CS200514B2 - Process for preparing derivatives of omega-aminoacylamidosulphonic acids - Google Patents

Description

The invention relates to processes for the preparation of the ω-aminoacylamdosulfonic acid derivatives of the general formula I

H 2 _{N -} (CH 2) _m - CO-NH- (CH 2) _n -SO 2 - OH (I) wherein m and n independently represent the numbers 2 or 3, as well as salts of these compounds.

Among the above compounds of formula I, novel are those wherein n = 3,

The compounds according to the invention show valuable pharmacological effects or are valuable intermediates which can be used for the synthesis of biologically or pharmacologically active substances.

Of the compounds of the invention, γ-aminobutyryltaurine and its salts are of particular pharmacological importance. These compounds lower blood sugar levels at very low doses (µg / kg body weight), increase serum vitamin A levels, and increase the amount of labeled sulfate ions introduced in the lung tissue of hen embryos.

The preparation of the novel compounds is considerably simpler and consists of fewer synthesis steps than in the case of the preparation of .alpha.-aminodicarboxylic acid amides, or the carboxyl group present in the .alpha. Position may not be protected.

It is a common property of the compounds of formula I that the α- or β-aminocarboxylic acid, optionally substituted at the amino group, is linked via its carboxyl group by the acid amide bond to the primary alkylamine whose side alkyl chain carries in the β- or χ- position a strongly acidic group.

The compounds of the formula I and their salts are prepared by the process according to the invention which is characterized in that the compounds of the formula II are prepared

R ¹ -NH-i (CH 2) _m -COOH (II) or a reactive derivative thereof, wherein

R ¹ is an aralkyloxycarbonyl group, in particular C 5 H 5 -OH 2 -O-CO and as defined above, reacted with compounds of formula III

IXn-lip-sH- (III) wherein n is as defined above, and the obtained compounds of the general formula IV-R-NH- (CH 2 CO-NH-CH 2 S 1) (IV) wherein

R ¹ , m and n are as defined above, are oxidized, then the taurine derivatives of the general formula V are obtained

R1-NH-, (CH2H-CO-NH- (CH2) _n -SO2-UH (Vj, where

R ¹ , m and m are as defined above, deprotected by hydrolysis or catalytic hydrogenolysis of the R ¹ group, and the compounds obtained are optionally converted in their salts or released from their salts.

The process according to the invention can be carried out by, for example, acylating cystamine with a derivative of a β- or γ-aminocarboxylic acid. Also in the acylation it is possible to choose between different coupling methods; for example, the active ester method is equally suitable as the mixed anhydride method. The compound obtained in the coupling is reacted with hydrogen peroxide or peracids and the disulfide bond is oxidatively ruptured. Upon completion of deprotection, the compound of formula (I) is formed.

The following experiments were carried out to demonstrate the pharmacological action of the compounds of formula (I).

Influence of blood sugar level with γ-aminobutyryltaurine control: 105 mg% χ-aminobutyryltaurine: 91% mg

The signification was in both cases around P <0.05. For the experiment, 20 rats were used per group which were not fed for 18 hours. The dose was 1 µg / kg body weight and was administered orally as a solution for 4 days.

Increasing effect of χ-aminoibutyryltaurine ί to vitamin A levels dose 0 .5 1 ... 0.3 0.1 0.05 0.01 0.005 (»« G / kg effect *) And vitamin tvug / kg) 9.0 11.5 *) 11,0 '*) 12,0 *) 15.5 *) .14.4 *) 14,5 *) 14,5 *)

*} Signification: P <0.01. :: swords of Wistar rats, weight 200 g.

The observation period was 6 days.

For the experiment, 20 sa effects of χ-aminobutyryltaurine 'on blood silicon blood levels (mg / g blood) were used per group.

0 h -. Day 5 7th day 13th day Day 20 Day 40 control 0,110 0.100 0.130 0.134 0.150 0,1.60 group i ···· ± 0.006 · ± 0.010 ± 0.015 ± 0.012 ± 0.010 ± 0.021, 5 / zg / day 0.100 0.140 0.152 0.180 0.310 0.310 +0,001 .. +0,005 +0,003 + 0.002 *) + 0.000 **) + 0.010 **) skupina II 0.100 0.164 0.156 0.195 0.354 0.350 10 '(Wg / day +0,004 +0,003 +0,004 +0,010 *) + 0.100 **) + 0.013 **)

*) signification P <0.01 **) signification P <0.001

Results are indicated from day 13 P <0.01, from day 20 P <0.001.

