EP1934215A1

EP1934215A1 - Isotopically substituted imidazopyridine derivatives for the treatment of gastrointestinal disorders

Info

Publication number: EP1934215A1
Application number: EP06793674A
Authority: EP
Inventors: Bernhard Kohl; Peter Jan Zimmermann; Karl Zech; Wilm Buhr; Andreas Palmer; Christof Brehm; Maria Vittoria Chiesa; Wolfgang Kromer; Stefan Postius; Wolfgang-Alexander Simon; Hans Christof Holst
Original assignee: Nycomed GmbH
Current assignee: Takeda GmbH
Priority date: 2005-09-22
Filing date: 2006-09-20
Publication date: 2008-06-25
Also published as: WO2007039464A1

Abstract

The invention provides deuterated compounds of the formula (1), in which the substituents and symbols are as defined in the description. The compounds inhibit the secretion of gastric acid.

Description

Title

ISOTOPICALLY SUBSTITUTED IMIDAZOPYRIDINE DERIVATIVES FOR THE TREATMENT OF GASTROINTESTINAL DISORDERS

Technical field

The invention relates to novel compounds which are used in the pharmaceutical industry as active compounds for the production of medicaments.

Background Art

U.S. Patent 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 suitable for treating peptide ulcer disorders. The International Patent Applications WO98/42707, WO98/54188, WO00/17200, 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, WO 03/014123, WO 03/068774, WO 03/091253 and WO 05/058325, WO 05/090358, WO 05/077949 and WO 06/040338 disclose tricyclic imidazopyridine derivatives having different substitution patterns, which compounds are likewise said to be suitable for treating gastrointestinal disorders.

In the International Patent Application WO 94/18199 and WO 04/046144, substituted, bicyclic imidazopyridine compounds are disclosed. The compounds are useful for treating gastrointestinal disorders.

Kaminski et. al., J. Med. Chem. 1991 , 34, 533-541 and 1997, 40, 427-436 describe the synthesis of imidazo[1 ,2-a]pyridines and their use as antiulcer agents.

In the international patent applications WO88/08843, WO89/00570 (= US Patent 5,112,834) and WO90/05136 imidazopyridine derivatives are disclosed, which are likewise said to be suitable for the treatment of gastric and intestinal diseases.

Further substituted imidazo[1 ,2-a]pyridines which are likewise useful in the treatment of ulcer diseases are known for example from EP 0033094 and US 4,450,164 as well as from EP 0204285 and US 4,725,601 and in particular from WO 99/055705, WO 99/055706, WO 00/11000, WO 03/018582, WO 04/1 13338, WO 04/113339 and WO 04/113340.

The US Patent 6,818,200 describes a method of enhancing the efficiency and increasing the duration of action of drugs (e.g. dihydropyridines and anti-bacterials) and particularly of nifedipine and penicillins wherein one or more hydrogen atoms are replaced by Deuterium. Among other drugs, a deuterated derivative of Omeprazole, a compound which is known to be a proton pump inhibitor, is described by way of example.

Disclosure of Invention

Technical problem

A whole series of compounds are known from the prior art which inhibit gastric acid secretion by blockade of the H+/K+-ATPase. The compounds designated as proton pump inhibitors (PPI^'s), for example omeprazole, esomeprazole, lansoprazole, pantoprazole or rabeprazole, bind irreversibly to the H+/K+-ATPase. PPI^'s are available as therapeutics for a long time already. A new class of compounds designated as reversible proton pump inhibitors (rPPI^'s), as acid pump antagonists (APA ^'s) or as potassium competitive acid blockers (P-CAB^'s) bind re- versibly to the H+/K+-ATPase. Although rPPI^'s, APA^'s and P-CAB^'s are known for more than 20 years and many companies are engaged in their development, rPPIs APAs or P-CABs are at present only very limited available for therapy. The technical problem underlying the present invention is therefore to provide acid pump antagonists which can be used in therapy.

Technical solution

The invention relates to compounds of the formula 1

in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1-4C-alkyl, R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-2-4C-alkyl or cyanomethyl, R3 is hydrogen, halogen, 1-4C-alkyl, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-

4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-

4C-alkyl or the group -CO-NR31 R32, where

R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, 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 where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, and wherein either R4 and R5 are each hydrogen and R6 is phenyl substituted by R61 and R62 wherein

R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl,

R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl, or wherein R4 and R5 together form a -CHR7-CHR8- group and R6 is phenyl substituted R61 and R62, wherein

R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl,

R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl,

R7 is hydrogen, hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C- alkoxy

R8 is hydrogen, hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C- alkoxy or wherein R4 is hydrogen and R5 and R6 together form a group gp,

(QP) wherein

Z has the meaning CHR11or CHR11-CHR12

R9 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl- carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C- alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,

R10 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy

R11 is hydrogen, 1-7C-alkyl, 2-4C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C- alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C- a I koxy- 1 -4C-a I koxy , 1 -4C-a I koxy- 1 -4C-a I koxy- 1 -4C-a I koxy , 3-7C-cycloa I koxy- 1 -4C- alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C- alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy- 1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy R12 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C- alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C- a I koxy- 1 -4C-a I koxy , 1 -4C-a I koxy- 1 -4C-a I koxy- 1 -4C-a I koxy , 3-7C-cycloa I koxy- 1 -4C- alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C- alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy- 1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy,

X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R3, R4, R5, R6 or of the core structure of the formula 1 or any combination of R1 , R2, R3, R4, R5, R6 and the core structure of the formula 1 is replaced with a deuterium atom, and their salts.

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

in which

4C-alkyl or the group -CO-NR31 R32, where

4C-alkyl and

R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,

R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl,

R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl,

X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R3, R61 , R62 or of the core structure of the formula 1-a or any combination of R1 , R2, R3, R61 , R62 and the core structure of the formula 1-a is replaced with a deuterium atom, and their salts.

Another aspect (aspect b) of the invention relates to compounds of the formula 1-b,

in which

4C-alkyl or the group -CO-NR31 R32, where

4C-alkyl and

R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where

R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, R6 is phenyl substituted by R61 and R62 wherein

R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl,

R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl, R7 is hydrogen, hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C- alkoxy, R8 is hydrogen, hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C- alkoxy

X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R3, R6, R7, R8 or of the core structure of the formula 1-b or any combination of R1 , R2, R3, R6, R7, R8 and the core structure of the formula 1-b is replaced with a deuterium atom, and their salts.

Another aspect (aspect c) of the invention relates to compounds of the formula 1-c

in which

4C-alkyl or the group -CO-NR31 R32, where

4C-alkyl and

R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, R9 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halo- gen, hydroxy, aryl, aryl- 1 -4C-al kyl , aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,

Z has the meaning CHR11or CHR11-CHR12 wherein

R11 is hydrogen, 1-7C-alkyl, 2-4C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1 -4C-a I koxy- 1 -4C-a I koxy- 1 -4C-a I koxy , 3-7C-cycloa I koxy- 1 -4C-a I koxy , 3-7C-cycloal kyl- 1 -4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy

R12 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1 -4C-a I koxy- 1 -4C-a I koxy- 1 -4C-a I koxy, 3-7C-cycloa I koxy- 1 -4C-a I koxy, 3-7C-cycloal kyl- 1 -4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy,

X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R3, R9, R10, z or of the core structure of the formula 1-c or any combination of R1 , R2, R3, R9, R10, z and the core structure of the formula 1-c is replaced with a deuterium atom, and their salts.

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

3-7C-Cycloalkyl denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, among which cyclopropyl, cyclobutyl and cyclopentyl are preferred.

3-7C-Cycloalkyl-1-4C-alkyl denotes one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals. Examples which may be mentioned are the cyclopropylmethyl, the cyclohexyl methyl and the cyclohexylethyl radicals.

1-4C-Alkoxy denotes radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy radicals.

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

1-4C-Alkoxycarbonyl (-CO-1-4C-alkoxy) denotes a carbonyl group to which is attached one of the abovementioned 1-4C-alkoxy radicals. Examples which may be mentioned are the meth- oxycarbonyl (CH₃O-C(O)-) and the ethoxycarbonyl (CH₃CH₂O-C(O)-) radicals.

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

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

Fluoro-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one or more fluorine atoms. An example which may be mentioned are the trifluoromethyl group, the difluoromethyl, the 2-fluoroethyl, the 2,2-difluoroethyl or the 2,2,2-trifluoroethyl group.

Hydroxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by a hydroxy group. Examples which may be mentioned are the hydroxy- methyl, the 2-hydroxyethyl, the 3-hydroxypropyl, the 2-hydroxypropyl and the 2- hydroxyisopropyl group. Hydroxy-1-4C-alkyl within the scope of the invention is understood to include 1-4C-alkyl groups with two or more hydroxy groups. Examples which may be mentioned are the 3,4-dihydroxybutyl and in particular the 2,3-dihydroxypropyl group.

