DK157011B - ANALOGY PROCEDURE FOR THE PREPARATION OF 2-CARBOXY PERHYDRO-INDUSTRIES - Google Patents

Description

DK 15701 1 B

The invention relates to an analogous process for the preparation of novel 2-carboxy-perhydroindole derivatives of the formula I or salts thereof with an inorganic or organic base or addition salts thereof with an inorganic or organic acid, and the process is characterized -1 g at the characteristic part of the claim.

The invention thus relates to the preparation of compounds of general formula I

CO 15, where 20 represents an alkyl group of 1 to 4 carbon atoms which can carry an amino group, R2 represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R3 represents a straight or branched chain alkyl group, a mono-25 or di-cycloalkylalkylalkyl or phenylalkyl group having not more than a total of 9 carbon atoms, or a substituted alkyl group of the formula: - (CH2) p - Y - CH - R5 in R4 where R4 is H , an alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, 3g R 5 is H, an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or an alkoxycarbonyl group, 2

DK 15701 1 B

Y is S or N - Q, where Q is H or benzyloxycarbonyl and / p is 1 or 2 in their racemic form or as optical isomers, or the salts thereof with an inorganic or organic base or their addition salts with an inorganic or organic acid.

The compounds prepared according to the process of the invention contain at least one carboxy group: two in the case where R 2 is hydrogen; and at least one salt-forming amino group: two when Y = NH or Rx = NH2alk.

The compounds of formula I contain at least 3 asymmetric carbon atoms. Depending on the position of the substituents and the degree of hydrogenation, there are from 3 t in 1 6 asymmetric centers. The racemic compounds can be divided into their diastereomeric summers or epimeric mixtures or split into their enantiomers in known manner. Preparation of the various isomers forms one they! of the invention, which also makes racemic compounds.

In particular, the preferred compounds which can be prepared by the process of the invention are those similar to Formula I wherein R 3 is a straight or branched alkyl group having from 3 to 8 carbon atoms, a cycloalkylalkyl group having 4 to 8 carbon atoms, or a substituted alkyl group -CH 2 -S -CHR 4 R 5, wherein R 4 is hydrogen or an alkyl group and R 5 is an alkoxy-carbonyl group wherein the alkyl and alkoxy groups have from 1 to 4 carbon atoms. In addition, R 2 may conveniently be a methyl group.

The compounds prepared according to the process of the invention and also the salts thereof have valuable pharmacological properties. Otherwise, they have an inhibitory effect on certain enzymes, such as carboxypolypeptidases, encephalinases or kinase II. In particular, they inhibit the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II, which is responsible for certain cases of arterial hypertension by affecting the transforming enzyme.

3

DK 15701 1 B

The therapeutic use of these compounds thus makes it possible to reduce or even eliminate the activity of these enzymes responsible for hypertension or heart failure. The effect on kininase II results in an increase 5 of circulating bradykinin and also in a reduction of arterial pressure.

The useful dosage can vary greatly depending on the patient's aids and weight, the severity of the symptoms and the mode of administration.

Oral administration is preferred, but intravenous administration is also suitable for the treatment of hypertension. The unit dose will, in general terms, preferably be in the range of 5 to 100 mg.

The compounds of formula II of claim 1 are disclosed in or may be prepared as described in European Patent Application Laid-Open No. 0031741. The reductive alkylation is carried out as described by R. F. Borch, M. D. Bernstein, and H. Dupont Durst, Jacs. 93, 2897 (1971). The process is preferably carried out in an alcoholic medium and in the presence of a neutral dehydrating agent and an organic or inorganic cyanoborohydride in d.

The process of the invention will be described in more detail in the following examples.

Example 1 1 - {(S) -N - [(1RS) -1-carboxyethyl] -alanyl} -2-carboxyperhydroindole

Step A

(2RS) -2-carboxyindole.

31.5 g of this indoline (86%) are prepared by saponification in 250 ml of normal sodium hydroxide solution and 150 ml of ethanol for 18 hours at room temperature of 43 g (0.224 mol) of the corresponding ethyl ester prepared as described by EJ Corey and others (J. Amer. Chem. Soc. 1970 92. page 24761.