The experiments were carried out on rabbits weighing 2.5 to 3 kg. The active ingredient was administered orally in the amounts indicated in the table. Silicon was determined by the Gaubatz method (Klíň. Wochenschrift 14, 1753/1935). For this purpose, 5 ml blood samples were taken from the ear vein.

The joint effect of γ-aminobutyryltaurine and vitamin A on the granuloma-inducing effect of implanted cotton wool vitamin A (topically) mg

Dose active substance (topically) (orally) dry granuloma weight, mg

I. control -

II. control + solvent. -

III. treated 2

IV. treated 2

V. treated -

VI. treated 2

The differences are indicated as follows:

between II. and III. group P <0.05, between II. and V. Group P <0.001, between V. and VI. P <0.01.

Granuloma formation was detected in male Sprague-Dawley rats weighing 110-120 g by the method of Lee et al. (Pharm. Sci 62, 895/1973). Dorsolaterally subcutaneously implanted swabs were removed after 10 days and dried at 65 ° C to constant weight.

The method will be further elucidated by way of examples, without being limited to these examples.

Example 1

1.30 g (5.5 mmol) of N-benzoxycarbonyl-γ-aminobutyric acid (J. Org. Chem. 24, 863/1959) was dissolved in 20 ml of absolute acetonitrile. The solution was cooled to -15 ° C, excluding air humidity. Then, with stirring, 0.77 ml (5.5 mmol) of absolute triethylamine is added and then 0.77 ml (5.5 mmol) of isobutyl chloroformate are added dropwise. The mixture was stirred for 40 minutes at -15 ^Q C and then added with 1.4 ml (10 mmol) of triethylamine, and 1,125 g (5 mmol) cystamindihydrochloridu and finally 10 ml of cold, absolute acetonitrile. The mixture was stirred at -15 ° C for 2 hours, then at room temperature for 4 hours. After the reaction time, the mixture was evaporated at 30 ° C under vacuum. The residue was mixed with 10 ml of ice cold water while cooling and stirring. The mixture was re-evaporated in vacuo at 35 ° C. The residue, together with 10 ml of water and 20 ml of ethyl acetate, was added to a separatory funnel. The organic phase is extracted first with 15 ml of water, then with 2X15 ml of 5% sodium carbonate solution, then again with 2X15 ml of water, then with 2X15 ml of hydrochloric acid and finally with 2X15 ml of water. Then, the organic phase is dried over anhydrous sodium sulphate and evaporated to dryness in vacuo at 30 ° C. The residue was dissolved in 5 ml of glacial acetic acid. A freshly prepared mixture of 5 ml of 30% hydrogen peroxide and 15 ml of glacial acetic acid was added dropwise to the solution under ice-cooling. After addition was complete, cooling was discontinued, the reaction mixture was - - 51+ 3.1 - - 53+ 5.6 - - 61+ 6.1

0.1 - 64+ 6.2 - 0.1 74 + 7.0 - 0.1 91 + 15.0.

The mixture was stirred at room temperature for 2 hours and then evaporated in vacuo at 30 ° C. The oily product is dried in a desiccator first over phosphorus pentoxide, then over solid potassium hydroxide. 1.41 g (82%) of N-benzoxycarbonyl-γ-aminobutyryltaurine are obtained.

Example 2

The obtained N-benzoxycarbonyl-γ-aminobutyryltaurine is dissolved in 10 ml of water and hydrogenated in the presence of 100 mg of 10% palladium activated carbon for 2 hours. The solution is filtered and then evaporated in vacuo at 35 ° C. The crude product was recrystallized from a 1: 10 v / v mixture of water and acetone to give 0.798 g (76%) of χ-aminobutyryltaurine. The substance melts at 247 ° C, the IR spectrum obtained in KBr shows the following characteristic bands:

= NH (amide) = 3325, -NH 3 ⁺ - 3200 to 2500, -CO (amide) = 1647, = NH = 1550, -SO3- = 1175, 1041, 550 cm = SO3- ^first

For C 6 H 14 N 2 O 4 S (M = 210.25) calculated: 34.27% C, 6.71% H, 13.23% N, 15.25% S;

Found:% C, 34.30;% H, 7.10;% N, 12.83.