Fluoro-2-4C-alkyl represents a 2-4C-alkyl group, which is substituted by one or more fluorine atoms. Examples which may be mentioned are the 2-fluoroethyl, the 2,2- difluoroethyl and in particular the 2,2,2-trifluoroethyl group.

3-7C-Cycloalkoxy represents a group, which in addition to the oxygen atom contains one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be mentioned are the cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cyclohep- tyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred. 3-7C-Cycloalkyl-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be mentioned are the cyclopropylmethoxy, the cyclohexylmethoxy and the 2-cyclohexylethoxy group.

Fluoro-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which substituted by one or more fluorine atoms. Examples of fluoro-1-4C-alkoxy groups which may be mentioned are the 2-fluoro-ethoxy, 1 ,1 ,1 ,3,3,3-hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the 1 ,1 ,1-trifluoro-2-propoxy, the perfluoro-tert-butoxy, the 2,2,3,3,4,4,4-heptafluoro-1-butoxy, the 4,4,4-trifluoro-1-butoxy, the 2,2,3,3,3- pentafluoropropoxy, the perfluoroethoxy, the 1 ,2,2-trifluoroethoxy, in particular the 1 ,1 ,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy group

Fluoro-1-4C-alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by a fluoro-1-4C-alkoxy group. Examples which may be mentioned are the 2-(1 ,1 ,2,2-tetrafluoroethoxy)-ethoxy, the 2-(2,2,2-trifluoroethoxy)- ethoxy, the 2-(trifluoromethoxy)-ethoxy and the 2-(difluoromethoxy)-ethoxy group.

Hydroxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by a hydroxy group. Examples which may be mentioned are the 2- hydroxyethoxy and the 3-hydroxypropoxy group. Hydroxy-1-4C-alkoxy within the scope of the invention is understood to include 1-4C-alkoxy groups with two or more hydroxy groups. Examples which may be mentioned are the 3,4-dihydroxybutoxy and in particular the 2,3-dihydroxypropoxy group.

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

1-4C-Alkoxy-1-4C-alkoxy denotes one of the abovementioned 1-4C-alkoxy radicals which is substituted by a further 1-4C-alkoxy radical. Examples which may be mentioned are the radicals 2-(methoxy)ethoxy (CH₃-O-CH₂-CH₂-O-) and 2-(ethoxy)ethoxy (CH₃-CH₂-O-CH₂-CH₂ -O-).

1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkyl denotes one of the abovementioned 1-4C-alkoxy-1-4C-alkyl radicals which is substituted by one of the abovementioned 1-4C-alkoxy radicals. An example which may be mentioned is the radical 2- (methoxy)ethoxymethyl (CH₃-O-CH₂-CH₂-O-CH₂-).

Fluoro-1-4C-alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by a fluoro-1-4C-alkoxy group. Fluoro-1-4C-alkoxy in this case represents one of the aforementioned 1-4C-alkoxy groups, which substituted by one or more fluorine atoms. Examples of fluoro-substituted 1-4C-alkoxy groups which may be mentioned are the 2-fluoro- ethoxy, 1 ,1 ,1 ,3,3,3-hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the 1 ,1 ,1 -trifluoro-2- propoxy, the perfluoro-tert-butoxy, the 2,2,3,3,4,4,4-heptafluoro-1-butoxy, the 4,4,4-trifluoro-1- butoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1 ,2,2-trifluoroethoxy, in particular the 1 ,1 ,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy group. Examples of fluoro-1-4C-alkoxy-1-4C-alkyl radicals which may be mentioned are, 1 ,1 ,2,2-tetrafluoroethoxymethyl, the 2,2,2-trifluoroethoxymethyl, the trifluoromethoxymethyl, 2-fluoroethoxyethyl, the 1 ,1 ,2,2-tetrafluoroethoxyethyl, the 2,2,2- trifluoroethoxyethyl, the trifluoromethoxyethyl and preferably the difluoromethoxymethyl and the difluoromethoxyethyl radicals.

1-7C-Alkyl denotes straight-chain or branched alkyl radicals having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, isoheptyl-(5-methylhexyl), hexyl, iso- hexyl-(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 radicals.

1-4C-Alkylcarbonyl denotes a radical which, in addition to the carbonyl group, contains one of the abovementioned 1-4C-alkyl radicals. An example which may be mentioned is the acetyl radical.

Carboxy-1-4C-alkyl denotes, for example, the carboxymethyl (-CH₂COOH) or the carboxyethyl (-CH₂CH₂COOH) radical.

1-4C-Alkoxycarbonyl-1-4C-alkyl denotes one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the abovementioned 1-4C-alkoxycarbonyl radicals. An example which may be mentioned is the ethoxycarbonylmethyl (CH₃CH₂OC(O)CH₂-) radical.

1-4C-Alkoxycarbonylamino denotes an amino radical which is substituted by one of the above- mentioned 1-4C-alkoxycarbonyl radicals. Examples which may be mentioned are the ethoxy- carbonylamino and the methoxycarbonylamino radicals.

1-4C-Alkoxy-1-4C-alkoxycarbonyl denotes a carbonyl group to which one of the abovementioned 1-4C-alkoxy-1-4C-alkoxy radicals is attached. Examples which may be mentioned are the 2-(methoxy)ethoxycarbonyl (CH₃-O-CH₂CH₂-O-CO-) and the 2-(ethoxy)ethoxycarbonyl (CH₃CH₂-O-CH₂CH₂-O-CO-) radicals.

1-4C-Alkoxy-1-4C-alkoxycarbonylamino denotes an amino radical which is substituted by one of the abovementioned 1-4C-alkoxy-1-4C-alkoxycarbonyl radicals. Examples which may be mentioned are the 2-(methoxy)ethoxycarbonylamino and the 2-(ethoxy)ethoxycarbonylamino radicals. 2-4C-Alkenyloxy denotes a radical which, in addition to the oxygen atom, contains a 2-4C- alkenyl radical. An example which may be mentioned is the allyloxy radical.

Aryl is phenyl or substituted phenyl with one, two or three identical or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro- methyl, nitro, trifluoromethoxy, hydroxy and cyano. An example which may be mentioned is the phenyl radical.

Aryl-1-4C-alkyl denotes an aryl-substituted 1-4C-alkyl radical. An example which may be mentioned is the benzyl radical.

Aryl-1-4C-alkoxy denotes an aryl-substituted 1-4C-alkoxy radical. An example which may be mentioned is the benzyloxy radical.

Mono- or di-1-4C-alkylamino radicals contain, in addition to the nitrogen atom, one or two of the abovementioned 1-4C-alkyl radicals. Preference is given to di-1-4C-alkylamino and in particular to dimethyl-, diethyl- or diisopropylamino.

Mono- or di-1-4C-alkylamino-1-4C-alkyl denotes one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the abovementioned mono- or di-1-4C-alkylamino radicals. Preferred mono- or di-1-4C-alkylamino-1-4C-alkyl radicals are the mono- or di-1-4C- alkylaminomethyl radicals. An Example which may be mentioned is the dimethylaminomethyl (CHa)₂N-CH₂ radical.

1-4C-Alkylcarbonylamino denotes an amino group to which a 1-4C-alkylcarbonyl radical is attached. Examples which may be mentioned are the propionylamino (C₃H₇C(O)NH-) and the acetylamino (acetamido, CH₃C(O)NH-) radicals.

1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-alkoxy groups. A preferred example which may be mentioned is the methoxyethoxyethoxy group.

3-7C-Cycloalkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkoxy groups. Examples which may be mentioned are the cyclopropoxymethoxy, the cyclobutoxymethoxy and the cyclohexy- loxyethoxy group.

3-7C-Cycloalkyl-1-4C-alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl-1-4C-alkoxy groups. Examples which may be mentioned are the cyclopropylmethoxyethoxy, the cyclobu- tylmethoxyethoxy and the cyclohexylethoxyethoxy group. 1-4C-Alkylcarbonyloxy represents a 1-4C-alkylcarbonyl group which is bonded to an oxygen atom. An example which may be mentioned is the acetoxy group (CH3CO-O-).