4

DK 15701 1 B

The aqueous alcoholic solution is concentrated to half, neutralized with 25 ml of ION hydrochloric acid, then the precipitate formed is filtered off, washed with water and terreshed.

The crude acid is purified by passage through an ion-exchange resin column (Dowex 50 W x 8 H +) and washed out with a 2N aqueous ammonia solution. The prepared ammonium salt is dissolved in a minimum amount of water and the acid is precipitated with the theoretical amount of HCl. It is terres, washed with water and air terres.

10

Analysis (of the ammonium salt) CgHi2N2 ° 2 C% H% N%

Calculated: 59.99 6.71 15.54

Found: 60.22 6.71 15.06 15 59.93 6.71 15.29

Step B

(2S) -2-carboxyindoline.

60.5 g (0.37 mole) of dl-2-carboxyindoline prepared in Step A are added to a solution of 44.9 g (0.37 mole) of (+) - α-methylbenzylamine in 400 ml of anhydrous ethanol. The resulting precipitate is filtered off and read into 350 ml of anhydrous isopropanol under reflux. After cooling, the suspension is filtered and the precipitate is washed with a little isopropanol and terres.

The weight of the prepared (1) -2-carboxyindoline, (+) - α-methyl-benzyl amine salt is 29.8 g.

A2l = 5.3e (C = 1% ethanol)

D

The (2S) -2-carboxyindoline is prepared in a theoretical yield by dissolving 10 g of the previously mentioned site (0.029 mol) in 50 ml of water and acidifying it with 29 ml of normal hydrochloric acid.

The precipitate is filtered off, washed with water, distilled and dried. Optical Purity *. 96¾ (VPC after conversion to (-) - camphanic acid amide.

5

DK 15701 1 B

The (2JR) -2-carboxyindole was prepared by the same procedure starting from (M) 'carboxyindoline and (-) - α-methylbenzylamine.

5 The absolute configurations of the (S) and (R) acids were determined as follows:

Analytical amounts (about 0.5 g) of each of the acids were converted to the ethyl esters by treatment with thionyl chloride and ethanol according to the procedure described in step C.

The esters are reduced with lithium aluminum hydride according to the procedure described by E. J. Corey (loc. Cit.) To the corresponding primary alcohols identified by their rotational ability 15 with the alcohols described by E. J. Corey, whose respective absolute configurations are known.

Step C

(2S) -2-ethoxycarbonylperhydroindole.

11 g of (1) -2-carboxyindoline, (+) -α-methylbenzylamine salt (0.032 mol) prepared in step B is dissolved in 100 ml of water and converted to the corresponding acid by the addition of 32 ml of N 25 HCl. The acid is terreshed, washed with water, terreshed in a phosphoric anhydride desiccator and suspended in 50 ml of anhydrous ethanol.

At a temperature of 0 to + 5 ° C, 3.9 ml of thionyl chloride is added over 10 minutes. with stirring, and stirring is continued for 1 hour at 25 ° C and then 1 hour at 50 ° C.

30

The mixture is left overnight at 25 ° C, then concentrated to dryness under vacuum from a water jet pump at 40 ° C, taken up in 50 ml of anhydrous benzene and filtered.

The prepared (2S) -2-ethoxycarbonylindoline hydrochloride is hydrogenated dissolved in 150 ml of water in the presence of 2 g of pal ladinized charcoal in 8 titers at 45 ° C under a pressure of 50 kg / cm 2.

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DK 15701 1 B

After cooling and filtration of the catalyst, the filtrate is evaporated to dryness. The residue remaining is the desired product in the form of its hydrochloride.

Weight: 6.9 g (93%) Analysis C11 H20 Cl2 NO2 C% H% N% Cl%

Calculated: 56.52 8.62 5.99 15.17

Found: 55.52 8.53 5.96 15.16.

Step D

(2S) -N - [(SJ-T-Boc.-alanyl] -2-ethoxycarbonylperhydroindol.

