DD264434A5 - PROCESS FOR PRODUCING NEW SUBSTITUTED THIAZOLE AND OXAZOLE - Google Patents

Abstract

The invention relates to a process for the preparation of novel substituted thiazoles and oxazoles of the general formula (I) in which, for example: A is an optionally mono- or disubstituted by methyl or ethyl groups n-alkylene group, X is an oxygen or sulfur atom, R1 is a hydrogen or halogen atom, a trifluoromethyl, alkyl, phenyl or piperidino group, and the like. a, R2 is a hydrogen atom or an alkyl group, R3 is a hydrogen atom or an alkyl group which may be substituted in the 2- or 3-position by a hydroxy group, u. a, R4 is a hydrogen atom, an optionally substituted by a phenyl, carboxy, alkoxycarbonyl or cyano group or in the 2- or 3-position by a hydroxy-substituted alkyl group or an alkenyl group and R5 is a hydroxy, alkoxy, carboxy, alkoxycarbonyl , Aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group and the like. a. Formula (I)

Description

Field of application of the invention

The invention relates to a method for the production of novel substituted thiazoles and oxazoles with valuable pharmacological properties "in particular with effect on the metabolism, preferably with blood sugar lowering and body fat reducing effect. The erfindungsgsmöß hergeetellen compounds are applied ale drugs, for example, for the treatment of diabetes mellltue, Adipoeitas and for the treatment and prophylaxis of arterio-sclerotic changes.

Characteristic of the known state of the art

Under the general formula of EP-A-0,005,846, u. a «compounds of the general formula

N «H

SM CH-CH ₂ -N-AIk- (O) _n

CONH ₂

in the

X is an oxygen or sulfur atom,

Alk is a geradket.tlge or branched alkylene group having 2 to 5 carbon atoms and

η represent the number O or 1. However, none of these compounds is explicitly described in the above-mentioned EP-A-0,005,848. These compounds are said to be valuable pharmacological

have -logical properties, in particular a stimulating effect on the cardiac ß-receptors, z. B, a positive inotropic or positive chronotropic effect.

Object of the invention

The aim of the invention is to provide novel compounds with valuable pharmacological properties.

Explanation of the essence of the invention

The invention has for its object to find «new thiazoles and oxazoles with the desired properties and processes for their preparation,

Surprising catfish has now been found that the new substituted thiazoles and oxazoles of the general formula

³

CH-CH₂-N-A- (Z^) (I)

R ₂

their optical isomers and diastereomers, since the new compounds contain one or more optically active carbon atoms, as well as their Sä'ureadssalze valuable properties.

To set the lactams of the general formula I, their optical isomers and diastereomers valuable intermediates for the preparation of the morpholines 1er general formula I represents in which R 3 and R ₄ together represent an ethylene group. These morpholines and the other compounds of the above general formula I (except the lactams), their optical isomers and their diastereomers and their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic or organic acids, have quite different pharmacological properties, namely an effect on the metabolism, preferably a hypoglycemic and Körperfettreduzierende effect, as well as a lowering effect on the atherogenic ß-lipoproteins VLDL and LDL. In addition, some of the compounds mentioned above also have an anabolic effect.

In the above general formula X means

A represents an optionally substituted by methyl or ethyl groups mono- or disubstituted n-alkylene group having 2 or 3 carbon atoms,

X is an oxygen or sulfur atom,

R _{1 represents} a hydrogen or halogen atom, a trifluoromethyl, alkyl, phenyl or piperidino group or an amino group optionally substituted by one or two alkyl groups or an alkanoyl or benzoyl group,

R _{2 is} a hydrogen atom or an alkyl group,

R3 is a hydrogen atom or an alkyl group which may be substituted in the 2- or 3-position by a hydroxy group

or R ₃ together with R _{4 may be} an alkoxycarbonylmethylene group or an ethylene group / where the methylene group adjacent to the N or O atom may be replaced by a carboxyl group,

R _{4 is} a hydrogen atom, an optionally substituted by a phenyl, carboxy, alkoxycarbonyl or cyano group or in the 2- or 3-position by a hydroxy-substituted alkyl group or an alkenyl group and

/ Rg is a hydroxy, alkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbo / "" nyl group, an alkoxy group having 1 to 6 carbon atoms which is terminally replaced by a carboxy, alkoxycarbonyl, aminocarbonyl, Alkylaminocarbonyl or dialkylaminocarbonyl group, an alkoxy group having 2 to 7 carbon atoms terminally substituted by a hydroxy, alkoxy, phenylalkoxy, amino, alkylamino, dialkylamino, pyrrolidino, piperidino or hexamethyleneimino group, or an ethenylene group optionally substituted by an alkyl group which is terminally substituted by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group,

wherein all the above-mentioned alkyl, alkoxy or alkanoyl groups, unless otherwise stated, may each contain 1 to 3 carbon atoms and the above-mentioned alkenyl groups may contain 3 to 5 carbon atoms.

For the meanings mentioned in the definition of the radicals at the outset, for example

for ethylene, 1-methyl-ethylene, 2-methyl-ethylene, 1-ethyl-ethylene, 2-ethyl-ethylene, 1,2-dimethyl-ethylene, 1,1-dimethyl ethylene, 1,1-diethyl-ethylene, 1-ethyl-1-methyl-ethylene, 2,2-dimethyl-ethylene, 2,2-diethyl-ethylene, 2-ethyl-2-methyl-ethylene , n-propylene, 1-methyl-n-pro-

_ 4 _ 2 6 4 4 3

pylen-, 2-methyl ~ n-propylene, 3-methyl-n-propylene, 1-Ethyln-propylene, 2-Ethyln-propylene, 3-Ethyln-propylene, I ₁ I-dimethyl n-propylene, 1,1-diethyl-n-propylene, 2,3-dimethyln-propylene, 3,3-dimethyl-n-propylene or 3-ethyl-3-methyln-propylene group,

R ₁ represents hydrogen, fluorine, chlorine or bromine, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, phenyl, amino, methylamines, ethylamino, isopropylamino, Dimethylamino, diethylaraino, di-n-propylamino, N-ethyl-methylamino, N-ethyl-n-propylamino, piperidino, formylamino, acetamino, propionylamino or benzoylamino,

for R ₂ those of the hydrogen atom, the methyl, ethyl, n-propyl or isopropyl group,

for R ₃ those of the hydrogen atom, the methyl, ethyl, n-propyl, isopropyl, 2-hydroxy-ethyl, 2-hydroxy-propylT

or 3-hydroxy-propyl group or

Rg together with R 1 represents the ethylene group in which a methylene group may be replaced by a carbonyl group, that of the methoxycarbonylmethylene, ethoxycarbonylmethylene, n-propoxycarbonylmethylene or isopropoxycarbonylmethylene group,

for R.sup. of the water atom, the methyl, ethyl, n-propyl, isopropyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenyl-n-propyl, carboxymethyl, 1-carboxyethyl , 2-carboxyethyl, 3-carboxy-n-propyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, n-propoxycarbonylmethyl, 1-ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-isopropoxycarbonyl-n-propyl , Cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyano-n-propyl, 2-hydroxyethyl, 3-hydroxy-n-propyl, allyl, buten-2-yl, butene 3-yl or penten-2-yl group and

2 6 4 4 3

for R _{5 is} hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl ·, dimethylaminocarbonyl -, Diethylaminocarbonyl, di-n-propylaminocarbonyl, N-ethyl-methylaminocarbonyl, N-ethyl-isopropylaminocarbonyl, 2-hydroxy-ethoxy, 3-hydroxy-n-propoxy, 4-hydroxy-n-butoxy, 5 Hydroxy-n-pentoxy, 6-hydroxy-n-hexoxy, 7-hydroxy-n-heptoxy, 2-methoxy-ethoxy, 2-ethoxy-ethoxy, 2-n-propoxy-ethoxy, 3 Ethoxy-n-propoxy, 4-methoxy-n-butoxy, 6-ethoxy-n-hexoxy, 2-phenethoxy-ethoxy, 2-amino-ethoxy, 2-methylamino-ethoxy, 2-dimethyl .laminoethoxy, 2-iso-> .propylaminoethoxy, 2-di-n-propylaminoethoxy, 2- (1-pyrrolidino) ethoxy, 2- (1-piperidino) ethoxy, 2 - (l-hexamethyleneimino) ethoxy, 3-amino-n-propoxy, 6-amino-n-hexoxy, 7-methylamino-n-heptoxy, 3-diethylamino-n-propoxy, 3- (1- Piperidino) -n-propoxy, 4-dimethylamino-n-butoxy, carboxymethoxy y, 2-carboxyethoxy, S-carboxy-n-propoxy, 4-carboxybutoxy, methoxycarbonylmethoxy, 2-methoxycarbonylethoxy, 6-methoxycarbonyl-hexoxy, ethoxycarbonylmethoxy, 2-ethoxycarbonyl ethoxy, 3-ethoxycarbonyl-n-propoxy, n-propoxycarbonylmethoxy, 2-isopropoxycarbonyl-ethoxy, 4-n-propoxycarbonyl-n-butoxy, aminocarbonylmethoxy, 2-aminocarbonylethoxy, 4-aminocarbonyl-n -butoxy-, Methylami nocarbonylmethoxy-, 2-methylaminocarbonyl-ethoxy, Dime-.

thylaminocarbonylmethoxy, 2-dimethylaminocarbonylethoxy, 4-dimethylaminocarbonyl-n-butoxy, diethylaminocarbonylmethoxy, 2-diethylcinnamycarbonylethoxy, 2-di-n-propylaminocarbonylethoxy, 2-carboxy-ethenyl, 2 Carboxy-1-methyl-ethenyl, 2-carboxy-2-methyl-ethenyl, 2-carboxyl-ethyl-ethenyl, 2-carboxy-in-propyl-eth-enyl, 2-methoxycarbonyl-ethenyl, 2-methoxycarbonyl-l-methyl-ethenyl, 2-ethoxycarbonyl-ethenyl, 2-ethoxycarbonyl-l-methylethenyl or 2-isopropoxycarbonyl-ethenyl group into consideration.

For example, in addition to the compounds mentioned in the examples, mention may also be made of the following compounds which fall under the abovementioned general formula I:

N-C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-dimethylaminothiazol-4-yl) ethanamine,

N-C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-methylamino-thiazol-4-yl) ethanamine,

N-C2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-amino-thiazol-4-yl) ethanamine,

N ~C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy- (2- (2-trifluoromethylthiazol-5-yl) ethanamine,

{\ N-C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethyl-4-methylthiazol-5-yl) ethanamine,

N-C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-methoxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine,

N-C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -N-methyl-2-methoxy-2- (2-trifluoromethyl-thiazol-4-yl) -ethanamine,

N-C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -N-methyl-2-hydroxy-2- (2-methyl-thiazol-4-yl) -ethanamine,

N-C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -N-allyl-2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine,

N-C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -N- (2-phenylethyl) -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethane amine,

N-C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -N-cyanomethyl-2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine,

N-C 2- (4-Methylaminocarbonylmethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-dimethylamino-thiazol-4-yl) ethanamine,

N-L 2- (4-Methylaminocarbonylmethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-methylamino-thiazol-4-yl) ethanamine

N- [2- (4-Methylaminocarbonylmethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-5-yl) ethanamine,

N-C2- (4-Methylaminocarbonylmethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-methyl-thiazol-5-yl) ethanamiη,

N-C2- (4-Methylaminocarbonylmethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluormethy1-4-methyl-thiazol-5-yl) ethanamiη,

N- [2- (4-methylaminocarbonylmethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-methyl-oxazol-4-yl) ethanamine,

N- [2- (4-Methylaminocarbonylmethoxyphenyl) -1-methylethyl] -2-methoxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamiη,

N- [2- (4-Methylaminocarbonylmethoxyphenyl) -1-methylethyl] -N-methyl-2-methoxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine,

N-C 2- (4-methylaminocarbonylmethoxyphenyl) -1-methylethyl] -N-methyl-2-hydroxy-2- (2-methylthiazol-4-yl) ethanamine,

N- [2- (4-Methylaminocarbonylmethoxypheny1) -1-methylethyl] -2-methoxy-2- (2-methyl-thiazol-4-yl) ethanamine,

N- [2- (4-Methylaminocarbonylmethoxyphenyl) -1-methylethyl] -N-allyl-2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamiη,

N- [2- (4-methylaminocarbonylmethoxyphenyl) -1-methylethyl] -N- (2-phenylethyl) -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine,

N-C 2- (4-methylaminocarbonylmethoxyphenyl) -1-methylethyl] -N-cyanomethyl-2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) -ethanamine,

Ν- [2- (4-Methylaminocarbonylmethoxyphenyl) ethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine,

N- [2- (4-Methylaminocarbonylmethoxyphenyl) ethyl] -2-hydroxy-2- (2-methyl-thiazol-4-yl) ethanamine,

N- [2- (4-aminocarbonylmethoxyphenyl) -1-methylethyl] -N- (2-hydroxyethyl) -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamide η,

N- [2- (4- (6-Hydroxyhexoxy) phenyl) -1-methylethyl] -2-hydroxy-2- (2-methyl-thiazol-4-yl) ethanamine,

N- [2- (4- (2- (l-piperidino) ethoxy) phenyl) -l-methylethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine,

N- [2- (4- (2-methylaminoethoxy) phenyl) -1-methylethyl] -2-hydroxy-2- (2-methylthiazol-4-yl) ethanamine,

N- [2- (4-Methylaminocarbonylmethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-methyl-thiazol-4-yl) ethanamine,

N- [ 2- (4-aminocarbonylmethoxyphenyl) -1-methylethyl] -2- (2-methylthiazol-4-yl) morpholine _/

N-C 2- (4-carbomethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholine,

N- [2- (4- (2- (l-piperidino) ethoxy) phenyl) -l-methylethyl] -2- (2-trifluoromethyl-thiazol-4-yl) morpholine,

Methyl 3-C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -5- (2-methylthiazol-4-yl) -2-oxazolidinecarboxylate,

3- [2 ~ (4-Aminocarbonylmethoxyphenyl) -l-methylethyl] -5- (2-methyl-thiazol-4-yl) -2-oxazolidincarbonsa'ure-methylester,

6 4 4 3

3- [2- (4-Methylaminocarbonylmethoxyphenyl) -l-methylethyl] -5- (2-methyl-thiazol-4-yl) -2-oxazolidincarbonsä'ure-methylester,

Methyl 3- [2- (4-carbomethoxymethoxyphenyl) ethyl] -5- (2-trifluoromethylthiazole) -YD ^ -oxazolidinecarboxylic acid,

3-C2- (4-Aminocarbonylmethoxypheny1) -1-methylethyl] -5- (2-trifluoromethyl-thiazol-4-yl) -2-oxazolldincarbonsa * uremethylester,

3- [2- (4-Methylaminocarbonylmethoxyphenyl) -1-methylethyl] -5- (2-trifluoromethyl-thiazol-4-yl) -2-oxazolidinecarboxylic acid methyl ester,

3 «[2- (4-carboxymethoxyphenyl) -1-methylethyl] -5- (2-trifluoromethyl-thiazol-4-yl) -2-oxazolidincarbonsa'ure-methylester #

3-C2- (4- (6-Hydroxyhexoxy) phenyl) -l-methylethyl] -5- (2-trifluoromethyl-thiazöl-4-yl) -2-oxa ^ oliclincär'büiisäurä-metliyleöteri

3- [2- (4- (2-hydroxyethoxy) phenyl) -l-methylethyl] -5- (2-trifluoromethyl-thiazol-4-yl) -2-oxazolidincarbonsä'ure-methylester,

Methyl 3- [2- (4- (2-methylaminoethoxy) phenyl) -1-methylethyl] -5- (2-trifluoromethyl-thiazol-4-yl) -2-oxazolidinecarboxylic acid,

3-C2- (4- (2- (1-piperidino) ethoxy) phenyl) -1-methylethyl] -5- (2-trifluoromethyl-thiazol-4-yl) -2-oxazolonecarboxylic acid methyl ester,

Methyl 3-C 3- (4-carboxamidophenyl) -1-methylpropyl-5- (2-trifluoromethyl-thiazol-4-yl) -2-oxazolidinecarboxylate,

N-C2- (4-MethylaminocarbonylmethoxyphenyI) -I-methylethyl] -2-hydroxy-2- (2-chloro-thiazol-4-yl) ethanamine,

N-C2- (4-carbomethoxymethoxyphenyl) -l-methylethyl] -2-methoxy-2- (2-chloro-thiazol-4-yl) ethanamine,

N-C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -N-methyl-2-hydroxy-2- (2-chloro-thiazol-4-yl) ethanamine,

N- [2- (4-carbomethoxymethoxyphenyl) - \ - methylethyl] -N-methyl-2-methoxy-2- (2-chloro-thiazol-4-yl) ethanamine,

N- [2- (4-carbomethoxymethoxyphenyl) -l-methylethyl] -5- (2-chloro-thiazol-4-yl) -2-oxazolidincarbonsituremethyle8ter,

N -C 2- (4- (2-ethoxyethoxy) phenyl) -1-methylethyl] -N- (2-hydroxyethyl) -2-hydroxy-2- (2-chlorothiazol-4-yl) ethanamine,

3-C 2- (4- (2-carbomethoxy-1-methylethenyl) phenyl) -1-methylethyl '] - 5- (2-chlorothiazol-4-yl) -2-oxazolidinocarboxylic acid methyl ester,

N-C 2- (4- (2-hydroxyethoxy) phenyl) -1-methylethyl] -2-hydroxy-Γ- (2-methyl-oxazol-4-yl) ethanamine,

N-C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-methyl-oxazol-4-yl) morpholine,

N-C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -N- {2-hydroxyethyl) -2-hydroxy-2- (2-methyl-cis-izol-4-yl) ethanamine,

3_ [2- (4- (2-carbomethoxy-1-methylethenyl) phenyl) -1-methylethyl] -5- (2-methyl-oxazol-4-yl) -2-oxazolidinecarboxylic acid methyl ester,

NC 2- (4- (2-hydroxyethoxy) phenyl) -1-methylethyl] -N-methyl-2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine,

N-C2- (4-carbomethoxymethoxyphenyl) -l-methylethyl] -N- (2-hydroxyethyl) -2-methoxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine,

N-C2- (4- (2-hydroxyethoxy) phenyl) -l-methylethyl] -2-methoxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine,

N-C 2- (4- (2-hydroxyethoxy) phenyl) -l-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholin-6-one,

N -C 2- (4-carboxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholin-6-one

N-C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-chlorothiazol-4-yl) morpholin-6-one,

N-C2- (4-Methylaminocarbonylmethoxyphenyl) -l-methylethyl] -2- (2-trifluoromethyl ~ thiazol-4-yl) morpholin-6-one,

N-C 2- (4-aminocarbonylmethoxyphenyl) -l-methylethyl] -N- (2-hy-

droxyethyl) -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethane _<t amine "

N-C2- (4-methylaminocarbonylmethoxyphenyl) -1-methylethyl] -N- (2-hydroxyethyl) -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine,

N-C 2- (4-hydroxyethoxy) phenyl) -l-methylethyl-N-carbethoxymethyl-2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine,

N-C2- (4- (2-methoxyethoxy) phenyl) -l-metnyiethyl] -2-hydroxy-2- (trifluoromethyl-thiazol-4-yl) ethanamine,

N-C 2- (4- (2-methoxyethoxy) phenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholine,

N -C 2- (4-carboxymethoxyphenyl) -1-methylethyl] -N-methyl-2-hydroxy-2- (2-trifluoromethyl-1-thiazol-4-yl) ethanamine

N-C2- (4- (2-ethoxyethoxy) phenyl) -l-methylethyl] -2-hydroxy-2- (2-chloro-thiazol-4-yl) ethanamine,

Ν- [2- (4- (2-ethoxyethoxy) phenyl) -1-methylethy1] -2- (2-chloro-thiazol-4-yl) morpholine,

N-C 2- (4- (2-phenethoxyethoxy) phenyl) -1-methylethyl] -2-hydroxy-2- (2-chlorothiazol-4-yl) ethanamine,

N- [2- (4- (2-Phenethoxyethoxy) phenyl) -l-methylethyl] -2- (2-chloro-thiazol-4-yl) morpholine,

N -C 2- (4- (2-phenethoxyethoxy) phenyl) -1-methylethyl] -N- (2-hydroxyethyl) -2-hydroxy-2- (2-chloro-thiazol-4-yl) ethanamine;

3- [2- (4- (2-ethoxyethoxy) phenyl) -l-methylethyl] -5 ~ (2-trifluoromethyl-thiazol-4-yl) -2-oxazolidincarbon8Sure-methylester,

their optical isomers, their diastereomers and their acid addition salts.

, However, preference is given to the compounds of the general formula I in which

A is an ethylene or n-propylene group optionally substituted by a methyl group,

X is an oxygen or sulfur atom,

R, a hydrogen or chlorine atom, an AlXyigruppe having 1 to 3 carbon atoms, a trifluoromethyl, phenyl, amino, methylamino, dimethylamino, piperidino, acetylamino or benzoylamino group,

R _{2 is} a hydrogen atom or a methyl group,

R, a hydrogen atom, a methyl group or R, and R _A together form a methoxycarbonylmethylene group or an ethylene group, wherein the methylene group adjacent to the O atom can be replaced by a carbonyl group,

R _{4 represents} a hydrogen atom, a methyl, 2-hydroxyethyl, carboxymethyl, carbethoxymethyl or benzyl group and

R _{5 represents} a hydroxy, methoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, carboxymethoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, aminoo-carbonylmethoxy, methylaminocarbonylmethoxy, 2-hydroxyethoxy, 2-ethoxyethoxy , 2-phenethoxy-ethoxy, 2-amino-ethoxy, 2-methylamino-ethoxy, 2- (1-piperidino) -ethoxy, 6-hydroxyn-hexoxy or 2-carbomethoxy-1-methyl ethenyl group represents 10 len mean.

However, particularly preferred are the compounds of the general formula

(Ia)

in the

R, a chlorine atom, a methyl or trifluoromethyl group,

R.J is a hydrogen atom or R, and R ^ together the ethylene or methoxycarbonylmethylene group,

R _{4 is} a hydrogen atom, a methyl, 2-hydroxyethyl or carbethoxymethyl group and

R _{5 represents} a carboxymethoxy, carbomethoxymethoxy, ethoxycarbonylmethoxy, aminocarbonylmethoxy, MetViyla.ninocarbonylmethoxy, 2-methylamino-ethoxy-, 2-hydroxy-ethoxy or 2-carbomethoxy-1-methyl-ethenyl group.

According to the invention, the new compounds are obtained by the following processes:

- 14 -

a) reaction of a compound of the general formula

OR ₃ R ₁ _ <f ^N J-CH-CH ₂ -Z ₁

R ₂ with e'iier Vei bond of the general formula

(HD

in which

R ₁ to R ₃ , A and X are as defined above,

^z i is a nucleophilic leaving group and Z _{2 is} an R ₄ ~ NH group or

Z2 is a nucleophilic leaving group and «

Z, represent an R ^ -NH group, wherein R * is as defined above, and

Rg the door Rg has the meanings mentioned above, but wherein R ₅ ^{1 can represent} none of the above-mentioned alkoxycarbonylmethoxy and a carboxy, amino or alkylandnegroup contained in the radical R may be protected by a protective radical, and optionally adjoining cleavage of a used protective moiety.

Examples of nucleophilic leaving groups are halogen atoms or sulphonyloxy groups, e.g. a chlorine, bromine or iodine atom, the methanesulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group,

protective groups for a carboxy group include, for example, the benzyl, tert-butyl, tetrahydropyranyl, trimethylsilyl, benzyloxymethyl, 2-chloroethyl or methoxymethyl group or a phenacyl group such as the benzoylmethyl group and

as Schutzresue for an amino or alkylamino group, the acetyl, benzoyl, tert.Butoxycarbonyl-, Banzyloxycarbonyl-, ethoxycarbonyl or benzyl group into consideration.

The reaction is conveniently carried out in a solvent or mixture of solvents such as acetone, diethyl ether, methylformamide, dimethylformamide, dimethylsulforide, benzene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane or in an excess of the compounds of the general formulas II and / or III and optionally in Presence of an acid-binding agent, for example an alcoholate such as potassium tert-butylate, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride, a tertiary organic base such as triethylamine, N, N-diisopropylethylamine or pyridine, the latter may also serve as a solvent, or a reaction accelerator such as potassium iodide, depending on the reactivity of the nucleophilically exchangeable radical expediently at temperatures between 0 and 150 ⁰ C, preferably at temperatures between 5 0 and 120 ⁰ C, for example at the boiling point of the solvent used, carried out. However, the reaction can also be carried out without a solvent. However, the reaction is carried out particularly advantageously in the presence of a tertiary organic base or an excess of the amine of general formula II or III used.

The optional subsequent cleavage of a protective moiety used is preferably carried out hydrolytically in an aqueous solvent, for example in water, isopropanol / water, 5® tetrahydrofuran / water or dioxane / water, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at

· »''.

Temperatures between 0 and 100 ⁰ C, preferably at the boiling temperature of the reaction mixture. However, the splitting off of a benzyl or benzyloxycarbonyl radical takes place with preference

- 16 -

hydrogenolytically, ζ.B _r with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, if appropriate with addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ⁰ C, but preferably at room temperature, and a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

b) reduction of a Schiff'sehen base of the general formula optionally formed in the reaction mixture

(IV)

in the

R ₁ , R ₂ and X are as defined above and Y is a group of the formula

-CH-CH ₂ -NA

Represent -CO-CH, where

Rg and A are as defined above, R_ "has the meanings mentioned for R_, but wherein an amino or alkylamino group contained in the radical R may be protected by a protective radical, and Rg together with a hydrogen atom of the adjacent carbon atom of the radical A another Binding, and optionally subsequent cleavage of a used protective moiety.

- 17 -

Protective radicals for an amino or alkylamino group include, for example, the acetyl, benzoyl, tert.-butoxycarbonyl, benzyloxycarbonyl, ethoxycarbonyl or benzyl group.

The reduction is carried out in a suitable solvent such as methanol, ethanol, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate or ethanol / ethyl acetate with a metal hydride such as lithium aluminum hydride, diborane, sodium cyanoborohydride or borane / dimethyl sulfide, but preferably with sodium borohydride, or with hydrogen in the presence of a hydrogenation catalyst such as Platinum, palladium / carbon or Raney nickel at a hydrogen pressure of 1 to 5 bar or with hydrazine in the presence of a hydrogenation catalyst such as platinum, palladium / carbon or Raney-Hickel, at temperatures between 0 and 50 ⁰ C, preferably at room temperature performed , - In the reduction with a complex metal hydride such as lithium aluminum hydride, diborane or borane / dimethyl sulfide, in the radical R ^ "existing carbonyl can be mitreduziert to a methylene group.

The optional subsequent cleavage of a protective moiety used is preferably carried out hydrolytically in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ^e C, preferably at the boiling point of the 'reaction mixture. However, if the cleavage of a benzyl or benzyloxycarbonyl group is preferably hydrogenolytically, eg with hydrogen in the presence of a catalyst such as palladium / charcoal in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 5O ⁰ C but preferably at room temperature, and a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

2Ä 4 4 3 4

c) For the preparation of compounds of the general formula I in which R ₃ and R _{4 are} as defined above, but where R ₃ and R _{4 are} not ethylene groups in which the methylene group adjacent to the N atom is replaced by a carbonyl group.