Halo-1-4C-alkoxy represents 1-4C-alkoxy groups which are completely or mainly substituted by halogen. "Mainly" in this connection means that more than half of the hydrogen atoms in the 1-4C-alkoxy groups are replaced by halogen atoms. Halo-1-4C-alkoxy groups are primarily chloro- and/or in particular fluoro-substituted 1-4C-alkoxy groups. Examples of halogen- substituted 1-4C-alkoxy groups which may be mentioned are the 2,2,2-trichloroethoxy, the hexachloroisopropoxy, the pentachloroisopropoxy, the 1 ,1 ,1-trichloro-3,3,3-trifluoro-2- propoxy, the 1 ,1 ,1-trichloro-2-methyl-2-propoxy, the 1 ,1 ,1-trichloro-2-propoxy, the 3-bromo- 1 ,1 ,1-trifluoro-2-propoxy, the 3-bromo-1 ,1 ,1-trifluoro-2-butoxy, the 4-bromo-3, 3,4,4- tetrafluoro-1-butoxy, the chlorodifluoromethoxy, the 1 ,1 ,1 ,3,3,3-hexafluoro-2-propoxy, the 2- trifluoromethyl-2-propoxy, the 1 ,1 ,1-trifluoro-2-propoxy, the perfluoro-tert-butoxy, the 2,2,3,3,4,4,4-heptafluoro-1-butoxy, the 4,4,4-trifluoro-1-butoxy, the 2,2,3,3,3-pentafluoro- propoxy, the perfluoroethoxy, the 1 ,2,2-trifluoroethoxy, in particular the 1 ,1 ,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the di- fluoromethoxy group.

Mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy represents a 1-4C-alkylcarbonyloxy group, which is substituted by one of the aforementioned mono- or di-1-4C-alkylamino groups. Examples, which may be mentioned, are the dimethylamino-methylcarbonyloxy and the dimethylamino-ethylcarbonyloxy group.

1-4C-Alkoxy-1-4C-alkylcarbonyloxy represents one of the aforementioned 1-4C- alkylcarbonyloxy radicals which is substituted by one of the aforementioned 1-4C-alkoxy groups. An example, which may be mentioned, is the methoxymethylcarbonyloxy group.

Possible salts of compounds of the formula 1 - depending on substitution - are especially all acid addition salts. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids customarily used in pharmacy. Those suitable are water-soluble and water-insoluble acid addition salts with acids such as, for example, 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, malonic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naph- thoic acid, where the acids are used in salt preparation - depending on whether a mono- or polybasic acid is concerned and on which salt is desired - in an equimolar quantitative ratio or one differing therefrom. Salts of the compounds of formula I according to the invention can be obtained by dissolving, the free compound in a suitable solvent (for example a ketone such as acetone, me- thylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or di- oxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid or to which the desired acid is then added, if necessary upon heating. The acid can be employed in salt preparation, depending on whether a mono- or polybasic acid is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom. The salts are obtained for example by evaporating the solvent or by precipitating upon cooling, by re-precipitating, or by precipitating with a non-solvent for the salt and separation, for example by filtration, of the salt after precipitation.

Pharmacologically intolerable salts, which can initially be obtained, for example, as process products in the production of the compounds according to the invention on the industrial scale, are converted into the pharmacologically tolerable salts by processes known to the person skilled in the art.

It is known to the person skilled in the art that the compounds according to the invention and their salts, if, for example, they are isolated in crystalline form, can contain various amounts of solvents. The invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula 1 , and also all solvates and in particular all hydrates of the salts of the compounds of the formula 1.

The compounds of the formula 1 may have one or more centers of chirality in the skeleton depending on their basic structure and the substitution pattern with deuterium. The invention thus provides all feasible stereoisomers of compounds of the formula 1 in any mixing ratio, including the pure stereoisomers, which are a preferred subject matter of the invention.

The pure stereoisomers of the compounds of the formula 1 and salts according to the present invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and by splitting up stereoisomeric mixtures obtained in synthesis. Preferably, the pure stereoisomers of the compounds of the formula 1 are obtained by using chiral starting compounds.

Stereoisomeric mixtures of compounds of the formula 1 can be split up into the pure stereoisomers by methods known to a person skilled in the art. Preferably, the mixtures are separated by chromatography or (fractional) crystallization. For enantiomeric mixtures the split up is preferably done by forming diastereomeric salts by adding chiral additives like chiral acids, subsequent resolution of the salts and release of the desired compound from the salt. Alterna- tively, derivatization with chiral auxiliary reagents can be made, followed by diastereomer separation and removal of the chiral auxiliary group. Furthermore, enantiomeric mixtures can be separated using chiral separating columns in chromatography. Another suitable method for the separation of enantiomeric mixtures is the enzymatic separation.

The compounds according to the present invention are characterized in that at least one hydrogen atom is replaced by a deuterium atom. This replacement / these replacements can take place in any desired position / positions of the molecule, that is either in any of its substituents R1 , R2, R3, R4, R5, R6 or at the core structure or in any combination thereof. The term "hydrogen atoms of the core structure" according to the present invention is to be understood to be the hydrogen atoms which are not the substituents or part of the substituents R1 , R2, R3, R4, R5 or R6 mentioned above. For further illustration by way of example, the hydrogen atoms of the core structures of the compounds of the formulae 1 and 1-a, which can be replaced by a deuterium, are indicated below by H/D.

The term "at least one of the hydrogen atoms is replaced with a deuterium atom" according to the present invention has the meaning that 1 , 2, 3, 4, 5, 6, 7, 8, 9 or more hydrogen atoms of the compound is / are replaced by a deuterium atom. If more than one hydrogen atom of the compound is replaced by a deuterium atom, this replacement can either lead to a compound where two, three or more deuterium atoms are attached to the same atom (e.g. leading to a - CD₂-, -CHD₂ or a -CD₃ group) and/or where deuterium atoms are attached to different atoms, for example to 2 or 3 different atoms, within the compound. If these different atoms to which deuterium atoms are attached, are part of different substituents R1 , R2, R3, R4, R5, R6 or of the core structure the compound, this is a compound according to the invention, whereby the hydrogen atoms of a "combination of R1 , R2, R3, R4, R5, R6 and the core structure of the formula 1 are replaced with a deuterium atom". The combination of different substituents R1 , R2, R3, R4, R5, R6 or of the core structure the compound according to the present invention can be a combination of 2, 3, 4 or more different substituents or positions in the core structure of the compound, in each of which one or more hydrogen atoms can be replaced with deuterium.

If, for example, one or more hydrogen atoms of R2 and one or more hydrogen atoms of R3 are replaced with a deuterium atom, this is a compound according to the invention, whereby hydrogen atoms of a combination of R2 and R3 are replaced with a deuterium atom. Preferred compounds according to aspect a of the invention are those compounds of the formula 1-a1 and 1-a2

R1

in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, S^C-cycloalkyl-I^C-alkyl, 1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy- 1-4C-a I kyl,

R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-2-4C-alkyl or cyanomethyl,

R3 is hydrogen, halogen, 1-4C-alkyl, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1- 4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1- 4C-alkyl or the group -CO-NR31 R32, where

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

R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,

R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl, R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl, X is O (oxygen) or NH whereby optionally one or more further hydrogen atoms of R1 , R2, R3, R61 , R62 or of the core structure of the formulae 1-a1 or 1-a2 or any combination of R1 , R2, R3, R61 , R62 and of the core structure of the formulae 1-a1 or 1-a2 is replaced with a deuterium atom, and their salts.

Particularly preferred compounds of the formula 1-a1 and 1-a2 are those in which

R1 is 1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl or hydroxy-1-4C-alkyl,

R3 is 1-4C-alkoxycarbonyl or the group -CO-NR31 R32, where

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, R61 is hydrogen, halogen or 1-4C-alkyl, R62 is hydrogen, halogen or 1-4C-alkyl, X is O (oxygen) or NH and whereby optionally one or more further hydrogen atoms of R1 , R2, R3, R61 , R62 or of the core structure of the formulae 1-a1 or 1-a2 or any combination of R1 , R2, R3, R61 , R62 and of the core structure of the formulae 1-a1 or 1-a2 is replaced with a deuterium atom, and their salts.

Particular emphasis is given to compounds of the formula 1-a1 and 1-a2, in which

R1 is 1-4C-alkyl,

R2 is 1-4C-alkyl,

R3 is 1-4C-alkoxycarbonyl or the group -CO-NR31 R32, where

R31 is hydroxy-1-4C-alkyl and

R32 is hydrogen, R61 is 1-4C-alkyl, R62 is 1-4C-alkyl, X is NH and and their salts.

Also preferred compounds according to aspect a of the invention are those compounds of the formula 1-a3

in which

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

R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-2-4C-alkyl or cyanomethyl, R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and

R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl, R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl, X is O (oxygen) or NH and whereby at least one of the hydrogen atoms in R31 is replaced with a deuterium atom, and whereby optionally one or more further hydrogen atoms of R1 , R2, R31 , R32, R61 , R62 or of the core structure of the formula 1-a3 or any combination of R1 , R2, R31 , R32, R61 , R62 and of the core structure of the formulae 1-a3 is replaced with a deuterium atom, and their salts.

