CS236700B2 - Manufacturing process of new 2-aminicarboxyl acides derivatives - Google Patents

Description

Process for the preparation of novel 2-anionic carboxylic acid derivatives of the general formula I

and their addition salts with inorganic or organic acids as well as bases, wherein the compound of formula II is converted to a diazonium salt by reaction with nitrite, which is then converted to a diazonium salt in the presence of sulfuric acid, copper or the corresponding monovalent copper salt. the corresponding desired compound, which is then optionally converted to its organic or inorganic acid or base addition salt.

The compounds produced have valuable pharmacological properties, in particular an effect on the intermediate metabolism, and can also be used as intermediates for the manufacture of other pharmaceuticals.

The present invention provides novel 2-aminocarboxylic acid derivatives of formula (I)

their acid addition salts, in particular their salts with inorganic or organic acids as well as with bases, processes for their preparation and the use of these novel 2-aminocarboxylic acid derivatives as medicaments and / or intermediates for the preparation of novel amide derivatives of the corresponding carboxylic acids.

The novel compounds of the formula I and their optically active antipodes, when they contain an asymmetric carbon atom, have valuable pharmacological properties, namely an effect on the intermedium metabolism. Thus, the compounds of formula I in particular reduce the lipid content.

In the general formula i, m is a number of 0 or 1,

R represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

X is CH or N,

R @ 1 - represents a hydrogen or halogen atom, a cyanosctipine or a hydroxyl group,

R _,; and R ₇ together with the nitrogen atom to which they are attached form a C 5 -C 10 alkyl substituted piperidino group, a C 7 -C 12 azabicycloalkyl group in the bicycloalkane ring optionally substituted with at least one C 1 -C 3 alkyl group carbon, furthermore an octahydro-az-azonine group, a hexahydroisoindolo group, an octahydroisoindolo group or a 1,3-dihydrolsoindolo group optionally substituted by a halogen atom, a C 1 -C 3 alkoxy group or an amino group and

R 1 is hydrogen or C 1 -C 3 alkyl.

The following are examples of individual meanings for the above-defined symbols R and R ₅ to R ₈ :

for R 5 is hydrogen, methyl, ethyl, propyl or isopropyl, for R ₅ is hydrogen, fluorine, chlorine or bromine, cyano or hydroxy, for R ₆ and R ₇ together with the nitrogen atom to which they are attached,

3-pentylpiperidino,

5-nonylpiperidino,

2-azabicyclononan-2-yl,

1,3-dihydroisoindolo, chloro-1,3-dihydroisoindolo, bromo-1,3-dihydroisoindolo, methoxy-1,3-dihydroisoindolo, ethoxy-1,3-dihydroisoindolo, isopropoxy-1,3-dihydroisoindolo, amino-1,3, 3-dihydroisoindolo, hexahydroisoindolo or octahydroisoindolo and, for R 5 _, a hydrogen atom, methyl, ethyl, propyl or isopropyl.

Preferred are those compounds of formula I wherein m is 0 or 1,

X is Cl or a nitrogen atom,

R represents a hydrogen atom or a methyl group,

_R is hydrogen or methyl,

R @ 1 is hydrogen, fluorine, chlorine or bromine, hydroxy or cyano,

R _(i and R7 ₎ together with the nitrogen atom to which they are attached form in the 4-position an alkyl group having 5 to 9 carbon atoms substituted piperidino, optionally chlorine or bromine atom, methoxy or amino substituted 1,3-dihydroisoindolo, hexahydroisoindolo or 2 -azabicyclononin-2-yl or also octahydroisoindolo in case ra is 1, or

X is N or m is 0,

R @ 1 is hydrogen, fluorine or bromine, hydroxy or cyano;

X represents a group CH, and in case they contain an asymmetric carbon atom, their optically active antipodes and their salts.

Particularly preferred are those compounds of formula (I) wherein m is 0 or 1,

X is CH,

R represents a hydrogen atom,

R @ - represents a hydrogen, chlorine or bromine atom at the 5-position,

R _G and R - together with the nitrogen atom to which they are attached form a piperidino group substituted in the 4-position with an alkyl group of 5 to 9 carbon atoms 1,3-dihydroisoindolo, optionally substituted with a chlorine or bromine atom, 2-azabicyclononan-3-yl or hexahydroisoindolo or

R _(i and R7 ₎ together with the nitrogen atom to which they are attached form an octahydroisoindolo group when m is 1 or m is 0 and

R @ 1 represents a bromine atom and

_R is hydrogen or methy2 3 6 7 Ο Π group, or a in the case that these compounds contain an asymmetric carbon atom, its optically active antipodes, and their physiologically tolerated addition salts with inorganic or organic acids as well as bases.

In accordance with the invention, the above novel compounds are prepared by the preparation of a compound of formula II

(II) in which

R, Rr; R _s , in and X have the same meaning, react with nitrite to form this! the diazonium salt is heated, optionally in the presence of copper or the corresponding copper salt.

Conveniently, the above reaction is carried out by converting a compound of formula II in a suitable solvent, for example a mixture of water and hydrochloric acid, methanol and hydrochloric acid or dioxane and hydrochloric acid, into a diazonium by treatment with a nitrite such as sodium nitrite or nitrous ester. salt. This reaction is carried out at lower temperatures, for example at -10 to 5 ^; C.

The corresponding diazonium salt thus obtained is then, for example, as the fluoroborate, as the hydrogen sulphate in sulfuric acid, as the hydrochloride in the presence of copper or in the presence of the corresponding monovalent copper salts such as cuprous chloride in hydrochloric acid, cuprous bromide in hydrobromic acid or Na _; Conversion at the pH 7 by heating, for example to a temperature of 15 to 90 ° C, is converted to the corresponding desired compound.