Reductive amination of a carbonyl compound of the general formula

in the

Ά as defined above,

R5 ¹ 'has the meanings mentioned for R ₅ , but wherein an amino or alkylamino group contained in the radical Rg may be protected by a protective radical, and Z ₃ together with a hydrogen atom of the adjacent carbon atom of the radical A represents an oxygen atom, with an amine the general formula

(VI)

the and X R »i - N OR ₃ · R _A ' R ₂ "Χ " ~ Π CH-CH-N-H R ₂ in as R ₁ , initially are defined

R ₃ ¹ and R ₄ 'have the meanings mentioned above for R ₃ and R ₄ , but where R ₃ and R ₄ together do not denote an ethylene group in which the methylene group adjacent to the N atom is replaced by a carbonyl group, in the presence of a suitable reducing agent and given fallo subsequent cleavage of a used protective moiety.

26443

- 19 -

Protective radicals for an amino or alkylamino group include, for example, the acetyl, benzoyl, tert.-butoxycarbonyl, benzyloxycarbonyl, ethoxycarbonyl or benzyl group.

The reductive amination is carried out in a suitable solvent such as methanol, ethanol, tetrahydrofuran, dioxane or acetonitrile in the presence of a suitable reducing agent such as a suitable complex metal hydride, but preferably in the presence of sodium cyanoborohydride at ( pH 10 to pH 5 to 7) at temperatures between 0 and 50 ⁰ C, but preferably at room temperature performed.

The optional subsequent cleavage of a protective moiety used is preferably carried out hydrolytically in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / Was3er or dioxane / water, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ^° C., preferably at the boiling point of the reaction mixture. However, if the cleavage of a benzyl or benzyloxycarbonyl group is preferably hydvogenolytisch, eg with hydrogen in the presence of a catalyst such as palladium / charcoal in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ⁰ C. but preferably at room temperature, and a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

d) For the preparation of compounds of general formula I in which R _{3 represents} a hydrogen atom:

Reduction of a compound of the general formula optionally formed in the reaction mixture

- 20 -

R, -CO-CH ₂ -NA- J / ^ C ⁵

in the

A, X, R ₁ , R ₂ and R _{4 are} as defined above and

R ₅ "has the definitions mentioned above for R ₅ , but where an amino or alkylamino group contained in the radical R_ can be protected by a protective radical, and optionally subsequent removal of a used protective radical.

Suitable protective radicals for an amino alkylamino group are, for example, the acetyl, benzyl, tert.butoxycarbonyl, benzyloxycarbonyl, ethoxycarbonyl or benzyl group.

The reduction is preferably in a suitable solvent such as methanol, ethanol, diethyl ether or tetrahydrofuran in the presence of a metal hydride such as sodium borohydride, lithium aluminum hydride, diborane, borane / dimethyl sulfide or sodium cyanoborohydride, but preferably with sodium borohydride in methanol or ethanol, between 0 and 40 ^° C., preferably however, at room temperature.

In the case of reduction with a complex metal hydride, such as lithium aluminum hydride, diborane or borane / dimethyl sulfide, it is possible to co-reduce a carbonyl group present in the radical Rg to form a methylene group.

The optional subsequent cleavage of a protective moiety used is preferably carried out hydrolytically in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ^° C., preferably at the boiling point of the reaction mixture. The cleavage of a benzyl or Benzyloxycarbonylrestes is preferably carried out hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ⁰ C _1, however, preferably at room temperature, and a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

e) For the preparation of compounds of general formula I in which R and R together form an alkoxycarbonylmethylene group:

Reaction of a compound of the general formula

in the

A, X, R and R are as defined above and

Rg "has the meanings mentioned for Rg, but wherein an amino or alkylamino group contained in the radical R, - may be protected by a protective radical, with a compound of the general formula

- 22 -

O »CH - COOR ₇ , (IX)

in the

Ry represents an alkyl group having 1 to 3 carbon atoms, and optionally subsequent cleavage of a used protective moiety.

Protective radicals for an amino or alkylamino group include, for example, the trityl, fluorenylmethyloxycarbonyl, benzyloxycarbonyl or benzyl groups in BetLacht.

The reaction is expediently carried out in a solvent such as methylene chloride, chloroform, dioxane, benzene or toluene and optionally in the presence of a water-tapping agent such as p-toluenesulfonic acid or a molecular sieve at temperatures between ⁰ ° C. and the boiling point of the solvent used, but preferably in benzene or toluene by azeotropic distillation of the reaction mixture.

The optional subsequent cleavage of a protective moiety used is preferably carried out hydrolytically under mildly acidic basic conditions in an aqueous solvent, rB in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as acetic acid or trifluoroacetic acid, or under nonaqueous conditions with tert. organic bases such as triethylamine or diazabicycloundecene (DBU), but preferably hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid and a Waseerstoffdruck from 1 to 7 bar, but preferably from 3 to 5 bar, at temperatures between 0 and 50 ⁰ C, but preferably at room temperature.

- 23 -

ti For the preparation of compounds of the general formula I in which R _{5 is} an alkoxy group having 1 to 3 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, which terminates permanently with a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group or an alkoxy group having 2 to 7 carbon atoms which is end-capped by a hydroxy, alkoxy, amino, alkylamino, dialkylamino, pyrrolidino, piperidino or hexamethyleneimino group

Reaction of a compound of the general formula

in the

A, X and R ₁ to R _{3 are} as defined above and R ₄ ' ^{1 has} the meanings mentioned above for R ₄ or represents an easily cleavable protecting group for an amino group, with a compound of general formula

Z ₄ - R ₈ , (XI)

in the

Rq is an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 6 carbon atoms terminally represented by a "carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group? substituted or an alkoxy group having 2 to 7 Koiüenstoffatomen, which terminates constantlyein'ndig substituted by a hydroxy, alkoxy, amino, alkylamino, dialkylamino, pyrrolidino, piperidino or Hexamethyleniminogruppe i3t, and

- 24 -

Z _{4 represents} a nucleophilic group such as a halogen atom or a sulfonyloxy group, for example a chlorine "bromine or iodine atom", the methanesulfonyloxy, p-toluenesulfonyloxy or ethoxysulfonyloxy group, or Z ^ together with a ß-hydrogen atom of the radical Rgein oxygen atom "and optionally subsequent Splitting off a used protective remainder.

Examples of readily removable protecting compounds for the central nitrogen atom (R ₄ ") are the acetyl, benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl, ethoxycarbonyl or benzyl group.

The reaction is more conveniently carried out in a solvent such as diethyl ether, tetrahydrofuran, dioxane, methanol, ethanol or dimethylformamide and preferably in the presence of a soaking agent such as sodium hydroxide or potassium tert-butylate, but preferably in the presence of potassium carbonate or sodium hydride, or pyridine. wherein an organic base such as pyridine can also serve as a solvent, or for the preparation of 2-hydroxy-ethoxy compounds of the general formula I with ethylene oxide at temperatures between 0 and 100'C, but preferably at temperatures between 20 and 80 ^e C performed.

The xgebenanfalle subsequent cleavage of a used protective moiety is preferably carried out hydrolytically in an aqueous solvent. for example, in water, isopropanol / Wdsser, tetrahydrofuran / water or dioxane / Waeser, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ⁹ C, preferably at the boiling temperature of the reaction mixture. However, the cleavage of a benzyl or BenzyloxycarbonyLrestes preferably hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium / carbon in a

- 25 -

Solvents such as methanol, ethanol, F.sigsa'ureethylester or glacial acetic acid optionally with the addition of an acid v / ie hydrochloric acid at temperatures between 0 and 50 ⁰ C, but preferably at room temperature, and a hydrogen pressure of up to 7 bar, but preferably from 3 to bar.

g) For the preparation of compounds of general formula I in which R 3 represents a hydrogen atom:

Reduction of a compound of the general formula

OR ₃ ¹ '

-fr- CH-CO-NA- ^ S

(XII)

R ₂

in the

A, X, R ,, R2 and R4 are as hereinbefore defined and R ₃ ¹¹ represents a hydrogen atom or an alkyl group.

The reduction is, in a suitable solvent such as diethyl ether or tetrahydrofuran with a reducing agent such as a metal hydride, for example with lithium aluminum hydride, diborane or diborane / dimethylsulfide, but preferably with sodium borohydride in the presence of glacial acetic acid or Trifluoressigsa'ure, at temperatures between 0 and 5O ⁰ C but preferably at temperatures between 10 and 2S ⁰ C performed. In the reduction, an optionally present in the radicals R ₄ and R5 carbonyl can be mitreduziert simultaneously to a methyl group. Furthermore, a cyano group present in the radical R ₄ can be mitreduziert to aminomethylene group.

h) For the preparation of compounds of the general formula I in which Rc represents or contains an alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group

- 26 -

Reaction of a compound of the general formula

R _C ^IM

in the

R ₁ to R _4, A and X are as hereinbefore defined are .and R ₅ ^"1 is a carboxy group or an alkoxy group having 1 to 6 carbon atoms which is endsta'ndig substituted by a carboxy group / group, or reactive derivatives thereof such as esters thereof , with a compound of the general formula

HR _g , (XIV)

in the

Rq represents an alkoxy, amino, alkylamino or dialkylamino group, wherein each of the alkyl or alkoxy moiety may contain from 1 to 3 carbon atoms.

The esterification or amidation is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, but particularly advantageously in an excess of a compound of general formula XIV, for example in methanol, ethanol, n-propanol, isopropanol, ammonia, methylamine, ethylamine, dimethylamine or diethylamine, if appropriate in the presence of a acid activating agent or a dehydrating agent, for example in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N, N ¹ -dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / -N-hydroxy-succinimide, N, N ¹ -carbonyl-

diimidazole or N, N ¹ -thionyldiimidazole or triphenylphosphine / carbon tetrachloride, or an amino group activating agent, for example phosphorus trichloride / and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine #, which may simultaneously serve as a solvent Temperatures between -25 ^e C and 250 ^e C, but preferably at temperatures between -10 ^e C and the boiling temperature of the solvent used, carried out.

i) For the preparation of compounds of the general formula I in which R * represents an alkyl group or an alkenyl group which is optionally substituted by a phenyl, carboxy, alkoxycarbonyl or cyano group or in the 2- or 3-position by a hydroxy group:

Reaction of a compound of the general formula

OR ^ H

/ ^r ~ \ - " ^R 5 ¹¹ "

(XV)

R ₂

in the

A, X and R ₁ to Ro are as defined above and

Re "" has the meanings mentioned above for Rg, but where an amino or alkylamino group contained in the radical R may, if required, be protected by a protective radical, with a compound of the general formula

Z ₅ - R ₄ ¹ ", (XVI)

- 28 ··

in the

R. "'with the exception of the hydrogen atom has the meanings mentioned for R. and Z _{5 is} a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group, for example a chlorine, bromine or iodine atom, the methanesulfonyloxy, p-toluenesulfonyloxy or ethoxysulfonyloxy group, or

Z ₅ together with an α- or ß-hydrogen atom of the alkyl radical R "" represent an oxygen atom, and optionally subsequent cleavage of a protective group.

The alkylation is carried out in a suitable solvent such as methanol, ethanol, diethyl ether, acetone, methylene chloride, tetrahydrofuran, dioxane, dimethylformamide or dimethylsulfoxide, optionally in the presence of a base such as sodium carbonate, potassium tert-butylate, triethylamine or pyridine, the two latter also simultaneously may serve as a solvent with a suitable alkylating agent such as methyl iodide, dimethyl sulfate, ethyl bromide, diethyl sulfate, benzyl chloride, n-propyl bromide, isopropyl bromide, allyl bromide, ethylene oxide, 2-hydroxy-ethyl bromide, 2-cyano-ethyl bromide or formaldehyde / formic acid or Presence of sodium cyanoboron, if a corresponding carbonyl compound is used, at temperatures between 0 and 100 ⁰ C, carried out.

The optional subsequent cleavage of a protective moiety used is preferably carried out hydrolytically in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ^° C., preferably at the boiling point of the reaction mixture. However, the cleavage of a benzyl or benzyloxycarbonyl radical is preferably carried out by hydrogenolysis, for example with hydrogen

- 29 -

in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ⁰ C, but preferably at room temperature, and a hydrogen pressure of 1 to 7 bar, preferably however from 3 to 5 bar.

k) For the preparation of compounds of general formula I in which R ₃ and R ₄ together represent an ethylene group:

Reduction of a compound of the general formula optionally formed in the reaction mixture

HO-CH ₂ V CH ₂

, (χνΐΐ) \ - /

** in the & 2

A, X, R ₁ , R ₀ and Re are as defined above, or its cyclic hemiacetal.

The reaction is preferably carried out in a solvent such as methylene chloride, chloroform or trifluoroacetic acid with a suitable hydride such as a complex metal hydride, e.g. with sodium borohydride, with catalytically-promoted hydrogen, e.g. with hydrogen in the presence of platinum, or a trialkylsilane, e.g. with triethylsilane, optionally in the presence of an acid such as boron trifluoride, e.g. in the presence of

* Bortrifluorid etherate, at temperatures between 0 and 60 ⁰ C, but preferably in trifluoroacetic acid as a solvent and at room temperature, carried out.

l) For the preparation of compounds of the general formula I in which R ₃ and R 1 together form an ethylene group in which the methylene group adjacent to the N or O atom is replaced by a carbonyl group,

Reaction of a compound of the general formula

in the

A, X, R ₁ , R ₂ and R _{5 are} as defined above, with

a haloacetyl halide or haloacetic ester.

The reaction is conveniently carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, benzene or toluene or an excess of the acylating agent optionally in the presence of a acid scavenger such as potassium carbonate, an alkali metal hydride such as sodium hydride or in the presence of a tertiary organic base such as triethylamine or pyridine. wherein the two latter can also serve as a solvent at temperatures between 0 and 100 ⁰ C, but preferably at temperatures between the room temperature and the boiling temperature of the reaction mixture, performed. If a haloacetic ester is used in the presence of potassium carbonate in the reaction, it is preferred to obtain -ian a corresponding lactone.

m) For the preparation of compounds of the general formula I in which R 1 and R ₄ together denote an ethylene group:

Reduction of a compound of the general formula

(XIX)

in the

A, X, R ,, 1 * 2 and Rg are as defined above.

The reduction is carried out in a suitable solvent such as diethyl ether or tetrahydrofuran with a reducing agent such as a metal hydride, for example with lithium aluminum hydride or sodium borohydride in the presence of glacial acetic acid or trifluoroacetic acid, but preferably with phosphorus oxychloride / sodium borohydride, diborane or diborane / dimethylsulfide at temperatures between 0 and 5O ⁰ C, but preferably at temperatures between 10 and 25 ⁰ C performed. In the reduction, an optionally present in the radical Rc carbonyl can be mitreduziert simultaneously to a methyl group.

n) For the preparation of compounds of the general formula I in which R ₃ and R ₄ together form an ethylene group in which the methylene group adjacent to the O atom is substituted by a carbonyl group,

Cyclization of a compound of the general formula optionally formed in the reaction mixture

OH

CH-CH ₂ -NA-

² \ ', (XX)

in the

A, X, R ,, Rj and R ^ are as defined above, or their reactive derivatives such as their esters or halides.

The cyclization is carried out in a suitable solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran, acetone, methyl ethyl ketone or dioxane, optionally in countercurrent conditions.

- J Λ -

wart of a hydrophilic agent such as thionyl chloride, PhoaphortriChlorid, N, N'-Dlcyclohexylcarbodiimid, N, N'-carbonyldimidazole or Ν, Ν'-thionyldiimidazole at temperatures between 0 and 10O ⁰ C, but preferably at the boiling temperature of the reaction mixture performed.

o) For the preparation of compounds of general formula I in which R _{1 is} a hydrogen or halogen atom, a trifluoromethyl or alkyl group and R _{3 is} a hydrogen

atom representi reaction of a compound of the general formula

-U CH - CH ₂ , (XXI)

^R 2

in the

X and R2 are as defined above and R 'is a hydrogen or halogen atom, a trifluoromethyl or alkyl group, with an amine of the general formula

(XXII)

in the

A, R4 and Rg are as defined above.

The reaction is carried out in a suitable solvent, e.g. in a polar solvent such as ethanol or isopropanol

- 33 -

or in an aprotic solvent such as dimethylformamide or dimethyl sulfoxide, at temperatures between 0 and 150 ⁰ C, but preferably at temperatures between 50 and 100 ⁰ C performed.

If erfindungsgemäQ is a compound of the general formula I in which R ₅ represents or contains an alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or Dinlkylaminocarbonylgruppe and / or R _{1 is} an amino group substituted by an alkanoyl or benzoyl group, this may by hydrolysis in a corresponding compound of the general formula I, in which R5 represents or contains a carboxy group and / or R _{1 represents} an amino group, or

a compound of the general formula I in which R- represents an alkoxy group substituted by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, this may be converted by reduction by a suitable metal hydride into a compound of the general formula I in which the above-mentioned substituted alkoxy group instead of the carbonyl group containing a methylene group, be transferred or

a compound of the general formula I in which R 1 represents an alkyl group and / or R represents one of the aforementioned alkoxy groups, then this micelles ether cleavage into a corresponding compound of the general formula I in which R is a hydrogen atom and / or R- a Hydroxy group or a hydroxy substituted alkoxy group.

The subsequent hydrolysis is carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, ethanol, ethanol / water, water / iso.

- 34 -

propanol or water / dioxane at temperatures between ~ 10 ^e C and 120 ⁰ C, for example at temperatures between room temperature and the boiling temperature of the reaction mixture, carried out.

The subsequent reduction is carried out in a suitable Löeungsmittel such as diethyl ether or tetrahydrofuran with a suitable metal hydride, for example with lithium aluminum hydride, diborane or diborane / Dimethylaulfid, but preferably with sodium borohydride in the presence of glacial acetic acid or Trifluoressigsä'ure, at temperatures between 0 and 50 C ^4, preferably but at temperatures between 10 and 25 ⁰ C, Runaway leads.

Subsequent ether cleavage is carried out in the presence of an acid such as hydrochloric acid, hydrogen bromide, sulfuric acid or boron tribromide in a suitable solvent such as methanol, ethanol, water / isopropanol, methylene chloride, chloroform or carbon tetrachloride at temperatures between -3O ⁰ C and the boiling temperature of the reaction mixture.

At the subsequent. Hydrolysis, reduction or ether cleavage, compounds of general formula I in which R ₃ and R ₄ together an ethylene group in which the adjacent to the O atom methylene group is replaced by a carbonyl group, means are cleaved simultaneously.

As already mentioned, the new compounds in the form of their enantiomers, mixtures of enantiomers or racemates, or if they contain at least 2 asymmetric carbon atoms, also exist in the form of their diastereomers or diastereomer mixtures.

Thus, the compounds of general formula I which contain only one optically active center can be resolved into their optical antipodes by methods known per se (see Allinger NL and Elich WL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) .

- 35 -

e.g. by recrystallization from an optically active solvent or by reacting with an optically active substance which forms salts with the racemic compound, in particular acids, and separating the salt mixture obtained in this way, e.g. due to different solubilities, into the diastereomeric salts from which the free antipodes can be released by the action of suitable agents. Particularly common optically active acids are e.g. the D and L forms of tartaric, di-o-toluenoic, malic, mandelic, camphorsulfonic, glutamic, aspartic or quinic acids.

Furthermore, the resulting compounds of general formula I having at least 2 asymmetric carbon atoms due to their physical-chemical differences according to known methods, 3.B. separated by chromatography and / or fractional crystallization, in their diastereomers. A pair of enantiomers thus obtained can then be separated into its optical antipodes as described above. If, for example, a compound of the general formula I contains two optically active carbon atoms, the corresponding (RR ¹ , S S ') and (RS ¹ , S R') forms are obtained.

The compounds used as starting materials, which of course can also be used in their optically pure forms, are obtained by literary methods (see "Thiazoles and its Derivatives" in Heterocyclic Compounds, Vol. 34, and Advances in Heterocyclic Chemistry, Vol. 17, from p. 100 (1974)) or are known from the literature. These are partially present only in the reaction mixture and therefore can not be isolated in part.

The compounds of general formula II used as starting substances, is in the Z, a nucleophilic leaving group, is obtained by reduction of a corresponding acetyl compound, for example with a complex metal - * * * hydride, and optionally subsequent alkylation.

- OD -

A compound of the general formula IV, which need not be isolated, is obtained by reacting a compound of the general formula

? ^R 3

_R // 4L-CH-CH ₂ -NH

R ₂

with a carbonyl compound of the general formula

or by reacting an amine of the general formula

.R "

", (XXIV)

with a glyoxal of the general formula

CO-CHO, (XXV)

in which

R ₁ to R ₃ , R ₅ , A and X are as defined above,

R ₅ "has the meanings mentioned for R ₅ ,

wherein, however, an amino or alkylamino group contained in the radical R_ may be protected by a protective radical, and Z ₃ together with a hydrogen atom of the adjacent carbon atom of the radical A represent an oxygen atom, in the presence of sodium cyanoborohydride in a suitable solvent such as methylene chloride, chloroform, dioxane, Benzene or toluene and optionally in the presence of a

dehydrating agent such as p-toluenesulfonic acid ouer a molecular sieve at temperatures between ^{0 0} C and the boiling temperature of the solvent used, but preferably in benzene or toluene by azeotropic distillation of the reaction mixture.

A compound of the general formula required for the preparation of the starting compounds

Y 4L CO-CH 2 Br x

in the ^c

R ₁ , R ₂ and X are as defined above, obtained by bromination of the corresponding acetyl compounds in glacial acetic acid or hydrogen bromide / glacial acetic acid at temperatures between 20 and 100 ⁰ C or even if R. in the 5-position represents a hydrogen atom and X represents a sulfur atom , By ring closure of the corresponding thicamides with Dibromdiacetyl

'5 in a solvent such as diethyl ether or acetonitrile. Further, for example, when Rj in the 4-membered group represents a methyl group and X represents a sulfur atom, the above-mentioned acetyl compounds are obtained by reacting a corresponding thioamide with 3-chloroacetylacetone in water, ethanol, water / ethanol or in the melt (see Z. Chem. % 187 (1969)) or, when R ₂ in the 5-position represents a methyl group and X represents an oxygen or sulfur atom, by reacting a corresponding acylamino-acetylacetone with dehydrating agents (see Chem. Ber. 84, 96

(1951) and Chem. Ber. £ 3, 1998 (I960)) or with phosphorus pentasulfide or with 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide.

An aminoketone of the general formula VII is obtained in the reaction mixture by reacting a corresponding bromoacetyl derivative with a corresponding amine or with urotropin and subsequent hydrolysis.

2 * 44 34

- 38 -

The compounds of the general formulas VIII, X, XIII, XV and XX used as starting materials are expediently obtained by alkylation of a corresponding amine.

The compounds of general formula XII used as starting materials are obtained by acylation of a corresponding amine.

A compound of the general formula XXI used as starting material is obtained, for example, by reacting a corresponding bromohydrin with aqueous potassium hydroxide solution or by reacting a corresponding aldehyde with dimethylsulfonium methylide at ⁰ ° C. in dimethyl sulfoxide / tetrahydrofuran.

A corresponding. Glyoxal is obtained, for example, by reacting a corresponding bromoacetyl compound of the general formula XXVI with dimethyl sulphoxide at room temperature.

Furthermore, the resulting compounds of the general formula I can be converted into their acid addition salts, in particular for the pharmaceutical application in their physiologically acceptable salts with inorganic or organic acids. Examples of suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

As already mentioned, the new compounds of the general formula I in which Ro and R _A together form ^? an ethylene group in which the methylene group linked to the N atom is replaced by a carbonyl group, represent valuable intermediates for the preparation of the morpholines of general formula I.

The other novel compounds of the general formula I (excluding the lactams), their enantiomers, mixtures of enantiomers or racemates, or if they contain at least 2 asymmetric

contain carbon atoms, their diastereomers or diastereomer mixtures and their acid addition salts, in particular for the pharmaceutical use of their physiologically acceptable Sä'ureaddit.ionssalze, have valuable pharmacological properties, in addition to an inhibitory effect on the Plä'ttchenaggregation in particular an effect on the Metabolism, preferably a hypoglycemic and Körperfettreduzierende effect, and a lowering effect on the atherogenic ß-lipoproteins VLDL and LDL. In addition, some of the compounds mentioned above also have an anabolic effect. - In this case, that Diaatereomer, if R _{1 represents} a trifluoromethyl group, has proved to be particularly preferred, its proton in the 5-position of the thiazole ring Jn of the morpholine series in the CDCl / CD OD-NMR spectrum and in the ethanolamine series in the CDCl-NMR spectrum lies at lower field.

For example, the following compounds were tested for their biological properties as follows:

A = N-C2- (4-carbomethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine,

B = N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine,

C = N- [2- (4-aminocarbonylmethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine,

D = N- [2- (4-methylaminocarbonylmethoxyphenyl) -1-methylethyl] -2-hydoxy-2- (2-trifluoroethylthiazol-4-yl) ethanamine,

E = ri- [2- (4-carboxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine,

F = N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethyl-thiazol-4-yl) morpholine,

- 40 -

G a 3- [2- (4-carbomethoxyphenyl) -l-methylethyl] - '5' (2-tr-fluoromethyl-thiazol-4-yl) -2-oxazolidinecarboxylic acid, ethyl ester (pairs of diastereomers A and B),

H = 3-Γ "> - (4-carbomethoxyphenyl) -1-methylethyl] -. 5- (2-trifluoromethyl-thiazol-4-yl) -2-oxazolldinecarboxylic acid methyl ester (pairs of diastereomers c and D),

= 3- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -5- (2-trifluoromethyl-thiazol-4-yl) -2-oxazolidinecarboxylic acid methyl ester (pairs of diastereomers A and B),

J = 3- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -5- (2-trifluoromethyl-thiazol-4-yl) -2-oxazolidinecarboxylic acid methyl ester (pairs of diastereomers C and D),

K = N- [2- (4-carbomethoxy-p-ethoxyphenyl) -1-methyl-ethyl] -N-methyl-2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) -ethanamine,

L = N-C2- (4-aminocarbonylmethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-methylthiazol-4-yl) ethanamine,

M = N-C2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-methylthiazol-4-yl) ethanamine,

20N = N-C2- (4-carbomethoxymethoxyphenyl) -1-methylethyl-2-hydroxy-2- (thiazol-4-yl) ethanamine,

= N-C2- (4-carboxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholine,

P = N-C2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-chlorothiazol-4-yl) ethanamine,

Q = N-C2- (4- (hydroxyethoxy) phenyl) -] - methylethyl] -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamide; and

R = 3- [2- (4- (2-carbomethoxy-1-methyl-1-ethyl) -phenyl) -l-methyl-ethyl] -5- (2-trifluoromethyl-thiazol-4-yl) -2-oxazolidinecarboxylic acid methyl ^ ter

1. Antidiabetic effects

The antidiabetic effect of the compounds according to the invention can be measured as a blood sugar-lowering effect in experimental animals. The substances to be examined were suspended in 1.5% methyl cellulose and applied to female mice of their own breed by gavage. Thirty minutes later, 1 g of glucose per kg of body weight was dissolved in water and administered subcutaneously. Another 30 minutes later, blood was withdrawn from the retroorbital venous plexus. From the serum, glucose was determined by the hexokinase method using an analysis photometer.

1Γ · The following table summarizes the blood sugar reductions observed in this experimental set-up in% of an entrained ontrial group. The statistical evaluation "follows the student's t-test with p = 0.05 as the significance limit.