Particularly preferred compounds of the formula 1-a3 are those in which

R1 is 1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl or hydroxy-1-4C-alkyl,

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,

R61 is hydrogen, halogen or 1-4C-alkyl,

R62 is hydrogen, halogen or 1-4C-alkyl,

X is O (oxygen) or NH and whereby at least one of the hydrogen atoms in R31 is replaced with a deuterium atom, and whereby optionally one or more further hydrogen atoms of R1 , R2, R31 , R32, R61 , R62 or of the core structure of the formula 1-a3 or any combination of R1 , R2, R31 , R32, R61 , R62 and of the core structure of the formulae 1-a3 is replaced with a deuterium atom and their salts.

Particular emphasis is given to compounds of the formula 1-a3, in which

R1 is 1-4C-alkyl,

R2 is 1-4C-alkyl,

R31 is hydroxy-1-4C-alkyl and

R32 is hydrogen,

R61 is 1-4C-alkyl,

R62 is 1-4C-alkyl,

X is NH and whereby at least one of the hydrogen atoms in R31 is replaced with a deuterium atom, and their salts. Preferred compounds according to aspect b of the invention are those compounds of the formula 1-b1

in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy- 1-4C-a I kyl, R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-2-4C-alkyl or cyanomethyl, R6 is phenyl substituted by R61 and R62 wherein

R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl,

R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl, R7 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C-alkoxy-1-4C- alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C-alkoxy, R8 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C-alkoxy-1-4C- alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C-alkoxy X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R6, R7, R8 or of the core structure of the formula 1-b1 or any combination of R1 , R2, R6, R7, R8 and of the core structure of the formula 1-b1 is replaced with a deuterium atom, and their salts.

Particularly preferred compounds of the formula 1-b1 are those in which

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

R2 is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl,

R6 is phenyl,

R7 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C-alkoxy-1-4C- alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C-alkoxy, R8 is hydroxyl, 1-4C-alkoxy or hydroxy-1-4C-alkoxy X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R6, R7, R8 or of the core structure of the formula 1-b1 or any combination of R1 , R2, R6, R7, R8 and of the core structure of the formula 1-b1 is replaced with a deuterium atom, and their salts.

Emphasis is given to compounds of the formula 1-b1 , in which

R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R6 is phenyl,

R7 is 1-4C-alkoxy-1-4C-alkoxy, R8 is hydroxyl, X is NH and whereby at least one of the hydrogen atoms of R1 , R2, R6, R7, R8 or of the core structure of the formula 1-b1 or any combination of R1 , R2, R6, R7, R8 and of the core structure of the formula 1-b1 is replaced with a deuterium atom, and their salts.

Particular emphasis is given to compounds of the formula 1-b1 , in which

R1 is 1-4C-alkyl,

R2 is 1-4C-alkyl,

R6 is phenyl,

R7 is 1-4C-alkoxy-1-4C-alkoxy,

R8 is hydroxyl,

X is NH and whereby at least one of the hydrogen atoms of R7 is replaced with a deuterium atom, and their salts.

Further preferred compounds of the formula 1-b1 are those wherein at least one of the hydrogen atoms in R2 is replaced with a deuterium atom.

Also preferred compounds according to aspect b of the invention are those compounds of the formula 1-b2

in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy- 1-4C-a I kyl, R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-2-4C-alkyl or cyanomethyl, R3 is hydrogen, halogen, 1-4C-alkyl, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-

4C-alkyl or the group -CO-NR31 R32, where

4C-alkyl and

R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, R6 is phenyl substituted by R61 and R62 wherein

R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl,

R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl, X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R3, R6 or of the core structure of the formula 1-b2 or any combination of R1 , R2, R3, R6 and of the core structure of the formula 1-b2 is replaced with a deuterium atom, and their salts.

Particularly preferred compounds of the formula 1-b2 are those in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or fluoro-1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

R3 is hydrogen, halogen, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31 R32, where

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

R32 is hydrogen or 1-7C-alkyl, or where

R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,

R6 is phenyl,

X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R3, R6 or of the core structure of the formula 1-b2 or any combination of R1 , R2, R3, R6 and of the core structure of the formula 1-b2 is replaced with a deuterium atom, and their salts.

Further preferred compounds of the formula 1-b2 are those wherein at least one of the hydrogen atoms in R2 or R3 or in R2 and R3 is replaced with a deuterium atom.

Preferred compounds according to aspect c of the invention are those compounds of the formula 1-c1

in which

4C-alkyl or the group -CO-NR31 R32, where

4C-alkyl and

R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, R9 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R10 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy R11 is hydrogen, 1-7C-alkyl, 2-4C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1 -4C-a I koxy- 1 -4C-a I koxy- 1 -4C-a I koxy , 3-7C-cycloa I koxy- 1 -4C-a I koxy , 3-7C-cycloal kyl- 1 -4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R3, R9, R10, R11 or of the core structure of the formula 1-c1 or any combination of R1 , R2, R3, R9, R10, R1 1 and of the core structure of the formula 1-c1 is replaced with a deuterium atom, and their salts.

Particularly preferred compounds according to aspect c of the invention are those compounds of the formula 1-c2

in which

R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1-4C-alkyl or fluoro-2-4C-alkyl,

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

R9 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R10 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy R11 is hydrogen, 1-7C-alkyl, 2-4C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1 -4C-a I koxy- 1 -4C-a I koxy- 1 -4C-a I koxy , 3-7C-cycloa I koxy- 1 -4C-a I koxy , 3-7C-cycloal kyl- 1 -4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R31 , R32, R9, R10, R1 1 or of the core structure of the formula 1-c2 or any combination of R1 , R2, R31 , R32, R9, R10, R1 1 and of the core structure of the formula 1-c2 is replaced with a deuterium atom, and their salts.

Particularly preferred compounds of the formula 1-c2 are those in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-1-4C-alkyl or hydroxy-1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or hydroxy-1-4C-alkyl,

R9 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R10 is hydrogen or 1-4C-a I kyl,

R11 is hydrogen, 1-7C-alkyl, 2-4C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1 -4C-a I koxy- 1 -4C-a I koxy- 1 -4C-a I koxy, 3-7C-cycloa I koxy- 1 -4C-a I koxy, 3-7C-cycloal kyl- 1 -4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R31 , R32, R9, R10, R1 1 or of the core structure of the formula 1-c2 or any combination of R1 , R2, R31 , R32, R9, R10, R1 1 and of the core structure of the formula 1-c2 is replaced with a deuterium atom, and their salts. Further preferred compounds of the formula 1 , 1-a, 1-b, 1-c, 1-a1 , 1-a2, 1-a3, 1-b1 , 1-b2, 1-c1 and 1- c2 are those wherein at least one of the hydrogen atoms in R2 is replaced with a deuterium atom. Examples of particularly preferred substituents R2 in this case are the D, CH₂D, CHD₂ radicals and in particular the CD₃ radical.

Exemplary preferred compounds are those of the formula 1-a in which R1 , R2, R3, R61 and R62 have the meanings given in the following table A and whereby X is NH and the salts of these compounds.

Exemplary also preferred compounds are those of the formula 1-a in which R1 , R2, R3, R61 and R62 have the meanings given in the following table A and whereby X is O and the salts of these compounds.

Exemplary particularly preferred compounds are those of the formula 1-a1 in which R1 , R2, R3, R61 and R62 have the meanings given in the following table A and whereby X is NH and the salts of these compounds.

Exemplary particularly preferred compounds are those of the formula 1-a2 in which R1 , R2, R3, R61 and R62 have the meanings given in the following table A and whereby X is NH and the salts of these compounds.

Exemplary also particularly preferred compounds are those of the formula 1-a1 in which R1 , R2, R3, R61 and R62 have the meanings given in the following table A and whereby X is O and the salts of these compounds.

Exemplary also particularly preferred compounds are those of the formula 1-a2 in which R1 , R2, R3, R61 and R62 have the meanings given in the following table A and whereby X is O and the salts of these compounds. Table A:

Particular emphasis is given to the compounds of the formula 1 given as final products iin the exam- pies, and the salts of these compounds.

The compounds of the formula 1 can be prepared in manner known to a person skilled in the art, for example in analogy to the processes disclosed in the patent applications mentioned in the outset for the undeuterated analogues, all of which are incorporated herein by reference, using the corresponding deuterated starting materials or corresponding deuterated reagents. The starting compounds are known from literature. For example, 4-amino-6-substituted imidazo[1 ,2-a]pyridines and 4-hydroxy-6- substituted imidazo[1 ,2-a]pyridines can be prepared as described in WO99/55706, WO03/014123, WO 04/046144 or they can be prepared using analogous process steps. Suitable deuterated starting materials or deuterated reagents are known to a person skilled in the art or can be prepared by methods known per se.