The compounds of the formula I obtained can be converted into physiologically tolerable salts with inorganic or organic acids or with bases.

Suitable acids in this case are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid and as the base sodium hydroxide, potassium hydroxide or cyclohexylamine.

The compounds of the formula (II) used as starting materials are known from the literature or can be obtained in a manner known per se. Thus, for example, a compound of formula (II) is prepared by reacting the corresponding 2-chloro or 2-bromo-carboxylic acid or derivative thereof with the corresponding amine, followed by reduction of the nitro group in the 2-amino compound thus formed by catalytically activated hydrogen, and converting the resulting amino group before the corresponding diazonium salt to the corresponding compound of formula II.

As mentioned above, the novel compounds of the formula I exhibit valuable pharmacological properties, namely an effect on the intermediate metabolism. Thus, the compounds of formula (I) act in particular to reduce lipid levels. In addition, the compounds of formula (I) are valuable intermediates for the production of novel amide derivatives of the corresponding carbosylic acids as described in our related Czechoslovak patent no. 236 668.

For example, the effects of the compounds were investigated as described below

Λ n-chloro-2-β-4- (3-methylpiperidino) benzoic acid; and ´ 5-bromo-2- (octahydroisoindol-2-yl) benzoic acid,

C 5-chloro-2- (2,3,3a, 4,7,7a hexahydro-1H-isoindol-2-yl) benzoic acid and D 5-chloro-2- (octahydroisoindol-2-yl) nicotinic acid for reducing lipid levels.

1. Lipid lowering effect

P. E. Schurr et al. “Atherosclerosis

Drug Discovery '(1976), ed. C.E. Day,

Plenum, New York, p. 215.

Young male rats of 100 g average weight induce hyperlipaemia by a four-day diet containing 10% coconut fat, 1.5% cholesterin, 0.5% cholic acid, 0.2% choline chloride, and 15% sucrose. With continuous feeding of the food, a suspension of the test substance in methylcellulose is then administered to the animals for two consecutive days using a swallowing probe. The animals are then fasted overnight, and blood is collected 4 and 24 hours after the last administration of the test substance to isolate the serum.

Total serum cholesterol (Boehringer Mannheim Test Combination 187 313) and triglycerides (Boehringer Mannheim Test Combination 126 039) are enzymatically determined in the serum obtained; The β-lipoproteins are determined nephelometrically in an autoanalyzer after precipitation with calcium ions and heparin.

The percent reduction compared to the control group is then calculated from the observed results.

The values found are summarized in the following table:

substance dose change in% vs. control (mg / kg) after double administration of total serum cholesterol / 3-lipoproteins in serum for hours

AND 5 20 May 50 —18 —49 —54 (B) 5 - 20 May - 37 50 —40 C 5 - 20 May - 43 50 —50 D 5 —43 20 May —48 50 -53

24 hours 4 o'clock 24 hours _ -39 —54 -54 -69 —43 —61 -57 —28 . .— —42 —51 —57 —66 —47 —47 —42 —34 - —36 —61 - 41 —62 —65 —54 —72 —45 - —47 -50 —45 -62 —48 —60 —67

The changes are statistically significant at p -, ¹

2. Acute toxicity

The toxic effect of the compounds according to the invention is determined in female and male mice weighing 20 to 26 g, coming from a single breed. Test substances are administered as a single oral suspension in 1% methylcellulose and the animals are observed for 7 days after this administration. The results are shown in the following table:

substance indicative toxicity

A> 1000 mg / kg (none of 10 animals died)

Owing to their pharmacological properties, the compounds of the formula I according to the invention are suitable for the treatment of hyperlipidemia, in particular type IIA, IIB and IV, and the associated atherosclerotic vascular system changes, and can be processed for pharmaceutical applications, optionally in combination with other to the usual pharmaceutical preparations such as dragees, tablets, capsules, suppositories, suspensions or solutions. The unit dose is 5 to 200 mg, preferably 5 to 50 mg, the daily dose is 10 to 500 mg, preferably 15 to 150 mg.

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention in any way. Example A

2- [2-azabioyklo (3,3,1) nonan-2-yl] -5-nitrobenzoic acid g (320 mmol) 2-azabicyclo (3,3,1) nonane, 64.5 g (320 mmol) 2 -chloro-5-nitrobenzoic acid and 74.3 g of sodium carbonate are heated to reflux in 600 ml of ethanol for 4 days. After distilling off the ethanol, the residue was dissolved in 800 ml of water, acidified to pH 4 with 2N hydrochloric acid and shaken with chloroform. The chloroform phases were dried over sodium sulfate, evaporated and the residue purified by silica gel column chromatography using toluene / ethyl acetate (6: 4) as the eluent.

The product melting at 167 ^DEG C. resulted in 11.6 g (12.5% of theory).

calculated:

H, 6.25; N, 9.65. found:

% C, 61.72;% H, 5.98;% N, 9.83

5-Nitro-2- [4- (3-pentyl) piperidin] benzoic acid

The title compound was prepared in a manner analogous to Example A from 2-chloro-5-nitrobenzoic acid and 4- (3-pentyl) piperidine.

The product melting at 146 DEG C. yields 60% of theory.

Analysis:

calculated:

% C, 63.73;% H, 7.55;% N, 8.74.

% C, 63.65;% H, 7.60;% N, 8.82

5-nitro-2- [4- (5-nonyl) piperidino] benzoic acid

The title compound was prepared in a manner analogous to Example A from 2-chloro-5-nitrobenzoic acid and 4- (5-nonyl) piperidine.

The product, m.p. 150 DEG-152 DEG C., yields 73% of theory.

Analysis:

calculated:

% C, 63.99;% H, 8.57;% N, 7.44.