Example 3

To 3.23 g of N-benzoxycarbonyl-γ-aminobutyryltaurine is added 10 ml of glacial acetic acid and 15 ml of a hydrogen bromide solution containing 3.3 mol / liter of hydrogen bromide. The mixture was allowed to stand at room temperature for 2 hours and then evaporated in vacuo at 35 ° C. The oily residue is triturated several times with ether, decanting off the ether solution. The product is dried in a desiccator over solid potassium hydroxide. The oily product was dissolved in 2 ml of water and precipitated with 20 ml of acetone. The crude product was recrystallized from a 1: 10 v / v mixture of water and acetone to give 1.89 g of γ-aminobutyryltauri200514 nu. This corresponds to a yield of 90% relative to the starting material taurine.

Example 1 a. D 4

From 1.35 g of N-benzoxycarbonyl- [3-alanyltaurine] was deprotected as described in Example 3. The crude product was recrystallized from a 1: 9 v / v mixture of water and acetone to give 0.745 g / 3-alanyl taurine. This corresponds to a yield of 76 percent based on the starting taurine. Melting point: 207 to 209 ^o C.

The IR spectrum found in KBr shows the following characteristic absorption bands:

= NH famid1 = 3315, 3300. —NHs + = 3200 to 2600, = CO (amide) = 1683.1648, —NHs ⁺ = = 1648, = NH (amide) = 1563.1540, —SOs- = 540, 535 am ^-1 .

Example 5

From 1.35 g of N-benzoxycarbonyl- [3-alanyltaurine] the protecting group was removed as described in Example 2. The crude product is recrystallized from a 1: 9 mixture of water and acetone ^. % ^; ethanol. 0.785 g (80%) of .alpha.-alanyltaurine is obtained.

Example 6

The protecting group was removed from 1.38 g of N-benzoxycarbonyl-5S-alanylhomotaurine as described in Example 3, using hydrogen bromide acidified with glacial acetic acid. The crude product is recrystallized from a 1: 9 v / v mixture of water and acetone, but also from 80% ethanol. 0.75 g (71%) of β-alanylhomotaurin is obtained. The product melts at 205-207 ° C.

The IR spectrum obtained in KBr shows the following characteristic absorption bands: = NH (amide) = 3338, 3305, —NH3 + = 3200 to 2600, i = CO (amide) i = 1681,1669, —NH3 + = = 1683, = NH ( amide) 1538, 1545, -SO 3 = 1190, 1043, -SO 3 ^- = 530 cm ^-1 .

Example 7

From 1.38 g of N- benzoxycarbonyl-3-alanylhomotaurin, the protecting group was removed as described in Example 2 by catalytic hydrogenation. 0.808 g (77%) of p-alanylhomotaurin is obtained.

Claims (4)

Subject A process for the preparation of the ω-aminoacylamidosulfonic acid derivatives of the general formula I H 2 N - CO - ΝΉ - (CH 2) _n - SO 2 - OH (I), where m and n independently represent the numbers 2 or 3, as well as the salts of these compounds, characterized in that the compounds of the general formula II R 1 -NH → (CH 2) _m -COOH (II) wherein R 1 is an aralkoxycarbonyl group, in particular a C 6 H 2 ΌΗ 2 -O-CO m group as defined above, or a reactive derivative thereof, reacted with compounds of the formula III as defined above, and obtained compounds of the formula IV (NH-CHC1COHW-1CH3 -S: (IV)) OF THE INVENTION where R ¹ , m and n are as defined above, are oxidized, then the taurine derivatives of the general formula V obtained are obtained RI ΝΉ- (CH?) _M -CO-NH- (CH 2) _n -, -SO2-OH (V) wherein R1, m and n are as defined above, deprotecting R1 by hydrolysis or catalytic hydrogenolysis, and optionally converting the compounds obtained into or released from their salts. 2. A process according to claim 1 for the preparation of .gamma.-aminobutyryltaurine and salts thereof, characterized in that N-benzoxycarbonyl-.gamma.-aminobutyric acid and cystamine are used as starting compounds. 3. A process according to claim 1 for the preparation of β-alanyltaurine and its salts, characterized in that the protecting group is removed from N-benzoxycarbonyl- [3-alanyltaurine] by hydrolysis or catalytic hydrogenolysis. 4. A process according to claim 1 for the preparation of [beta] -alanylhomotaurin and its salts, characterized in that the protecting group is removed from the N-benzoxycarbonyl- [beta] -alanylhomotaurin by hydrolysis or hydrogenolysis.