- 42 -

264431

15 connection % Change from the value of 0.3 1 t -32 3 10 control group Dose [mg / kg] -40 -64 -73 30 A -68 -63 ul B -65 -70 20 C -57 -76 D -61 -64 -68 e -56 -70 F -59 10 G -68 -72 H -36 -60 I -42 J -61 R -58 -60 L -23 M -60 N -52 O P -56 Q R

2. anti-adipose effect;

The anti-adipose activity of the compounds according to the invention was demonstrated in two experimental arrangements:

a) In the first experiment, the increase in lipolysis was measured by the increase in serum glycerin. The experimental procedure is identical to the test procedure described above for testing the hypoglycemic effect.

- 43 -

Order. Glycerol was determined in a combined enzymatic colorimetric assay using an analytical photometer. The results are listed in the following table in% of an entrained control group.

connection % Change from the value of 0.3 I 3 10 control group Dose Cmg / kg] 88 312 326 30 A 504 B 433 C 226 732 D 413 430 439 e 209 305 F 168 G 204 228 H 260 391 I 283 J 220 K 307 453 416 L (8th) M 336 N 217 O 221 P 758 Q R

() - not significant (p ^ ₃ 0.05)

b) In the second test arrangement for detecting anti-adipose activity of the compounds according to the invention, the decrease in adipose tissue was measured using the example of the ovarian fetal tissue. The compounds were applied for this purpose Ma'usen once a day by gavage in 1.5% methyl cellulose suspension. On the fifth day the ovary

- 44 -

fottengewebe prepared and weighed. The following table shows the results in% of an initiated control group.

connection % Change from the value of the control group 5 Dose is 10 [mg / kg] A -36 B -60 C -35 D -30 10 F -47 G -33 H -20 I -28 J -11 15 K -12 L -53 M -48

3. Cardiac Adverse Events *

The occurrence of undesired side effects on the heart could be ruled out for the compounds according to the invention for the therapeutically desired metabolic active dose range. As proof, the measurement of the heart rate in mice was used during the test for hypoglycemic effect (see above). One hour after the oral administration of the compounds, the heart rate was determined by means of an ECG-triggered tachograph. The following table shows the change in heart rate in% of the control group.

- 45 -

connection % Change from the value of the control group 0.3 1 3 Dose [mg / kg] (21) (0) A (11) 5 B 17 C 17 D (9) e (3) F (0) 10 I (-4) J (-1) K (7) M O

() = not significant (p> 0.05)

Furthermore, no toxic side effects were observed in the above-described studies of the substances according to the invention at the applied doses. These are therefore well tolerated.

Due to their pharmacological properties, therefore, the new compounds of general formula I, in which R is not a hydrogen atom, as well as their physiologically acceptable acid addition salts with inorganic or organic acids for the treatment of diabetes mellitus as well as obesity, especially for the treatment of the obese Di «., Oetikers. In addition, the new compounds can be used for the prophylaxis and treatment of atherosclerotic changes in the vessels, which are more common especially in diabetics and Obesen occur. Here, the required dose can be fully tailored to the metabolic-physiological needs of the individual patient,

- 46 -

In adults, therefore, the daily doses are between 1 and 30000 mg, but preferably 1 to 1000 mg, distributed over 1 to 4 doses per day. The above-mentioned can be used for this purpose Incorporate compounds, optionally in combination with other active substances, in the usual galenisohen preparations such as powders, tablets, dragees, capsules, Suppoeitorien or suspensions.

Furthermore, the compounds mentioned above can be used for the treatment of obese animals such as dogs and as a result of their body fat reducing (lipolytlecher) effect to reduce unwanted fat deposits in fattening, ie to improve the quality of meat of fattening animals such as pigs, cattle, sheep and poultry the animals, the application of the above compounds orally or non-orally, z. B ₄ carried out as a feed additive or by injection or via implanted minipumps · The daily dose is in this case between 0.01 and 100 mg / kg, preferably jedooh between 0.1 to 10 mg / kg body weight.

Au8führungebeispielt

The following examples are intended to explain the invention in more detail:

- 47 -

Example Λ

2-trifluoromethyl-4-bromoacetyl-thiazole

9.2 g (0.071 mol) of trifluoromethylthioacetamide dissolved in 200 ml of acetonitrile are added dropwise in 2.5 hours to a boiling solution of 17.4 g (0.071 mol) of dibromodiacetyl in 200 ml of acetonitrile. The solvent is distilled off and the remaining product is extracted with cyclohexane. The extract is concentrated and the remaining oily residue is purified on a silica gel column with toluene / cyclohexane as the eluent.

Yield: 8.2 g (42.7% of theory), Melting point: 36-37 ⁰ C

Example B

2, 4-dimethyl-5-acety.l-thiazole

1 * 3 A mixture of 34 g (0.25 mol) of 3-chloroacetylacetone and 19 g (0.25 mol) of thioacetamide are slowly heated with stirring. At about 6O ⁰ C begins an exothermic reaction. The heating bath is removed, the mixture is stirred for a further 1 hour and the product is allowed to cool. The precipitated hydrobromide is triturated with petroleum ether / ethanol = 5/1 and filtered with suction. For conversion to the free base, the salt is dissolved in water and made alkaline with sodium bicarbonate. The mixture is then extracted several times with methylene chloride, the organic phase dried over sodium sulfate, concentrated and the residue was purified over a.Kieselgelsäule with toluene as the eluent.

Yield: 19.7 g (51% of theory) ¹ H-NMR spectrum (CDCl ₃ ): ί = 2.50 ppm (s, CH)

Example C 2,4-dimethyl-5-bromoacetyl-thiazole

A solution of 20.8 g (0.13 mol) of bromine in 50 ml of glacial acetic acid is slowly added to a stirred solution of 20.2 g (0.13 mol) of 2,4-dimethyl-5-acetyl-thiazole in glacial acetic acid dropwise. After 1 hour, it is concentrated to dryness, dissolved in water and neutralized with a sodium carbonate solution. The mixture is then extracted several times with methylene chloride, the organic phase is dried and concentrated. The resulting oil was used without further purification for further reactions

 Yield: 24 g (79% of theory).

Example D 2-phenyl-4-formyl-thiazole-cyanohydrin

16.4 g (0.0607 mol) of 2-phenyl-4-formyl-thiazole hydrobromide are heated in 230 ml of water and 150 ml of dioxane in a steam bath at 30 ⁰ C, wherein about 80-90% of the substance solves. It is then cooled in an ice bath to 2O ⁰ C and 22 g (0.162 mol) of potassium dihydrogen phosphate added in portions with vigorous Küiuen. Subsequently, 6.1 g (0.124 mol) of sodium cyanide are added in portions and the mixture is stirred at room temperature for 1.5 hours. The precipitated product is extracted with ether, the organic phase dried over sodium sulfate, concentrated and the residue dried in vacuo.

Yield: 13 g (100% of theory),

Melting point: 140-141 ⁰ C

Calc .: C 62.20 H 3.72 N 12.95 S 14.82 F .: 62.35 3.91 12.89 14.93

Example E

2- (2-trifluoromethyl-thiazol-4-yl) glyoxal

3 g (0.011 mol) of 2-trifluoromethyl-4-bromoacetyl-thiazole are dissolved in 30 ml of dimethyl sulfoxide and kept at room temperature for 70 hours. Thereafter, the solution is poured onto 100 g of ice, extracted several times with ether, the organic phase dried over sodium sulfate, concentrated and the residue over a silica gel column with toluene / ethyl acetate = 7/3 as eluent

 Yield: 1.3 g (56% of theory).

Beiopiel F

2-trifluoromethyl-5-methy1-4-bromoacetyl-oxazol

a) 3-Trifluoroacetamino-acetylacetone 10 g (0.0662 mol) of 3-amino-acetylacetone hydrochloride are carefully mixed with 56 g (0.266 mol) of trifluoroacetic anhydride. The reaction mixture foams strongly and then forms a clear solution. The mixture is refluxed for 30 minutes, then the solvent is removed, the residue is taken up in 500 ml of ether and shaken three times with 100 ml of saturated sodium bicarbonate solution each time. The ether phase is dried over sodium sulfate and concentrated.

Yield: 12 g (86% of theory), Melting point: 44-46 ⁰ C

Ber. : C, 39.81, H, 3.81, N, 6.63, Gef.: J9.80, 3, 67, 6, 87

- 50 -

h) 2-Trifluoromethyl- 5- methyl-4-acetyl-oxa-ol 5 g (0.0237 mol) of 3-trifluoroacetamino-acetylacetone are heated with 5 ml of trifluoroacetic anhydride for 4 hours on a steam bath , The Löpung thereby discolored and the Trifluoressigsä'ureanhydrid evaporates almost completely. The residue is dissolved in 100 ml of chloroform and shaken three times with 50 ml of saturated sodium bicarbonate solution. The chloroform phase is dried over sodium sulfate and evaporated

 Yield: 3.2 g (70% of theory),

^ • H-NMR spectrum (CDCl): S = 2.52 ppm (s, CH }}

2.65 ppm (s, CH).

c) 2-Trifluoromethyl: ^r -methyl-4-bromoacetyl- oxazole 3.8 g (0.02 mol) 2-trichloromethyl-5-methyl-4-acetyl-oxazole are dissolved in 30 ml glacial acetic acid and washed with 3 ml 33 % hydrogen bromide solution in glacial acetic acid added. The mixture is heated to 8O ⁰ C and in the course of one hour with a solution of 3.2 g (0.02 mol) of bromine in 10 ml of glacial acetic acid. After another 30 minutes, the glacial acetic acid is withdrawn. The residue remains a dark oil, which is further reacted as a crude product.

Yield 4.4 g (81% of theory),

¹ H-NMR spectrum (CDCl / CD OD): 8 = 2.72 ppm (s, CH)

4.52 ppm (s, CH ₂ )

Example G

2, S-dimethyl - ^ - bromoacetyl-oxazole

2.8 g (0.02 mol) of 2, S-dimethyl ^ -acetyl-oxazole are dissolved in 30 ml of glacial acetic acid and washed with 3 ml of 35% strength. Hydrobromic acid solution is added in glacial acetic acid. The mixture is heated to 100 ⁰ C and in the course of 1 hour with a solution of 3.2 g (0.02 mol) of bromine in 10 ml of glacial acetic acid. After a further 2 hours, the solvent is stripped off, the residue is triturated with 50 ml of ether and filtered with suction

Yield: 4.4 g (74% of theory), Melting point: 175-176 ⁰ C.

Calc .: C 28.12 H 3.03 N 4.68 Br 53.45 V: 28.29 2.93 4.78 53.37

Example H 2-methyl-4-formyl-thiazole-cyanohydrin

Prepared analogously to Example D by reaction of 2-methyl-4-formyl-thiazole with sodium cyanide and potassium dihydrogen phosphate in dimethylformamide / water = 1/1. After extraction with ethyl acetate, drying of the extract with sodium sulfate is purified over a Kieselgelsä'uls with toluene / ethyl acetate = 8/2 as eluent, yield: 41% of theory, melting point: 116-117 ° C ¹ H-NMR spectra (DMSO / CD ^ D): i = 7.580 ppm (s, lH)

- 52 - 2 6 4 4 3

Example I 4-Formyl-thiazole-cyanohydrin

Prepared analogously to Example D by reacting 4-formylthiazole hydrobromide with sodium cyanide and potassium dihydrogen phosphate in water. The precipitate is filtered off with suction and washed with water. After drying in a vacuum desiccator gives an almost colorless crystals _: which is reacted without further purification. Yield: 53% of theory, Melting point: 113-115 ⁰ C.

Example K

2-trifluoromethyl-5-methyl-4-bromoacetyl-thiazole

a) 2-trifluoromethyl-5-methyl-4-acetyl-thiazole

5.8 g (0.0275 mol) of 3-trifluoroacetamino-acetylacetone are reacted with 6.4 g (0.0158 mol) of 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetan-2 , 4-disulfide in 35 ml of absolute toluene with stirring and nitrogen for 10 hours at 100 ⁰ C heated. The resulting clear solution is concentrated and the residue is purified over a silica gel column with methylene chloride as the eluent.

Yield: 3.1 g (54% of theory),

Ber. : C 40.19 H 2.88 N 6.69 S 15.32 V: 40.45 2.69 6.87 15.33

b) 2-trifluoromethyl-5-methyl-4-bromoacetyl-thiazole ·

3 g (0.0144 mol) of 2-trifluoromethyl-5-methyl-4-acetyl-thiazole are dissolved in 30 ml of glacial acetic acid and 2.1 ml of 33% hydrogen bromide solution in glacial acetic acid. The l.ischung is heated to 80 ⁰ C and in the course of 30 minutes with a solution

of 2.3 g (0.0144 mol) of bromine in 15 ml of glacial acetic acid. After another 20 minutes, the glacial acetic acid is removed. The residue remains a dark oil, which is further reacted as a crude product

 Yield: 3.8 g (92% of theory),

₁ H NMR spectrum (CDCl 3 / CD 3 OD): = 2.90 (S ₁ CH ₃ );

4.70 (S, CH ₂ ).

Example L

2-hydroxy-2- (2-propyl-thiazol-4-yl) ethanamine

Prepared analogously to Example P by reduction of 4- (α-cyano-α-hydroxy-methyl) -2-propyl-thiazole (melting point: 68-7O ⁰ C) with sodium borohydride in a tetrahydrofuran / Trifluoressigsä'ure mixture. For workup is added with cooling with water, stirred until the solution of the formed low-impact, with conc. Hydrochloric acid and heated at 20 ^° C. for 30 minutes and at 100 ^° C. for 60 minutes. After cooling and adding water, the organic phase is separated and discarded. The acidic aqueous phase is extracted once more with ethyl acetate, which is discarded. Then it is made strongly alkaline with 6N sodium hydroxide solution under ice-cooling. By repeated extraction with chloroform and drying, filtration and evaporation of the chloroform solution in vacuo, nanocrystals crystallize the evaporation residue from ether. -

Yield: 75% of theory, melting point: 73-75 ⁰ C.

Example M

2-hydroxy-2- (2-isopropyl-thiazol-4-yl) ethanamine

Prepared analogously to Example L by reduction of 4- (a-Cy-

- 54 -

Ano-α-hydroxy-methyl) -2-isopropyl-thiazole (melting point t 56-58 ⁰ C) with sodium borohydride in a tetrahydrofuran / trifluoroacetic acid mixture

Yield «72% of theory, melting point: 82-85 ^e C

Example N 2-Hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) -ethylamine

4.6 g (0.033 mol) of urotropin are added to a solution of 9 g (0.033 mol) of 2-trifluoromethyl-4-bromoacetyl-thiazole in 30 ml of methylene chloride at 10 ⁰ C with stirring and cooling. After a few seconds, a thick crystal cake precipitates. It is cooled to 0-3 ⁰ C, after 20 minutes, the precipitate was filtered off with suction and washed with ether. After drying at 4O ⁰ C, colorless crystals are obtained.

Yield: 11.1 g (81.3% of theory), m.p .: 134-137 ° C

This urotropin salt is dissolved in 330 ml of ethanol and heated to boiling together with a solution of 70 ml of concentrated hydrochloric acid in 600 ml of water for 2 hours. It is then concentrated to dryness. The solid residue thus obtained is dissolved in 300 ml of methanol, cooled to ⁰ ° C. and washed successively with 2.4 g of sodium hydrogencarbonate. and in small portions with 4.2 g of sodium borohydride. After 2 hours, 30 ml of 30% sodium hydroxide solution are added and the mixture is stirred

² ^ 20 minutes after. After dilution with 200 ml of water and repeated shaking with methylene chloride, the organic phase is dried over sodium sulfate, concentrated and purified over a Kxeselgelsä'ule with methanol as eluent. Yield: 2.9 g (51% of theory),

¹ H-NMR spectrum (CDCl ₃ ZCD ₃ OD): ί = 7.675 ppm (s, IH)

Example 0

2- (2-trifluoromethyl-thiazol-4-yl) morpholine

A solution of 0.9 g (0.036 mol) of 2- (2-trifluoromethyl-thiazol-4-yl) morpholin-5-one in 40 ml of tetrahydrofuran is added at 3 ⁰ C with 1.35 g (0.036 mol) of sodium borohydride. At 5-8 ⁰ C are then very slowly with vigorous stirring 2.43 g (0.036 mol) of glacial acetic acid dissolved in 20 ml of tetrahydrofuran, added dropwise. After 2 hours, the cooling is removed and stirred at room temperature for 16 hours. After concentration to dryness, the residue obtained is mixed with 15 ml of 20% strength hydrochloric acid and heated to 90 ^° C. for 30 minutes. It is then evaporated to dryness, the product obtained is taken up in water and made alkaline with sodium carbonate solution. The mixture is then extracted several times with Mothylenchlorid, the organic phase over sodium sulfate getrock net, concentrated and the residue over a silica gel column with ethyl acetate / methanol = 8: 2 purified as eluent. Yield: 0.56 g (65% of theory), ¹ H-NMR spectrum (CDCl ₃ ZCD ₃ OD): S = 4.750 ppm (dd, »CH-O)

Example P

2-Hydroxy-2- (2-phenylthiazol-4-yl) etnanamine

To a suspension of 11.4 g (0.3 mol) of sodium borohydride in 200 ml of absolute tetrahydrofuran 34.2 g (0.3 mol) of trifluoroacetic acid in 60 ml of absolute tetrahydrofuran are added dropwise with ice cooling. Subsequently, 13 g (0.06 mol) of 2-phenyl-4-formyl-thiazol-cyanohydrin are added in portions and then stirred for 20 hours at room temperature. The solvent is removed, the residue carefully with

- 56 -

100 g of ice added, ι It dilute hydrochloric acid acidified and heated for 1 hour in a steam bath. The mixture is cooled to room temperature, made alkaline with ammonia solution and extracted with chloroform. The extract is dried over sodium sulfate, concentrated and purified on a silica gel column with methanol as eluent

Yield: 10.2 g (77.3% of theory), mp 92-94 ⁰ C.

Ber. t C 59.97 H 5.49 N 12.71 Fe.j 60.15 5.61 12.83

Example Q 2-hydroxy-2- (thiazol-4-yl) ethanamine

Prepared analogously to Example P by reacting 4-formylthiazole with Nat-iumborhydrid and trifluoroacetic acid in tetrahydrofuran. The product obtained by extraction with methylene chloride is purified on a Kieselgelsä'ule with methanol as the eluent

Yield »19% of theory V-NMR spectrum (CDCl ₃ ZCD ₃ OD): S = 4.880 ppm (dd, = CHOH)

Example R

2-hydroxy-2- (2-methyl-thiazol-4-yl) ethanamine

Prepared analogously to Example P by reacting 2-methyl-4-formyl-thiazole with sodium borohydride and trifluoroacetic acid in tetrahydrofuran

 Yield: 63% of theory,

¹ H-NMR spectrum (CDCl / DD OD): S = 7.150 ppm (s, IH)

«J« 3

Example S 2- (2-trifluoromethylthiazol-4-yl) morpholin-5-one

0.3 g (0.0064 mol) of a sodium hydride dispersion (50-55% in oil) are added at 3O ⁰ C in small portions with stirring to a solution of 1 g (0.0047 mol) of 2-hydroxy-2 (2-trifluoromethyl-thiazol-4-yl) -ethylamine in 15 ml of toluene. After 1 hour, a solution of 0.55 g (0.0045 mol) of ethyl chloroacetate in 2 ml of toluene is added dropwise. After 2 hours, 1 ml of ethanol and then 4 ml of water are added dropwise.

It is then made acidic with hydrochloric acid, extracted several times with methylene chloride and the extract dried over sodium sulfate. The product obtained is purified on a Kieselgelsä'ule with ethyl acetate / methanol = 1 / l as the eluent and digested after concentration to dryness with a little ether.

Yield: 0.36 g (32% of theory), melting point 139-141 ⁰ C ι

Example T 2- (2-methylthiazol-4-yl) morpholin-5-one

Prepared analogously to Example S by reaction of 2-hydroxy-2- (2-methyl-thiazol-4-yl) ethylamine with ethyl chloroacetate and purification on a silica gel column with ethyl acetate / methanol = 19: 1 as the eluent.

Yield: 29% of theory,

Melting point: 125-126 ° C Calc .: C 48.47 H 5.08 N 14.13 S 16.17 Vig .: 48.63 5.07 14.10 16.47

Example U 2- (2-methylthiazol-4-yl) morpholine

Prepared analogously to Example 0 by reduction of 2- (2-methyl-thiazol-4-yl) morpholin-5-one with lithium aluminum hydride, and without purification of the base. Via a silica gel column with chloroform / methanol / ammonia β 93t7j 0.7 as eluent , Exploits 4 (>% of theory,

Ber.i C 52.15 H 6,56 N 15,20 S 17,40 F .: 52,37 6,52 15,27 17,32

Example V

2-hydroxy-2- (2-methyl-thiazol-5-yl) ethanamine

a) 2-methyl-5-formyl-thiazole-cyanohydrin

0.5 g (0.004 mol) of 2-methyl-5-formyl-thiazole are dissolved in 3 ml of water and cooled to 15 ⁰ C. In succession, 1 g of potassium dihydrogen phosphate and 0.4 g of sodium cyanide are added. Almost immediately a colorless product precipitates, which is stirred for 25 minutes at 1O ⁰ C and then filtered with suction. The crude product obtained is reacted further without further purification

 Yield: 0.5 g (81% of theory)

b) 2-hydroxy-2- (2-methylthiazol-5-yl) ethanamine

Prepared analogously to Example P by reacting 2-methyl-5-formyl-thiazol-cyanohydrin in tetrahydrofuran with sodium borohydride and trifluoroacetic acid. The base is purified over a Kieselgelsä'ule with methanol as the eluent and used as a crude product for further reactions. Yield: 87% of theory

Example W 2- (N, N-dimethylamino) -4-bromoacetyl-thiazole

133.5 g of dibromo diacetyl are refluxed in 2.1 'x 1 ether over 2.5 days with 57 g of Ν, Ν-dimethylthiourea in a Soxhlet apparatus. After cooling the reaction mixture and concentration, the residue obtained is taken up in water, neutralized with saturated sodium bicarbonate solution and extracted several times with methylene chloride. The combined extracts are dried, filtered, concentrated and then purified on a silica gel column with toluene / ethyl acetate = 8: 2 as eluent

Yield: 50 g (27.7% of theory), Melting point: 113-115 ⁰ C Calc .: C 33.75 H 3.64 N 11.26 S 12.87 Br 32.08 Found .: 33,90 3 , 63 11,25 12,69 32,25

Example X

2-hydroxy-2- (2-methyl- oxazol-4-yl ) -ethanamine

a) 2-methyl-4-formyl-oxazole-cyanohydrin

Prepared analogously to Example V by reacting 6 g (0.0543 mol) of 2-methyl-4-formyl-oxazole with 5.45 g (0.11 moles) of sodium cyanide and 14.4 g (0.1 g mol) of potassium dihydrogen phosphate in 180 ml of water and 60 ml of dioxane.

Yield: 6.2 g (83% of theory),

The substance is oily

 Calc .: C 52.17 H 4.37 N 20.28 F .: 52.08 4.50 19.98

b) 2-Hydroxy-2- (2-methyl-oxazol-4-yl) ethanamine Prepared analogously to Example P by reacting 6 g

(0.0435 mol) of 2-methyl-4-formyl-oxazol-cyanohydrin with 8.25 g (0.217 mol) of sodium borohydride in tetrahydrofuran and 24.6 g (0.214 mol) of trifluoroacetic acid

 Yield: 2.7 g (44% of theory), The substance is oily.

Calc .: C 50.69 H 7.09 N 19.70 V: 50.32 7.22 19.68 ¹ (80 MHZ) (CDCl ₃ ): S - 7.55 ppm (s, lH)

Example Y 2-chloro-4-bromoacetyl-thiazole

7.6 g (6.0344 mol) of 2-amino-4-bromoacetyl-thiazole are dissolved in 20 ml of water and 50 ml of concentrated hydrochloric acid. At ⁰ ° C., a solution of 3.44 g (0.0499 mol) of sodium nitrite in 15 ml of water is then added dropwise with stirring. The resulting diazonium salt solution is then introduced, while stirring vigorously, into a cold solution of 4.93 g (0.0449 mol) of copper (IChloride in 15 ml of concentrated hydrochloric acid in portions and the mixture is stirred at room temperature for 20 hours Water and extracted with ether.The ether extract is dried over sodium sulphate and evaporated.For purification, the crude product is purified over a silica gel column with methylene chloride as the eluent

 Yield: 4g (48% of theory),

Melting point: 72 ^° C.