H, 8.43; N, 7.23.

Example D

5-Nitro-2- (octahydroisoindol-2-yl) benzoic acid

The title compound was prepared in a manner analogous to Example A from 2-chloro-5-nitrobenzoic acid and octahydroisoindole.

188 DEG-190 DEG C., 77.5% of theory.

Analysis:

calculated:

% C, 62.05;% H, 6.25;% N, 9.64.

62.20% C 6.19% H 9.63% N EXAMPLE E (5-nitro-2-acid piperidlnofenylJoctová g (260 mmolj (2-chloro-5-nitrophenyl) acetic acid [m.p. 127 ^C C prepared by nitration of (2-chlorophenyl) acetic acid with nitration mixture] in 230 ml of piperidine at reflux for 48 hours After addition of 400 ml of water, the reaction mixture was acidified with hydrochloric acid to pH 5.5, precipitating the reaction product which precipitated. after aspiration, wash with acetone and ether.

The product, m.p. 119 DEG, yields 64 g (93% of theory).

Analysis:

calculated:

% H, 6.10;% N, 10.60. Found:

% H, 6.15;% N, 10.46.

EXAMPLE 1 F (2-octahydro-1H-azomino-5-nitro-phenyl) -acetic acid g (240 romol) of (2-chloro-5-nitrophenyl) -acetic acid together with 260 ml of octahydro-1H-azonine 24 The mixture was heated to 110-120 [deg.] C. After evaporation to dryness, the residue was dissolved in 400 ml of water, acidified to pH 2-3 with hydrochloric acid, and extracted with chloroform. The chloroform extract was dried and the chloroform was distilled off and the crystalline residue was washed with petroleum ether / ether (5: 1).

The product, m.p. 100-103 ° C, yields 31 g (42% of theory). Analysis:

calculated:

% C, 62.72;% H, 7.24;% N, 9.04.

H, 7.44; N, 9.15.

Example G (2 (octahydroisoindol-2-yl) -5-nitrophenyl) acetic acid

The title compound was prepared in an analogous manner to that in Example F from (2-chloro-5-nitrophenyl-acetic acid and octahydroisolndole).

The product, m.p. 228 DEG C., yields 53% of theory.

Analysis:

calculated:

63.14% C, 6.62% H, 9.20 Ti N, found:

% H, 6.51;% N, 9.13.

Example H

2- (2,3,3a, 4,7,7a-hexahydro-1H-isoindol-2-yl) -5-nitrobenzoic acid

The title compound was prepared in an analogous manner to Example A from 2-chloro-5-nitrobenzoic acid and 2,3,3a, 4,7,7a-hexahydro-1H-isoudole.

Melting point 231: 85% of theory.

Analysis:

calculated:

% H, 5.59;% N, 9.71.

62.50% C, 5.67To II, 9.61% N. Example I

2- (1,3-dihydroisol) di-2-yl] -5-nitrobenzoic acid

The title compound was prepared in a manner analogous to Example A from 2-chloro-5-nitrobenzoic acid and 1,3-dihydrolsoindole.

M.p. 185-186 ° C; yield 52% of theory.

Analysis:

calculated:

% C, 63.37;% H, 4.25;% N, 9.85.

% C, 63.53;% H, 4.30;

Example 1 a d K

DL-2- (2-chloro-5-nitrophenyl) propionic acid

To a solution of 2.9 g (157 mmol) of DL-2- (2-chlorophenyl) -propionic acid in 70 ml of concentrated sulfuric acid is added dropwise 23.5 ml of nitration mixture (7.5 ml of fuming nitric acid 1) at 15 ° C. 5 and 16 ml of concentrated sulfuric acid) slowly so that the temperature does not exceed 0 ° C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour, then poured into ice water, the precipitated acid was filtered off with suction, dissolved in chloroform and the solution was washed with water. The chloroform extracts were dried, evaporated and the residue crystallized from a mixture of pethol ether and ether.

Melting point 129 DEG-131 DEG C. yields 95% of theory.

Analysis:

calculated:

% C, 47.07;% H, 3.51;% N, 6.10;% Cl, 15.43.

H, 3.77; N, 6.15; Cl, 14.88.

The following compounds were prepared in an analogous manner:

DL-2- [2- (octahydroisoindol-2-yl) -5-nitrophenyl] propionic acid,

DL-2- (2-octahydro-1H-azonino-5-nitrophenyl) propionic acid,

DL-2- (5-nitro-2-piperidinophenyl) propionic acid.

Example L

2- (5-chloro-1,3-dihydroisoindol-2-yl) -5-nitrobenzoic acid

The title compound was prepared in a manner analogous to Example A from 2-chloro-5-nitrobenzoic acid and 5-chloro-1,3-dihydroisoindole.

The product, m.p. 163 DEG C., yields 27% of theory.

Analysis:

calculated:

% C, 56.52;% H, 3.48;% N, 8.79.

% H, 3.57;% N, 8.85.

Example M

2- (1,3-dihydro-5-methoxyisoindol-2-yl) -5-nitrobenzoic acid

The title compound was prepared in a manner analogous to Example A from 2-chloro-5-nitrobenzoic acid and 5-methoxy-1,3-dihydroisoindole.

152 DEG C. yields 57% of theory.

Analysis:

calculated:

% C, 61.40;% H, 4.48;% N, 8.91.

% C, 61.24;% H, 4.32;% N, 9.05. Example N (5-nitro-2-pyrrolidinophenyl) acetic acid

The title compound was prepared in an analogous manner to Example E from (2-chloro-5-nitrophenyl) acetic acid and pyrrolidine.

The product, m.p. 208 DEG C, yields 90% of theory.

Analysis:

calculated:

% C, 57.59;% H, 5.64;% N, 11.20.