A solution consisting of 3 g (0.0128 mole) of (2S) -2-ethoxycarbonyl perhydroindole hydrochloride prepared in step C, 15 ml of tort dimethylformamide (DMF) and 1.8 ml of triethylamine is added to an + 5 ° C cooled and stirred solution of 2.42 g (0.0128 mol) of 1-t-Boc.-alanine in 15 ml of DMF. To the resulting mixture is first added a solution of 1.7 g (0.0128 mole) of N-hydroxybenztriazole in 20 ml of DMF, then a solution of 2.64 g (0.0128 mole) of dicyclohexylcarbodiimide in 15 ml of dry chloroform. .

After stirring for 65 hours at 25 ° C, the resulting dicyclohexylurea is filtered off and washed with ethyl acetate. The combined filtrates are first washed with 80 ml of a saturated aqueous solution of NaCl, then with 2 x 40 ml of concentrated citric acid solution, then with 2 x 40 ml of a saturated aqueous solution of NaHCO3 and then again with 2 x 40 ml. NaCl solution.

The organic solution is triturated over CaSO 4, filtered, concentrated to dryness under vacuum from a water jet pump, and the residue is taken up in 100 ml of ethyl acetate. The solution is filtered to remove the last traces of dicyclohexylurea and the filtrate concentrated to dryness leaves a residue which is the desired product in the form of a highly viscous oil.

Weight: 3.8 g (81%)

Analysis C1gH32N2O5 7

DK 15701 1 B

C% H% N%

Calcd: 61.93 8.75 7.60

Found: 61.76 8.56 7.77

Step E

(2 Si) -N - [(S) -t-Boc-alanyl] -2-carboxyperhydroindole.

3.6 g (0.0098 mol) of ester prepared in Step D dissolve 10 in 30 ml of methanol under 10 ml of 11 ml of a normal aqueous sodium hydroxide solution.

After 20 hours at 25 ° C, the methanol is evaporated under vacuum from a water jet pump and 60 ml of water is added. The solution is washed with 2 x 50 ml of ethyl acetate to remove unsaturated material, then acidified with 11 ml of N hydrochloric acid. The white precipitate formed is extracted with 2 x 50 ml of ethyl acetate, the extracts are collected and washed with water, triturated over CaSO 4, filtered and concentrated to dryness. The residual residue is the 20 individual product.

Weight: 1.9 g (57%)

Analysis CJ7H28N2O5 C% H% N%

Calculated: 59.98 8.29 8.23 Found: 59.10 8.16 7.81

Step F

(2S) -l - [(S) -alanyl] -2-carboxyperhydroindole.

1.6 g (0.0047 mol) of the acid prepared in step E is stirred at a temperature of 0 to + 5 ° C dissolved in 10 ml of trifluoroacetic acid for 1 hour and then further for 15 minutes, at room temperature.

After evaporation to dryness in vacuo from a wing pump, the residual residue dissolved in 15 ml of water passes over an ion exchanger packet column (Dowex W + 8 H +). The column is washed with 35 8

DK 15701 1 B

1 1 of a 2 N aqueous ammonia solution. The wash liquid is concentrated to dryness under vacuum. The residual residue is the individual product.

Weight; 0.90 g (95%) Analysis 0 ^ 2 ^ 20 ^ 2 ^ 3 C% H% N%

Calculated: 59.98 8.39 11.10

Found 58.53 8.24 11.43

Step G

(2S) -l - {(S) -N - [(1 RS) -1-carboxyethy1] -alanyl} -2-carboxyperhy-droindol.

0.7 g (0.00291 mol) (2S) -N- [(_S) -al any 1] -2-carboxyperhydro-n-dole prepared in step F and 1.67 g (0.0183 mole) pyruvic acid is dissolved in 18 ml of a normal aqueous sodium hydroxide solution and 40 ml of pH 7 buffer, and the solution thus prepared is subjected to reduction with 0.400 g (0.0064 mole) of sodium cyanoborohydride, as described in Example 1, step F.