Calc .: C 24.96 H 1.25 N 5.82 F .: 25.12 13.30 6.00

Example Z 2-pipetidino-4-bromoacetyl-thiazole

7, 2 g (0.05 mol) of piperidino-thiourea are heated in a Soxhlet apparatus for 10 hours with a solution of 12.2 cj (0.05 mol) Dibromdiacetyl in 1 1 of ether to reflux. The precipitated yellow compound is filtered off, in 500 ml

Dissolved chloroform and the chloroform solution extracted with 400 ml of saturated sodium bicarbonate solution. The chloroform solution is then dried over sodium sulfate and evaporated to -10. The crude product is purified on a silica gel column with toluene as the eluent

Yield: 7.5 g (52% of theory), Melting point: 78-80 ^r 'C

Calc.: C 41.53 H 4.52 N 9.68 Br 27.63 "15 Found: 41.80 4.47 9.40 27.57

Example ZA

2-methoxy-2- (2-methyl-thiazol-4-yl) ethanamine

Prepared analogously to Example L by reduction of 4 - (ot-cyano-methoxy-methyl) -2-methyl-thiazole [obtained from 4- (dimethoxymethyl) -2-methyl-thiazo.l by reaction with trimethylsilyl cyanide in ether in the presence of boron trifluoride etherate 3 using sodium borohydride in a tetrahydrofuran / trifluoroacetic acid mixture

 Yield: 80% of theory (oil),

Mass spectrum: Ber. (M + H ⁺ ) = 173

Gef. (M + H ⁺ ) = 173

Example ZB

2- (2-trifluoromethyl-thiazol-4-yl) ethylene oxide

a) 1- (2-trifluoromethyl-thiazol-4-yl) -1-hydroxy-2-bromoethane

6 g (0.022 mol) of 2-trifluoromethyl-4-bromoacetyl-thiazole are dissolved in 150 ml of methanol, cooled to 10 ⁰ C and treated with 0.63 g of sodium borohydride. After 15 minutes, ice is added, acidified with hydrochloric acid, rendered alkaline with ammonia and extracted by shaking with methylene chloride. The organic phase is dried over sodium sulfate, filtered and concentrated. An oil is obtained which is reacted further as crude product

 Yield: 5.4 g (89% of theory)

"• H-NMR spectrum (80 ΜΗε) (CDCl ₃ ): = = 7.7 ppm (s, IH)

b) 2- (2-trifluoromethyl-thiagol-4-yl) ethylene oxide

5 g (0.018 mol) of 1- (2-trifluoromethyl-thiazol-4-yl) -l-hydroxy-2-bromoethane are suspended in 4 ml of 50% sodium hydroxide solution and stirred for 5 minutes. Then ir.it is diluted with ice water and extracted by shaking with methylene chloride. The organic phase is dried over sodium sulfate, concentrated in vacuo at 20 ⁰ C and the resulting oil was purified over a Kieselgelsä'ule with methylene chloride as the eluent. Yield: 2.15 (67% of theory),

¹ H-NMR spectrum (80 MHz) (CDCl 3): £ = 7.5 ppm (s, IH)

Example ZC (2-methyl-thiazol-4-yl) ethylene oxide

10.2 g (0.048 mol) of trimethylsulfonium iodide are dissolved in 42 ml of dimethyl sulfoxide and added with stirring to a cooled to ⁰ ° C solution of 1.14 g of sodium hydride in 50 ml of dimethyl

- 63 -

sulfoxide / tetrahydrofuran (1: 1) was added dropwise. After 60 minutes is added dropwise at ^{0 0} C, a solution of 6.1 g of 2-methyl-4-formylthiazol in 25 ml of tetrahydrofuran and stirred for 3 hours at room temperature. It is then cooled to ⁰ ° C., 9.6 ml of water are added dropwise and the mixture is extracted with ether. The ethereal phase is shaken out 2 × with water, dried and concentrated. The resulting oil is purified on a silica gel column with toluene / ethyl acetate (65:35) as eluent. Yield: 1.6 g (24% of theory), "" H-NMR spectrum (80 MHz) (CDCl-): J = 7.1 ppm (s, IH)

example 1

N -C 2- (4-carbomethoxyphenyl) -1-methylethyl ") N-benzyl-2-hydroxy-2- (2-benzoylamino-thiazol-4-yl) ethane amine

3.5 g (0.011 mol) of 2-benzoylamino-4-bromoacetyl-thiazole are dissolved in 20 ml of dimethylformamide and stirred at room temperature to a solution of 2.6 g (0.092 mol) of N-benzyl-2- (4-carbomethoxyphenyl ) -l-methyl-ethylamine and 1.1 g (0.011 mol) of triethylamine, dissolved in 40 ml of dimethylformamide, added dropwise. After 1.5 hours, ice / water is added and extracted with methylene chloride. The extract is used. Dried sodium sulfate and concentrated, the resulting aminoketone is taken up in 100 ml of methanol and treated at room temperature with 0.6 g of sodium borohydride. After 1 hour, the mixture is evaporated to dryness, mixed with water and acidified with hydrochloric acid. After 10 minutes, it is made alkaline with ammonia and extracted with methylene chloride. The extract is dried over sodium sulfate, concentrated and purified on a silica gel column with toluene / ethyl acetate = 8: 2 as the eluent

Yield: 1.4 g (29% of theory), Ber. : C 68.03 H 5.90 N 7.93 Found: 68.13 6.11 7.88 ^ -NMR spectrum (CDCl ₃ ZCD ₃ OD): S = 6.875 ppm (s, IH)

Example 2

N- [2- (4-Carboxyphenyl) -1-methylethyl] -N-benzyl-2-hydroxy-2- (2-amino-thiazol-4-yl) ethanamine

13.6 ml (0.0136 mol) of 1 N sodium hydroxide solution are added at room temperature to a solution of 1.5 g (0.0034 mol) of N- [2- (4-carbonyl)

- 65 -

methoxyphenyl) -1-methylethyl] -tl-benzyl-2-hydroxy-2- (2-aminothiazol-4-yl) ethanamine in dioxane / methanol = 1: 1 added dropwise within 10 minutes with stirring. After 1 hour, 20 ml of water are added dropwise so slowly that always a solution is maintained. After 16 hours, 13.6 ml (0.0136 mol) of 1N hydrochloric acid are added and the mixture is extracted with methylene chloride, dried over sodium sulfate, concentrated to dryness and the resulting base is purified over a silica gel column with ethyl acetate / methanol = 9: 1

 Yield: 0.36 g (26% of theory),

Calc .: C 64.21 H 6.12 N 10.21 Found: 64.12 6.12 9.99 ¹ H-NMR spectrum (DMSO): $ »6.250 ppm (s, IH)

Example 3

N- [2- (4-Carboethoxyphenyl) ethyl] -2-hydroxy-2- (2-benzoylaminothiazol-4-yl) ethanamine

9.6 g (0.03 mol) of 2-benzoylamino-4-bromoacetyl-thiazole are dissolved in 100 ml of methylene chloride and added with stirring at room temperature to a solution of 11.5 g (0.06 mol) of 2- (4-Carboethoxyphenyl ) ethylamine in 150 ml of methylene chloride was added dropwise. After 1.5 hours, it is cooled to 5 ^° C., diluted with 200 ml of methanol, and 3 g of sodium borohydride are added in small portions to reduce the aminoketones obtained at ⁰ ° -5 ° C. After 3 hours, the solution is evaporated to dryness, treated with ice / water and acidified with hydrochloric acid. After 10 minutes, make alkaline with sodium bicarbonate solution and extract with methylene chloride. The extract is dried over sodium sulfate, concentrated and purified over a Kieselgelsa'ule with chloroform / methanol = 9: 1 with the addition of 2% with ammonia-saturated ethanol as eluent. The product obtained is brought to crystallization with petroleum ether.

- 66 -

Exploits 3.4 g (26% of theory), mp j 83-85 ^e C

Calc .: C 62.03 H 5.73 N 9.56 Gef. »62.75 5.78 9.41

Example 4

N -C 2- (4-carboxyphenyl) ethyl] -2-hydroxy-2- (2-benzoylamino-thiazol-4-yl) ethanamine

Prepared analogously to Example 2 by reaction of N- [2- (4-

Carboethoxyphenyl) ethyl] -2-hydroxy-2- (2-benzoylamino-thia-10th-zol-4-yl) -ethanamine with 1 N sodium hydroxide solution and subsequent

Purification of the crude product over a silica gel column Chloroform / methanol "ItI and trituration with Wassor / ethanol

9il.

Yield: 36% of theory, Melting point: 143-145 ⁰ C (dec.)

The. C 61.29 H 5.14 N 10.14Gef.j 61.19 5.18 10.06

Example 5

N -C? - (4-carboethoxyphenyl) ethyl]? -2-hydroxy-2- (2-benzoylamino. 4-methylthiazol-5-yl) ethanamine

Prepared analogously to Example 3 by reaction of 2- (4-CarboethoxyphenyDethylamin and sttfchiometirisehen amounts of triethylamine with 2-benzoylamino-4-) ethyl-5 ~ bromoacetyl-thiazole, followed by reduction and purification of the base on a Kieselgelsa'ule with chloroform / methanol = * 9: 1 as Eluens and Trituration with Petrolethei.

Exploits 33% of theory »Melting point: 96-98 ^e C

Ber.j C 63,55 H 6,00 N 9,26 Gef.t 63,45 5,85 9,19

Example 6

N -C 2- (4-Carboethoxyphenyl) ethyl] -2-hydroxy-2- (2-acetylamino-4-methylthiazol-5-yl) ethanamine

Prepared, analogously to Example 3 by reaction of 2- (4-car-

BoethoxyphenyDethylamin and stoichiometric amounts of triethylamine with 2-acetylamino-4-methyl-5-bromoacetyl-thiazole, followed by reduction and purification of the base over a

Kieeelgelsä'ule with Eseigester / methanol 19ti as Eluens and Trituration with ether.

Exploits 33% of theory, 1f; Melting point t 97-99 ⁰ C

Ber. »C 58,29 H 6,44 N 10,73Ft. 58.40 6.58 10.61

Example 7

N -C 2- (4-Carboxyphenyl) ethyl] -2-hydroxy-2- (2-acetylamino-4-methylthiazol-5-yl) ethanamine

Prepared analogously to Example 2 by reacting N-C 2- (4-carboethoxyphenyl) ethyl] -2-hydroxy-2- (2-acetylamino-4-methyl-thiazol-5-yl) ethanamine with 1 N sodium hydroxide solution. After neutralization with 1 N hydrochloric acid is evaporated to dryness and the residue is recrystallized from 10 ml of water. Exploits 80% of the theory ·

Melting point ·, j 156-158 ⁰ C

-es- 26443

Ber.ι C 56 18 H 5, 83 N 11 56 Gef .: 56 20 5, 95 11 61 Example 8

N- [2- (4-Carboethoxyphenyl) ethyl] -2-hydroxy-2- (2-amino-4-methylthiazol-5-yl) ethanamine dihydrochloride

3 g (0.013 mol) of 2-amino-4-methyl-5-bromoacetyl-thiazole are added with stirring at room temperature in small portions to a solution of 5.2 g (0.026 mol) of triethylamine in 300 ml of tetrahydrofuran. After 2 hours turns to dry

ΙΟ concentrated. The residue obtained is dissolved in ethanol and to reduce the aminoketone formed in small portions 1.5 g of sodium borohydride are added at 15 ⁹ C with stirring. After 16 hours, the solution is concentrated to dryness, treated with water and acidified with hydrochloric acid.

Then it is made alkaline with ammonia and extracted with methylene chloride. The extract is dried over sodium sulfate, concentrated and purified on a Kieselgelsä'ule with chloroform / methanol ^a 8: 2 as eluent. The resulting base is dissolved in ethanol, converted to the dihydrochloride with isopropanolic hydrochloric acid and acetone and washed with ether.

Exploits 3.5 g (64% of theory), melting point 160 ⁰ C t Ber.t C 48.34 H 5.97 N 9,95Gef. j 48,23 6,20 9,97

Example 9

N- [2- (4-Carboxyphenyl) ethyl] -2-hydroxy-2- (2-amino-4-thiazole-4-yl) ethanamine dihydrochloride

Dissolve 1.5 g (0.0043 mol) of N- [2- (4-carboxyphenyl) ethyl-2-hydroxy-2- (2-acetylamino-thiazol-4-yl) ethanamine in 30 ml of 1 N hydrochloric acid and dissolve Heated to 90 ⁰ C for 2.5 hours and then concentrated to dryness. The remaining residue is recrystallized from a mixture of 50 ml of ethanol and 3 ml of water and the resulting crystals are washed with ether.

Yield: 1.4 g (85% of theory), Melting point: 218-219 ⁰ C.

Ber.:, C 44,21 H 5,04 N 11,05 Found: 44,40 5,17 10,94

Example 10

N- [2- (4-Carbomethoxypheny1) -1-methylethy1] -2-hydroxy-2- (2-acetylamino-thiazol-4-yl) ethanamine hydrochloride

Prepared analogously to Example 3 by reacting 2- (4-carbomethoxyphenyl) -l-methylethylamine and triethylamine in tetrahydrofuran with 2-acetylamino-4-bromoacetyl-thiazole, followed by reduction and purification of the base over a silica gel column with ethyl acetate / methanol - 9 : 1 as eluent and precipitation of the hydrochloride with isopropanolic hydrochloric acid from ether.

Yield: 36% of theory, melting point 118-120 ⁰ C.

Calc .: C 52.23 H 5.84 N 10.15 Found: 51.98 6.01 9.97 According to ¹ H-NMR spectrum (400 MHz), there is an approx. 35:65 diastereomer mixture.

Example 11

N -C 2- (4-Carboxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-amino-thiazol-4-yl) ethanamine dihydrochloride

Prepared by Example 9 by reacting N- [2- (4-carboxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-acetylamino-thiazol-4-yl) ethanamine and 1N hydrochloric acid. Yield: 79% of theory, melting point: 167 ^° C.

Calc .: C 45.69 H 5, 37 N 10.66 V .: 45.49, 5.51, 10.54

According to ¹ H-NMR-SPeKtTUm (400 MHz), there is an approx. 40-60 diastereomeric mixture.

Example 12 _H

N- [2- (4-carbomethoxyphenyl) -1-methylethyl] -2-hydrox y-2- (2-trifluoromethylthiazol-4-yl) ethanamine

1.3 g (0.0062 mol) of 2- (2-trifluoromethyl-thiazol-4-yX) glyoxal and 1.2 g (0.0057 mol) of 2- (4-carbomethoxyphenyl) -l-methylethylAt.ir. are combined at 0 ° C and stirred at room temperature for 4 hours. To reduce the Schiff'sehen base formed is added with 0.75 g of sodium borohydride in portions at 20 ⁰ C and stirred for 16 hours. It is then poured onto ice, acidified with hydrochloric acid, made alkaline with Natriumbicarbonc'tlösung and extracted with methylene chloride. The extract is dried over sodium sulfate, concentrated and purified on a silica gel column with methylene chloride / methanol = 40: 1 as eluent. Yield: 1.5 g (68% of theory),

- 71 -

SSSR. i C 52.57 H 4.93 N 7.21 Gef.i 52.71 5.08 7.30

¹ H-NMR SPeKtTUm _(CDCl3): S = 4.735 ppm (dd, "CH-OH);

4.895 ppm (dd, = CH-OH)

According to ¹ H-NMR SPeKtTUm (400 MHz), there is an approx. 60:40 diastereomer mixture.

Example 13

N -C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-phenylthiazol-4-yl) ethanamine

1.32 g (0.006 mol) of 2-hydroxy-2- (2-phenylthiazol-4-yl) ethanamine and 1.33 g (0.006 mol) of 1- (4-carbomethoxymethoxyphenyl) -propan-2-one are dissolved in Dissolved 40 ml of absolute methanol, treated with 0.34 ml (0.006 mol) of glacial acetic acid and 0.37 g (0.006 mol) of sodium cyanoborohydride and stirred for 20 hours at room temperature. It is then poured onto ice, acidified with hydrochloric acid, made alkaline with sodium bicarbonate solution and extracted with chloroform. The extract is dried over sodium sulphate, concentrated and purified on a silica gel column with ethyl acetate / methanol = 9: 1 as the eluent. Yield: 2.2 g (86% of theory),

Ber. : C, 4.76; H, 6.14; N, 6.56; S, 7.51; Found: 64.50; 6.42; 6.39; 7.30; ¹ H NMR SPeCTTM (CDCl3): S = 4.88 ppm (dd , = CH-OH);

4.93 ppm (dd, = CH-OH)

According to ¹ H-NMR-SPeKtTUm (400 MHz) there is an approx. 5O: 5O-diastereomeric mixture.

Example 14

N- [2- (4-Aminocarbonylmethoxyphenyl) -1-methylethy1] -2-hydroxy-2- (2-methyl-thiazol-4-yl) ethanamine

1 g (0.0027 mol) of N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-methyl-thiazol-4-yl) ethanamine are dissolved in 5 ml of methanol and washed with 5 ml of concentrated ammonia stirred for 3 hours at room temperature. It is then diluted with water and extruded with methylene chloride. The extract is dried over sodium sulfate, concentrated and purified on a Kieselgelsä'ule with Essigester / metha nol ^ O ^a 9: as eluent. 1 Yield: 0.76 g (81% of theory), m.p .: 148 ^e C

Calc .: C 58, ^ 43 H 6,63 N 12,02 Found: 58,62 6,69 12,00

According to the ¹ H-NMR spectrum (400 MHz), an approximately 25:75 diastereomeric mixture is present.

Example 15

N -C 2- (4-Methylaminocarbonylmethoxyphenyl) -1-methylethyl] 2-hydroxy-2- (2-L-difluoromethylthiazol-4-yl) ethanamine

Prepared analoy example 3 by reaction of 2-trifluoromethyl-4-bromoacetyl-thiazole and 2- (4-methylaminocarbonylmethoxyphenyl) -l-methylethylamine, followed by reduction and purification of the base over a Kieselgelsä'ule with methylene chloride / methanol = 9: 1 as eluent ,

Yield: 10% of theory, calc .: C 51.79 H 5.31 N 10.17 V .: 51.79, 5.55, 10.91

- 73 -

¹ H-NMR spectrum (CDCl- / CD-OD): S = 7.575 ppm (s, IH),

Oh, J

7.595 ppm (s, IH);

According to the ^ -H NMR spectrum (400 MHz), there is an approx. 50:50 diastereomeric mixture.

Example 16

N- [2- (4-carboxyphenyl) -l-methylethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine

Prepared analogously to Example 2 by reacting N- [2- (4-carbomethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine with 1 N sodium hydroxide solution. After neutralization with hydrochloric acid, the mixture is evaporated to dryness and the residue is treated with a mixture of ethyl acetate / ethanol = 6: 1. The extract is concentrated to dryness and triturated with 5 ml of water. After washing off the water, the remaining residue is taken up in methanol, brought to dryness, triturated with ether and filtered with suction.

Yield: 52% of theory, Melting point: 107-109 ⁰ C,

Ber. : C 51 33 H 4, 58 N 7, 48 Gef .: 51 41 4, 74 7, 42

According to '• H-NMR spectrum (400 MHz), there is an approx. 60:40 diastereomeric mixture.

Example 17

N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholine

Prepared analogously to Example 13 by reacting 2- (2-trifluoromethyl-thiazol-4-yl) morpholine with 1- (4-carbomethoxymethoxyphenyl) propan-2-one and then purifying the base on a silica gel column with toluene / ethyl acetate = 8t.sub.2 as eluent.

Yield: 54% of theory, Ber.t C 54.04 H 5.22 N 6.30 Found: 54.28 5.24 6.46 "H-NMR spectrum (CDCl ₃ ): ί »7.610 ppm (s, IH);

7.575 ppm (s, IH)

According to ¹ H-NMR SPeKtTUm (400 MHz), there is an approx. 50:50 diastereomeric mixture.

Example 18

Methyl 3- [2- (4-carbomethoxymethoxyphenyl) -1-ethylethyl] -5- (2-trifluoromethyl-thiazol-4-yl) -2-oxazolidinecarboxylate

0.52 g (0.0012 mol) of N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine and 0.211 g (0, 0024 mol) of methyl glyoxylate are heated in 25 ml of toluene for 10 minutes at 100 ° C and then boiled for 1 hour on a water. The solution is mixed after cooling with 50 ml of ethyl acetate and shaken with 30 ml of water. The organic phase is separated, dried over sodium sulfate and concentrated. The residue

is purified via a laboratory finished column, size B (Merck) with toluene / ethyl acetate = 20: 1.5 as eluent. Fraction A (pairs of diastereomers A and B): Yield: 90 mg (15.4% of theory), ¹ H-NMR spectrum (CDCl ₃ ZCD ₃ OD): S = * 5.10 ppm (s, IH);

5.24 ppm (s, IH)

According to the ¹ H NMR spectrum (400 MHz), there is an approx. 50:50 diastereomeric mixture.

Fraction E (pairs of diastereomers C and D): yield: 110 mg (18.8% of theory),

^ NMR Spectrum (CDCl ₃ ZCD OD): £ = 4.97 ppm (s, IH);

5.21 ppm (s, IH) m (400 MHz) lieeren mixture before.

According to the '• H-NMR spectrum (400 MHz), there is an approximately 50:50 diaste-

Example 19

Methyl 3- [2- (4-carbomethoxyphenyl) -1-methylethyl] -5- (2-trifluoromethyl-thiazol-4-yl) -2-oxazolidinecarboxylate

Prepared analogously to Example 18 by reacting N- [2- (4-carbomethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine with methyl glyoxylate. Fraction A (pairs of diastereomers A and B): yield: 25% of theory),

¹ H-NMR spectrum (CDCl ₃ ZCD ₃ OD): I = 5.07 ppm (s, IH); 5.26 ppm (s, IH) According to the ¹ H NMR spectrum (400 MHz), there is an approximately 45:55 diastereomeric

Romerengemisch ago.

Fraction B (pairs of diastereomers} C and D): yield: .23% of theory),

H-NMR spectrum (CDCl ₃ ZCD ₃ OD): S = 5.08 ppm (s, IH);

⁵ » ²² PP ^m < ^s '

According to ¹ H-NMR SPeKtTUm (400 MHz) there is an approx. 35:65 diastereomeric mixture.

Example 20

N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethy1] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine

Prepared analogously to Example 3 by reaction of 2- (4-carbomethoxymethoxyphenyl) -1-methylethylamine with 2-trifluoromethyl-4-bromoacetyl-thiazole, followed by reduction and purification of the base over a silica gel column with methylene chloride / methanol = 20: 1 as eluent

Yield: 51% of theory, Calc .: C 51.66 H 5.06 N 6.70 Found ..: 51.40, 5.14, 6.64 ¹ H-NMR SPeKtTUm _(CDCl3): S = 4.835 ppm (dd, = CH-OH);

4.895 ppm (dd, = CH-0II)

According to ¹ H-NMR SPeKtTUm (400 MHz), there is an approx. 60:40 diastereomer mixture.

Example 21

N- [2- (4-carbomethoxyphenyl) -l-methylethyl] -2-hydroxy-2- (4-methyl-oxazol-5-yl) ethanamine dihydrochloride

2.6 g (0.009 mol) of 4-methyl-5-bromoacetyl-oxazole and 1.16 g (0.009 mol) of Ν, Ν-diisopropyl-ethylamine are dissolved in 50 ml of methylene chloride. This solution is added dropwise to 3.47 g (0.018 mol) of 2- (4-carbomethoxyphenyl) -1-methylethylamine in 100 ml of methylene chloride within 20 minutes and the

- 77 - 20 443 ⁴

Stir for 2 hours at room temperature and stirred at 35 ⁰ C for one hour. The reaction solution is cooled in an ice bath and treated with 150 ml of methanol. To reduce the resulting aminoketone then 1 g of sodium borohydride are added in portions over 30 minutes, stirred for 20 hours at room temperature Tempe and evaporated. The residue is then treated with ice-water, acidified with hydrochloric acid, made alkaline with aqueous concentrated ammonia and extracted with chloroform. The extract is dried over sodium sulphate, concentrated and concentrated over a pine gel column

Ethyl acetate / methanol «· 9t1 purified as Eluenu. Subsequently

the hydrochloride is precipitated with ethereal hydrochloric acid.

Exploits 1.1 g (31% of theory),

Melting point "80 ⁰ C (dec.) Ber.i C 52.17 H 6.18 N 7.13 Cl 18,14Gef .: 52.00 6.10 6.90 17.90

According to the ¹ H NMR spectrum (400 MHz), there is an approx. 50-50 diastereomeric mixture.

Example 22

N ~ C2- (4-carbomethoxyphenyl) -l-methylethyl] -2-hydroxy-2- (thiazol-4-yl) ethanamine

Prepared analogously to Example 3 by reaction of 2- (4-carbomethoxyphenyl) -3, ~ methylethylamine with 4-bromoacetyl-thiazole, followed by reduction and purification of the base over a silica gel plate with ethyl acetate / methanol = »8: 2 as eluent. Yield: 9 % of theory, Ber. i C 59.97 H 6, 29 N 8.75 Yield j 60.09 6.01 8.56! H-NMR spectrum (CDCl 3): S = 4.900-4.970 ppm (m, = CH-0H);

According to ¹ H-NMR-SPeKtTUm (400 MHz), an approximately 6Oi40-Diaeteromerengemiech is present.

Example 23

N -C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -N-methyl.2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine

Prepared analogously to Example 3 by reacting 2-trifluoromethyl-4-bromoacetyl-thiazole and N-methyl-2- (4-carbomethoxymethoxyphenyl) -1-methylethylamine, followed by reaction. Production and purification of the base over a silica gel column with Essigsfcer / methanol 40il as eluent. Exploiting 53% of theory, Ber.t C 52.77 H 5.36 N 6.48 Gef.t 53.00 5.06 6.64 ¹ H-NMR spectrum (CDCl ^ / CD OD) ti »7,555 ppm (s, IH) 7.575 ppm (s, IH)

According to ¹ H-NMR SpGUrUm (400 MHz) is an approximately 5O »5O Diaeteromerengemisch before.

Example 24

N- [2- (4-aminocarbonylmethoxyphenyl) - * l -methylethyl] -2-hydroxy 2- (2-trifluoromethylthiazol-4-yl) ethanamine

Prepared analogously to Example 14 by reaction of NC 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine with concentrated ammonia and subsequent purification of the base via a kieselgolsa 'column with methylene chloride / methanol ^a 9t 1 as eluons.

- 79 - 2 6 4 4 3

Exploits 65 % of the theory »Der. 5 C 50, H e H 5.00 N 10.42 Qef.t 50.43 5.19 10.37 ^L H-NMR spectrum (CDCl) ι £ 4,850 ppm (dd, -CH-OH); 4.775 ppm (dd, -CH-OH)

According to ¹ H NMR spectra (400 MHz), there is approximately 60i40 diastereomeric.

Example 25

N- [2- (4-CarbomethoxymrLhoxyphenyl) -l-methylethyl] -2 'hydroxy-2 - (^ - methyl-thinzol-4-yl) ethanamine

Prepared analogously to Example 13 by reacting ^ 2-hydroxy-2- (2-methyl-thiazol-4-yl) ethylamine with 1- (4-carbomethoxy · mfii-hoxyphenyUpropan-2-one and subsequent purification of the Daee ü one he KieselgolsKule with ethyl acetate / Methonol 9tl as eluent.

Exploits 55% of the theory,

Ber. t C 59.32 H 6.64 N 7.69

Gef.i 59.20 6.45 7.91

^ I-NMR spectrum (CDCl ₃₎ I J- 4.825 ppm (dd, -CH-OH);

4.775 ppm (dd, -CH-OH)

According to the ^ -NMR spectrum (400 MHz), there is approximately 50t50 diastereomeric.

- 80 -

Example 26

N -C 2- (4-carbomethoxymethoxyphenyl) -1-trethylethyl] -2-hydroxy-2- (thiazol-4-yl) ethanamine

Prepared analogously to Example 13 by reacting 2-hydroxy-2- (thiazol-4-yl) ethylamine with 1- (4-carbomethoxymethoxyphenyl) propan-2-one and then purifying the base on a silica gel column with Bssigester / Mothanol 8i2 as Eluene.

Exploits 48% of theory, Ber.i C 58.26 H 6.33 N 8.00 Gef.i 58.41 6.36 8.22 ^ NMR Spectrum (CDCl ₃ ) I £ - 4.945 ppm (dd, -CH-OH);

4,900 ppm (dd, -CH-OH)

According to the ¹ H NMR spectrum (400 MHz), there is approximately 50t50 diastereomeric.

Example 27

N -C 2- (4-carbomethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2,5-dimethyl-oxazol-4-yl) ethanamine dihydrochloride

Prepared analogously to Example 21 by reaction of 2,5-dimethyl-4-biromacetyl-oxazole with 2- (4-carbomethoxyphenyl) -l-methylethylamine, followed by reduction and filling of the

Dihydrochlorides with ethereal hydrochloric acid. Notwithstanding 47% of theory,

Melting point! 78 ^S C (Zers.) Ber. »C 53.33 H 6.46 N 6.90 Cl 17.51

Oef.t 53.10 6.50 6.80 17.32

- 81 -

According to ¹ H NMR SPeKtrum (400 MHz), there is an approximately 5O 5O diastereomer mixture.

Example 28

N- [2- (4-Carbomethoxymethoxypheny1) -1-methylethy1] -2-hydroxy-2- (2,5-dimethyl-oxazol-4-yl) ethanamine dihydrochloride

Prepared analogously to Example 21 by reacting 2,5-dimethyl-4-bromoacetyl-oxazole with 2- (4-carbomethoxymethoxyphenyl-1-methylethylamine, followed by reduction and precipitation of the dihydrochloride with ethereal hydrochloric acid. Yield: 47% of theory, melting point: 82 ⁰ C (Zers.)

Calc .: C 52.41 H C, 48 N 6.43 Cl 16.28 F .: 52.21 6.55 6.50 16.40

According to the ¹ H NMR spectrum (400 MHz), there is an approximately 5O: 5O diastereomeric mixture.

Example 29

N-C2- (4-CarbomethoxymethoxyphenyI) -I-methylethyI] -2-hydroxy-2- (2,4-dimethyl-thiazol-5-yl) ethanamine

Prepared analogously to Example 3 by reacting 2,4-dimethyl-5-bromoacetyl-thiazole with 2- (4-carbomethoxymethoxy) yl-methylethylamine, followed by reduction and purification of the Ease on a silica gel column with ethyl acetate / methanol = 17: 3 ,

Yield: 45% of theory, calc .: C 60.29 H 6.92 N 7.40 Gef.: 60, 53 6.85 7.60

S = 4.890-4.970 ppm (m, -CH-OH);

According to the ^ -INMR spectrum (400 MHz), there is an approximately 53t47 diastereomeric Sch.