57.24% C, 5.50% H, 11.29% N. Example O (2-hexamethylenimino-5-nitrophenyl) acetic acid

The title compound was prepared in a manner analogous to Example F starting from (2-chloro-5-nitrophenyl) acetic acid and hexamethylenimine.

The product, m.p. 144 DEG C., yields 96% of theory.

Analysis:

calculated:

% C, 60.42;% H, 6.52;% N, 10.07.

60.48% C, 6.82% H, 10.17% N. Example P (2-Heptamethylenimino-5-nitrophenyl) acetic acid

The title compound was prepared in an analogous manner to that described in the Example. F from (2-chloro-5-nitrophenyl) acetic acid and heptamethylenimine.

M.p. 136 DEG C. yields 93% of theory.

Mass spectrum:

molecular signal: calculated m / e - 292 found m / e - 292.

Example Q

5-Amino-2- [2-azabicyclo [3.3.1] nonan-2-yl] benzoic acid g 2- [2-azabicyclo (3,3,1) nonan-2-yl] -5-nitrobenzoic acid is dissolved in 100 ml of dlmethylformamide and hydrogenated at room temperature under 0.5 MPa of hydrogen in the presence of 10% palladium on carbon catalyst. and petroleum ether.

215 DEG-217 DEG C. (7.5 g, 76%).

calculated:

% C, 69.70;% H, 7.74;% N, 10.76.

% C, 69.09;% H, 7.44;

5-Annno-2- (2,3,3a, 4,7,7a-hexahydro-1H-isoindol-2-yl) benzoic acid

3,4 g (11,8 mmol) of 2- {2,3,3a, 4,7,7a-hexahydro-1H-isoindol-2-yl} -5-nitrobenzoic acid are suspended in 32 ml of a mixture of equal parts of concentrated acid of hydrochloric acid and methanol at 0 ° C is reduced by successively adding 15.6 g (69 mmol) of stannous chloride dihydrate. After the addition was complete, the reaction mixture was stirred at room temperature for several hours, then diluted with 300 l of water, adjusted to pH 4 with sodium hydroxide solution and extracted with chloroform. The chloroform extracts are dried, the chloroform is distilled off in vacuo and the residue is crystallized from a mixture of acetone and ether.

The product, m.p. 287 DEG C., yields 2.3 g (75% of theory).

Mass spectrum: molecular signal calculated m / e - 258 found m / e - 258.

Analysis:

calculated:

% C, 69.74;% H, 7.02;% N, 10.84.

69.20%. H, 7.01; N 11.07.

The following compounds were prepared in an analogous manner to Examples A to R:

5-Amino-2- [4- (3-pentyl) piperidinobenzoic acid, m.p. 218 ^DEG C. Analysis:

calculated:

70.31% C, 9.02 O / o H, 9.65% N, found:

H, 8.87; N, 9.53.

amino-2- (4- (5-nonyl) piperidino) benzoic acid, m.p. 130 DEG C. Analysis:

calculated:

% C, 72.79;% H, 9.89;% N, 8.24.

% C, 72.63;% H, 10.19;% 8.35.

5-Amino-2- (octahydroisoindol-2-yl) benzoic acid, m.p. 244-245 ° C

Analysis:

calculated:

% C, 69.20;% H, 7.74;% N, 10.75.

% C, 69.20;% H, 7.86;% N, 10.82.

5-Amino-2- (1,3-dihydroisoindol-2-yl) benzoic acid, m.p. 260 ° C.

calculated:

% C, 70.85;% H, 5.55;% N, 11.0.1.

H, 5.59; H, 11.03.

(5-amino-2-pyrrolidinophenyl) acetic acid, m.p. 158 ^DEG C. Analysis:

calculated:

% H, 7.32;% N, 12.72; iP7Pnn '

H, 7.33; N, 12.72.

152 DEG-154 DEG C. (5-amino-2-heptamphithylenimethylphenyl) acetic acid

Analysis:

calculated:

68.67% C, 8.45% H, 10.67% N, found:

% C, 63.50;% H, 8.25;

[5-amino-2- (octahydroisoindol-2-yl) phenyl] acetic acid, m.p. 202-203 ° C

Analysis:

calculated:

% C, 70.04;% H, 8.08;% N, 10.20.

% C, 69.90;% H, 7.93;% N, 10.46.

187 DEG-189 DEG C. [5-Amino-2- (octahydro-1H-azonino) phenyl] acetic acid.

calculated:

% H, 8.75;% N, 10.14;

69.45% C, 8.74 ° / o H, 10.40% N.

156 DEG C. (5-Amino-2-hexamethylenimino-phenyl) -acetic acid

Analysis:

calculated:

% C, 67.71;% H, 8.12;% N = 11.28.

H, 8.10; N, 11.51.

179 DEG-181 DEG C. (5-Amino-2-piperidinophenyl) acetic acid.

calculated:

% C, 66.64;% H, 7.74;% N, 11.96.

% H, 7.51;% N, 12.21.

DL-2- (5-amino-2-piperidinophenyl) propionic acid, m.p. 207 ° C.

calculated:

% C, 67.71;% H, 8.11;% N = 11.28.

% H, 8.41;% N, 11.35.

DL-2- (5-amino-2-octahydro-1H-azoninophenyl) propionic acid, m.p. 218 degrees Celsius

Analysis:

calculated:

% C, 70.31;% H, 9.02;% N, 9.64.

C, 70.51; H, 9.14; N, 9.78. DL-2- [5-amino-2- (octahydroisoindol-2-yl) 18-phenyl] propionic acid, m.p. 243 ° C.

Analysis:

calculated:

% C, 70.80;% H, 8.38;% N, 9.71.

H, 8.47; N, 9.88.

