-amino) -2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid methyl ester

To a suspension of 2.0g (9.1mmol) of methyl 8-amino-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylate in 50ml of toluene was added 1ml (10mmol) of benzaldehyde and the reaction was heated under reflux (Dean-Stark apparatus) for 6h under azeotropic dehydration. The solution was concentrated in vacuo and the residue was crystallized from n-hexane to give 2.7g (98%) of the title compound as a yellow solid.

m.p.170-172℃。

G.2, 3-dimethyl-8- (1-phenyl-allylamino) -imidazo [1, 2-a ] pyridine-6-carboxylic acid methyl ester

A solution of 1.2g (3.9mmol) of methyl 8- (benzylidene-amino) -2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylate in 50ml of dichloromethane is cooled to-60 ℃ and 11.7ml (11.7mmol) of vinylmagnesium bromide (1M in THF) are added dropwise. After 3h, the solution was poured into 20ml of saturated aqueous ammonium chloride solution and extracted with dichloromethane (3X 200 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (toluene/dioxane 10: 1) to give 1.1g (91%) of the title compound as an off-white solid. m.p.139-140 deg.C

8- (Di-tert-Butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid carboxamide

To a solution of 0.4g (0.78mmol)8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid in 20ml dichloromethane are added 0.36g (1.17mmol) O- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and the reaction is stirred at room temperature for 5H. 1.2ml (1.8mmol) of methylamine are added and the mixture is stirred at room temperature for 12 h. The solvent was removed in vacuo and the residue purified by silica gel column chromatography (dichloromethane/methanol 9: 1) to yield 0.26g (62%) of the title compound as a yellow oil.

I8- (di-tert-Butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

To a solution of 0.4g (0.78mmol)8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid in 20ml dichloromethane are added 0.36g (1.17mmol) O- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and the reaction is stirred at room temperature for 5H. 1.1ml (1.8mmol) of dimethylamine are added and the mixture is stirred at room temperature for 12 h. The solvent was removed in vacuo and the residue purified by silica gel column chromatography (dichloromethane/methanol 9: 1) to yield 0.3g (63%) of the title compound as a yellow oil.

J.8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid (2-hydroxy-ethyl) -amide

To a solution of 0.2g (0.5mmol)8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid in 10ml dichloromethane are added 0.23g (0.7mmol) O- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and the reaction is stirred at room temperature for 5H. 0.08g (0.9mmol) ethanolamine was added and the mixture was stirred at room temperature for 12 h. The solvent was removed in vacuo and the residue purified by silica gel column chromatography (dichloromethane/methanol 9: 1) to yield 0.18g (70%) of the title compound as a yellow oil.

K.1- [8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridin-6-yl ] -1-pyrrolidin-1-yl-methanone

To a solution of 0.5g (0.9mmol)8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid in 10ml dichloromethane are added 0.47g (1.4mmol) O- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and the reaction is stirred at room temperature for 12H. 0.13g (1.8mmol) pyrrolidine was added and the mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue purified by silica gel column chromatography (dichloromethane/methanol 9: 1) to yield 0.5g (90%) of the title compound as a yellow oil.

L.8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid (2-methoxy-ethyl) -amide

To a solution of 0.5g (0.95mmol)8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid in 10ml dichloromethane are added 0.47g (1.4mmol) O- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and the reaction is stirred at room temperature for 12H. 0.14g (1.8mmol) 2-methoxy-ethanolamine is added and the mixture is stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue purified by silica gel column chromatography (dichloromethane/methanol 9: 1) to yield 0.5g (89%) of the title compound as a yellow oil.

M.8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid amide

To a solution of 0.4g (0.78mmol)8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid in 20ml dichloromethane are added 0.36g (1.17mmol) O- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and the reaction is stirred at room temperature for 5H. 8ml (1.8mmol) of ammonia are added and the mixture is stirred at room temperature for 12 h. The solvent was removed in vacuo and the residue purified by silica gel column chromatography (dichloromethane/methanol 9: 1) to yield 0.3g (71%) of the title compound as a yellow oil.