Example 30

N- [2- (4-Carboethoxymethoxyphenyl) -1-methylethyl] -N- (2-hydroxyethyl) -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine

Prepared analogously to Example 3 by reacting 2-trifluoromethyl-4-bromoacetylthiazole and N- (2-hydroxyethyl) -2- (4-carbomethoxymethoxyphenyl) -1-methylethylamine. Prior to reduction with sodium borohydride, the reaction is heated to boiling for 3 hours to complete the reaction. Subsequently, the base is purified over a Kieselgelsa'ule with ethyl acetate as eluant

 Exploits 50% of the theory,

Calc .: C 51.94 H 5.45 N 6.06 Found: 52.00 5.33 6.09

¹ H-NMR SPeKtTUm (CDCl) ι S = 0.930 ppm (d, -CH-);

³ I

CH ₃

0.970 ppm (d, -CH-)

CH ₃

Example 31

N- [2- (4-Carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethyl-5-methyl-oxazol-4-yl) ethanamine hydrochloride

Prepared analogously to Example 21 by reacting 2-trifluoro-ethyl-5-methyl-4-bromoacetyl-oxazole with 2- (4-carbomethoxymethoxyphenyl) -l-methylethylamine and subsequent reduction. The compound is purified on a Kieselgelsa'ule with Essic / ester / methanol = 20: 1 as eluent and then-Qend the hydrochloride precipitated with ethereal hydrochloric acid. Yield: 0.43 g (10% of theory), m.p .: 58 ^° C.

Calc .: C 50.38 H 5.34 N 6.18 Cl 7.82 F .: 50.58 5.33 5.93 8.20

Example 3 2

N -C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholine

Prepared analogously to Example 3 by reacting 11.6 g (0.043 mol) of 2-trifluoromethyl-4-bromoacetyl-thiazole with 23 g (0.086 mol) of N- (2-hydroxyethyl) -2- (4-carbomethoxymethoxyphenyl) -1-methylethylamine , For complete reaction is heated to boiling for 6 hours. The mixture is then concentrated in vacuo, the residue obtained is dissolved in 85 ml of trifluoroacetic acid and treated with 7 g (0.06 mol) of triethylsilane at room temperature. After 90 hours, the solution is poured onto ice, treated with concentrated ammonia and extracted several times with methylene chloride. The organic phase becomes

- 84 -

dried over sodium sulfate, concentrated and the residue over a Kieselgelsä'ule with toluene / ethyl acetate = 8/2 as eluent.

Yield · 11 g (58% of theory), ¹ H-NMR spectrum: S = 7.610 ppm (s, IH); 7,578 ppm (s, IH)

According to the ^ -NMR spectrum (400 MHz), there is an approx. 43:57 mixture of diastereomers.

Example 33

NC 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy- 2- (2-trifluoromethyl-5-methylthiazol-4-yl) ethanamine

Prepared analogously to Example 3 by reacting 2-trifluoromethyl-5-methyl-4-bromoacetyl-thiazole with 2- (4-carbomethoxymethoxyphenyl) -1-methylethylamine and subsequent reduction. The compound is purified on a Kieselgelsä'ule with ethyl acetate / methanol = 9/1 as eluent. Yield: 8% of theory, Ber ,: C 52.77 H 5.36 N, 6.47

Found .: 52.60 5.44 6.55 ¹ H-NMR spectrum _(CDCl3) S i- 4.765 ppm (dd, = CH-OH); "4.810 ppm (dd, = CH-OH)

According to ¹ H-NMR-SPeKtTUm (400 MHz) there is an approx. 54:46 diastereomeric mixture.

Example 34

N-C3- (4-carboxamidophenyl) -l-methylpropyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine

Prepared analogously to Example 13 by reaction of 2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine with 1- (4-carboxamidophenyl) butan-3-one and subsequent purification of the base over a silica gel column with ethyl acetate / methanol = 5/1 as eluent.

Yield: 26% of theory, Melting point: 119-121 ⁰ C.

Calcd .: C 52.70 H 5.20 N 10.85 F .: 52.61 5.35 10.84

According to the ^ -NMR spectrum (400 MHz), there is an approximately 50:50 diastereomeric mixture.

Example 35

N- [2- (4-Carboxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholine

Prepared analogously to Example 16 by reaction of N- [2- (4-Car ^ of "thoxymethoxyphenyl) -l-methylethyl] -2- (2-trifluoromethyl-thiazol-4-yl) morpholine in methanol with sodium hydroxide solution. After neutralization with In hydrochloric acid is extracted by shaking with methylene chloride, the extract was concentrated to dryness and the remaining residue triturated with petroleum ether and

aspirated.

Yield: 94% of theory, melting point: 86 ^° C.

Calc .: C 53.01 H 4, 92 N 6.51 F .: 53.14 4.85 6.54

Example 36

N- [2- (4-carboxymethoxyphenyl) -l-methylethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine

Prepared analogously to Example 16 by reacting N- [2- (4-carbomethoxymethoxyphenyl) -l-methylethyl-2- (2-trifluoromethylthiazol-4-yl) ethaneamine in methanol with sodium hydroxide solution. After neutralization with In hydrochloric acid is extracted by shaking with methylene chloride, the extract was concentrated to dryness and triturated the remaining residue with petroleum ether and filtered with suction.

Yield: 50% of theory, Melting point: 80-82 ⁰ C (decomp.) Calc .: C 50.49 H 4.74 N 6.93 Found .:. 50.60 4.61 7.04

Example 37

N ~ [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-chloro-thiazol-4-yl) ethanamine hydrochloride

Prepared analogously to Example 13 by reaction of 2-hydroxy-2- (2-chloro-thiazol-4-yl) ethanamine with 1- (4-carbomethoxymethoxyphenyl) propan-2-one and subsequent precipitation of the hydrochlorides with ethereal hydrochloric acid

 Yield: 43% of theory, melting point: 58 ° C (dec.) Calc .: C 48.45 H 5.26 N 6.64 Cl 16.82 S 7.60 Found: 48.48 5.23 6, 61 16.67 7.87

fa · - ⁸⁷ 2 6 4 4 3

Example 38

N- [2- (4- (2-carbomethoxy-1-methylethenyl) phenyl] -1-methylethyl] -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine

Prepared analogously to Example 13 by reaction of 2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine with 1- [4- (2-carbomethoxy-1-methylethenyl) phenyl] propan-2-one and subsequent purification the base over a Kieselgelsa'ule with chloroform / methanol / methanolic ammonia «9.5 / 0.4 / 0.1 as eluent

 Yield: 43% of theory,

Calc .: C 56.00 H 5.41 N 6.54 S 7.48

Gef.i 56,00 5,57 6,37 7,76

According to ¹ H NMR SPeJtrum (400 MHz), there is an approximately 3: 4 diastereomeric mixture.

Example 39

W-C 2- (4- (2-carbomethoxy-1-methylethenyl) phenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholine

, Prepared analogously to Example 13 by reaction of 2- (2-trifluoromethyl-thiazol-4-yl) morpholine with 1- [4- (2-carbomethoxyl-methylethenyl) phenyl] propan-2-one and subsequent purification of the base over a silica gel column Chloroform / ethyl acetate = 19: 1 as eluant

 Yield: 29% of theory, calc .: C, 58.14, H, 5.54, N, 6.16, S, 5.05, Gef., 58.38, 5.49, 5.9, 7.40

According to the ^ I NMR spectrum (400 MHz), there is an approximately 5O: 5O diastereomeric mixture.

- ββ - 2 6 4 4 3

Example 40

N -C 2- (4- (2-carbomethoxy-1-ethylethenyl) phenyl) -1-methylethyl] -2-hydroxy-2- (2-methylthiazol-4-yl) ethanamine

Prepared analogously to Example 13 by reacting 2-hydroxy-2- (2-methyl-thiazol-4-yl) ethanamine with 1- [4- (2-carbomethoxymethylethenyl) phenyl] propane-2 "one and then purifying the base on a Kieselgelsä'ule with toluene / methanol »19: 1 as eluent

 Yield: 32% of theory,

Calc .: C 65.97 H 7.05 N 6.99 S 8.01 • Found: 65.70 7.16 6.88 8.05

According to ¹ H-NMR spectrum (400 MHz), there is an approximately 5O: 5O diastereomeric mixture.

Example 41

N- [2- (4- (2-carbomethoxy-1-methylethenyl) phenyl) -1-methylethyl] -2- (2-methylthiazol-4-yl) morpholine

Prepared analogously to Example 13 by reacting 2- (2-Mechyl-thiazol-4-yl) morpholine with 1- [4- (2-carbomethoxy-l-mechyiethenyl) phenyl] propan-2-one and then purifying the base over a Silica gel column with chloroform / methanol / ammonia = 9: 1: 0.1 as eluent

 Yield: 59% of theory,

Calc .: C 64.13 H 7.00 N 7.48 S 8.56 F .: 63.90 6.86 7.20 8.28

According to the ¹ H NMR spectrum (400 MHz), there is an approximately 5: 50 diastereomeric mixture.

- 89 -

Beispiol 42

N- [2- {4-hydroxyphenyl} -1-methylethyl] -2- (2-methylthiazol · 4-yl) morpholine

Prepared analogously to Example 13 by reaction of 2- (2-methyl-thiazol-4-yl) morpholine with 1- (4-hydroxyphonyl) -propan-2-one and subsequent purification of the base over a silica gel column with toluene / methanol ^a 9 «1 as eluent. Yield: 46% of theory,

Ber. j C 64.12 H 6.96 N 8.80 S 10.07 Found: 63.90 7.03 8.73 9.83

According to ¹ H NMR SPeKLrUm (400 MHz), there is an approx. 50:50 mixture of diastereomers.

Example 43

N -C 2- (4-carbomethoxymethoxyphenyl) ethyl] -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine

Prepared analogously to Example 3 by reaction of 2-trifluoromethyl-4-bromoacetyl-thiazole with 2- (4-Carbomethoxymethoxyphenyliethanamin and subsequent reduction. Yield: 15% of theory, Melting point: 91-92 ⁰ C

Calcd .: C, 50.49, H, 4.74, N, 6.93; S, 7.93; F: 50.74, 4.94, 6.84, 8.10

6 95 N 12 60 S 9 61 7, 15 12 34 9 65

- 90 - 2 6 4 4 3

Example 44

N -C 3- (4-carboxamidophenyl) -1-methylpropyl] -2-hydroxy-2- (2-methylthiazol-4-yl) ethanamine

Prepared analogously to Example 13 by reacting 2-hydroxy-2- (2-methyl-thiazol-4-yl) ethanamine with 1- (4-carboxamidophenyl) butan-3-one

Exploits 46% of theory, melting point 94-95 ^e C Ber.t C 61.24 H Gef.i 61.50

According to ¹ H-NMR-SPe) Ctrum (400 MHz) is a 50:50 mixture of diastereomers.

Example 45

N-C3- (4-carboxamidophenyl) -1-methylpropyl] -2- (2-trifluoroolethylthiazol-4-yl) morpholine

Prepared analogously to Example 32 by reacting N- (2-hydroxyethyl) -3- (4-carboxamidophenyl) -1-methylpropylamine with 2-trifluoromethyl-4-bromoacetylthiazole and subsequent reduction of .alpha.-triethylsilane.

Yield "19.7% of theory, Melting point» 95-105 ⁰ C

Calc .: C 55.19 H 5.36 N 10.16 S 7.76 Found 55.20 5.45 9.98 7.91 ¹ H-NMR Spectrum (CDCl) $ f << 4.74 ppm (dd , IH) £ = 4.815 ppm (dd, IH)

According to ¹ H-NMR spectrum (400 MHz) is a 48:52 mixture of diastereomers.

Example 46

N- [2- (4-carbomethoxymethoxyphenyl) ethyl] -2-hydroxy-2- (2-methylthiazol-4-yl) ethanamine hydrochloride

a) N- (4-hydroxyphenyl-acetyl) -2-hydroxy-2- (2-methyl-thiazol-4-yl) ethanamine ₌

3.16 g (20 mmol) of 2-hydroxy-2- (2-methylthiazol-4-yl) ethanamine are dissolved in 80 ml of absolute tetrahydrofuran and washed successively with 3.84 g (20 mmol) of 4-hydroxy-phenylacetic acid , 6.3 g (24 mmol) of triphenylphosphine, 5.6 ml (40 mmol) of triethylamine and 2 ml (20 mmol) of carbon tetrachloride. After stirring overnight, concentrated, taken up in 2N hydrochloric acid and extracted three times with methylene chloride. The aqueous phase is then adjusted to pH 7 with 2N sodium hydroxide solution and concentrated to dryness. The concentration residue is boiled out several times with a mixture of chloroform / methanol (1: 1). The extracts are concentrated and the residue is purified on a silica gel column with ethyl acetate / methanol = 50: 1 as eluent

 Yield: 4.4 g of oil (75.9% of theory), Ber. : C 57.51 H 5, 52 N 9.58 Gef: 57.63 5.59 9.41

b) N- (2- (4-Hy 3 -oxyphenyl) ethyl] -2-hydroxy-2- (2-methylthiazol -4-yl) ethanamine hydrochloride

4.2 g (14.4 mmol) of N- (4-hydroxyphenyl-acetyl) -2-hydroxy-2- (2-methyl-thiazol-4-yl) -ethanamine are dissolved in 30 ml of absolute tetrahydrofuran and refluxed Suspension of 1.37 g (36 mmol) of lithium aluminum hydride in 30 ml of absolute tetrahydrofuran was added dropwise. After 1 hour, cooled, decomposed with 2N sodium hydroxide solution and concentrated. Then it is taken up with 20 ml of 2N hydrochloric acid and washed with water

Ammonia made alkaline. After renewed concentration with chloroform / Mf.'thanol = 10: 1 hot extracted. The extracts are concentrated and purified on a Kieselgelsä'ule with ethyl acetate / melanol = 4: 1 as eluent. Subsequently, the hydrochloride is precipitated in ethyl acetate with ethereal hydrochloric acid

Yield: 760 mg (19% of theory), Melting point: 110-113 ⁰ C.

Calcd .: C, 53.41, H, 6.08, N, 8.90, Cl, 11.26, Found: 53.12, 6.84, 8.80. 11.31

c) N- [2- (4-Carbomethoxymethoxyphenyl) ethyl] -2-hydroxy-2- (2 -methylthiazol-4-yl) ethanamine hydrochloride

To 280 mg (1 mmol) of N- [2- (4-hydroxyphenyl) ethyl] -2-hydroxy-2- (2-methylthiazol-4-yl) ethanamine hydrochloride dissolved in 7 ml of absolute dimethylformamide is added 100 mg (2.1 mmol) of sodium hydride dispersion (50% in paraffin oil) After stirring for 15 minutes at room temperature, a solution of 153 mg (1 mmol) of ethyl bromoacetate in 3 ml of absolute dimethylformamide is added dropwise Stirred overnight, treated with 20 ml of saturated sodium bicarbonate solution and extracted with methylene chloride The extracts are dried, concentrated and, after dissolving in ether / methanol with ethereal hydrochloric acid, the hydrochloride is precipitated Yield: 20 mg (21% of theory),

Melting point: lbJ-165 ° C (decomp.)

Calc .: C 52.78 H 5, 99 N 7.24 F .: 52.41 5.76 7.32

Example 47

N- [2- (4-carbomethoxymethoxyphenyl) ethyl] -. 2- (2-trifluoromethylthiazol-4-yl) morpholine

a) NC 2- (4-methoxy-phenyl) -ethyl] -2- (2-trifluoro-1-fluoro- 4-yl) -morpholine

Prepared analogously to Example 32 by reacting N- (2-hydroxyethyl) -2- (4-methoxyphenyl) ethanamine with 2-trifluoromethyl-4-tarometacetylthiazole and subsequent reduction with triethylsilane

 Yield: 24% of theory, oil,

Calc .: C 54.82 H 5.14 N 7.52 S 8.61 F .: <55.00 5.24 7.42 8.86

b) N - ^ - H-Carbomethoxymethoxyphenyethyl- ^ - ^ - trifluoro- methyl-thiazol-4-yl) morpholine

0.6 g (1.6 mmol) of N- [2- (4-methoxyphenyl) ethyl] -2- (2-trifluoromethyl-thiazol-4-yl) morpholine are dissolved with 6 ml of 48% aqueous hydrobromic acid for 3 hours heated in the steam bath. It is then concentrated, treated with toluene and concentrated again to dryness. The foamy residue is refluxed in 15 ml of acetone with 1.2 g (8.7 mmol) of potassium carbonate and 0.3 ml (1.65 mmol) of methyl bromoacetate for one hour. It is then filtered, the filtrate is concentrated and the residue is purified over a silica gel column with toluene / acetone = 4: 1.

Yield: 0.5 g (72% of theory), Calc .: C 53.01 H 4.92 N 6.51 S 7.45 V .: 53.07 4.88 6.72 7.62

Example 48

N-C2- (4-carboethoxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholine

a) NC 2- (4-hydroxyphenyl) -1-methylethyl] -2- (2-tr1 1 lurrmethyl thiazol-4-yl) morpholine

Prepared analogously to Example 32 by reacting 2-trifluoromethyl-4-bromoacetyl-thiazo. ¹ . with N- [2- (4-hydroxyphenyl) -l-methylethyl] -2-hydroxy-ethane-f.min and subsequent purification of the base over a silica gel column with chloroform / vinegar-10. ester = 3: 1 as eluant.

Yield: 29% of theory,

Calc .: C 54.83 H 5.14 N 7.52 Vessel: 53.83 5.07 6.93 According to ¹ H-NMR SPeXtTum (400 MHz), a 50:50 mixture of the diastereomers is present.

b) N- [2- (4-Carboethoxymethoxyphenyl) -1-methylethyl] -2- (2- trifluoromethylthiazol-4-yl) morpholine

280 mg (0.75 mmol) of N- [2- (4-hydroxyphenyl) -l-methylethyl] -2- (2-trifluoromethyl-thiazol-4-yl) -morpholine are combined with 101 mg (0.82 mmol) of ethyl chloroacetate and 113 mg (0.82 mmol) of potassium carbonate in 2 ml acetone wasworfreiem 6 hours om refluxed then filtered off, the residue was washed 2 times with acetone, and the filtrate was concentrated the crude base is on a silica gel column with chloroform / methanol = 20..: 1 cleaned as eluent.

Yield: 50% of theory,

Calc .: C 55.01 H 5, 50 N 6.11 S 6.99 Found: 55.48 5.62 5.85 6.62

Example 49

N- [2- (4-Carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-isopropylthiazol-4-yl) morpholin-6-one hydrochloride

A solution of 0.50 g (1.27 mmol) of N- [2- (4-methoxycarbonylmethoxy-phe-1-yl) -1-methyl-ethyl] -2-hydroxy-2- (2-isopropyl-thiazol-4-yl) ethanamine in 5 ml of anhydrous dimethylformamide is added sequentially with 0.194 g (1.27 mmol) of methyl bromoacetate, 0.175 g (1.27 mmol) of potassium carbonate and a small crystal of potassium iodide. After 4 hours of stirring at 20 ⁰ C, the dimethylformamide is distilled off in vacuo and the residue partitioned between chloroform and water. The dried and filtered chloroform extract is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel (toluene / acetone = 4/1).

Yield: 0.20 g (36% of theory), viscous oil. · According to the "" H NMR spectrum (400 MHz, CDCl ₃ ZCD ₃ OD), there is a 50:50 mixture of diastereomers S = 5.59 ppm (dd, = CH-O-C0-) S = 5 , 62 ppm (dd, = CH-C-CO-)

By treating the B ise using hydrogen chloride / ether and subsequent drying at 2O ⁰ C and 0.1 Torr to obtain a foamy hydrochloride.

Melting range: 40-50 ⁰ C.

Calc .: (x 1.2 HCl) C 54.44 H 6.27 Cl 8.77 V .: 54.70 6.57 8.48

Example 50

N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-isopropylthiazol-4-yl) morpholine

a) N-C2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2- isopropylthiazol-4-yl) morpholin-5-one

To the stirred solution of 3.10 g (7.89 mmol) of N- [2- (4-methoxycarbonylmethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-isopropylthiazol-4-yl) ethanamine and of 1.10 ml (7.89 mmol) Triä'thylamin in 20 ml of chloroform at 25 ⁰ C Innentempsratur 0.60 ml (7.89 mmol) of chloroacetyl chloride is added dropwise. After standing overnight at 20 ⁰ C is concentrated in vacuo and the residue dissolved in 30 ml of anhydrous dimethylformamide. To this is added 0.888 g (15.78 mmol) of a 55% dispersion of sodium hydride in oil, whereupon short foaming is observed. It is stirred for 3 hours at 2O ⁰ C, concentrated in vacuo and the residue partitioned between water and ether. After drying and filtration, the ether solution is concentrated in vacuo and the oily residue is purified on silica gel (toluene / acetone - 4: 1).

Yield: 1.40 g (41% of theory), melting range: 60-7O ⁰ C.

Calc .: C 61.10 H 6.53 N 6.48 S 7.41 F .: 61.20 6.57 6.77 ·>, 58 According to ¹ H NMR spectrum (400 MHz, CDCl) is present 50:50 mixture of diastereomers

ί = 4.72 ppm (dd, = CH-O-) S = 4.85 ppm (dd, = CH-O-)

b) N- [2- (4-Carbomethoxymethoxyphenyl) -1-methylethyl] -2- ( 2- isopropylthiazol-4-yl) morpholine

To 0.425 ml (4.56 mmol) of phosphorus oxychloride are added 0.200 g

_97- ο * ♦ * f w ^

(0.462 mmol) of N- [2- (4-carbomethoxymethoxyphenyl) -l-methylethyl] -2- (2-isopropyl-thiazol-4-yl) -moirpholin-5-one.

After 15 minutes of stirring at 2O ⁰ C is concentrated in vacuo and the residue dissolved in 4 ml of 1,2-dimethoxy-ethane. After addition of 0.052 g (1.39 mmol) sodium borohydride and stirring overnight at 20 ⁰ C the mixture is concentrated in vacuo and the residue partitioned between chloroform and water. After drying and filtration and concentration of the chloroform solution is heated for one hour at 100 ⁰ C with hydrogen chloride solution. After concentration in vacuo, the residue is partitioned between chloroform and aqueous sodium carbonate solution, and the chloroform extract is purified over silica gel (toluene / acetone = 3: 1). Yield: 0.028 g (14.5% of theory), Ber .: Molpeak m / e = 418

- * Gef .: Basepeak m / e = 239

According to 'H-NMR spectrum (400 MHz, CDCl ₃ ZCD ₃ OD) is a 50 .50 mixture of diastereomers. S = 4.72 ppm (dd, = CH-O-) S = 4.74 ppm (dd, = CH-0-)

Example Ll

N- [2- (4-Caromethoxmethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-isopropylthiazol-4-yl) ethanamine dihydrochloride

Prepared analogously to Example 13 by reaction of 2-hydroxy-2- (2-isopropyl-thiazol-4-yl) ethanamine with 1- (4-carbomethoxymethoxyphenyl) -propan-2-one and subsequent purification of the base by column chromatography on silica gel (Chloroform / methanol = 10: 1).

Yield: 89% of theory,

Mp: Molpeak m / e = 418 Gef.: Basepeak m / e = 239

- 98 -

264431

1 H NMR spectrum (400 MHz, CDCl ₃ ):

S = 4.80 ppm (dd, = CH-OH) S = 4.84 ppm (dd, = CH-OH)

According to ¹ H NMR SPeKtrum there is an approximately 5Oi5O mixture of diastereomers.

For conversion into the dihydrochloride, the base is treated with hydrogen chloride / diethyl ether. After evaporation of the ether in vacuo is dried for three days at 20 ⁰ C and 0.1 Torr

Melting range j 55-7O ⁰ C

Calcd .: C, 51.61, H, 6.49, N, 6.02, S, 6.88. Fp: 51.40, 6.64, 5.86, 6.88

Example 52

N -C 2 - (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-propylthiazol-4-yl) ethanamine dihydrochloride

Prepared analogously to Example 13 by reaction of 2-hydroxy-2- (2-propyl-thiazol-4-yl) ethanamine with 1- (4-carbomethoxymethoxyphenyl) propan-2-one and subsequent purification of the base by column chromatography on silica gel ( Chloroform / methanol = 10: 1).

Yield: 52% of theory, ¹ H-NMR spectrum (400 MHz, CDCl ₃ ZCD ₃ OD)! S = 4.72 ppm (dd, = CH-OH) S = 4.78 ppm (dd, = CH-0H)

According to the H-NMR spectrum, there is an approx. 50:50 mixture of the diastereomers.

For conversion into the dihydrochloride, the viscous base is treated with hydrogen chloride / methanol. After evaporation of the

- 99 - t *

Methanol in vacuo is first dried at 0.1 torr and 40 to 50 ° C and then dried overnight at 35 ° C and 0.1 Torr over phosphorus pentoxide.

Melting range: 5O-7O ° C

Calc .: C 51.61 H 6.49 N 6.02 S 6.88 F .: 51.38 6.13 6.28 7.00

Example 53

N- [2- (4-carboxymethoxyphenyl) -l-methylethyl] -2-hydroxy-2- (2-propyl-thiazol-4-yl) ethanamine

Prepared analogously to Example 16 by reacting N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-propyl-thiazolyl-4-γΙ) ethanamine in methanol and in sodium hydroxide solution. After neutralization with 1N hydrochloric acid, it is concentrated in vacuo and then partitioned between chloroform and water.

The chloroform extract is dried over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue gives a powdery solid which is dried for 6 hours at 50 ⁰ C and 0.1 Torr on trituration with ether. Yield: 79% of theory,

Melting range: 79-85 ⁰ C

Ber. (x 0.75 H ₂ O): C, 58.23, H, 7.07, N, 7.15, S, 8.1, Gef., 58.10, 6.75, 6.91, 8.56

According to '• H-NMR spectrum (400 MHz, CDCl ₃ ZCD ₃ OD) is a 50:50 mixture of diastereomers.

S = 5.14 ppm (dd, = CH-OH) S = 5.17 ppm (dd, = CH-OH)

Example 54

N- [2- (4-Carboxymothoxypheny1) -1-methylethy1] -2-hydroxy-2- (2-ipopropyl-thiazol ~ 4-yl) ethanamine hydrochloride

Prepared analogously to Example 16 by reacting N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-i3-propyl-thiazol-4-yl) ethanamine in methanol with 1N sodium hydroxide solution. After adding IN hydrochloric acid until reaching pH = 6, it is concentrated in vacuo and then partitioned between chloroform and water. The dried and filtered chloroform extract is evaporated in vacuo. Trituration of the evaporation residue with ether to obtain a achaumartige solid, which still contains after drying for several hours at 3O ⁰ C and 0.1 Torr on phosphorus pentoxide about 5% chloroform.

Yield: 22% of theory, Melting range: 80-90 ⁰ C

Ber. (+ 5% CHCl ₃ ): C 54.35 H 6.48 N 6.66 Cl 9.69 Vessel: 54.19 6.27 6.53 9.26

According to ¹ H-NMR-SPeKtTUm (400 MHz, d_-DMSO) an approx.

^50υ 50:50 mixture of diastereomers before.

= 5.00 ppm (dd, = CH-OH) S = 5.04 ppm (dd, = CH-Oh)

Example 55

N- [2- (4-Methoxyphenyl) -l-methylethyl] -2-hydroxy ~ 2- (2-trifluorthiazol-4-yl) ethanamine hydrochloride

Prepared analogously to Example 13 by reacting 2-hydroxy-2- (2-trifluoromethyi-1-thiazol-4-yl) ethanamine with 4-methoxyphenyl-prcpan-2-one, followed by purification of the base over a

^2ί4434

Silica gel column with ethyl acetate / methanol = 92: 8 as eluent and precipitation of the hydrochlorides with ethereal hydrochloric acid.