5-Amino-2- (1,3-dihydro-5-chloroisoindol-2-yl) benzoic acid, m.p. 235 ° C.

calculated:

% C, 62.39;% H, 4.54;% N, 9.70.

% C, 62.47;% H, 4.67;% N, 9.90.

5-Amino-2- (1,3-dihydro-5-methoxyisoindol-2-yl) benzoic acid, m.p. 202 degrees Celsius.

Analysis:

calculated:

% C, 67.59;% H, 5.67;% N, 9.85.

67.65 ° C, 5.75% H, 9.98% N. Example 1

5-chloro-2- [2-azabicyclo (3.3.1) nonan-2-yl] benzoic acid

6,5 g (25 mmol) of 5-amino-2- (2-azabicyclo (3,3,1) nonan-2-yl] benzoic acid are dissolved in 90 ml of dilute hydrochloric acid and diazotized at 0 ° C by addition of solution of 1.5 g (27 mmol) of sodium nitrite in 18 ml of water The diazonium salt solution was added dropwise with stirring to a solution of 3 g (30 mmol) of cuprous chloride in 45 ml of concentrated hydrochloric acid. After stirring for 3 hours, the resulting chloro-derivative was shaken with chloroform and purified by column chromatography using ethyl acetate as eluent.

The product melting at 85-87 ° C yielded 5.2 g (75% of theory).

Analysis:

calculated:

% H, 6.48;% N, 5.01. Found:

H, 6.12; N, 5.04. Example 2

5-chloro-2- [4- (3-pentyl) piperidino] benzoic acid

The title compound was prepared in an analogous manner to Example 1 by the Sandmeyer reaction using 5-amino-2- [4- (3-pentyl) piperidino] benzoic acid as the starting material.

The product, m.p. 150 DEG C., yields 60.6% of theory.

Analysis:

calculated:

% C, 65.90;% H, 7.80;% N, 4.52.

65.80% C, 7.67% / H, 4.62% N. Example 3

5-chloro-2- [4- (5-nonyl} piperidino] benzoic acid

The title compound was prepared in a manner analogous to Example 1 by the Sandmeyer reaction using 5-amino-η 4 (5-nonyl) piperidino] benzoic acid as the starting material.

M.p. 148 DEG-150 DEG C., yielding 58% of theory.

Analysis:

calculated:

68.92% C, 8.82% II, 3.83% N, found:

Found: C, 68.70; H, 8.76; N, 3.78

5-Broin-2- (octahydroisoindol-2-yl) benzoic acid

The title compound was prepared in an analogous manner to Example 1 by the Sandmeyer reaction using 5-amino-2- (octahydroisoindol-2-yl) benzoic acid as the starting material.

The product, m.p. 176 ^DEG C., yields 21% of theory.

Analysis:

calculated:

% C, 55.56;% H, 5.59;% N, 4.31.

H, 5.70; N, 4.53. Example 5

5- [iodo-2- (octahydroisoindol-2-yl) benzoic acid

The title compound was prepared in an analogous manner to that described in Example 1 by the Sandmeyer reaction using 5-amino-2- (octahyclroisoindol-2-yl) benzoic acid as the starting material.

The product, m.p. 174 DEG C., yields 19% of theory.

Analysis:

calculated:

% C, 48.53;% N, 4.87;% J, 34.18;

% C, 48.56;% H, 4.69;% N, 3.76

5-Cyano-2- (octahydroisoindol-2-yl) benzoic acid

The title compound was prepared in an analogous manner to Example 1 by the Sandmeyer reaction using 5-amino-2- (octahydroisoindol-2-yl) benzoic acid as the starting material.

The product, m.p. 190 DEG C., yields 33% of theory.

Analysis:

calculated:

7.1.08% G, 6.71% H, 10.36% N, found:

H, 6.47; N, 10.02.

Example 1 a d 7

5-Fluoro-2- (octahydroisoindol-2-yl) benzoic acid

The title compound was prepared from 5-amino-2- (octahydroisoindol-2-yl) benzoic acid via 5-diazonium-2- (octahydroisoindol-2-yl) benzoic acid tetrafluoroborate [yield 73%, m.p. 173 ° C ( decomposition)] and subsequent thermal decomposition. The resulting product resulted in a yield of 2% of theory.

Mass spectrum: molecular signal calculated m / e = 263 found m / e - 283.

Example 8

5-hydroxy-2- (octahydroisoindol-2-yl) benzoic acid

The title compound was prepared from 5-amino-2- (octahydroisoindol-2-yl) benzoic acid by diazotization followed by heating the diazonium salt in 50% sulfuric acid to 80-90 ° C.

The product melting at 222 ^DEG- 223 ^DEG C. yields 61% of theory.

Analysis:

calculated:

% C, 68.94;% H, 7.37;% N, 5.35.

H, 7.36; N, 5.30.

3 to 7 Π Π ρ ί ^; ί kids

5-Chloro-2- (2,3,3a, 4,7,7a-hc: thi-isoindol-2-yl) benzoic acid

The title compound was prepared in an analogous manner to Example 1 by the Sandmeyer reaction using 5-amino-2- (2,3,3a, 4,7,7a-bexahydro-1H-isoindol-2-yl) benzoic acid as the starting material.

The product, m.p. 201 DEG C., yields 12% of theory.

Analysis:

calculated:

% C, 67.34;% H, 6.71;% N, 14.72.

% C, 67.25;% 6.74;% N, 14.70.

Example 10

2- (2,3,3a, 4,7,7a-hexahydro-1H: soindol-2-yl) benzoic acid

The title compound was prepared from (R) -9-methyl-2-η 2,3,3a, 4,7,7a-thixahydro-1H-isoindol-2-yl] -benzoic acid by diazotration with sodium nitrite followed by reduction with copper and hydrochloric acid.