As an example deuterated imidazo[1 ,2-a]pyridines derivatives of the general formula 1-a1 and 1-a2 can be obtained by reacting imidazo[1 ,2-a]pyridines of the formula 2 with deuterated arylmethyl halo- genides. Preferentially, benzyl halogenides of the formula 3 as shown in scheme 1 are used, wherein Hal is a halogen atom like for example chlorine or bromine, and which are once or twice deuterated at the benzylic carbon. For example d₂-2-methylbenzyl bromide is known from Smith et al., Can. J. Chem. 1986, 64, 1060-1071 or d₂-2,6-dimethylbenzyl bromide from Luz et al., Phys. Chem. Chem. Phys. 2001 , 3, 1891-1903. Compounds of the formula 3 can be prepared for example by reaction of the corresponding deuterated benzylalcohol with halogenating reagents by methods known to the expert. If for example Hal is chlorine, compounds of the formula 3 can be obtained by reaction with chlorination reagents like for example thionyl chloride. Scheme 1 :

(1-a1 ) (1-a2)

If, for example, compounds of formula 1-a, 1a-1 or 1-a2 which are deuterated in R1 , R2, R3 or any other position are desired, the corresponding imidazo[1 ,2-a]pyridines of formula 2, which is deuterated in the desired position, can be used.

Analogously, compounds of the general formula 1-c1 are obtained by reacting deuterated imidazo[1 ,2- a]pyridines of formula 2 with epoxyindanes 4, carrying any desired substituent R9 and R10 (scheme 2). Scheme 2:

1-c1 , X = O, NH with R11 = hydroxyl

The reaction steps outlined above are carried out in a manner known per se, e. g. as described in more detail in the examples. The derivatization, if any, of the compounds obtained according to the above Scheme 1 and 2 (e.g. conversion of a group R3 into another group R3, or of R2 = H into another group R2, or conversion of the hydroxyl group into an alkoxy or ester group) is likewise carried out in a manner known per se. If compounds where R3 = -CO-1-4C-alkoxy or R3 = -CO-NR31 R32 are desired, an appropriate derivatization can be performed in a manner known per se (e. g. metal catalysed carbonylation of the corresponding bromo compound or conversion of an ester into an amide) at the stage of the benzimidazoles of formula 2 (scheme 1 and 2) or more conveniently at a later point in time. If a deuteration of the R3 = -C0-NR31 R32 substituent is desired, the use of a deuterated amine in the amide formation reaction can be used.

The following examples serve to illustrate the invention in greater detail without restricting it. Likewise, further compounds of the formula 1 whose preparation is not described explicitly can be prepared in an analogous manner or in a manner familiar per se to the person skilled in the art using customary process techniques. The abbreviation min stands for minute(s), h for hour(s) and m.p. for melting point.

Advantageous effects

The compounds of the formula 1 according to the present invention were found, unexpectedly, to possess advantageous properties which make them particularly suitable for use in human and veterinary medicine. In particular the compounds according to the present invention are characterized for example by an advantageous metabolization profile, in particular by an advantageous stability with regard to metabolic degradation. The compounds according to the present invention thus show inter alia an increased effect and an increased duration of action with regard to inhibition of gastric acid secretion and gastric protective activity when compared to their un-deuterated analogous. These improved metabolization properties allow for example a reduction of the amount of a compound according to the invention, which is needed for treatment and/or prophylaxis. Related with these properties are further advantages such as for example patient safety or economical aspects, e.g. like drug costs etc.

The inhibition of the H+/K+-ATPase can be demonstrated for example in investigations using in-vitro systems. The advantageous metabolization profile of the compounds according to the invention can also be demonstrated using suitable in-vitro test systems for example by incubation of isolated liver enzymes of rats, humans or other warm blooded animal. The compounds of the formula 1 according to the invention investigated in the enzymatic assay mentioned below have been provided with numbers which correspond to the numbers of these compounds in the examples.

IC₅₀ determination using the malachite green assay modified from Yoda and Hokin

(Yoda, A., and Hokin, L. E. Biochem Biophys Res Commun 1970, 40, 880-886.)

Table A

Methodology

Final assay concentrations:

4mM PIPES (piperazine-1 ,4-bis(2-ethanesulfonic Acid) / 8mM TRIS

(tris(hydroxymethyl)aminomethane) buffer pH 7,4

0.25M Sucrose

1 mM KCI

1 mM MgCI2

0,5 to 1 μg/1 OOμl Nigericin (1 :1 ratio with enzyme)

0,5 to 1 μg/1 OOμl Enzyme (dependent on K+ stimulated, specific activity)

1 mM Na-ATP (high grade)

Reaction volume: 101 μL Pipes, Sucrose, Nigericin, Na-ATP and Malachite green were purchased from Sigma-AIdrich, Tris, KCI and Ammonium molybdate (Ammoniumheptamolybdate tetrahydrate) from Merck and MgCI₂ from Fluka.

"Enzyme" refers to H+/K+-ATPase-containing vesicles prepared from hog gastric mucosa as described in Rabon, E. C, Bin Im, W., and Sachs, G. Methods Enzymol 1988, 757, 649-654.

Procedure:

A PIPES / TRIS buffer based solution with Sucrose and MgCI₂ was prepared. Nigericin and enzyme were added to reach abovementioned final concentrations. 80μl_/well of this mixture were placed into 96 well flat bottom plates (clear, polystyrol, Greiner bio-one). 10μl_/well KCI (1 mM final) was used for stimulation of H/K ATPase activity. Test substances were dissolved as 1OmM solutions in 100% DMSO. 1 μl_ of Substances was added as DMSO solutions in dilutions ranging from 1x10⁴ to 1x10^-9M (final). The enzymatic reaction was started by addition of 10μl_ ATP (1 mM final). The assay was incubated for 30min at room temperature. The reaction was stopped by addition of 150μl_ malachite green reagent and incubated for another 15 min prior to photometric reading of the plate at 680nm in a Pow- erWave HT Microplate spectral photometer (BioTek). Results were analyzed with GraphPad Prism software (Version 4.02) to calculate IC₅₀ values by sigmoidal curve fitting.

Preparation of malachite green reagent:

stock solution Malachite-Green: dissolve 0,45 g/l (1 ,2M) in H₂O protect from light and use within 12 weeks

stock solution Ammonium molybdate: dissolve 42g/l in 4N HCI

Two parts malachite green stock solution were mixed with 1 part ammonium molybdate stock solution and kept for 30 min at room temperature prior to use.

Mode(s) for Carrying Out the Invention

The examples below serve to illustrate the invention in more detail without limiting it. Further compounds of the formula 1 whose preparation is not described explicitly can likewise be prepared in an analogous manner or in a manner known per se to the person skilled in the art, using customary process techniques. The compounds named expressly as examples, and the salts of these compounds, are preferred subject matter of the invention. The abbreviation min stands for minute(s), h stands for hour(s), m.p. stands for melting point and ee for enantiomeric excess.

I. Final Compounds of the formula 1

1. Methyl 8-((2,6-dimethylphenyl)-dideuteriomethyl-amino)-2,3-dimethylimidazo[1,2- a]pyridine-6-carboxylate

A mixture of 0.28 g (2.0 mmol) d₂-2,6-dimethylbenzylalcohol in 2 ml thionyl chloride was stirred for 1 h at ambient temperature and evaporated to dryness. The residue was dissolved in 10 ml acetone and 0.45 g (2.1 mmol) methyl 8-amino-2,3-dimethylimidazo[1 ,2-a]pyridine-6-carboxylate, 0.42 g (3.0 mmol) potassium carbonate and 0.36 g (2.2 mmol) sodium iodide were added. After stirring overnight, the reaction mixture was partitioned between water and dichloromethane. The combined organic phases were dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography (silica gel, ethyl acetate/light petroleum ether 4:1 ) and crystallization from diethyl ether yielded 0.32 g (46 %) of the title compound as a colourless solid (m.p. 184-185 ⁰C).

2. 8-((2,6-Dimethylphenyl)-dideuteriomethyl-amino)-N-(2-hydroxyethyl)-2,3- dimethylimidazo-6-carboxamide

A mixture of 0.30 g (0.88 mmol) methyl 8-((2,6-dimethylphenyl)-dideuteriomethyl-amino)-2,3- dimethylimidazo[1 ,2-a]pyridine-6-carboxylate in 10 ml ethanolamine was heated to 100 ⁰C. After 1 h, the reaction mixture was cooled down and partitioned between water and dichloromethane. The combined organic phases were dried over anhydrous magnesium sulphate and evaporated. Crystallization of the residue from diethyl ether yielded 0.24 g (73 %) of the title compound as a colourless solid (m.p. 241-242 ⁰C).

3. Methyl (2-(((3-hydroxydeuteriomethyl-2-methylimidazo[1,2-a]pyridin-8-yl)amino)methyl)- 3-methylphenyl)carbamate

To a suspension of 1.9 g (5.4 mmol) methyl (2-(((3-formyl-2-methylimidazo[1 ,2-a]pyridin-8- yl)amino)methyl)-3-methylphenyl)carbamate in 20 ml methanol were added 0.15 g (3 mmol) sodium borodeuteride in small portions. After 30 min, the mixture was evaporated to dryness and the residue redissolved in water. The mixture was neutralized with acetic acid and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethyl acetate/diethyl ether yielded 1.5 g (78 %) of the title compound as a colourless solid (m.p. 173-174 ⁰C).