Yield: 57% of theory,

Melting point: 147-149 ⁸ C (Zers.)

Ber. : C 48.42 H 5.08 N 7.06 Cl 8.93 F .: 48.65 5.39 7.11 9.19

According to the ¹ H NMR spectrum (400 MHz), there is a 1: 1 mixture of the diastereomers.

Example 56

3- [2- (4-Methoxyphenyl) -l-methylethyl] -5- (2-trifluoromethylthiazol-4-yl) -2-oxazolidine carboxylic acid, methylester

Prepared analogously to Example 18 by reaction of N- [2- (4-methoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine with methyl glyoxylate and subsequent purification of the base over a silica gel column Chloroform / petroleum ether / ethyl acetate = 5: 4.5: 0.5 as eluant. Yield: 25% of theory,

Calc .: C 53.02 H 4.92 N 6.51 S 7.45 F .: 53.29 4.86 6.32 7.54

Example 57

N-C2- (4-hydroxyphenyl) -l-methylethyl] -2-hydroxy-2, 2-trifluorthiazol-4-yl) ethanamine

Prepared analogously to Example 13 by reaction of 2-hydroxy-2- (2-trirluormethyl-thiazol-4-yl) ethanamine with 4-hydroxypiienyl-propan-2-one and subsequent purification of the base over a silica gel column with chloroform / methanol as eluent.

- 102 -

Yield: 63% of theory,

Melting point: from 77 ⁰ C ₁ clear melt from 97 ⁰ C Ber. : C 52.01 H 4.95 N 8.09 S 9.26

Gei .: 52.05 4.98 8.17 9.19 According to ¹ H-NMR spectrum, diastereomers are present.

According to ¹ H-NMR spectrum (400 MHz) is a 1: 1 mixture of

Example 58

N -C 2- (4-hydroxyphenyl) -1.-methylethyl] -2-hydroxy-2- (2-methylthiazol-4-yl) ethanamine

Prepared analogously to Example 13 by reaction of 2-hydroxy-2- (2-methyl-thiazol-4-yl) ethanamine with 4-hydroxyphenyl-propan-2-one and subsequent purification of the base over a silica gel column with chloroform / methanol / ammonia. 9: 1: 1 ols eluent. · "

Yield: 52% of theory, m.p .: 146-15A ⁰ C

Calc .: C 61.62 H 6.89 N 9.58 S 10.97 Fe: 61.96 6.90 9.65 11.24 According to H-NMR spectrum (400 MHz), an O: 30 Mixture of diastereomers.

Example 59

N -C 2- (4-methoxyphenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholine

Prepared analogously to Example 13 by reaction of 2- (2-trifluoromethyl-thiazol-4-yl) morpholine with 4-methoxyphenyl-propan-2-one and subsequent purification of the base over a silica gel column with chloroform / ethyl acetate = 9: 1 as eluent.

Yield: 80% of theory, melting point: 146-154 ° C

Ber. : C 55.95 H 5.48 N 7.25 Found: 56.09 5.62 6.83

According to ¹ H NMR spectroscopy (400 MHz), a 50:50 mixture of the diastereomers is present.

Example 60

3-C 2- (4- (2-carbomethoxy-1-methylethenyl) phenyl) -1-methyl-ethyl] -5- (2-trifluoromethyl-thiazol-4-yl) -2-oxazolidinearous acid methyl ester

Prepared analogously to Example 18 by reacting N- [2- (4- (2-carbomethoxy-1-methylethenyl) phenyl) -1-methyl-ethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl ) ethanamine with methyl glyoxylate and subsequent purification of the base

a silica gel column with chloroform / petroleum ether / ethyl acetate = 5: 4.5: 0.5 as eluent

 Yield: 66% of theory,

Calc .: C 55.41 H 5.05 N 5.62 S 6.43 F .: 55.33 5.23 4.96 6.64

^ -NMR spectrum (CDCl ₃ ZCD ₃ OD): C = 5.10 ppm (s, 2H)

5.23 ppm (s, IH) 5.27 ppm (s, IH) According to the "" H-NMR spectrum (400 MHz), there is a 1: 1: 1: 1 mixture

the diastereomers.

Example 61

3- [2- (4-hydroxyphenyl) -l-methylethyl] -5- (2-trifluoromethylthiazol-4-yl) -2-oxazolidincarbonsä'ure-methylester

Prepared analogously to Example 18 by reaction of N- [2- (4-hydroxyphenyl) -2-methylethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine with methyl glyoxylate, followed by purification of the base on a silica gel column with chloroform / ethyl acetate = 9: 1 as eluent and precipitation of the hydrochlorides with ethereal hydrochloric acid.

Yield: 37% of theory, Melting point: from 158 ⁰ C (dec.)

Calc .: C 47.74 H 4, 45 N 6.19 S 7.08 Cl 7.08 Found: 47.49 4.72 6.38 7.22 "7.98

Example 62

Methyl 3- [2- (4- (2-carbomethoxy-1-methylethenyl) phenyl) ^-1- ethyl] -5- (2-methylthiazol-4-yl) -2-oxazolidinecarboxylate

Prepared analogously to Example 18 by reacting N- [2- (4- (2-carbomethoxy-1-methylethenyl) phenyl) -1-methylethyl] -2-hydroxy-2- (2-methylthiazol-4-yl) ethanamine with methyl glyoxylate and subsequent purification of the base over a silica gel column with petroleum ether / ethyl acetate = 7: 3 as the eluant. Yield: 18% of theory, oil, calc .: C, 62.14, H, 6.35, N, 6.30; S, 7.2, Found: 61.90, 6.60, 6.34, 7.03

Example 63

3-C 2- (4-Hydroxyphenyl) -1-methylethyl] -5- (2-methylthiazol-4-yl) -2-oxazolidinecarboxylic acid methyl ester

Prepared analogously to Example 18 by reaction of N- [2- (4-hydroxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-methyl-thiazol-4-yl) ethanamine with methyl glyoxylate and subsequent purification of the base over a Silica gel column with ether / petroleum ether = 8: 2 as eluant

 Yield: 25% of theory, oil,

Calc .: C 59.65 H 6.12 N 7.73 S 8.85 V: 60.00 5.98 7.23 8.97

Example 64

N-C2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethyl-t-> iazol-4-yl) morpholin-6-one

¹ ^ 2.1 g (0.005 mol) of N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine are dissolved in 70 ml of acetone and 5 ml of bromoacetic acid methyl ester and 5 g of potassium carbonate are added with stirring. The whole is stirred for 16 hours at room temperature and then heated at reflux for 4 hours. The inorganic products are filtered off, the solvent is distilled off and the residue obtained is purified over a silica gel column with toluene / ethyl acetate = 8.5: 1.5 as eluent. Yield: 0.8 g of oil (35% of theory), Calc .: C 52.39 H 4.62 N 6.11 Found: 52.50 4.51 5.85 "• H-NMR spectrum (400 MHz) (CDCl / CD OD):

£ = 7.596 ppm (d, IH) ί a 7.686 ppm (d, IH)

Thereafter, a 50:50 mixture of the diastereomers is present.

Example 65

N-C 2- (4-Carboethoxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethylthiazole) -γ-morpholine hydrochloride

0.5 g (0.0012 mol) of N- [2- (4-carboxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethyl-thiazol-4-yl) morpholine are dissolved in 150 ml of chloroform, with stirring 2 ml of ethanol and 0.25 g of concentrated sulfuric acid and then heated for 1 hour on Wasserabs aider to RUckfluß. It is then cooled, mixed with ice-water, made alkaline with ammonia and the phases are separated. It is then shaken out again with chloroform, the organic phase is dried over sodium sulfate, filtered off and concentrated to dryness. The residue obtained is dissolved in ether, treated with ethereal hydrochloric acid, concentrated to dryness, triturated with acetone and filtered with suction

Yield: 0.37 g (63% of theory), Melting point: 122-123 ⁰ C Calc .: C 50.95 H 5, 30 N 5.66 Gef .: 50.85 5.49 5.68

According to the ¹ H NMR spectrum (400 MHz), a 5O: 5O mixture of the diastereomers is present.

Example 66

N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy- 2- (2-methylthiazol-5-yl) ethanamine dihydrochloride

Prepared analogously to Example 13 by reacting 2-hydroxy-2- (2-methyl-thiazol-5-yl) ethanamine with 1- (4-carbomethoxymeth-

, ₁₀₇ . 2 6 443 ^

oxyphenyl) propan-2-one, Purification of the base over a silica gel column with ethyl acetate / ethanol = 8: 2 as eluent and subsequent precipitation of the dihydrochloride with ethereal Salzsa'ure.

Yield: 32% of theory, Melting point: 190-192 ⁰ C Ber.j C 49.43 H 5.99 N 6.40 Found .: 49.43 5.90 6.49 According to ¹ H-NMR SPeKtTUm (4 ^ 0 MHz) is a 50:50 mixture of diastereomers.

Example 67

N-C2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine (diastereomer B)

Prepared analogously to Example 13 by reaction of 2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine with 1- (4-carbomethoxymethoxyphenyl) propan-2-one and sodium cyanoborohydride in methanol (reaction time: 5 hours). and subsequent purification on a silica gel column with methylene chloride / methanol = 20: 1. This gives a 50:50 mixture of diastereomers of the base. This is recrystallized from a mixture of ether / ethyl acetate = 65:10. The mother liquor obtained is mixed with ethereal hydrochloric acid and brought to dryness. The residue thus obtained is crystallized from a mixture of ether / ethyl acetate / methanol = 100: 60: 1 μm. The mother liquor obtained after filtering off the crystals is evaporated to dryness, by alkaline shaking with methylene chloride, the base is released and purified on a silica gel column with methylene chloride / methanol = 20: 1 as eluent. This gives the diastereomer B in approx.

92-94% purity than oil

 Yield: 4% of theory,

C 54, 66 H 5.06 - 108 - 26 44 3 4 Ber. : 54 43 5.13 N 6.70 Gef .: * -Spektru m ( 400 MHz) 6.88 ¹ H-NMI (CDCl ₃ / CD OD) I ' 7 : , 56 ppm (s , 1H)

Example 68

N- [2 ~ (4-Carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine (Diastereomer A)

Prepared analogously to Example 13 by reacting 2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine with 1- (4-carbomethoxymethoxyphenyl) propan-2-one and sodium cyanoborohydride in methanol (reaction time: 5 hours) and then Purification on a silica gel column with methylene chloride / methanol = 2OjI. Where _# is erhä'lt an approximately 50:50 diastereomer mixture of the base. This is recrystallized from a mixture of ether / ethyl acetate = 65:10, and a further two times from ethyl acetate. This gives the diastereomer A in 98-99% purity.

Yield: 14% of theory, Melting point: 104-105 ⁰ C.

Calc .: C, 51.66; H, 5.06; N, 6.70; F: 51.90; 4.82; 6.82; NMR spectrum (400 MHz) (CDC1 ₃ / CD OD):

V = 7.59 ppm (s, lH)

Example 69

N- [2- (4-carboxymethoxyphenyl) -1-methylethyl] -2-trifluoromethylthiazol-4-yl) morpholine (Diastereomex A)

Prepared analogously to Example 16 by reaction of N- [2- (4-

- 109 -

2 6 A 434

Carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholine (diastereomer A) in methanol with sodium hydroxide solution. After neutralizing with Ir. Hydrochloric acid is extracted by shaking with methylene chloride, the extract is concentrated to dryness and the remaining residue triturated with petroleum ether and filtered with suction

Yield: 96% of theory, melting point: from 70 ^° C. (sintered) Ber. : C 53.01 H 4, 92 N 6.51 Gef.i 53.15 4.97 6.53 ^ NMR spectrum (400 MHz) (CDCl / CD, OD) j

7.757 ppm (s, lH)

Example 70

N -C 2- (4-carboxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholine (diastereomer B)

Prepared analogously to Example 16 by conversion of N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethyl-thiazol-4-yl) morpholine (diastereomer B) in methanol with sodium hydroxide solution. After neutralization with 1N hydrochloric acid, the mixture is extracted by shaking with methylene chloride, the extract is concentrated to dryness and the remaining residue is triturated with petroleum ether and filtered with suction.

Yield: 88% of theory,

Melting point: 70 ⁰ C (Sint.) Calc .: C 53.01 H 4.92 N 6.51 Found .: 53.19 5.19 6.48 ^ H-NMR spectrum (400 MHz) (CDCl / CD OD):

(= 7, 786 ppm (s, lH)

Thereafter, the compound still contains about 6-7% diastereomer A.

-no- 2 6 4 4 3 *

Example 71

N- [2- (4- (2-hydroxyethoxy) phenyl) -1-methylethyl] -2- (2-trifluoro-methylthiazol-4-yl) morpholine (Diastereomer A)

1 g (0.0022 mol) of N- [2- (4-carbomethoxymethoxyphenyl) -l-methylethyl] -2- (2-trifluoromethyl-thiazol-4-yl) -morpholin-5-one (diastereomer A) are dissolved in υ ml absolute tetrahydrofuran dissolved. At room temperature, 15 ml (0.015 mol) of a 1 molar solution of diborane in tetrahydrofuran are added dropwise within 15-20 minutes. The solution warmed it to about 35-40 ⁰ C. After 30 minutes, concentrated to dryness and the remaining residue dissolved in 40 ml of methanol and 2 ml of concentrated hydrochloric acid and allowed to stand for 30 minutes. Under ice-cooling is made alkaline with ammonia and extracted several times with methylene chloride. The organic phase is dried over sodium sulfate and the base is purified on a silica gel column with toluene / ethyl acetate = 7.5: 2.5 as the eluent

Yield: 0.28 g (31% of theory), Melting point: 76-78 ⁰ C

Calc .: 54.90 H 5, 57 N 6.73 Found: 54.90 5.71 6.54 ^ -NMR spectrum (400 MHz) (CDC ^ / CD OD):

S 7.614 ppm (s, lH)

Example 72

N- [2- (4-Carboxymethoxyphenyl) -1-methylethyl] -2-hydroxy- 2- (2-trifluoromethylthiazol-4-yl) ethanamine (Diastereomer A)

Prepared analogously to Example 16 by reacting N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethyl)

- Ill -

thiazol-4-yl) ethanamine (diastereomer A) in methanol with sodium hydroxide solution. After neutralization with 1N hydrochloric acid, the mixture is extracted by shaking with methylene chloride, the extract is concentrated to dryness and the remaining residue is triturated with petroleum ether and filtered with suction

Yield: "89% of theory, Melting point: 119-121 ⁰ C Calc .: C 50.49 H 4, 74 N, 6.93 Found .: 50.62 4.69 6.90 -" - H-NMR spectrum ( 400 MHz) (CDCl ₃ ZCD ₃ OD):

A = 7.771 ppm (s, lH)

Example 73

N- [2- (4-Carboxymethoxyphenyl) -1-methylethyl] -N- (2-hydroxyethyl) -2-hydro-; y-2- (2-trifluoromethylthiazol-4-yl) ethanamine

Prepared analogously to Example 16 by reacting N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -N- (2-hydroxyethyl) 2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine in methanol with in caustic soda. After neutralization with 1N hydrochloric acid, it is concentrated to dryness, treated with 10 ml of ethanol and the inorganic residues are filtered off. The ethanol phase is diluted with 60 ml of methylene chloride and again filtered off. The mother liquor is concentrated to dryness and the residue triturated with ether and filtered with suction. Yield: 90% of theory,

² ^ mp 83-85 ⁰ C

Calc .: C 50.88 H 5, 17 N 6.25

Found: 50.70 5.44 6.11 According to ¹ H-NMR spectrum, a mixture of theomers.

According to the ¹ H NMR spectrum (400 MHz), there is a 60:40 diaste-

Example 74

N-C 2- (4-carbomethoxyurethoxyphenyl) -1-methylethyl 3-2- (2-trifluoromethylthiazol-4-yl) morpholine (Diaetereomer A)

a) N- [2- (4-Carbomethoxymothoxyphenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholin-5-one

(Diastereomer A)

1.2 g (0.0029 mol) of N- [ ^> .- (4-carbomethoxymethoxyphenyl) -lmethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) -ethanamine (diastereomer A) are obtained in Dissolved 12 ml of methylene chloride, cooled to 12 ⁰ C and added 0.4 ml (0.0029 mol) of triethylamine. While stirring, 0.22 ml (0.0029 mol) of chlorotrylchloride are added dropwise. The temperature rises to 24 ⁰ C at. After 30 minutes, the organic phase is extracted by shaking with water, dried over sodium sulfate and concentrated to dryness. The resulting oil is taken up in 12 ml of dimethylformamide and reacted with stirring at 22-24 ⁰ C with 130 mg / 50% sodium hydride dispersion in oil. After one hour, a further 90 mg of 50% sodium hydride dispersion are added to complete the reaction. After a total of 1.5 hours, neutralized with ethereal hydrochloric acid and added 100 ml of methylene chloride. The organic phase is extracted by shaking with water and this extracted 2 χ with methylene chloride. After drying the organic phases over sodium sulfate is evaporated to dryness. The resulting oil is purified on a silica gel column with toluene / ethyl acetate = 6: 4 as eluent. Yield: 1.2 g (90% of theory)

b) N- [2- (4-Carbomethoxymethoxyphenyl) -1-methylethyl] -2- ( 2- trifluoromethylthiazol-4-yl) morpholine (Diastereomer A)

1.2 g (0.0026 mol) of N- [2- (4-carbomethoxymethoxyphenyl) -methylethyl] -2- (2-trifluoromethyl-thiazol-4-yl) -morpholin-5-one

- 113 -

6 44 34

(Diastereomer A) are dissolved at 22 ⁰ C in 10 ml of absolute tetrahydrofuran. 2.8 ml (0.0028 mol) of a 1 molar solution of diborane in tetrahydrofuran are added dropwise at intervals of 30 minutes each time to this solution. After 1.5 hours, the mixture is evaporated to dryness. The obtained residue is taken up in 80 ml of methanol and allowed to stand at room temperature for 16 hours. It is concentrated again to dryness, the residue obtained is taken up in methylene chloride and the organic phase extracted with a cold aqueous ammonia solution. The methylene chloride phase is extracted 2 χ with water and the organic phase is concentrated after drying over sodium sulfate. The residue obtained is purified on a silica gel column with toluene / ethyl acetate = 8: 2 as the eluent. This gives a colorless oil.

Yield: 0.8 g (69.3% of theory), calc .: C 54.04 H 5.22 N 6.30 Found: 54.20, 5.53 6.41 ¹ H-NMR spectrum ( 400 MHz) (CDCl / CD OD):

£ = 4.807 ppm (dd, IH)

Example 75

N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholine (diastereomer B)

a) N-C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl-2- (2-trifluoromethyl-thiazol-4-yl) -morpholin-5-one (diastereo-

mer B)

Prepared analogously to Example 74a by reacting N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine (diastereomer B)

- 114 -

2 6 A 4 3 4

with chloroacetyl chloride and sodium hydride and purification of the base over a silica gel column with toluene / ethyl acetate ^a 6: 4 as eluent

 Yield: 71% of theory.

b) N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2- trifluoromethyl-thiazol-4-yl) morpholine (Diaetereomer B)

Prepared analogously to Example 74b by reacting N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholin-5-one (diastereomer E) with diborane in tetrahydrofuran And subsequent purification of the base over a silica gel column with toluene / ethyl acetate = 8: 2 as eluant.

Yield: 53% of theory,

Calc .: C 54.04 H 5, 22 N 6.30

Gef.: '54,31 5,35 6,22 ^ -NMR spectrum (400 MHz) (CDCl / CD OD):

f4.829ppm (dd, IH)

Example 76

N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -N- (carboethoxymethyl) -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine

0.21 g (0.005 mol) of N- [2- (4-carbomethoxymethoxyphenyl) -methylethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) -ethanamine are dissolved in 10 ml of butan-2-one dissolved, treated with 0.5 ml of ethyl bromoacetate and 0.5 g of potassium carbonate and stirred for 16 hours at room temperature. The inorganic products are filtered off and the solvent distilled off. The remaining oil is purified over a Kieselge.lsa'ule with toluene / ethyl acetate = 85:15 as eluent. A colorless oil is obtained.

- 115 -

Yield: 0.14 g (56% of theory), Calc .: C 52.47 H 5.41 N 5.56 V .: 52.71 5.42 5.57

According to ¹ H-NMR-SPeKtL-Um (400 MHz), there is an approx. 5O: 5O mixture of the diastereomers.

Example 77

N -C 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -N- (carboxymethyl) -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine

1.4 g (0.0031 mol) of N- [2- (4-carbomethoxymethoxyphenyl) -lmethylethyl] -2- (2-trifluoromethyl-thiazol-4-yl) -inorpholin-6-one are dissolved in 10 ml of methanol. 3 ml (0.003 mol) of sodium hydroxide solution are added to this solution while stirring at room temperature. After 5 minutes, 1.5 ml of ice water are added and neutralized with 3 ml of hydrochloric acid. The aqueous phase is extracted by shaking 3 × with methylene chloride. The organic phase is dried over sodium sulfate, filtered off and concentrated to dryness. The residue obtained is purified over a silica gel column with methylene chloride / methanol = 20: 1 as the eluent. This gives colorless crystals after concentration.

Yield: 0.29 g (21% of theory), m.p .: 128 ^? C

Calc .: C 50.41 H 4, 86 N 5.88 F .: 50.19 4.89 5.74

According to the ¹ H NMR spectrum (400 MHz), there is an approx. 5O: 5O mixture of the diastereomers.

- 116 -

Example 78

N- [2- (4- (2- (l-piperidino) ethoxy) phenyl) -l-methylethyl] -2-hydroxy-2- (2-methyl-thiazol-4-yl) ethanamine

Prepared analogously to Example 13 by reacting 2-hydroxy-2- (2-methyl-thiazol-4-yl) ethanamine with 1- (4- (2- (1-piperidinyl) phenyl) propan-2-one and subsequent purification. Over a silica gel column with methanol as eluent.

Evidence: 13% of theory,

Melting point: 128 ⁰ C Calc .: C 65.48 H • Found .: 65.39

^ -NMR spectrum (CDCl):

8th, 24 N 10.41 S 7, 94 8th, 17 10.29 7, 79 V · 4.75 (Dd, "CH-OH) 4.70 (Dd, = CH-OH)

According to ¹ H NMR SPeKtTUm (400 MHz), there is an approximately 1: 1 mixture of diastereomers.

Beispiel 79

N -C 2- (4- (2-Hydroxyethoxy) phenyl) -1-methylethyl] -2-hydroxy-2- (2-methylthiazol-4-yl) ethanamine

Prepared analogously to Example 13 by reaction of 2-hydroxy-2- (2-methyl-thiazol-4-yl) ethanamine with 1- [4- (2-hydroxyethoxy) phenyl] propan-2-one and subsequent purification on a silica gel column Methylene chloride / methanol ~ 9: 1 as eluant.

Yield: 61% of theory,

Calc .: C 60.69 H 7, 19 N 8.33 S 9.53 "Gef.: 60, 59 7.13 8.25 9.47

^X H NMR spectrum (CDCl ₃ ):

S = 4.78 (dd, = CH-OH) i => 4.83 (dd, = CH-OH)

According to ¹ H NMR SPeKtTUm (400 MHz), there is an approximately 1: 1 mixture of diastereomers.

Example 80

N- [2- (4-Carbomethoxypheny1) -1-mothylethy1] -2-hydroxy-2- (2-dimethylamino-thiazol-4-yl) ethanamine

5 g of 2- (N, N-dimethylamino) -4-bromoacetyl-thiazole are heated in 250 ml of acetone with 10 g of potassium bicarbonate and 9.5 g of 2- (4-carbomethoxyphenyl) -l-methylethylamine hydrochloride for 3 hours to reflux. "After cooling the reaction mixture, the inorganic products] are ABFI hriert and the filtrate is concentrated on a rotary evaporator. Car obtained oily residue is taken up in 150 ml of absolute methanol and mixed at 0-5 ⁰ C with 1.75 g of sodium borohydride in small portions. The mixture is then for one hour at 0-5 ⁰ C and 24 hours at room temperature stirred. Then the reaction mixture with ice / water is added, acidified with concentrated hydrochloric acid, made alkaline with ammonia under ice-cooling and extracted with methylene chloride. the extract is dried over sodium sulfate, concentrated and purified on a silica gel column with ethyl acetate / methanol = 8: 2 as eluent.

Yield: 0.5 g (6.8% of theory), Ber. C 59.43 H 6, 93 N 11.56 S 8.82 Found: 59.38 7.07 11.39 9.04 ¹ H-NMR spectrum (CDCl ₃ ZCD ₃ OD):

S = 6.39 ppm (s, IH) S = 6, 37 ppm (s, IH)

According to the '' • H-NMR spectrum (400 MHz) there is an approximately 2: 1 mixture

the diastereomers.

- 118 -

4434

Example 81

N- [2- (carbomethoxymethoxyphenyl) -1-methylethy1] -2- (2-methylthiazol-4-yl) morpholine

Prepared analogously to Example 13 by reaction of 2- (2-methyl-thiazol-4-yl) morpholine with 1- (4-carbomethoxymethoxyphenyl) propan-2-one and subsequent purification on a silica gel column with toluene / ethyl acetate = 6: 4 as eluent. Yield: 22% of theory,

Ber. C 61.52 H 6, 71 N 7.17 S 8.21 F .: 61.68 6.89 6.98 8.32 "H-NMR spectrum (CDCl ₃ ZCD ₃ OD):

S = 2.71 ppm (s, IH) J = 2.72 ppm (s, IH)

According to the H-NMR spectrum (400 MHz), there is an approximately 1: 1 mixture of the diastereomers.

Example 82

N-C2- (4- (2-hydroxyethoxy) phenyl) -1-methylethyl] -2-hydroxy-2 ~ (2-trifluoromethylthiazol-4-yl) ethanamine

Prepared analogously to Example 13 by reaction of 2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine with 1- (4- (2-hydroxyethoxy) phenyl) propan-2-one and then with a column of silica gel Essigester / Metnanol = 9: 1 as Eluens.

Yield: 27.6% of theory, calc .: C, 52.30; H, 5.42; N, 7.18; S, 8.21, Gef .: 52, 19, 5.57, 7.13, 8.40 ^ NMR spectrum (CDCl3) / CD OD):

S = 7.60 ppm (s, IH) ζ- 7, 57 ppm (s, IH)

- 1 »- 2 6 4 4 3

According to the ¹ H NMR spectrum (400 MHz), there is an approximately 1: 1 mixture of the diastereomers.

Example 83

N- [2- (4- (2-methylaminoethoxy) phenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine

1.2 ml borane dimethyl sulfide complex are added to a solution of 0.38 g of N- [2- (4-methylaminocarbonylmethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl). ethanamine in 20 ml of absolute tetrahydrofuran and heated to reflux for 3 hours. Subsequently, 4 ml of methanol are carefully added dropwise to the reaction mixture and heated to reflux for one hour. After cooling to room temperature, ethereal hydrochloric acid is added. The resulting solution is evaporated, the residue obtained taken up in 15 ml of water, made alkaline with concentrated ammonia and extracted several times with methylene chloride. The combined extracts are dried with sodium sulfate, evaporated and purified on a silica gel column with methylene chloride / methanol = 8: 2 as the eluent.