The product with a melting point of 156 Cl results in a yield of 5% of theory.

Analysis:

calculated:

% C, 74.05;% H, 7.04;% N, 5.75.

H, 7.08; N, 6.00.

Example 1 .1

5-Chloro-2- (1,3-diliydroisoindol-2-yl) benzoic acid a.

The title compound was prepared in an analogous manner to Example 1 by the Sandmeyer reaction using 5-amino-2- (1,3-dibyddiisoindol-2-yl) benzoic acid as the starting material.

The product, m.p. 162 DEG C., yields 37% of theory.

Analysis:

calculated:

% H, 4.41;% N, 5.11;% Cl, 12.95.

65.73% ^! H, 4.84; N, 5.05; Cl, 12.86. Example 12 Bromo-2- (1,3-dihydroisoindol-2-yl) benzoic acid

The title compound was prepared in a manner analogous to Example 1

Sandmeyer reaction using 5-amino-2- (1,3-dibydroisolndol-2-yl) benzoic acid as starting material.

The product melting at 178 DEG C. yields 63% of theory.

Analysis:

calculated:

% C, 56.62;% H, 3.80;% N, 4.40.

% H, 3.90;% N, 4.43.

At k1 and d 13

5-chloro-2- (1,3-dihydro-5-chloro-isoindol-2-yl) -benzoic acid

The title compound was prepared in an analogous manner to Example 1 by the Sandmeyer reaction using 5-amino-2- (1,3-dihydro-5-chloroisoindol-2-yl) benzoic acid as the starting material.

M.p. 157 DEG C. yields 18% of theory.

Analysis:

'/ counted:

% C, 53.46;% H, 3.60;% N, 4.55.

% C, 58.64;% H, 3.82;% N, 4.70.

1 'd 1: d 1 4

5-chloro-2 (1,3-dihydro-5-methoxyisoindolyl) benzoic acid

The title compound was prepared in an analogous manner to Example 1 by the Sandmeyer reaction using 5-amino-2- (1,3-dihydro-5-methoxyisoindol-2-yl) banzoic acid as starting material.

148 DEG C., 34% of theory.

Analysis:

calculated:

% C, 63.27;% H, 4.64;% N, 4.60.

% C, 63.34;% H, 4.53;% N, 4.71.

Example 1 and cl 1 5

5-Bromo-2- [4- (3-pentyl) piperidino] benzoic acid

The title compound was prepared according to the analogous procedure in Example 1, using the dimeric reaction using 5-amino-2- [4- (3-pentyl) piperidino] benzoic acid as the starting material.

Melting point 157 DEG-158 DEG C. yields 21% of theory.

Analysis:

calculated:

H, 6.82; N, 3.95; Br, 21.40. Found:

H, 6.76; N, 3.91; Br, 21.55. Example 16

5-Cyano-2- [4- (3-pentyl) piperidino] benzoic acid

The title compound was prepared in an analogous manner to Example 1 by the Sandmeyer reaction using 5-amino-2- (4- (3-pentyl) piperidino] benzoic acid as starting material.

The product, m.p. 171 DEG C., yields 19% of theory.

Analysis:

calculated:

% C, 71.97;% H, 8.04;% N, 9.32.

% C, 72.42;% H, 8.09;% 9.36

DL-2- (5-chloro-2-piperidinophenyl) propionic acid

The title compound was prepared in a manner analogous to Example 1 by the Sandmeyer reaction using DL-2- (5-aino-2-piperidinophenyl) propionic acid as the starting material.

M.p. 134-135 ° C, yielding 45% of theory.

Analysis:

calculated:

% C, 62.80;% H, 6.77;% N, 5.23;% Cl, 13.23.

% C, 63.03;% H, 6.53;% N, 5.27. Example 18

DL-2- (5-chloro-2-octahydro-1H-azoninophenyl) propionic acid

The title compound was prepared in a manner analogous to Example 1 by the Sandmeyer reaction using DL-2- (5-amino-2-octahydro-1H-azoninophenyl) propionic acid as the starting material.

The product, m.p. 139 DEG-140 DEG C., yields 17% of theory.

Analysis:

calculated:

H, 7.80; N, 4.52; Cl, 11.44. Found:

H, 7.64; N, 4.44; Cl, 11.40.

Example 19

DL-2- [5-chloro-2- (octahydroisoindol-2-yl) phenyl] propionic acid

The title compound was prepared in an analogous manner to Example 1 by the Sandmeyer reaction using DL-2- [5-amino-2- (octahydroisoindol-2-yl) phenyl] propionic acid as the starting material.

The product, m.p. 351 DEG-152 ^DEG C., yields 27% of theory.

Analysis:

calculated:

% C, 66.33;% I-J;% N, 4.55;

66.59% C, 7.19% H, 4.70% N. Example 20 f 5-Chloro-2-octahydro-1H-azoninophenyl acetic acid

The title compound was prepared in an analogous manner to Example 1 by Sar dmeyer reaction using (5-amino-2-octahydro-1H-azoninophenyl) acetic acid as the starting material.

Melting point 63-65 ° C yielded 58% of theory.

Analysis:

calculated:

% C, 64.96;% H, 7.50;% N, 4.74.

64.88% C, 7.41% H, 4.53% N. Example 21 (5-chloro-2-heptamethyleniminophenyl) acetic acid

The title compound was prepared in a manner analogous to Example 1 by the Sandmeyer reaction using (5-amino-2-heptamethylenimino-phenyl) -acetic acid as the starting material.

The product, m.p. 78 DEG C., yields 43% of theory.

Mass spectrum: molecular signal calculated m / e - 280/2 found rn / e = 280/2.