N.8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid

To a suspension of 5.5g (10.2mmol) of methyl 8- (di-tert-butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylate in dioxane (70ml) was added a solution of 1.5g (6.1mmol) of lithium hydroxide in 15ml of water and the reaction was refluxed for 3 h. After cooling to room temperature, the pH was adjusted to pH 4 by addition of 2N HCl solution and the reaction mixture was concentrated in vacuo. The residue was suspended in 100ml of water and extracted with dichloromethane (3X 100 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from diethyl ether to yield 4g (80%) of the title compound as a white solid. m.p.224-228 deg.C

O.8- (Di-tert-Butoxycarbonylamino) -2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid methyl ester

A solution of 3.4g (11.9mmol) of methyl 8-amino-2, 3-dimethyl-7- ((E) -3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylate in 100ml of dichloromethane is treated with 3.1g (14.2mmol) of Boc-anhydride and the catalyst DMAP and the reaction mixture is heated at reflux for 8 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was crystallized from diethyl ether to yield 5.5g (91%) of the title compound as a white solid. m.p.199-201 ℃.

Commercial use

The synthesis of the compounds of formula 1 and formula 2 as described above provides an efficient route to the compound of formula 2 and can be used to synthesize various compounds of formula 2 having different substituents R1, R2, R3 and Arom. These reaction procedures are also useful and applicable for large scale synthesis of the compound of formula 2.

The compounds of formula 2 and their salts possess valuable pharmacological properties which make them commercially available. In particular, they exhibit a marked inhibition of gastric acid secretion and an excellent gastrointestinal protective effect on warm-blooded animals, especially humans. In this connection, the compounds of the invention are characterized by a high selectivity of action, a favorable duration of action, particularly good intestinal activity, no significant side effects and a large therapeutic range.

By "gastric and intestinal protection" it is understood the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and injuries (e.g. gastric ulcers, peptic ulcers, including peptic ulcer bleeding, duodenal ulcers, gastritis, gastric hyperacidity or drug-related functional dyspepsia), which may be caused by, for example, microorganisms (e.g. helicobacter pylori), bacterial toxins, drugs (e.g. certain anti-inflammatory and antirheumatic drugs, such as NSAIDs and COX-inhibitors), chemicals (e.g. ethanol), gastric acid or stress states. "gastrointestinal protection" is understood to include gastroesophageal reflux disease (GERD) the symptoms of which include, but are not limited to, heartburn and/or acid reflux, according to common sense.

In various models for determining antiulcer and antisecretory properties, the compounds of formula 2 according to the invention surprisingly prove to be clearly superior to the compounds known from the prior art in terms of their superior properties. Due to these properties, the compounds of formula 2 and their pharmaceutically acceptable salts are outstandingly suitable for use in human and veterinary medicine, and they are therefore used, inter alia, for the treatment and/or prophylaxis of gastric and/or intestinal diseases.

Therefore, a further subject of the present invention is a compound of formula 2 according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.

The invention likewise comprises the use of a compound of the formula 2 according to the invention for the preparation of a medicament for the treatment and/or prophylaxis of the abovementioned diseases.

Furthermore, the present invention includes the use of the compounds of formula 2 according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.

A further subject of the invention is a medicament comprising one or more compounds of formula 2 and/or pharmaceutically acceptable salts thereof.

The medicaments are prepared by methods known per se and familiar to the person skilled in the art. The pharmacologically active compounds of formula 2 according to the invention (═ active compounds) can be used as medicaments as such or preferably in the form of tablets, coated tablets, capsules, suppositories, patches (for example as Transdermal Therapeutic Systems (TTS)), emulsions, suspensions or solutions, preferably together with suitable pharmaceutical auxiliaries or excipients, the active compound content preferably being between 0.1 and 95%, it being possible, by appropriate selection of auxiliaries and excipients, to achieve a mode of administration which is completely suitable for the active compound and/or for the desired onset and/or duration of action (for example, slow-release form or enteric form).

Auxiliaries and excipients suitable for the desired pharmaceutical preparations are known to the person skilled in the art on the basis of his expert knowledge. In addition to solvents, gel formers, suppository bases, tablet auxiliaries and other active compound excipients, it is also possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (e.g. cyclodextrins).

The active compounds can be administered orally, parenterally or transdermally.