4. (7R,8R,9R)-7-(2-Methoxy-tetradeuterioethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10- tetrahydroimidazo[1,2-h]-1,7-naphthyridin-8-ol

A mixture of 1.6 g crude (7R,8R,9R)-10-acetyl-7-(2-methoxy-tetradeuterioethoxy)-2,3-dimethyl-9- phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h]-1 ,7-naphthyridin-8-yl pivalate and 1.3 ml 6N potassium hydroxide in 3 ml hydrazine hydrate and 3 ml methanol was heated to 60 ⁰C. After 4 h, the reaction mixture was cooled down and partitioned between water and dichloromethane. The combined organic phases were dried over anhydrous magnesium sulphate and evaporated. The residue was dissolved in acetone and 0.43 g (3.7 mmol) maleic acid were added. The precipitate was collected and washed with acetone. The precipitate was redissolved in saturated aqueous sodium hydrogen carbonate and extracted with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethyl acetate yielded 0.9 g of the title compound as a colourless solid (m.p. 140-141 ⁰C).

II. Starting Compounds

A. Trifluoromethanesulphonic acid 2-methoxy-tetradeuterioethyl ester

To a solution of 1.1 ml (6.7 mmol) trifluoromethanesulphonic anhydride in 2 ml dichloromethane was slowly added a solution of 0.49 ml (6.1 mmol) pyridine and 0.49 g (6.1 mmol) 2-methoxy- tetradeuterioethanol in 4 ml dichloromethane at 0 ⁰C. After 30 min, the solids were filtered off and the filtrate was washed with ice water. The organic layer was dried over anhydrous magnesium sulphate and evaporated in the cold. The residue was used without further purification in the next step.

B. (7R,8R,9R)-10-Acetyl-7-(2-methoxy-tetradeuterioethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10- tetrahydroimidazo[1,2-h]-1,7-naphthyridin-8-yl pivalate

To a solution of 1.6 g (3.7 mmol) (7R,8R,9R)-10-acetyl-7-(hydroxy)-2,3-dimethyl-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h]-1 ,7-naphthyridin-8-yl pivalate was added a solution of the crude trifluoromethanesulphonic acid 2-methoxy-tetradeuterioethyl ester of step A in 5 ml dichloromethane at -30 ⁰C. To the mixture were added 0.29 g (7.4 mmol) sodium hydride (60 %) and stirring was continued for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography (silica gel, diethyl ether/triethylamine 9:1 ) yielded 1.6 g of a yellow oil which was used without further purification in the next step. Degree of deuteration

The degree of deuteration was determined for several selectivly deuterated compounds of the formula 1 by ¹H NMR spectroscopy. The calculated degree of deuteration applies to the deuterated position with respect to a non-deuterated position within the same molecule (i.e. the value of the integral of a non-deuterated position is calibrated to the number of attached protons). This includes the assumption that non-deuterated positions are substituted by protons (¹H) to an extent of 100%. The degree of deuteration is then calculated using the resulting integral value for the residual proton signal of the deuterated position (Ires): degreeof deuteration = (1 - — ) ^• 100 % n

Results

The degree of deuteration was determined for compounds of the formula 1 according to the invention. In the following table these compounds have been provided with numbers which correspond to the numbers of these compounds in the examples.

* For reason of signal overlap compound was dissolved in an acetonitrile-d3/deuteriumoxide mixture instead of DMSO-d6, which was the solvent for the other compounds.

NMR spectrometer and experimental conditions

NMR spectrometer: DRX 400, Bruker Biospin

Probe: 5 mm BBI with actively shielded z-gradient

Sample Temperature: 303.2K

Transmitter frequency: 400.1324023 MHz

Spectral width: 8012.820 Hz

Dwell time: 62.400 μs

No. of data points: 65536

Acquisition time: 4.1 s Recycle delay: 30.0 s

No. of transients: 64 / 2 dummy scans

About 10 mg of every batch were dissolved in 0.6 ml_ of DMSO-d6* and filled into a 5 mm NMR-tube. For each sample a proton spectrum was measured applying 30° pulses without spinning of the tube. The experiments were executed under fully automated spectrometer control using the NMR software package XWIN-NMR 3.5. The Fourier transformation of the raw free induction decay curves was performed with an exponential apodization function using a line broadening factor of 0.3 Hz. The phase correction and baseline correction were performed automatically and optimized manually if necessary. The integration of the relevant Signals was done manually.

The present invention relates to compounds wherein at least one of the hydrogen atoms is replaced with a deuterium where in the position of replacement the degree of deuteration is higher than the naturally occurring degree of deuteration.

If in one position within the molecule all of the hydrogen atoms are to be replaced by deuterium (for example leading to a -CD₂- or a -CD₃ ) the preferred degree of deuteration in this position is preferably between 60 and 100%, more preferably between 90 and 100% and most preferably between 95 and 100%.

If in one position within the molecule not all of the hydrogen atoms are to be replaced by a deuterium (for example leading to a -CHD-, a -CHD₂ or a -CH₂D group) the preferred, more preferred and most preferred degree of deuteration in this position is calculated from the preferred, more preferred and most preferred ranges given above multiplied by the exchange rate of hydrogen atoms in that position. An exchange rate of 0.5 is given for example in a -CHD- group, leading to a preferred degree of deuteration in this position between 30 and 50%, more preferred between 45 and 50% and most preferred between 47.5 and 50%. Analogously, an exchange rate of 0.333 is for example given in the case of a -CH₂D group.

lndustrial applicability

The compounds of the formula 1 , 1-a, 1-b, 1-c, 1-a1 , 1-a2, 1-a3, 1-b1 , 1-b2, 1-c1 and 1-c2 and their pharmaceutically acceptable salts (= active compounds according to the invention) have valuable pharmacological properties which make them commercially utilizable. In particular, they exhibit marked inhibition of gastric acid secretion and an excellent gastric and intestinal protective or curative action in warm-blooded animals, in particular humans. In this connection, the active compounds according to the invention are distinguished by a high selectivity of action, a fast onset of action, an advantageous duration of action, efficient control of the duration of action by the dosage, a particularly good antisecretory efficacy, the absence of significant side effects and a large therapeutic range.

"Gastric and intestinal protection or cure" in this connection is understood to include, according to general knowledge, the prevention, the treatment and the maintenance treatment of gastrointestinal diseases, in particular of gastrointestinal inflammatory diseases and lesions (such as, for example, reflux esophagitis, gastritis, hyperacidic or drug-related functional dyspepsia, and peptic ulcer disease [including peptic ulcer bleeding, gastric ulcer, duodenal ulcer]), which can be caused, for example, by microorganisms (e.g. Helicobacter pylori), bacterial toxins, drugs (e.g. certain antiinflammatories and antirheumatics, such as NSAIDs and COX-inhibitors), chemicals (e.g. ethanol), gastric acid or stress situations. The term "gastrointestinal diseases" is understood to include, according to general knowledge,

A) gastroesophageal reflux disease (GERD), the symptoms of which include, but are not limited to, heartburn and/or acid regurgitation and/or non-acid regurgitation.

B) other extra-esophageal manifestations of GERD that include, but are not limited to, acid-related asthma, bronchitis, laryngitis and sleep disorders.

C) other diseases that can be connected to undiagnosed reflux and/or aspiration include, but are not limited to, airway disorders such as asthma, bronchitis, COPD (chronic obstructive pulmonary disease).

D) Helicobacter pylori infection whose eradication is playing a key role in the treatment of gastrointestinal diseases.

E) Furthermore, "gastrointestinal diseases" comprise other gastrointestinal conditions that might be related to acid secretion, such as Zollinger-Ellison syndrome, acute upper gastrointestinal bleeding, nausea, vomiting due to chemotherapy or post-operative conditions, stress ulceration, IBD (inflammatory bowel disease) and particularly IBS (irritable bowel syndrome).

In their excellent properties, the active compounds according to the invention surprisingly prove to be clearly superior to the compounds known from the prior art in various models in which the antiulcero- genic and the antisecretory properties are determined. On account of these properties, the active compounds according to the invention are outstandingly suitable for use in human and veterinary medicine, where they are used, in particular, for the treatment and/or prophylaxis of disorders of the stomach and/or intestine and/or upper digestive tract, particularly of the abovementioned diseases. A further subject of the invention are therefore the active compounds according to the invention for use in the treatment and/or prophylaxis of the abovementioned diseases.

The invention likewise includes the use of the active compounds according to the invention for the production of medicaments which are employed for the treatment and/or prophylaxis of the above- mentioned diseases.