Analysis:

calculated:

% C, 63.94;% H, 7.15;% N, 4.96.

% C, 64.30;% H, 7.13;% N, 4.84.

2 6 fi fi

EXAMPLE 2 2 (5-Chloro-2-hexamethyleneiminatenyl) acetic acid

The title compound was prepared in an analogous manner to that described in Example i by the Sandmeyer reaction using (5-amino-2-hexamethylenimiophenyl) acetic acid as the starting material.

The product melting below 10 ° C resulted in a yield of 77% of theory.

Analysis:

calculated:

% C, 62.80;% N, 5.23;% Found:

62.85% C, 6.58% H, 5.40% N. Example 23 (5-chloro-2-piperidino [enyl] acetic acid

The title compound was prepared in a manner analogous to Example 1 by the Sandmeyer reaction of using (5-amino-2-piperidinophenyl) acetic acid as the starting material.

M.P. 105 DEG C results in a yield of 63 ⁰ / T) theory.

Analysis:

calculated:

% C, 61.53;% H, 6.36;% N, 5.52.

61, Art. % H, 6.58% H, 5.56% N.

EXAMPLE 2 4 (5-Chloro-2-pyrrolidinophenyl) acetic acid

The title compound was prepared in a manner analogous to Example 1 by the Sandmeyer reaction using (5 amino-2-pyrrolidinophenyl) acetic acid as the starting material.

Melting point 105 DEG-107 DEG C. yields 54% of theory.

Analysis:

calculated:

% C, 60.13;% H, 5.89;% N, 5.84.

% H, 5.81;% N, 5.76.

Example 25 [5-chloro-2- (octahydroisoindol-2-yl) phenyl] acetic acid

The title compound was prepared in a manner analogous to Example 1 by the Sandmeyer reaction using 15-amino-2- (octahydroisoindol-2-ylphenyl) acetic acid as the starting material.

Melting point 156 DEG-157 DEG C. yields 40% of theory.

Analysis:

calculated:

% C, 65.41;% H, 6.86;% N, 4.76.

% C, 65.54;% H, 6.63;% N, 4.70.

EXAMPLE 26 6 2- (octahydroisoindol-2-ylphenyl) acetic acid

The title compound was prepared in an analogous manner to that in Example 10 from 5-amino-2- (octahydroisoindol-2-yl) phenyl] acetic acid.

M.p. 135 DEG-136 DEG C. yields 15% of theory.

Analysis:

calculated:

74.10% C, 8.15% H, 5.39% N, found:

% C, 74.29;% H, 8.31;% N, 5.30%. Example 27 5-chloro-2- (4- (3-pentyl) piperidino) phenyl] fatty acid

The title compound was prepared in an analogous manner to Example 1 by the Sandmeyer reaction using (5-amino-2- (4- (3-putyl) piperidino) phenyl) acetic acid as the starting material.

The product melting below 20 ° C resulted in a yield of 17% of theory.

.Analysis:

calculated:

66.76% C, 8.09% t-I, N 4.33%, Cl 10.95%, found:

H, 8.24; N, 4.21; Cl, 11.23. Example 28

3-chloro-2-piperidinobenzoic acid

The title compound was prepared in an analogous manner to Example 1 by the Sandmeyer reaction using 3-amino-2-piperidinobenzoic acid as starting material.

Yield: 54%.

Mass spectrum: molecular signal calculated m / e = 239/241 (1 Cl) found m / e = 239/241 (1 Cl).

Analysis:

calculated:

% C, 60.13;% H, 5.89;% C, 14.79;% N, 5.84.

C 59.91, H 5.78, Cl 14.93, N 5.81. Example 29

3-Chloro-2- (octahydroisoindol-2-yl) benzoic acid

The title compound was prepared in an analogous manner to Example 1 by the Sandmeyer reaction using 3-amino-2- (octahydroisindol-2-yl) benzoic acid as the starting material.

The product resulted in a yield of 59% (theory). Analysis: calculated:

% C, 64.40;% H, 6.48;% N, 12.67;

64.27% C, 6.40% 11, 12.49% Cl, 5.12% N.

Mass spectrum: molecular signal calculated m / e - 279/281 (1 Cl) found m / e - 279/281 (1 Cl).

The following compounds were prepared in an analogous manner to Examples 29:

5-chloro-2- (2,3,3a, 4,7,7a-hexahydro-1H-isoindol-2-yl) benzoic acid, m.p. 201 ° C

Analysis:

calculated:

% H, 6.71;% N, 14.72.

H, 6.74; N, 14.70.

146 DEG-148 DEG C. 2- (1,3-dihydroisoindol-2-yl) benzoic acid.

calculated:

% C, 75.29;% H, 5.47;% N, 5.85.

H, 5.26; N, 5.75.

2- (1,3-dihydro-5-methoxyisoindol-2-yl) benzoic acid, m.p. 140 ° C

calculated:

% C, 71.36;% H, 5.61;% N, 5.19.

% H, 5.82;% N, 5.34.

Analysis:

calculated:

% C, 74.14;% H, 9.15;% N, 5.03.

H, 9.26; N, 5.24.

4- [4- (3-Pentyl) piperidino] isoitalic acid, m.p. 265 ° C

calculated:

% C, 67.68;% H, 7.88;% N, 4.38.

H, 7.69; N, 4.41.

(2-Piperidinodiphenyl) acetic acid hydrochloride melting with decomposition at 195 to 200 degrees Celsius

Analysis:

calculated:

% C, 68.77;% H, 6.68;% N, 4.22.

H, 6.84; N, 4.50; Cl, 10.50.

2- (octahydroisoindol-2-yl) nicotinic acid, m.p. 217-218 ° C

calculated:

% C, 68.27;% H, 7.37;% N, 11.38.