In general, in the case of human medicine, it is advantageous, in the case of oral administration, to administer the active compound in a daily dose of from about 0.01 to about 20, preferably from 0.05 to 5, particularly preferably from 0.1 to 1.5, mg/kg of body weight, if appropriate in several, preferably from 1 to 4, single doses, to achieve the desired effect. In the case of parenteral treatment, similar or, especially in the case of intravenous administration of the active compounds, generally lower doses can be used. Based on the expert knowledge of the person skilled in the art, the person skilled in the art can easily determine the optimal dosage and the manner of administration of the active compound required in each case.

If the compounds of formula 2 according to the invention and/or their salts are used for the treatment of the above-mentioned diseases, the pharmaceutical preparations may also contain one or more pharmacologically active ingredients from other classes of drugs, for example: tranquilizers (e.g. benzodiazepines , such as diazepam), spasmolytics (e.g. bistreamine or camirofene), anticholinergics (e.g. oxybenzylamine or phenacarbamide), local anesthetics (e.g. tetracaine or procaine), and if appropriate enzymes, vitamins or amino acids.

In this connection, it is emphasized that, in particular, the compounds of the formula 2 according to the invention are used with drugs which inhibit acid secretion, for example H, in order to increase the main effect in the sense of addition or superadditive and/or to eliminate or reduce side effects₂Retarding agents (e.g., cimetidine, ranitidine), H⁺/K⁺Adenosine triphosphate (ATPase) inhibitors (e.g. omeprazole, pantoprazole) or also in combination with so-called peripheral anticholinergics (e.g. pirenzepine, telenzepine) and with gastrin antagonists or in combination with antibacterial active substances (e.g. cephalosporins, tetracyclines, penicillins, macrolides, nitroimidazoles or alternatively bismuth salts) for the control of helicobacter pylori. Suitable antibacterial components which may be mentioned are, for example, mezlocillin, ampicillin, amoxicillin, cephalothin, cefoxitin, cefotaxime, sulfinpyrazoneAmipenem, gentamicin, amikacin, erythromycin, ciprofloxacin, metronidazole, clarithromycin, azithromycin, and combinations thereof (e.g., clarithromycin + metronidazole).

Due to their excellent gastrointestinal protective effects, the compounds of formula 2 are suitable for free or fixed combination with drugs known to have some ulcerogenic potential (e.g. certain anti-inflammatory and antirheumatic drugs, such as NSAIDs). In addition, the compounds of formula 2 are also suitable for free or fixed binding to exercise regulating drugs.

Pharmacology of

The excellent gastric protection and gastric acid secretion inhibition of the compound of formula 2 of the present invention can be confirmed by studies on animal experimental models. The compounds of formula 2 of the present invention studied in the model mentioned below are provided in letters corresponding to those of the compounds in the examples.

Test for secretion inhibition in perfused rat stomach

In table a below, the effect of the compounds of formula 2 of the present invention on the pentagastrin-stimulated acid secretion of the stomach of perfused rats after in vivo duodenal administration is shown.

TABLE A

Numbering	Dose (. mu. mol/kg) intradermally	Inhibition of acid secretion (%)
Numbering	Dose (. mu. mol/kg) intradermally	Inhibition of acid secretion (%)	c	1.0	＞50
e	1.0	＞50	c	1.0	＞50
e	1.0	＞50	f	1.0	＞50
h	1.0	＞50	f	1.0	＞50
h	1.0	＞50	j	1.0	＞50
k	1.0	＜50	j	1.0	＞50
k	1.0	＜50	l	1.0	＜50
m	1.0	＞50	l	1.0	＜50
m	1.0	＞50	n	1.0	＜50
o	1.0	＞50	n	1.0	＜50
o	1.0	＞50	p	1.0	＜50
q	1.0	＞50	p	1.0	＜50

Method

The abdomen of anesthetized rats (CD rats, female, 200-; 250 g; 1.5g/kg intramuscular urethane injection) was opened via a middle-upper laparotomy after tracheotomy, the PVC catheter was fixed orally in the esophagus, the other one passed through the pylorus, so that the ends of these tubes just protruded into the gastric cavity. The catheter leading out from the pylorus was introduced from the outside into the right abdominal wall through the side opening.

After thorough rinsing (about 50-100ml), a warm (37 ℃) physiological NaCl solution was passed continuously through the stomach (0.5ml/min, pH 6.8-6.9; Braun-Unita I). The pH (pH meter 632, glass electrode EA 147; phi. 5mm, Metrohm) and the HCl excreted in the effluents collected in each case at 15-minute intervals were determined by titration with freshly prepared 0.01N NaOH solution to pH 7(Dosimat 665 Metrohm).