Yield: 0.06 g (13.6% of theory), Calc .: C 53.59 H 6.00 N 10.42

Gef .: 53.40 6 19 60 10 20 IH) ¹ H-NMR spectrum (CD ci ₃ / c ID ₃ OD 57 IH) S = 7, ppm (S, s = 7, ppm (S,

the diastereomers.

According to the H-NMR spectrum (400 MHz), there is an approximately 1: 1 mixture

Example 84

N -C 2- (4-methylaminocarbonylmethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholine

Prepared analogously to Example 32 by reaction of 2-trifluoromethyl-4-bromoacetyl-thiazole with N- (2-hydroxyethyl) -2- (4-methylaminocarbonylmethoxyphenyl) -1-methylethylamine and potassium bicarbonate in acetone at room temperature and subsequent reduction with sodium borohydride in Trifluoressigsä'ure. The resulting crude product is purified over a silica gel rot with toluene / ethyl acetate = 2: 8 alo eluent. Yield: 47.4% of theory, m.p .: 96-98 ° C. Calc .: C, 54.17, H, 5.46, N, 9.48, S, 7.23

Found: 53.99 5.42 9.38 7.39 ¹ H-NMR spectrum (CDCl / CD OD):

0 = 7.61 ppm (s, IH)

S = 7.59 ppm (s, IH)

According to the ¹ H NMR spectrum (400 MHz), there is an approximately 1: 1 mixture of the diastereomers.

Example 85

N- [2- (4- (2-hydroxyethoxy) phenyl) -1-methylöLhyl] -2- (2-methy1-thiazol-4-yl) morpholine

Prepared analogously to Example 13 by reaction of 2-hydroxy-2- (2-methyl-thiazol-4-yl) morpholine with 1- [4- (2-hydroxyethoxy) phenyl] propan-2-one and subsequent purification on a silica gel column Methylene chloride as the eluent. Yield: 42% of theory, calc .: C 63.13 H 6.97 N 7.75 V .: 63.03 6.95 7.68

- 121 -

••• H NMR spectrum

£ ₃ = 7.14 ppm (s, IH) J = 7.13 ppm (s, IH)

According to the H-NMR spectrum (400 MHz), there is a ca., 2: 3 mixture of the diastereomers.

Example 86

N -C 2- (4-carboxymethoxyphenyl) -1-methylethyl] -2- (2-methylthiazol-4-yl) morpholine

Prepared analogously to Example 13 by reaction of 2- (2-methyl-thiazol-4-yl) morpholine with 1- [4-carbomethoxyphenyl] propane-2-one and subsequent purification on a silica gel column with ethylene chloride / ethyl acetate / methanol / ammonia 4: 4: 2: 1 as eluent

 Yield: 28% of theory,

Calc .: C, 60.62; H, 6.42; N, 7.44; S, 8.52, Found: 60.58, 6.40, 7.40, 8.50 ¹ H-NMR spectrum (CDCl / CD OD):

S = 7.13 ppm (s, IH) S = 7.14 ppm (s, IH)

According to the ¹ H NMR spectrum (400 MHz), there is an approximately 1: 1 mixture of the diastereomers.

Example 87

N- [2- (4- (b-hydroxyhexoxy) phenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholine

Prepared analogously to Example 32 by reacting N- (2-hydroxyethyl) -2- (4- (6-hydroxyhexoxy) phenyl) -1-methylethylamine

with 2-trifluoromethyl-4-bromoacetyl-thiazole and potassium bicarbonate in acetone at room temperature and subsequent reduction with sodium borohydride in trifluoroacetic acid. The crude product obtained is purified over a Kieselgelsa'ule with ToIu-5 ol / ethyl acetate = 6: 4 as eluent. Yield: 10.8% of theory,

Calcd .: C, 58.46, H, 6.61, N, 5.93, S, 6.78, 58.57, 6.49, 5.79, 6.91, ^1, H-NMR SpOKU-Um (CDCl ₃ ZCD ₃ OD): Ί0 * ^e 7.61 ppm (s, IH)

ie 7.57 ppm (s, IH)

According to the ¹ H NMR spectrum (400 MHz), there is an approximately 1: 1 mixture of the diastereomers.

Example 88

N -C 2- (4-methylaminocarbonylmethoxyphenyl) -1-methylethyl] 2- (2-methylthiazol-4-yl) morpholine

Prepared analogously to Example 13 by reaction of 2- (2-methyl-thiazol-4-yl) morpholine with 1- (4-methylaminocarbonylmethoxyphenyl) propan-2-one and subsequent purification on a silica gel column using ethyl acetate as the eluent. Yield: 22.3% of theory,

Calc .: C 61.67 H 6.99 N 10.79 S 8.23 F .: 61.70 6.97 10.67 8.42 ¹ H-NMR spectrum (CDCl ₃ ZCD ₃ OD):

S = 2.72 ppm (s, 3H)

£ = 2.71 ppm (s, 3H)

According to the H-NMR spectrum (400 MHz), there is an approximate 1: 1 mixture of the diastereomers.

- 123 -

Example 89

N- [2- (4-aminocarbonylmethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholine

Prepared analogously to Example 24 by reaction of N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethyl-thiazol-4-yl) morpholine with ammonia and subsequent purification on a silica gel column with ethyl acetate / toluene 8: 2 as eluent.

Yield: 51.7% of theory,

Calc .: C, 53.14, H, 5.16, N, 9.78, S, 7.47, F, 53.26, 5.34, 9.63, 7.59, ¹ H-NMR spectrum (CDCl / CD OD):

7.71 ppm (s, IH)

7.69 ppm (s, IH) According to ¹ H NMR SPeKtrum (400 MHz), there is an approximately 1: 1 mixture

the diastereomers.

Example :, 90

N- [2- (4- (2-Methylaminoethoxy) phenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholine

Prepared analogously to Example 83 by reaction of N- [2- (4-methylaminocarbonylmethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethylthiazol-4-yl) morpholine with borane dimethylsulphide complex and subsequent purification on a silica gel column using ethyl acetate / Methanol (8: 2) as eluent.

Yield: 26% of theory,

Calc .: C 55.93 H 6.10 N 9.78 F .: 56.08 6.21 9.65

- 124 -

₃ 7.63 ppm (s, IH)

7.59 ppm (s, IH) According to the ¹ H-NMR spectrum (400 MHz), there is an approximately ltl mixture of the diastereomers.

Example 91

N- [2- (4- (6-Hydroxyhexoxy) phenyl) -1-methylethyl] -2- (2-trifluoromethyl-thiazol-4-yl) ethanamine

Prepared analogously to Example 13 by reaction of 2-hydroxy-2 - (? - trifluoromethyl-thiazol-4-yl) ethanamine with 1- (4- (6-hydroxyhexoxyphenyl) propan-2-one and subsequent purification on a Kieselgelsä'ule with ethyl acetate / methanol (9.5: 0.5) as eluant.

Yield: 17.4% of theory, calc .: C, 56.49, H, 6.55, N, 6.27, S, 7.1, Found: 56.32, 6.47, 6.34, 7.28 • "H-NMR spectrum (CDCl ₃ ZCD ₃ OD):

$ => 7.59 ppm (s, IH) £ <7.55 ppm (s, IH) According to the H-NMR spectrum (400 MHz), there is an approx. 1: 1 mixture of the diastereomers.

Example 92

N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-trifluoromethyl-5-methylthiazol-4-yl) morpholine

Prepared analogously to Example 32 by reacting 4.2 g (0.0146 mol) of 2-trifluoromethyl-5-methyl-4-bromoacetyl-thiazole with 8 g (0.03 mol) of N- (2-hydroxyethyl) -2- (4 carbomethoxy

-W5- 2Ä4434

methoxyphenyl) -1-methylethylamine in methylene chloride by stirring at room temperature for 20 hours and refluxing for 2 hours. The reduction is carried out in 28 ml of trifluoroacetic acid with 2.4 g (0.02 mol) of triethylsilane. The crude product is purified on a silica gel column with toluene / ethyl acetate = 7: 3 as eluent

 Yield: 1.7 g (28% of theory), calc .: C 55.01 H 5.49 N 6.10 S 6.99 Found: 55.20 5.60 6.30 7.20 Hl NMR Spectrum (CDCl / CD OD):

£ = 4.775 ppm (t, IH)

S = 4.810 ppm (t, IH)

According to the ^ -H NMR spectrum (400 MHz), there is an approximately 3: 2 mixture of the diastereomers.

Example 93

N- [2- (4-carbomethoxymethoxyphenyl) -l-methylethyl] -2- (2-acetamino-thiazol-4-yl) morpholine

Prepared analogously to Example 32 by reacting 2.23 g (0.0085 mol) of 2-acetylamino-4-bromoacetyl-thiazole with 2.26 g (0.0085 mol) of N- (2-hydroxyethyl) -2- (4- carbomethoxymethoxyphenyl) -1-methylethylamine and 0.86 g (0.0085 mol) of triethylamine in 30 ml of methylene chloride and 30 ml of methanol over 20 hours at room temperature. The reduction is carried out in 9 ml of trifluoroacetic acid with 1.48 g (0.0128 mol) of triethylsilane.

The crude product is purified on a Kieselgelsä'ule with ethyl acetate / methanol = 9: 1 as eluent.

Yield: Ig (27% of theory), Melting point: 65-7O ⁰ C

Calc .: C, 58.18, H, 6.27, N, 9.69, S, 7.33, Mp., 57.90, 6.40, 9.49, 7.48

- 126 -

24443 *

• H-NMR spectrum (CDCl ₃ ZCD ₃ OD) *

ί = 6.875 ppm (d, IH) ί = 6.850 ppm (d, IH)

According to the H-NMR spectrum (400 MHz), there is an approximately 2-liter mixture of the diastereomers.

Example 94

N- [2- (4-carbomethoxymethoxyphenyl) -l-methylethyl3-2-hydroxy-2- (2-methyl-oxazol-4-yl) ethanamine dihydrochloride

Prepared analogously to Example 13 by reacting 0.7 g (0.005 mol) of 2-hydroxy-2- (2-methyl-oxazol-4-yl) ethanamine and 1.1 g (0.005 mol) of 1- (4-carbonethoxymethoxyphenyl) propane. 2-on in 40 ml of absolute methanol with 0.3 g (0.005 mol) of acetic acid and 0.32 g (0.005 mol) of sodium cyanoborohydride The crude product is purified on a silica gel column with ethyl acetate / methanol = 9t1 as eluent and by precipitation with ethereal hydrochloric acid the dihydrochloride prepared. yield: 0.6 g (28% of theory), melting point: sinter 16O ⁰ C, from 168 ⁰ C dec Calc .: C 51.30 H 6.21 N 6.64 S 16.84 Found. .: 51.50 6.10 6.76 16.57 ¹ H-NMR spectrum (CDCl / CD OD):

S = 7.49 ppm (d, IH) £ = 7.51 ppm (d, IH)

According to the H-NMR spectrum (400 MHz), there is an approx. 50:50 mixture of the diastereomers.

- 127 -

Example 95

N- Γ 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-chlorothiazol-4-yl) morpholine

Prepared analogously to Example 32 by reacting 5 g (0.0208 mol) of 2-chloro-4-bromoacetyl-thiazole with 5.6 g (0.021 mol) of N- (2-hydroxyethyl) -2- (4-carbomethoxymethoxyphenyl) -1 Methylmethylamine in 200 ml of acetone and 6.3 g (0.063 mol) of potassium bicarbonate within 20 hours at room temperature. The reduction was carried out in 41 ml of trifluoroacetic acid with 3.5 g (0.029 mol) of triethylsilane over 24 hours. The crude product is purified on a Kieselgelsä'ule with methylene chloride / methanol = 20: 1 as eluent. Yield: 1.2 g (16% of theory), m.p .: '. C 55.53 H 5.64 N 6.81

Gef .: 55.41 5.70 6.57 • "H-NMR spectrum (CDCU / CD OD):

S = 7.21 ppm (d, IH) S = 7.22 ppm (d, IH) According to the H-NMR spectrum (400 MHz), there is an approximately 2: 3 mixture of the diastereomers.

Example 96

N- [2- (4-Carboxyethoxyphenyl) -1-methylethyl] -2- (2-amino-thiazol-4-yl) morpholine dihydrochloride

1.6 g (0.0037 mol) of N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-acetamino-thiazol-4-yl) morpholine are dissolved in 100 ml of 18% hydrochloric acid over 48 Cooked under reflux under nitrogen. The reaction solution is mixed with 1.5 g of activated charcoal, stirred well and filtered off. The solution is then concentrated and the product is dried in vacuo over potassium hydroxide.

- 128 - S 2 64 4 34 15 76 : Theory), 15 78 N 8,32 7 , 11 Cl 8.99 7 , 18

Calc .: C 47.99 H 9.32 Found: 48.20 9.45

According to H-NMR spectrum (400 MHz) is a 2: 1 mixture of diastereomers.

Example 97

N- [2- (4-Carboxymethoxyphenyl) -1-methylethyl] -2- (2-chloro-thiazol-4-yl) morpholine

0.55 g (0.0013 mol) of N- [2- (4-carbomethoxymethoxyphenyl) -l-t-methylethyl] -2- (2-chloro-thiazol-4-yl) morpholine are stirred at room temperature for 10 minutes in 4 ml of methanol and 4 ml stirred in sodium hydroxide solution. It is then neutralized with 4 ml of hydrochloric acid and the product is recovered by extraction with methylene chloride.

Yield: 0.52 g (100% of theory), Melting point: 80-90 ⁰ C (dec.)

Calc .: C 54.47 H 5.33 N 7.05 Cl 8.93 Found: 54.40 5.42 7.00 8.90 According to ¹ H-NMR spectrum (400 MHz) is a 2: 3 Mixture of diastereomers.

Example 98

N- [2- (4- (2-hydroxyethoxy) phenyl) -1-methylethyl] -2- (2-chloro-thiazol-4-yl) morpholine

Prepared analogously to Example 71 by reacting N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-chlorothiazol-4-yl) morpholine with borane-tetrahydrofuran complex (1 molar solution in Tetrahydrofuran) over 60 hours.

- 129 -

Yield: 35% of theory ^ H-NMR spectrum (CDCl ₃ ZCD ₃ OD):

£ = 7.209 ppm (d, IH) S = 7.228 ppm (d, IH)

According to ¹ H NMR SPeICtrum (400 MHz), a 2: 3 mixture of diastereomers is present.

Example 99

N- [2- (4- (2-Hydroxyethoxy) phenyl) -1-methylethyl] -2- (2-hydroxy-2- (2-chlorothiazol-4-yl) ethanamine

Prepared analogously to Example 71 by reacting N- [2- (4-carboxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-chlorothiazol-4-yl) ethanamine with borane-tetrahydrofuran complex (1 molar solution in Tetrahydrofuran) over 24 hours. Yield: 20% of theory

15 ¹ H-NMR spectrum (CDCl ₃ ZCD ₃ OD):

S = 7.195 ppm (d, IH) S = 7.22 ppm (d, IH)

According to the H-NMR spectrum (400 MHz), there is an approximately 1: 1 mixture of the diastereomers.

20 Example 100

N- [2- (4-carboxymethoxyphenyl) -1-methylethyl] -2 ~ hydroxy-2- (2-chloro-thiazol-4-yl) ethanamine

Prepared analogously to Example 97 by reacting N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-chlorothiazol-4-yl) -ethanolamine with 1N sodium hydroxide solution in methanol. Yield: 0.19 g (100% of theory) Melting point: 58-63 ⁰ C

- 130 -

4 4 3

Ber. i C 51, 82 H 5, 16 N 7, 55 Gef .: 51 75 5, 22 7, 58 example 101

N- [2- (4- (2-hydroxyethoxy) phenyl) -1-methylethyl] -N- (2-hydroxyethyl) -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine

Prepared analogously to Example 71 by reacting N- [2- (4-carboxymethoxyphenyl) -1-methylethyl-N- (2-hydroxyethyl) -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine in tetrahydrofuran with diborane in tetrahydrofuran and purification of the base over a Kieselgelsa'ule with ethyl acetate / methanol »20: 1 as eluent

 Yield: 54% of theory, oil,

Calc .: C 52.52 H 5.80 N 6.45 F .: 52.19 5.72 6.39 ¹ H-NMR SPeKtTUm (400 MHz) (CDCl / CD OD):

£ = »7.828ppm (s, IH) £ = 7.839ppm (s, IH) There is a 60:40 mixture of diastereomers.

Example 102

N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2- (2-piperidino-thiazol-4-yl) morpholine

Prepared analogously to Example 32 by reacting 2.9 g (0.01 mol) of 2-piperidino-4-bromoacetyl-thiazole with 3.2 g (0.012 mol) of N- (2-hydroxyethyl) -2- (4-carbomethoxyphenyl) -lmethylethylamine in 200 ml of acetone in the presence of 3 g (0.03 mol) of potassium bicarbonate and subsequent reduction in 60 ml of trifluoroacetic acid with 2.9 g (0.076 mol)

- 131 - ^ ¹

Sodium borohydride over 24 hours. The substance is purified on a silica gel column with ethyl acetate as the eluant to give a yellow oil

Yield: 0.8 g (17% of theory), Calc .: C 62.71 H 7,23 N 9,14 S 6,97 F .: 62,50 7,33 9,40 6,92 According to ¹ H NMR spectrum (400 MHz), there is a ca. 33i66 mixture of diastereomers: * ^a 6.33 ppm (d, IH)

* 6.44 ppn (d, IH)

Example 103

NC 2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-piperidino-thiazol-4-yl) ethanamine hydrochloride

Prepared analogously to Example 3 by reacting 2-piperidino-4-bromoacetyl-thiazole with 2- (4-carbomethoxymethoxyphenyl) -1-methylethylamine and subsequent reduction. The compound is purified on a Kieselgelsä'ule with ethyl acetate / methanol = 9: 1 as the eluent and the base is converted with ethereal hydrochloric acid in the hydrochloride. Yield: 13% of theory,

Melting point: from 100 ⁰ C dec.

Calc .: C 52.16 H 6.56 N 8.29 S 6.32 Cl 14.01 V .: 51.80 6.83 8.17 6.48 13.72 According to the ^ -NMR spectrum (400 MHz ) is an approximately 50:50 mixture of diastereomers.

- 132 -

Example 104

N- [2- (4-carbomethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine

0.54 g (0.030 mol) of 2- (2-trifluoromethyl-thiazol-4-yl) -ethylene-5-oxide are dissolved in 5 ml of ethanol and added to a boiling solution of 0.58 g (0.0030 mol) 2- (4- Carbomethoxyphenyl) -methylethylamine in 13 ml of ethanol was added dropwise within 1 minute. The mixture is then refluxed for 5 hours, the solvent is distilled off and the base is purified over a silica gel column with methylene chloride / methanol ^a 20tl as eluent.

, Yields 0.45 g (38% of theory), Ber.t C 52.57 H 4.93 N 7.21 V: 52.34 5.11 7.11 ¹ H-NMR spectrum (400 MHz) ( CDCl ₃ ZCD ₃ OD):

£ = 7.58 ppm (s, IH)

S = 7.61 ppm (s, IH) There is an approx. 50:50 mixture of the diastereomers.

Example 105

N- [2- (4-Carbomethoxymethoxypheny1) -1-methylethy1] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine

Prepared analogously to Example 104 by reaction of 2- (2-trifluoromethyl-thiazol-4-yl) ethylene oxide with 2- (4-carbomethoxymethoxyphenyl) -l-methyl-ethylamine and dimethyl sulfoxide at 90 ⁰ C for 16 hours. The base is purified by shaking with ether and purifying on a silica gel column with methylene chloride / methanol = 20: 1 as the eluent.

, ₁₃₃ -

2 6 4 4 3

Yield: 24% of theory, calc .: C 51.66 H 5.06 N 6.70 Found: 51.50 4.99 6.71 ¹ H-NMR spectrum (400 MHz) (CDCl ₃ ZCC S = 7.57 ppm (d, IH)

J = 7.61 ppm (d, IH) There is an approximately 5O: 5O mixture of the diastereomers,

Example 106

N -C 2- (4- (2-Hydroxyethoxy) phenyl) -1-methylethyl] -N- (2-hydroxyethyl) -2-hydroxy-2- (2-chlorothiazol-4-yl) ethanamine

Prepared analogously to Example 30 by reaction of 2-chloro-4-bromoacety.lthiazole with N- (2-hydroxyethyl) -2- (4-carbomethoxymethoxyphenyl) -1-methylethylamine and subsequent reduction in methanol with sodium borohydride at room temperature. The crude product is purified over a silica gel column with chloroform / ethyl acetate / methanol = 10: 9: 1 as eluent. Yield: 15% of theory,

Calc .: C 53.92 H 6.29 N 6.99 S 8.00 Cl 8.84 F .: 53.68 6.30 6.57 7.61 8.72

¹ H-NMR spectrum (400 MHz) (CDCl ₃ ZCD ₃ OD):

S = 7.22 ppm (d, IH) S = 7.11 ppm (d, IH)

According to the H-NMR spectrum (400 MHz), there is an approximately 1: 1 mixture of the diastereomers.

- 134 -

Example 107

N -C 2- (4-methoxycarbonylmethoxyphenyl) -1-methylethyl] - (2-methoxy-2 "- (2-methylthiazol-4-yl) ethanamine dihydrochloride x 1.5 HoO

Prepared analogously to Example 13 by reaction of 2-methoxy-2- (2-methyl-thiazol-4-yl) ethanamine with 1- (4-methoxycarbonylmethoxyphenyl) propan-2-one and subsequent purification of the base by column chromatography on silica gel with chloroform / Methanol = 10/1 as eluent

 Yield: 58% of theory,

¹ H-NMR SPeKtTUm (400 MHz) (CDCl) t

i " 4.40 ppm (dd," CH-OMe) " m 4.44 pp _m (dd," CH-OMe)

According to the H-NMR spectrum, there is an approx. 5O: 5O mixture of the diastereomers.

The oily base is converted by means of hydrogen chloride / methanol iw a foam-like dihydrochloride.

Melting point: 60-8O ⁰ C,

Calc .: (x 1.5 H ₂ O) C 47.69 H 6.53 N 5.86 S 6.70 Cl 14.82 F .: 47.77 6.68 6.01 7.07 14.98

Example 108

N- [2- (4-Carboxymethoxyphenyl) -1-methylethyl] -2-methoxy-2- (2-methyl-thiazol-4-yl) ethanamine χ 0.5 H ₂ O

Prepared analogously to Example 16 by reacting N- [2- (4-methoxycarbonylmethoxyphenyl) -1-methylethyl] -2-methoxy-2- (2-methylthiazol-4-yl) -gentanamine in methanol with 1N sodium hydroxide solution. After neutralization with IN hydrochloric acid in vacuo

6 73 N 7, 50 S 8th, 59 6 75 7, 68 8th, 61

evaporated and then partitioned between chloroform and water. The chloroform extract is evaporated in vacuo. The foamy evaporation residue is dried at 50 ° C / 0.01 Torr

Yield »47% of theory, melting point: 80-90 ^e C Ber.i (x 0.50 H ₂ O) C 57.88 H

Gef .: 57.73

¹ H NMR spectrum (400 MHz) (CDCl / CD OD):

i » 1.03ppm (dd," CH-Me)

S = 1.08 ppm (dd, -CH-Me) There is an approx. 50:50 mixture of the diastereomers.

Example 109

N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -N- (2-hydroxyethyl) -2-hydroxy-2- (2-chloro-thiazol-4-yl) ethanamine

Prepared analogously to Example 106 by reaction of 2-chloro-4-bromoacetylthiazole with N- (2-hydroxyethyl) -2- (4-carbomethoxymethoxyphenyl) -1-methylethylamine and subsequent reduction at ⁰ ° C. The crude product is passed through a silica gel column with chloroform / ethyl acetate = 3:17 as eluant, yield: 12% of theory, oil,

Der .: C 53.20 H 5.87 N 6, 53 S 7.48 Cl 8.27 Gef .: 52.96 5.83 6.26 7.65 8.37 ¹ H-NMR spectrum (400 MHz ) (CDCl / CD OD):

7.22ppm (d, IH) S = 7.13ppm (d, IH)

According to the H-NMR spectrum, an approximate 50:50 mixture of the diastereomers is present.

- 136 - 2 6 4

Example 110

N -C 2- (4-carbomethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine

1 g (0 _# 0036 mol) of 1- (2-trifluoromethyl-thiazol-4-yl) -1-hydroxy-2-bromoethane are dissolved in 20 ml of ethanol, with 15 g of 2- (4-carbomethoxyphenyl) -l Added methylamine and heated for 2 hours to Rückfluß. The solvent is distilled off, the remaining residue is taken up in methylene chloride and shaken out with 2N sodium hydroxide solution. The organic phase is dried, concentrated by evaporation and the crude product is purified on a silica gel column with methylene chloride / methanol 20: 1 as eluent

 Exploits 0.9 g (65% of theory),

Ber. : C 52.57 H 4.93 N 7.21 F .: 52.27 5.04 7.17

¹ H-NMR spectrum (400 MHz) (CDCl ₃ ZCD ₃ OD):

8 = 7.58 ppm (s, IH)

£ = 7.61 ppm (s, IH) According to the H-NMR spectrum, there is an approx. 50:50 mixture of the diastereomers.

Example 111

N- [2- (4- (2-ethoxyethoxy) phenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine

Prepared analogously to Example 13 by reaction of 2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine with 1- (4- (2-ethoxyethoxy) -phenyl) propan-2-one and subsequent purification of the Crude product over a Kieselgelsa'ule with methylene chloride / methanol = 95: 5 as eluent.

- 137 - 2 6 4

Yield: 34% of theory, oil, Ber. : C 54.53 H 6, 02 N 6.69 S 7.66 Gef ι 54.45 6.12 6.71 7.63

^ • H-NMR spectrum (400 MHz) (CDCl ₃ ZCD ₃ OD): S = 7.60 ppm (s, IH)

S = 7.57 ppm (s, IH)

According to the H-NMR spectrum, there is an approx. 50:50 mixture of the diastereomers.

Example 112

N- [2- (4- (2-Ethoxyethoxy) phenyl) -1-methylethyl] -2- (2-trifluoro-methylthiazol-4-yl) morpholine

Prepared analogously to Example 87 by reacting N- (2-hydroxyethyl) -2- (4- (2-ethoxyethoxy) phenyl) -1-methylethylamine with 2-trifluoromethyl-4-bromo-cetyl-thiazole in the presence of potassium bicarbonate , followed by reduction and purification of the crude product over a silica gel column with toluene / ethyl acetate = 8: 2 as the eluent. Yield: 35% of theory, oil, calc .: C 56.74 H 6.12 N 6.30 S 7.21 V: 56.65 6.21 6.15 7.30

• "• H-KMR spectrum (400 MHz) (CDCl ^ / CD.OD):

«= 7.60 ppm (s, IH)

7.57 ppm (s, IH) is around

astereomers.

According to the ^ -H-NMR spectrum, there is about a 50:50 mixture of the di-

Example of construction 113

N- [2- (4- (2-ethoxyethoxy) phenyl) -1-methylethyl] -N- (2-hydroxyethyl) -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine

prepared analogously to Example 106 by reacting 2-trifluoromethyl-4-bromoacetyl-thiazole with N- (2-hydroxyethyl) -2- (4- (2-ethoxyethoxy) phenyl) -1-methylethylamine in the presence of potassium bicarbonate, followed by reduction with sodium borohydride in glacial acetic acid and purification of the crude product over a Kieselgelsa'ule with toluene / ethyl acetate = 6: 4 as eluent.