H, 7.33; N, 1.1.14.

5-chloro-2- (octahydroisoindol-2-yl) nicotinic acid, m.p. 233-235 ^e C

Analysis:

calculated:

% H, 6.11;% N, 9.98. Found:

% H, 6.05;% N, 10.32.

6-methyl-2-piperidinonicotinic acid, m.p. 120-122 ° C

Analysis:

calculated:

65.43% C, 7.32% I-I, 12.72 O / o N, found:

H, 7.27; N, 12.41.

5-chloro-6-methyl-2-piperidinonikotinová acid, m.p. ^130-132? 'C

2- [4- (3-Pentyl) piperidino] benzoic acid, m.p. 134-136 ° C

236780

Analysis:

calculated:

% C, 56.58;% H, 5.93;% N, 11.00;

C, 56.32; H, 5.67; N, 10.98; Cl, 13.71.

154 DEG-156 DEG C. 5-chloro-2-octahydro-1H-azoninonicotinic acid

calculated:

H, 6.77; N, 9.91; Cl, 12.54. found:

H, 6.54; N, 10.08; Cl, 12.45.

5-chloro-2- (cis-3,5-diethylpiperidino) nicotinic acid, m.p. 78-80 ° C.

calculated:

H, 6.37; N, 10.43; Cl, 13.19. Found:

% C, 58.32;% H, 6.49;% N, 10.21.

5-cblor-2-piperidinonikotin.ová acid, m.p. 149-152 C. Analysis ^iJ:

calculated:

% C, 54.89;% H, 5.44;% N, 11.64. found:

% C, 54.91;% H, 5.56;% N, 11.47;

108 DEG-111 DEG C. 5-bromo-6-methyl-2-piperidinonicotinic acid.

calculated:

% C, 48.18;% H, 5.05;% N, 9.31;% Br;

H, 5.16; N, 9.07; Br, 26.43.

5-Bromo-2-piperidinonicotinic acid, m.p. 172-174 ° C

Analysis:

calculated:

C, 46.33; H, 4.59; N, 9.82; Br, 28.02.

% C, 46.45;% H, 4.81;% N, 9.55;

112 DEG-115 DEG C. [2-piperidinopyrid-3-yl] acetic acid

calculated:

H, 7.32; N, 12.72. Found:

% H, 7.71;% N, 12.56.

124 DEG-126 DEG C. [5-chloro-2-piperidinopyrid-3-yl] acetic acid

calculated:

% C, 56.58;% H, 5.93;% N, 11.06;

C 56.41, H 5.98, N 10.57, Cl 13.51.

5-chloro-6-methyl-2- (cis-3,5-dimethylpiperidino) nicotinic acid, melting below 20 ° C

calculated:

H, 6.77; N, 9.91; Cl, 12.54. Found:

% C, 59.31;% H, 6.68;% N, 9.75.

5-bromo-6-methyl-2- (cis-3,5-dimethylpiperidinoyl) nicotinic acid melting below 20 ° C

calculated:

51.39% C, 5.85% H, 8.56% N, 24.42 _0/0 Br Found:

% C, 51.12;% H, 5.76;% N, 8.47.

methyl 2-piperidinobenzoic acid, m.p. 126-128 ° C

calculated:

% C, 71.20;% H, 7.81;% N, 6.39.

71.35% C, 7.74% H, 6.27% N. 3-chloro-2-piperidinobenzoic acid

calculated:

H, 5.89; H, 14.79; N, 5.84. Found:

H, 5.78; H, 14.93; N, 5.81.

3-Methyl-2- (octahydroisoindol-2-yl) benzoic acid

Analysis:

calculated:

74.10% C, 8.16 o / o h, 5.40% N, found:

H, 8.29; N, 5.53.

3-Chloro-2- (octahydroisoindol-2-yl) benzoic acid

Analysis:

calculated:

H, 6.48; Cl, 12.67; N, 5.00. Found:

% C, 64.27;% H, 6.40;% Cl, 12.49;

2- (2,3,3a, 4,7,7a-hexahydro-1H-isoindol-2-yl) benzoic acid, m.p. 156 ° C

Claims (3)

Subject 1. A method of producing new derivatives! 2-aminocarboxylic acids of general formula (III) in which m is a number of 0 or 1, X represents a nitrogen atom or a CH group, R represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R ₅ represents a hydrogen or halogen atom, a cyano group or a hydroxyl group; R _(i and R ₇ together with the nitrogen atom to which they are attached form a C 5 -C 10 alkyl substituted piperidino group, a C 7 -C 12 azabicycloalkyl group) a bicycloalkane ring optionally substituted with at least one C 1 -C 3 alkyl, octahydro-1H-azonium, hexahydroisoindol, octahydroisoindol or 1,3-dihydroisoindol, optionally substituted with halogen, C 1 -C 3 alkoxy or amino and R ₈ represents a hydrogen atom or an alkyl group 30 Analysis: calculated: 74.05% C, 7.04% li, 5.75% N, found: H, 7.08; N, 6.00. A C 1 -C 3 group, and their addition salts with inorganic or organic acids as well as bases, characterized in that the compound of formula (II): R, _(i-R?, M and X are as hereinbefore defined, by reaction with the nitrite is converted to a diazonium salt which is then, in the presence of sulfuric acid in the presence of copper or in the presence of an appropriate salt of monovalent copper by heating to a temperature of 15-90 ° C The compound of formula (I) is optionally converted into its addition salt with an organic or inorganic acid or with a base. 2. A process according to claim 1 wherein the reaction is carried out in a solvent. 3. Process according to claim 1 or 2, characterized in that the reaction of the compound of the formula II with the nitrite is carried out at a temperature of -10 to 5 ° C.