The invention furthermore includes the use of the active compounds according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.

A further subject of the invention are medicaments which comprise one or more active compounds according to the invention.

As medicaments, the active compounds according to the invention are either employed as such, or preferably in combination with suitable pharmaceutical excipients in the form of tablets, coated tablets (e.g. film-coated tablets), multi unit particulate system tablets, capsules, suppositories, granules, powders (e.g. lyophilized compounds), pellets, patches (e.g. as TTS [transdermal therapeutic system]), emulsions, suspensions or solutions. The content of the active compound is advantageously being between 0.1 and 95wt% (weight percent in the final dosage form), preferably between 1 and 60wt%. By means of the appropriate selection of the excipients, it is possible to obtain a pharmaceutical administration form adapted to the active compound and/or to the desired onset and/or duration of action (e.g. a sustained release form or a delayed release form).

The active compounds according to the invention can be administered orally, parenterally (e.g. intravenously), rectally or percutaneously. Oral or intravenous administration is preferred.

The excipients or combinations of excipients which are suitable for the desired pharmaceutical formulations are known to the person skilled in the art on the basis of his/her expert knowledge and are composed of one or more accessory ingredients. In addition to solvents, antioxidants, stabilizers, surfactants, complexing agents (e.g. cyclodextrins), the following excipients may be mentioned as examples: For oral administration, gelling agents, antifoams, plasticizer, adsorbent agents, wetting agents, colorants, flavorings, sweeteners and/or tabletting excipients (e.g. carriers, fillers, binders, disintegrating agents, lubricants, coating agents); for intravenous administration, dispersants, emulsifiers, preservatives, solubilizers, buffer substances and/or isotonic adjusting substances. For percutaneous administration, the person skilled in the art may choose as excipients, for example: solvents, gelling agents, polymers, permeation promoters, adhesives, matrix substances and/or wetting agents.

In general, it has been proven advantageous in human medicine to administer the active compound(s) in the case of oral administration in a daily dose (given continuously or on-demand) of approximately 0.01 to approximately 20, preferably 0.02 to 5, in particular 0.02 to 1.5, mg/kg of body weight, if appropriate in the form of several, preferably 1 to 2, individual doses to achieve the desired result. In the case of a parenteral treatment, similar or (in particular in the case of the intravenous administration of the active compounds), as a rule, lower doses can be used. Furthermore, the frequency of administration can be adapted to intermittent, weekly, monthly, even more infrequent (e.g. implant) dosing. The establishment of the optimal dose and manner of administration of the active compounds necessary in each case can easily be carried out by any person skilled in the art on the basis of his/her expert knowledge.

The medicaments may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmaceutical science. All methods include the step of bringing the active compounds according to the invention into association with the excipients or a combination of excipients. In general the formulations are prepared by uniformly and intimately bringing into association the active compounds according to the invention with liquid excipients or finely divided solid excipients or both and then, if necessary, formulating the product into the desired medicament.

The active compounds according to the invention or their pharmaceutical preparations can also be used in combination with one or more pharmacologically active constituents from other groups of drugs [combination partner(s)]. "Combination" is understood to be the supply of both the active compound^) according to the invention and the combination partner(s) for separate, sequential, simultaneous or chronologically staggered use. A combination is usually designed with the aim of increasing the principal action in an additive or super-additive sense and/or of eliminating or decreasing the side effects of the combination partner(s), or with the aim to obtain a more rapid onset of action and a fast symptom relief. By choosing the appropriate pharmaceutical formulation of the drugs contained in the combination, the drug release profile of the components can be exactly adapted to the desired effect, e.g. the release of one compound and its onset of action is chronologically previous to the release of the other compound.

A combination can be, for example, a composition containing all active compounds (for example a fixed combination) or a kit-of-parts comprising separate preparations of all active compounds. A "fixed combination" is defined as a combination wherein a first active ingredient and a second active ingredient are present together in one unit dosage or in a single entity. One example of a "fixed combination" is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture of simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture. A "kit-of-parts" is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit. One example of a "kit-of-parts" is a combination wherein the said first active ingredient and the said second active ingredient are present separately. The components of the kit-of-parts may be administered separately, sequentially, simultaneously or chronologically staggered.

"Other groups of drugs" are understood to include, for example: tranquillizers (for example from the group of the benzodiazepines, like diazepam), spasmolytics (for example butylscopolaminium bromide [Buscopan®]), anticholinergics (for example atropine sulfate, pirenzepine, tolterodine), pain perception reducing or normalizing agents (for example, paracetamol, tetracaine or procaine or especially oxeta- cain), and, if appropriate, also enzymes, vitamins, trace elements or amino acids.

To be emphasized in this connection is in particular the combination of the active compounds according to the invention with pharmaceuticals which buffer or neutralize gastric acid (such as, for example, magaldrat, aluminium hydroxide, magnesium carbonate, magnesium hydroxide or other antacids), or especially with pharmaceuticals which inhibit or reduce acid secretion, such as, for example:

(I) histamine-H2 blockers [e.g. cimetidine, ranitidine], or

(II) proton pump inhibitors [e.g. omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole, tenatoprazole, ilaprazole, leminoprazole, all including their salts and enantiomers] or

(III) other potassium-competitive acid blockers [e.g. soraprazan and its stereoisomers, linaprazan, revaprazan, all including their salts]), or

(IV) so-called peripheral anticholinergics (e.g. pirenzepine), with gastrin antagonists such as CCK2 antagonists (cholestocystokinin 2 receptor antagonists).

An important combination to be mentioned is the combination with antibacterially active substances, and especially substances with a bactericidal effect, or combinations thereof. These combination partners) are especially useful for the control of Helicobacter pylori infection whose eradication is playing a key role in the treatment of gastrointestinal diseases. As suitable antibacterially active combination partner(s) may be mentioned, for example:

(A) cephalosporins, such as, for example, cifuroximaxetil

(B) penicillines, such as, for example, amoxicillin, ampicillin

(C) tetracyclines, such as, for example, tetracyline itself, doxycycline

(D) β-lactamase inhibitors, such as, for example, clavulanic acid

(E) macrolide antibiotics, such as, for example, erythromycin, clarithromycin, azithromycin

(F) rifamycines, such as, for example, rifamycine itself

(G) glycoside antibiotics, such as, for example, gentamicin, streptomycin

(H) gyrase inhibitors, such as, for example, ciprofloxaxin, gatifloxacin, moxifloxacin (I) oxazolidines, such as, for example, linezolid

(J) nitrofuranes or nitroimidazoles, such as, for example, metronidazole, tinidazole, nitrofurantoin (K) bismuth salts, such as, for example, bismuth subcitrat (L) other antibacterially active substances and combinations of substances selected from (A) to (L), for example clarithromycin + metronidazole. Preferred is the use of two combination partners. Preferred is the use of two combination partners selected from amoxicillin, clarithromycin and metronidazole. A preferred example is the use of amoxicillin and clarithromycin.

In view of their excellent activity regarding gastric and intestinal protection or cure, the active compounds according to the invention are especially suited for a free or fixed combination with drugs, which are known to cause "drug-induced dyspepsia" or are known to have a certain ulcerogenic potency, such as, for example, acetylsalicylic acid, certain antiinflammatories and antirheumatics, such as NSAIDs (non-steroidal antiinflammatory drugs, e.g. etofenamate, diclofenac, indometacin, ibupro- fen, piroxicam, naproxen, meloxicam), oral steroids, bisphosponates (e.g. alendronate), or even NO- releasing NSAIDs, COX-2 inhibitors (e.g. celecoxib, lumiracoxib).

In addition, the active compounds according to the invention are suited for a free or fixed combination with motility-modifying or -regulating drugs (e.g. gastroprokinetics like mosapride, tegaserod, itopride, metoclopramid), and especially with pharmaceuticals which reduce or normalize the incidence of transient lower esophageal sphincter relaxation (TLESR), such as, for example, pharmaceuticals modulating (activating) directly or indirectly the GABA-B receptor, such as, for example, GABA-B receptor agonists (e.g. baclofen, (2R)-3-amino-2-fluoropropylphosphinic acid), GABA-B receptor positive allos- teric modulators (e.g. 3,5-bis(1 ,1-dimethylethyl)-4-hydroxy-β,β-dimethylbenzenepropanol (CGP7930), N.N-dicyclopentyl^-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783)), GABA-B receptor positive allosteric modulators in combination with GABA-B receptor agonists, or substances that enhance the endogenous GABA tone such as GABA re-uptake inhibitors (e.g. tiagabine), pharmaceuticals antagonising the metabotropic glutamate receptor type 5 (mGluR5), such as metabotropic glutamate receptor type 5 (mGluR5) antagonists (e.g. 2-methyl-6-(phenylethynyl)pyridine hydrochloride), pharmaceuticals modulating (activating) directly or indirectly the cannabinoid (CB) receptor, in particularly the cannabinoid receptor type 1 (CB1 ), such as, for example, cannabinoid (CB) receptor agonists (e.g. [(3R)-2,3-dihydro-5-methyl-3-(4-morpholinyl-methyl)pyrrolo[1 ,2,3,de]-1 ,4-benzoxazin-6-yl]-1- naphthalenyl-methanone (WIN55, 212-2), or pharmaceuticals acting as selective cholecystokinin subtype 1 (CCK1 ) receptor antagonists (e.g. loxiglumide).