Yield: 37% of theory, oil, calc .: C 54.53 H 6.32 N 6.06 S 6.93 Found: 54.41 6.76 5.95 7.15! H-NMR spectrum 1400 MHz) (CDCl / CD OD) ι 8 = 7.60 ppm (s, IH)

5 = 7.49 ppm (s, IH)

According to the H-NMR spectrum, there is an approximately 3: 2 mixture of the diastereomers.

Example 114

N- [2- (4- (2-Phenethoxyethoxy) phenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine

Prepared analogously to Example 13 by reacting 2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethenamine and 1- (4- (2-phenethoxy) phenyl) propan-2-one and then purifying the base over a Silica gel column with ethyl acetate / methanol = 8: 2 as eluent.

Yield: 43% of theory, oil, calc .: C, 60.71, H, 5.91. N. 5,66 S 6,48 Found: 60,55 6,03 5,71 6,80

- 139 -

• "H-NMR spectrum (400 MHz) (CDCl ₃ ZCD ₃ OD):

i = 7.62 ppm (s, IH) & = 7.55 ppm (s, IH)

According to the H-NMR spectrum, there is an approx. 50:50 mixture of the diastereomers.

Example 115

N- [2- (4- (2-phenethoxyethoxy) phenyl) -1-methylethyl] -2- (2-trifluorothiazol-4-yl) morpholine

Prepared analogously to Example 87 by reacting N- (2-hydroxyethyl) -2- (4- (2-phenethoxyethoxy) phenyl) -1-methylethylamine with 2-trifluoromethyl-4-bromoacetyl-thiazole in the presence of potassium bicarbonate, followed by reduction and purification of the crude product About a silica gel column with methylene chloride / methanol =: as eluent. Yield:% of theory, oil, calc .: C 62.29 H 6.00 N 5.38 S 6.16 Gef.

 'H-NMR spectrum (400 MHz) (CDCl /):

ή = ppm ()

% = ppm ()

According to the H-NMR spectrum, there is about a 50:50 mixture of the

astereomers.

Example 116

N- [2- (4- (2-Phenethoxyethoxy) phenyl) -l ~ methyl-ethyl] -N- (2-hydroxyethyl) -2-hydroxy-2- (2-trifluormethy '- thiai, ol-4-yl) ethane-amine

Prepared analogously to Example 106 by reaction of 2-tri-

fluoromethyl-4-bromoacetyl-thiazole with N- (2-hydroxyethyl) -2- (4T- (2-phenethoxyethoxy) phenyl) -1-methylethylamine in the presence of potassium hydrogen carbonate, followed by reduction and purification of the crude product over a Kieselgelsä'ule with methylene chloride / Methanol = ζ as eluent. Yield:% of theory, oil, Ber. : C 60.21 H 6.18 N 5.20 S 5.95

! Found .:

! ¹ H-NMR spectrum (400 MHz) (CDCl /):

6 = ppm ()

S = ppm (): L ^ .ut H NMR spectrum is a 50:50 mixture of the di-

asteroomeren ago.

Example 117

N- [2- (4- (3-hydroxypropoxy) phenyl) -l-methylethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine

Prepared analogously to Example 13 by reaction of 2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine and 1- (4- (3-hydroxypropoxy) phenyl) propan-2-one and subsequent purification of the base over a Silica gel column with ethyl acetate / methanol = 9: 1 as eluent.

Yield: 33% of theory, oil, calc .: C 53.46 H 5, 73 N 6.93 Found: 53.34 5.88 6.78 ^ -NMR spectrum (400 MHz) (CDCl ₃ CD ₃ OD):

S = 7.57 ppm (s, IH) (> = 7.60 ppm (s, IH)

According to the H-NMR spectrum, there is an approx. 50:50 mixture of the diastereomers p.

- 141 -

Example I

10 0 mg 69, 0 mg 35, 0 mg 5, 0 mg 1, 0 mg 120 0 mg

Dragee with 10 mg of N- [2- (4-carbomethoxymethoxyphenyl) -methylethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) -ethanamine

composition t

1 dragee contains:

(1) Active substance

(2) lactose

(3) corn starch

(4) polyvinylpyrrolidone (5) magnesium stearate

production:

(1) + (2) + (3) are mixed and moistened with (4) in an aqueous solution. The moist mass is beaten through a sieve with 1.6 mm mesh size and dried at 45 ⁰ C in a convection oven. The dry granules are passed through a 1 mm mesh screen and mixed with (5). The finished mixture is pressed into dragee cores,

Core weight: 120.0 mg Diameter: 7.0 mm Camber radius: 6.0 mm

The coated dragee cores are coated in a known manner with a layer consisting essentially of sugar 2-> and talc. This layer.: Ann also color separations included. The finished dragees are polished with wax.

Dragee weight: 180.0 mg

- 142 Example II

Dragee with 50 mg of N- [2- (4-carbomethoxymethoxyphenyl) -methylethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethanamine

Composition: 50.0 mg 1 dragee contains: 110.8 mg (1) Active substance 50.0 mg (2) lactose 8.0 mg (3) corn starch 1.2 mg (4) polyvinylpyrrolidone 220.0 mg (5) magnesium stearate

manufacture;

The preparation is carried out analogously to Example I.

Core weight: 220.0 mg

Diameter: 9.0 mm

Buckling radius: 8.0 mm

Dragee weight: 300.0 mg

- 143 -

6 4 434

Example III

Tablets containing 150 mg of N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethanamine

Composition:

1 tablet contains »

(1) Active substance. 150.0 mg

(2) lactose 86.0 mg (3) corn starch 50.8 mg (4) Microcrystalline celluloae 25.0 mg (5) polyvinylpyrrolidone 7.0 mg (6) magnesium stearate 1.2 mg

320.0 mg

production:

(1) + (2) + (3) + (4) + (5) are mixed and moistened with water. The feuclu ι mass is beaten through a sieve with 1.6 mm mesh size and dried at 45 ⁰ C. The dry granules are again passed through the same sieve and mixed with (6). From the finished mixture tablets are pressed.

Tablet weight: 320.0 mg Diameter: 10.0 mm

The tablets are provided with a partial notch to allow halving.

-144-

Example IV

4434

Hard gelatin capsules to 100 mg of N- [2- (4-carbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy-2- (2-trifluoromethyl-thiazol -4-yl) ethanamine

5 composition t

1 capsule contains »

KapselhUllet Hard Gelatin Capsules Size 3 Capsule ingredients:

(1) Active substance 10 (2) Lactose χ IH ₂ O

(3) corn starch dried

(4) Magnesium stearate capsule oil weight:

(5) Oest. Water q.s.

15 production;

A small portion of lactose is about 10% in dist. Water dissolved (granulating liquid). The active ingredient, the remaining lactose and corn starch are mixed and moistened with the granulating liquid. The mass is sieved, dried and mixed again with Magticiiumstearat after repeated sieving. The fine-grained granules are filled into capsules on a suitable machine.

100.0 mg 38.0 mg 60.0 mg 2.0 mq 200.0 mg

- 145 Example V

Haitgelatinekapseln to 200 mg of N- [2- (4-carbomethoxymethoxyphenyl) -l-methylethyl] -2-hydroxy-2- (2-trifluoromethyl-thia zol-4-yl) ethanamine

κ composition t

Capsule Hard Gelatin Capsules Size 1 Capsule Ingredients:

(D Wirhsubstanz 200.0 mg (2) Lactose χ IH ₂ O 47.0 mg (3) Corn starch dried 70.0 mg (4) magnesium stearate 3.0 mg KapselfUligewichtt 320.0 »9

(5) Dest. Water q.s.

manufacture;

A small portion of lactose is about 10% in dist. Water dissolved (granulating liquid). The active ingredient, the remaining lactose and corn starch are mixed and moistened with the GranulierflUssigkeit. The mass is sieved, dried and, after repeated sieving, homogeneously mixed with magnesium stearate. The fine-grained granules are filled into capsules on a suitable machine.

Claims (39)

claims 1) for the preparation of compounds of general formula I in which R ₃ and R _{4 are} added to each other. · An ethylene group in which the methylene group adjacent to the N or O atom is replaced by a carboxyl group, a compound of the general formula OH H CH-CH ₂ -NA - (/ ^) (XVIII) in the A, X "R ^, R ₂ and R _{5 are} as defined above, reacted with a haloacetyl halide or halogenene ester, or m) for the preparation of compounds of general formula I in which R ₃ and R ₄ together represent an ethylene group, a compound of the general formula (XIX) in the A, X, R ₁ , R ₂ and R- are as defined in claim 1, is reduced or n) for the preparation of compounds of the general formula I in which R ₃ and R ₄ together represent an ethylene group in which the methylene group adjacent to the O atom is replaced by a carbonyl group, an optionally formed in the reaction mixture of the general formula COOH
I Well Un ₀ ρ _ ^ ^ μ_ Ah-ch, -La- ^ '(XX) in the A, X, R ₁ , R ₂ and R are as defined above, or their reactive derivatives such as their esters or halides is cyclieiert or o) zur.Herstellung of compounds of general formula I, in which R _{1 is} a hydrogen or halogen atom, a trifluoromethyl or alkyl group and R, a Was-. represent eeretoffatom, a compound of the general formula (XXI) in the X and R _{2 are} as defined above and R., a hydrogen or halogen atom, a trifluoro * » methyl or alkyl group represented by an amine of the general formula (XXII) in the A ₁ R and R _{5 are} as defined above is reacted if desired, a compound of the general formula I in which R _r represents or contains an alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group and / or R 1 represents an amino group substituted by an alkanoyl or benzoyl group, by hydrolysis into a corresponding compound of the general formula I in which R ₅ represents or contains a carboxy group and / or R _{1 represents} an amino group, is converted and / or a compound of the general formula I in which R _{5 is} an alkoxy group substituted by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, by reduction by a suitable metal hydride to a compound of the general formula I in which above-mentioned substituted alkoxy group instead of the carbonyl group contains a methylene group is converted and / or a compound of the general formula I in which R _{3 is} an alkyl group and / or R _{5 is} an alkoxy group mentioned in claim 1, by ether cleavage into a corresponding compound of the general formula I in which R _{3 is} a hydrogen atom and / or or R _{5 represents} a hydroxy group or an alkoxy group substituted by a hydroxy group, is converted, and / or one compound of the general formula I thus obtained is separated into its optical isomers and oiastereomers and / or a compound of the general formula I thus obtained is converted into its acid addition salts, in particular into its physiologically tolerated acid addition salts, and optionally the compounds of the formula I are incorporated in one or more inert debris and / or diluents in customary pharmaceutical application forms. 1, Process for the preparation of new substituted thiazoles and oxazoles of the general formula _M OR, R. _R / s ^] 'I / T ^ S ⁵ R ₁ -AU CH-CH ₂ -NA- (/ X) (I) in the A represents an optionally substituted by methyl or ethyl groups mono- or dlsubstltuierte n-alkylene group having 2 or 3 carbon atoms, X is an oxygen or sulfur atom, R _{1 represents} a hydrogen or halogen atom, a trifluoromethyl, alkyl, phenyl or piperidino group or an amino group optionally substituted by one or two alkyl groups or an alkanoyl or benzoyl group, R _{2 is} a hydrogen atom or an alkyl group, R, a hydrogen atom or an alkyl group which may be substituted in the 2- or 3-position by a hydroxy group, or R ₃ together with R ₄ an alkoxycarbonylmethylene group or an ethylene group, wherein the N- or O-adjacent atom methyl group by a carbonyl group can be replaced Berlin, 4 * 8,1988 68 288/12 R _{4 is} a hydrogen atom, optionally substituted by a phenyl, carboxy, alkoxycarbonyl or cyano group or in the 2- or 3-position by a hydroxy group-substituted alkyl group or an alkenyl group and R _{5 is} a hydroxy, alkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or D1-alkylaminocarbonyl group, an alkoxy group having 1 to 6 carbon atoms, which is terminally substituted by carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or D1-alkylaminocarbonyl group an alkoxy group having 2 to 7 carbon atoms which is terminally substituted by a hydroxy, alkoxy, phenylalkoxy, amino, alkylamino, dialkylamino, pyrrolidino, piperidino or hexamethyleneimino group, or optionally substituted by an alkyl group Ethenylene graft which is terminally substituted by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylamino-carbonyl group, wherein all the above-mentioned alkyl, alkoxy or alkanoyl groups, unless otherwise stated, each containing 1 to 3 carbon atoms and the aforementioned alkenyl groups may contain 3 to 5 carbon atoms, their optical isomers and their diastereomers and their acid addition salts and optionally the usual pharmaceutical application forms, characterized in that a) a compound of the general formula OR, I ³ CH-CH ₂ -Z ₁ (II) R ₂ with a compound of the general formula (III) in which R ₁ to R ₃ , A and X are as defined in claims 1 to 8, Z _{1 is} a nucleophilic impurity and Z ₂ oine R ₄ -NH group or Z _{2 is} a nucleophilic leaving group and Z _{1 represents} a R.-NH group, wherein R _{4 is} as defined above, and R ₅ , which has the meanings mentioned for R ₅ in claims 1 to 8, but where R-, can not represent any of the alkoxycarbonylmethoxy groups claimed in claims 1 to 8 and a carboxy, amino or alkylamino group contained in the radical R ₅ by a Schutzreet can be protected «implemented and given · if subsequently a used protection remnant is split off or b) an optionally formed in the reaction mixture Schiff base of the general formula (IV) in the R ^ i R ₂ and X are as defined above and Y is a group of the formula OR R ι O | O-CH-CH ₂ -NA or -CO-CHAN / represent, wherein R ₃ and A are as defined above R ₅₁ . has the meanings mentioned for R ₅ in the claim, but wherein an amino or alkylamino group contained in the radical R ₅ may be protected by a protective radical, and
R _c together with a hydrogen atom of the adjacent Carbon atom of the radical A is a further bond, reduced and, if appropriate, then a used protective moiety is cleaved or c) for the preparation of compounds of general formula I, wherein R ₃ and R _{4 are} as defined above, wherein however, R ₃ and R _{4 are} not an ethylene group in which the methylene group adjacent to the N atom is replaced by a carbonyl group, a carbonyl compound of the general formula in the A as defined above R ₅₁ . has the meanings mentioned for R ₅ in the claim, but wherein an amino or alkylamino group contained in the Reet R ₅ may be protected by a protective radical, and Z ₃ together with a Waeserstoffatom dos adjacent carbon atoms of the radical A represents an oxygen atom, with an amine of general formula CH-CH ₂ -NH in the ^R l * ^R 2 ^unc * ^X are defined ^as ° k ^en , R 1 and R _{41 have} the meanings mentioned for R 1 and R ₄ in the claim, but where R 1 and R ₄ together do not denote an ethylene group in which the methylene group adjacent to the N atom is replaced by a carbonyl group, in the presence of a suitable reducing agent aminiert redulctiv and, if appropriate, then a used protective moiety is cleaved or d) for the preparation of compounds of the general formula I in which R _{3 represents} a hydrogen atom, a compound optionally formed in the reaction mixture of the general formol ^R 4 R ₅ .. .-4J CO-CH ₂ -NA - ^ / Λ) (VII) ^S 2 in the A »X« R- »R ₂ and R are as defined in the claim and R-, which has the meanings mentioned above for R-, but wherein an amino or alkylamino group contained in the radical R ₅ can be protected by a protective rust, reduced and, if appropriate, subsequently a protective moiety used is eliminated or e) for the preparation of compounds of general formula I in which R and R ₄ together represent an alkoxycarbonylmethylene group, a compound of the formula NEN OH H _R CH-CH ₂ -NA- ^ ^) (VIII) R ₂ in the
A, X, R ₃ , and R _{2 are} as defined above and R _g "has the meanings mentioned for R ₅ in the claim, but wherein an amino or alkylamino group contained in the radical R ₅ may be protected by a protective radical, with a compound of the general formula O CH - COOK ₇ (IX) in the R _{7 represents} an alkyl group having 1 to 3 carbon atoms, reacted and, if appropriate, then a protective residue used is removed or f) for the preparation of compounds of the general formula I ₁ in which R _{P is} an alkoxy group having 1 to 3 carbon atoms, an alkoxy group having 1 to 6 carbon atoms which is terminally substituted by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group , or an alkoxy group having 2 to 7 carbon atoms, which is permanently substituted by a hydroxy, alkoxy, amino, alkylamino, oialkylamino, pyrrolidino, piperidino or hexamethylene imino group, represents a compound of the general formula CH-CH ₂ -N- / in the A, X and R ₁ to R _{3 are} as defined above and R ₄ , which has the meanings mentioned for R ₄ in claim 1 or represents an easily removable protecting group for an amino group, with a compound of the general formula Z ₄ - R ₈ (XI) in the Rg is an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 6 carbon atoms which is terminally substituted by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylamino-carbonyl group, or an alkoxy group having 2 to 7 carbon atoms which are terminal is substituted by a hydroxy, alkoxy, amino, alkylamino, Dielkylamino-, pyrrolidino, piperidino or Haxamethyleniminogruppe, and Z _{4 is} a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group or Z ₄ zücqmmen with a ß-hydrogen atom of the radical Rq represent an oxygen atom, reacted and, if appropriate, then a protective moiety used is cleaved or g) for the preparation of compounds of the general formula I in which R _{3 represents} a hydrogen atom, a compound of the general formula h) for the preparation of compounds of the general formula I, wherein R ~ represents or contains an alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or Oialkyleminooarbonylgruppe, a compound of the general formula / y ^N ^ I ³ I ^4/7 "TS / V 'R ₁ // U CH-CH ₂ -N-Ay / Λ \ (XIII) ^R 2 in the R ₁ to R ₄ , A and X are as defined above and R - represents a carboxy group or an alkoxy group having 1 to 6 carbon atoms which is terminally substituted by a carboxy group, or their reactive derivatives, with a compound of the general formula formula HR _Q ; XIV) in the Rg represents an alkoxy, amino, alkylamino or dialkylamino group, wherein each of the alkyl or alkoxy moiety may contain 1 to 3 carbon atoms, is reacted or i) for the preparation of compounds of the general formula I, in which R _{4 represents} an alkyl group or an alkenyl group which is optionally substituted by a phenyl, carboxy, alkoxycarbonyl or cyano group or in a 2- or 3-membered hydroxy-substituted group Compound of the general formula CH-CH ₂ -NA - (/ ^) (XV) in the A, X and R _{1 to} R _{3 are} as defined above and R ₅ «,. has the meanings mentioned for R ₅ in claim 1, but wherein an amino or alkylamino group contained in the radical R ₅ can, if necessary, be protected by a protective radical, with a compound of the general formula Z- - R _A ", (XVI) ₂ -N-CH-CH ₂ - ^ \\ - R ₅ be prepared in the R _{1 represents} a chlorine atom, a methyl or trifluoromethyl group, R _{3 is} a hydrogen atom or R ₃ and R ₄ together represent the ethylene or methoxycarbonylmethylene group, R _{4 is} a hydrogen atom, a methyl, 2-hydroxyethyl or carbethoxymethyl group and R ₅ a. Carboxy-methoxy, carbomethoxymethoxy, ethoxycarbonylmethoxy, aminocarbonylmethoxy, methylamino carbonylmothoxy, 2-methylamino-ethoxy, 2-hydroxy-gethoxy or 2-carbomethoxy-l-methyl-ethenyl group, their optical isomers and their Diaeteroomere and their acid addition salts. - 2 6 4 4 3 Rg is a hydroxy, methoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, carboxymethoxy, methoxycarbonylmethoxy, ethoxycarbonylinethoxy, amino carbonylmethoxy, methylaminocarbonylmethoxy, 2-hydroxyethoxy, 2-ethoxyethoxy, 2 Phenoxy-ethoxy, 2-amino-ethoxy, 2-methylamino-ethoxy, 2- (1-piperidino) -ethoxy, 6-hydroxy-n-hexoxy or 2-carbomethoxy-methyl-ethenyl group . their optical isomers and their oiastereomers and their acid addition salts » 2. The method according to claim 1, characterized in that the reaction is carried out in a solvent « 3 »process according to claims la and 2, characterized in that the reaction is carried out in the presence of an acid-binding agent and / or in the presence of a Reaktionsbeechleuniger8 · 4 · Process according to claims la «2 and 3» characterized «that the reaction at temperatures between 0 and 150 ⁰ C, preferably at temperatures between 50 and 120 ⁰ C, is performed. Process according to Claims Ib and 2, characterized in that the reduction is carried out with a metal hydride, with hydrogen in the presence of a hydrogenation catalyst or with hydrazine in the presence of a hydrogenation catalyst, 5 4 in the R. . ,, with the exception of the hydrogen atonies for R ₄ possesses mentioned Bodeutungen and Z _r a nucleophilic Oetrittegruppe or Z _K together with an &> - or ß-Waeeeretoffatom dee the Alkylreetee Ru, a Saue retoffatom mean, umbneetzt and if necessary afterwards jin used Schutzreet is eliminated, or k) for the preparation of compounds of general formula I »in which R ₃ and R ₄ together represent an ethylene group« an optionally formed in the reaction mixture compound of the general formula HO-CH ₂ (XXII) in the A, X, R ₁ , R ₂ and R _{5 are} as defined above, or its cyclic hemiacetals is reduced or 6. The method according to claims Ib, 2 and 5, characterized in that the reduction at temperatures between 0 and 50 ⁰ C, preferably at room temperature, is performed. 7. Process according to claims Ic and 2, characterized in that the reduction is carried out in the presence of a complex metal hydride « 8. The method according to claims Ic, 2 and 7, characterized in that the reduction at temperatures between 0 and 50 ⁰ C, preferably at room temperature, is performed. 9. Process according to claims 1 and 2, characterized in that the reduction is carried out in the presence of a metal hydride. 44 10, Process according to claims Id ₁ 2 and 9, characterized in that «the reduction is carried out at temperatures between 0 and 40 ^° C, preferably at room temperature, 11, Process according to claims 1e and 2, characterized in that »the reaction is carried out in the presence of a dehydrating agent, 12, Process according to claims Ie ₄ 2 and 11, characterized in that the reaction is carried out at temperatures between 0 ⁰ C and the boiling temperature of the solvent used, 13, Process according to claims If and 2, characterized in that the reaction is carried out in the presence of an acid-binding agent, 14, Process according to claims If and 2, characterized in that for the preparation of a 2-hydroxyetiioxy compound of general formula I, the alkylation is carried out with ethylene oxide, Process according to Claims If, 2, 13 and 14, characterized in that the reaction is carried out at temperatures between 0 and 100 ^° C, but preferably at temperatures between 20 and 80 ^° C, 16, Process according to claims Ig and 2, characterized in that the reduction is carried out in the presence of a metal hydride. -fit- 2 6 44 Process according to claims 1 and 2, characterized in that the reduction is carried out at temperatures between 0 and 50 ^° C., but preferably at temperatures between 10 and 25 ^° C. Process according to claims 1 and 2, characterized in that the reaction is carried out in the presence of an acid activating agent or a dehydrating agent « Process according to claims 1 and 2, characterized in that the reaction is carried out in the presence of an acid-binding agent. 20, Process according to claims lh, 2, 18 and 19, characterized in that the reaction at temperatures between -25 and 250 ⁰ C, but preferably at temperatures between -10 ⁰ C and the boiling temperature of the solvent used, carried out, 21. The method according to claims 11 and 2, characterized in that the reaction is carried out in the presence of an acid-binding agent · 22, Process according to claims Ii, 2 and 21, characterized in that the reaction is carried out at temperatures between 0 and 100 ⁰ C, 23. The method according to claims Ik and 2, characterized in that the reaction is carried out in the presence of a hydride. 24, Process according to claims Ik, 2 and 23 «characterized in that the reaction at temperatures between 0 and 60 ⁰ C, Vorzugsv
temperature, is performed between O and 60 ⁰ C, preferably at room jedooh Process according to claims 11 and 2, characterized in that the reaction is carried out in the presence of an acid-binding agent « Process according to Claims 11, 2 and 25, characterized in that the reaction is carried out at temperatures between 0 and 100 ° C, but preferably at temperatures between the room temperature and the boiling point of the reaction mixture. Process according to claims 1 and 2, characterized in that the reaction is carried out in the presence of a metal hydride. Process according to claims 1, 2 and 27, characterized in that the reaction is carried out at temperatures between 0 and 50 ^° C., but preferably at temperatures between 10 and 25 ^° C. 29. Process according to claims 1 and 2, characterized in that the reaction is carried out in the presence of a dehydrating agent. 30, Process according to claims in, 2 and 29, characterized in that the reaction at temperatures between 0 and 100 ⁰ C, but preferably at the boiling temperature of the reaction mixture is carried out. 31 · The method of claim lo, characterized in that the reaction is conducted in a polar or aprotiechen solvent at temperatures between 0 and 150 ⁰ C, preferably at temperatures between 50 and 100 ⁰ C ₁ performed " 32. Process according to claims 1 to 31, characterized in that new substituted thiazoles and oxazoles of general formula I are prepared, in which A is an ethylene or n-propylene group optionally substituted by a methyl group, X is an oxygen or sulfur atom, R. represents a hydrogen or chlorine atom, an alkyl group having 1 to 3 carbon atoms, a Trifluormothyl-, phenyl, amino, Methylamine-, Dimethylamine-, piperidino, acetylamino or benzoylamino ^v, R _{2 is} a hydrogen atom or a methyl group, R _{3 is} a hydrogen atom, a methyl group or R ₃ and R ₄ together form a methoxycarbonyltnethylene group or an ethylene group, where the methylene group adjacent to the O atom may be replaced by a carbonyl group, R _{4 is} a hydrogen atom, a methyl, 2-hydroxy-9thyl, carboxymethyl, carbethoxymethyl or Benzy! Group and 33. Process according to claims 1 to 31 »characterized in that new substituted thiazoles and oxazoles of the general formula OR, R "CH, j 3 | 4 | 3 / CH-CH ₂ -N-CH-CH ₂ - ^  \\ - R ₅ (Ia) 34 * Process according to claims 1 to 31ι characterized in that N- £ 2- (4-Carbomethoxymethoxypheryl) -l-methylethyl] J-2-hydroxy-2- (2 "trifluoromethyl-thiazol-4-yl) ethanamine whose optical isomers and its diate isomers and its acid addition salts are prepared « 35 * Process according to claims 1 to 31, characterized in that N- (2- (4-carboxymethoxyphenyl) -methyl) -2- (2-trifluoromethyl-thiazol-4-yl) -morpholine _J its optical isomers and its diastereomers and its Acid addition & 3-salts are produced » Process according to Claims 1 to 31, characterized in that N- (2- (4-carbomethoxymethoxyphenyl) -1-methylethyl) JN- (2-hydroxyethyl) -2-hydroxy-2- (2-trifluoromethyl-) thiazol-4-yl) -ethanamine, its optical isomers and its oiastereomers and its acid addition salts are prepared. 37. Process according to claims 1 to 31, characterized in that N-r2- (4- (2-hydroxyethoxy) phenyl) -lmethylethyl!-2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl ) ethanamine, whose optical isomers and its oiastereomers as well as its acid addition salts are produced * 38. The method according to Aneprüchen 1 to 31, characterized in that 3 "/ 2 ~ (4- (2-carbomethoxy-l ~ methylethenyl) -phenyl) -lmethylethyl / -5- (2-trifluoromethyl-thiazole-4 -yl) -2-oxazolidine-carbonic acid methyl ester, whose optical
Isomers and their diastereomers and its acid addition salts are prepared « 39. A method according to Aneprüchen 1 to 31, characterized in that physiologically acceptable salts of the compounds according to claims 1 to 8 have been prepared with inorganic or organic acids ·