About 30 minutes after the end of the surgery (i.e., after completion of the first two-part assay), gastric secretion was stimulated by continuous infusion of pentagastrin (left femoral vein) intravenously at 1 μ g/kg (═ 1.65 ml/h). The substance to be tested is intraduodenally administered in a liquid volume of 2.5ml/kg 60 minutes after the start of the continuous infusion of pentagastrin.

The body temperature of the animals was maintained at 37.8-38 ℃ by infrared irradiation and a heating pad (automatic, stepless control by rectal temperature sensor).

Claims

1. A compound of formula 1 and salts thereof

Wherein

wherein

or therein

wherein

r6 is hydrogen, 1-4C-alkyl or halogen and

r7 is hydrogen, 1-4C-alkyl or halogen,

wherein

2. A compound of formula 1 as claimed in claim 1 and salts thereof, wherein

wherein

R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and

r32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or wherein

wherein

r6 is hydrogen, 1-4C-alkyl or halogen and

r7 is hydrogen, 1-4C-alkyl or halogen,

wherein

3. A compound of formula 1 as claimed in claim 1 and salts thereof, wherein

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl,

r3 is halogen, 1-4C-alkoxycarbonyl or a radical-CO-NR 31R32,

wherein

R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and

r32 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

or therein

arom is phenyl.

4. A compound of formula 1 as claimed in claim 1 and salts thereof, wherein

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl,

r3 is halogen or 1-4C-alkoxycarbonyl,

arom is phenyl.

5. A compound of formula 2

Is selected from

2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid- (2-methoxy-ethyl) -amide,

2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid ethyl ester,

2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid methylamide,

2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid (2-hydroxy-ethyl) -amide,

2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid dimethylamide,

2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid amide,

1- (2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalen-5-yl) -1-morpholin-4-yl-methanone,

1- (2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalen-5-yl) -1-pyrrolidin-1-yl-methanone,

(2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalen-5-yl) -methanol,

2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid cyclopropylamide,

and salts thereof.

6. Compounds of formula 2a and salts thereof

Wherein

wherein

or therein

wherein

r6 is hydrogen, 1-4C-alkyl or halogen and

r7 is hydrogen, 1-4C-alkyl or halogen,

wherein

7. A compound of formula 2a

Is selected from

(8S) -2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid- (2-methoxy-ethyl) -amide,

(8S) -2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid ethyl ester,

(8S) -2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid methylamide,

(8S) -2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid (2-hydroxy-ethyl) -amide,

(8S) -2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid dimethylamide,

(8S) -2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid amide,

(8S) -1- (2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalen-5-yl) -1-morpholin-4-yl-methanone,

(8S) -1- (2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalen-5-yl) -1-pyrrolidin-1-yl-methanone,

(8S) - (2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalen-5-yl) -methanol,

(8S) -2, 3-dimethyl-8-phenyl-6, 7, 8, 9-tetrahydro-1, 3a, 9-triaza-cyclopenta [ a ] naphthalene-5-carboxylic acid cyclopropylamide,

and salts thereof.

8. A method for synthesizing a compound of formula 2,

wherein R1, R2, R3 and Arom have the meanings as defined in claim 1, which comprises converting a compound of formula 1 as claimed in claim 1 into a compound of formula 2, followed by, if necessary, further derivatizing the resulting compound of formula 2 into another compound of formula 2.

9. A process for the synthesis of a compound of formula 1 as claimed in claim 1, which comprises converting a compound of formula 5, wherein R1, R2, R3 and Arom have the meanings indicated in claim 1, into the corresponding compound of formula 1, and subsequently, if desired, further derivatizing the compound of formula 1 so formed into another compound of formula 1

10. A medicament comprising a compound as claimed in claim 5, claim 6 or claim 7 and/or a pharmaceutically acceptable salt thereof and conventional pharmaceutical adjuvants and/or excipients.

11. Use of a compound as claimed in claim 5, claim 6 or claim 7 and/or a pharmaceutically acceptable salt thereof in the prevention and treatment of gastrointestinal diseases.