Pharmaceuticals used for the treatment of IBS or IBD are also suitable combination partner(s), such as, for example: 5-HT4 receptor agonists like mosapride, tegaserod; 5-HT3 receptor antagonists like alosetron, cilansetron; NK2 antagonists like saredutant, nepadutant; κ-opiate agonists like fedotozine.

Suitable combination partner(s) also comprise airway therapeutica, for example for the treatment of acid-related asthma and bronchitis. In some cases, the use of a hypnotic aid (such as, for example, Zolpidem [Bikalm®]) as combination partner(s) may be rational, for example for the treatment of GERD-induced sleep disorders.

Claims

1. A compound of the formula 1

in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy- 1-4C-a I kyl, R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-2-4C-alkyl or cyanomethyl, R3 is hydrogen, halogen, 1-4C-alkyl, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-

4C-alkyl or the group -CO-NR31 R32, where

4C-alkyl and

R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, and wherein either R4 and R5 are each hydrogen and R6 is phenyl substituted by R61 and R62 wherein

R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl,

R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl,

R7 is hydrogen, hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C- alkoxy R8 is hydrogen, hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C- alkoxy or wherein

R4 is hydrogen and R5 and R6 together form a group gp,

wherein

Z has the meaning CHR1 1or CHR11-CHR12

R9 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl- carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C- alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, I^C-alkoxy-I^C-alkoxycarbonylamino or sulfonyl, R10 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy

R11 is hydrogen, 1-7C-alkyl, 2-4C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C- alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C- a I koxy- 1 -4C-a I koxy , 1 -4C-a I koxy- 1 -4C-a I koxy- 1 -4C-a I koxy , 3-7C-cycloa I koxy- 1 -4C- alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C- alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy- 1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy R12 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C- alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C- a I koxy- 1 -4C-a I koxy, 1 -4C-a I koxy- 1 -4C-a I koxy- 1 -4C-a I koxy, 3-7C-cycloa I koxy- 1 -4C- alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C- alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy- 1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R3, R4, R5, R6 or of the core structure of the formula 1 or any combination of R1 , R2, R3, R4, R5, R6 and the core structure of the formula 1 is replaced with a deuterium atom, and its salts.

2. A compound of the formula 1 as claimed in claim 1 , characterized by the formula 1-a, in which

4C-alkyl or the group -CO-NR31 R32, where

4C-alkyl and

R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl, R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl, X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R3, R61 , R62 or of the core structure of the formula 1-a or any combination of R1 , R2, R3, R61 , R62 and the core structure of the formula 1-a is replaced with a deuterium atom, and its salts.

3. A compound of the formula 1 as claimed in claim 1 , characterized by the formula 1-b

in which

4C-alkyl or the group -CO-NR31 R32, where

4C-alkyl and

R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl,

X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R3, R6, R7, R8 or of the core structure of the formula 1-b or any combination of R1 , R2, R3, R6, R7, R8 and the core structure of the formula 1-b is replaced with a deuterium atom, and its salts.

4. A compound of the formula 1 as claimed in claim 1 , characterized by the formula 1-c

in which

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

R9 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,

Z has the meaning CHR11or CHR11-CHR12 wherein

R11 is hydrogen, 1-7C-alkyl, 2-4C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1 -4C-a I koxy- 1 -4C-a I koxy- 1 -4C-a I koxy , 3-7C-cycloa I koxy- 1 -4C-a I koxy , 3-7C-cycloal kyl- 1 -4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-'MC-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy

R12 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1 -4C-a I koxy- 1 -4C-a I koxy- 1 -4C-a I koxy , 3-7C-cycloa I koxy- 1 -4C-a I koxy , 3-7C-cycloal kyl- 1 -4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy,

X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R3, R9, R10, z or of the core structure of the formula 1-c or any combination of R1 , R2, R3, R9, R10, z and the core structure of the formula 1-c is replaced with a deuterium atom, and its salts.

5. A compound of the formula 1 as claimed in claim 1 , characterized by the formula 1-a1 or 1-a2

in which

R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl, R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl, X is O (oxygen) or NH whereby optionally one or more further hydrogen atoms of R1 , R2, R3, R61 , R62 or of the core structure of the formulae 1-a1 or 1-a2 or any combination of R1 , R2, R3, R61 , R62 and of the core structure of the formulae 1-a1 or 1-a2 is replaced with a deuterium atom, and its salts.

6. A compound of the formula 1-a1 or 1-a2 as claimed in claim 5, in which

R1 is 1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl or hydroxy-1-4C-alkyl, R3 is 1-4C-alkoxycarbonyl or the group -CO-NR31 R32, where

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, R61 is hydrogen, halogen or 1-4C-alkyl, R62 is hydrogen, halogen or 1-4C-alkyl, X is O (oxygen) or NH and whereby optionally one or more further hydrogen atoms of R1 , R2, R3, R61 , R62 or of the core structure of the formulae 1-a1 or 1-a2 or any combination of R1 , R2, R3, R61 , R62 and of the core structure of the formulae 1-a1 or 1-a2 is replaced with a deuterium atom, and its salts.

7. A compound of the formula 1-a1 or 1-a2 as claimed in claim 5, in which

R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 is 1-4C-alkoxycarbonyl or the group -CO-NR31 R32, where

R31 is hydroxy-1-4C-alkyl and

R32 is hydrogen, R61 is 1-4C-alkyl, R62 is 1-4C-alkyl, X is NH and and its salts

8. A compound of the formula 1 as claimed in claim 1 , characterized by the formula 1-a3

in which

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

R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl,

R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl,

X is O (oxygen) or NH and whereby at least one of the hydrogen atoms in R31 is replaced with a deuterium atom, and whereby optionally one or more further hydrogen atoms of R1 , R2, R31 , R32, R61 , R62 or of the core structure of the formula 1-a3 or any combination of R1 , R2, R31 , R32, R61 , R62 and of the core structure of the formulae 1-a3 is replaced with a deuterium atom, and its salts.

9. A compound of the formula 1 as claimed in claim 1 , characterized by the formula 1-b1

in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-I^C-alkyl, 1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy- 1-4C-a I kyl,

R6 is phenyl substituted by R61 and R62 wherein

R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl, R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl,

R7 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C-alkoxy-1-4C- alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C-alkoxy,

R8 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C-alkoxy-1-4C- alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C-alkoxy

X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R6, R7, R8 or of the core structure of the formula 1-b1 or any combination of R1 , R2, R6, R7, R8 and of the core structure of the formula 1-b1 is replaced with a deuterium atom, and its salts.

10. A compound of the formula 1 as claimed in claim 1 , characterized by the formula 1-b1 as claimed in claim 9, in which

R1 is 1-4C-alkyl,

R2 is 1-4C-alkyl,

R6 is phenyl,

R7 is 1-4C-alkoxy-1-4C-alkoxy,

R8 is hydroxyl,

X is NH and whereby at least one of the hydrogen atoms of R7 is replaced with a deuterium atom, and its salts.

11. A compound, which is selected from the group consisting of

Methyl 8-((2,6-dimethylphenyl)-dideuteriomethyl-amino)-2,3-dimethylimidazo[1 ,2-a]pyridine-6- carboxylate

8-((2,6-Dimethylphenyl)-dideuteriomethyl-amino)-N-(2-hydroxyethyl)-2,3-dimethylimidazo-6- carboxamide

Methyl (2-(((3-hydroxydeuteriomethyl-2-methylimidazo[1 ,2-a]pyridin-8-yl)amino)methyl)-3- methylphenyl)carbamate

(7R,8R,9R)-7-(2-Methoxy-tetradeuterioethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h]-1 ,7-naphthyridin-8-ol and its salts.

12. A medicament comprising a compound as claimed in any of claims claim 1 to 11 and/or a pharmacologically acceptable salt thereof together with customary pharmaceutical auxiliaries and/or ex- cipients.

13. The use of a compound as claimed in any of claims 1 to 11 and its pharmacologically acceptable salts for the prevention and treatment of gastrointestinal disorders.

14. The use of a compound as claimed in any of claims 1 to 11 and its pharmacologically acceptable salts for the production of medicaments, which are employed for the treatment and/or prophylaxis of gastrointestinal diseases.