After treatment with concentrated hydrochloric acid and after passing over an ion-exchange resin (Dowex 50 H +), the ammonia wash liquid after evaporation to dryness leaves 0.76 25 g (79%), which is the desired product in the form of the monoammonium salt.

Analysis C15H27N3O5 C% H% N%

Calculated: 54.70 8.26 12.76 Found: 54.10 7.78 12.77 35 9

DK 15701 1 B

Example 2 (2S) -1- {N- [2 - ((1RS) -1-ethoxycarbonylethylthio) - (1RS) -1-ethoxy-carbonylethyl] - (S) -alanyl} -2-carboxyperhydroindole.

5 g (4.17 mol) (2S) -1 - [(S) -alanyl] -2-carboxyperhydroindole prepared as described in Example 1, Step F, and 4.72 g (19 mol) ethyl - [(1RS) -1-ethoxycarbonylethylthio] pyruvate is dissolved in 50 ml of anhydrous ethanol in the presence of 15 g of molecular sieve 4 Â. After 45 min. stirring at room temperature, 0.25 g of sodium cyanoborohydride dissolved in 2.25 ml of anhydrous ethanol is added over 5 hours.

After the molecular sieve has been separated by filtration, the filtrate is concentrated to dryness under reduced pressure and the residue is dissolved in 100 ml of sulfuric acid ether. The solution is extracted with 2 x 100 ml of distilled water, quenched over calcium sulfate, filtered, chromatographed over 200 g of s 1 ica (Merck F 254), washed with a 180/20 methylene chloride / 20 methanol mixture. 0.5 g (25%) of the desired product is obtained in the form of the sodium salt.

Analysis C22H3sN2Na O7S

C% H% N% S%

Calculated: 53.43 7.13 5.66 6.48 Found: 53.28 7.09 5.19 5.92

The intermediate ethyl - [(1RS) -1-ethoxycarbonylethylthio] pyruvate is prepared by condensing ethyl bromo-pyruvate with (RS) ethylthiolactate in the presence of pyridine according to the procedure described for related compounds in J. of Heter. Chem. (1973) 10/4 pp. 679-681).

Boiling point = 165-170 ° C.

Yield 67%.

35 10

DK 15701 1 B

Example 3 (2S) -1- N - (2-Ethoxycarbonylmethylthio- (1RS) -1-ethoxycarbonyl-ethyl) - (S +) - alanyl] -2-carboxyperhydroindole.

5

This product was prepared as described in Example 2 starting from 1 g (4.17 mmol) of (2S) -1 - [(S) -alanyl] -2-carboxyperhydroindole, 4.45 g (1, 9 moles) of ethyl ethoxycarbonylmethyl-thiopyruvate and 0.25 g of sodium cyanoborohydride.

10

After purification by chromatography, 0.26 g (14%) of the desired product was obtained.

Analysis C21H34N2O7S

C% H% N% S% Calculated: 55.00 7.47 6.11 6.99

Found: 54.71 7.32 5.94 7.01

The intermediate ethylethoxycarbonylmethylthiopyruvate product is prepared by condensing ethylbromopyruvate with ethylthioglycolate 20 according to the procedure described by reference in Example 2. Boiling point = 165-175 ° C. Yield 50%.

Example 4 (2S) -1- {N- [3- (N-Benzyloxycarbonyl-N-dicyclopropylmethylamino) - (1RS) -1-ethoxycarbonylpropyl] - (S) -alanyl} -2-carboxyperhydro-n-dol.

The procedure was as described in Example 2, but starting from 0.6 g of 30 (2SJ-1 - [(S) -alanyl] -2-carboxyperhydroindole, 4.3 g of ethyl 4- [N- (benzyloxycarbonyl) - dicyclopropylamino] -2-oxobutyrate and 0.15 g sodium cyanoborohydride.

After purification by chromatography, 1 g (67%) of the desired product was obtained.

Analysis C33H47N3O7 C% H% N%

Calcd: 66.31 7.93 7.03

Found: 66.11 7 «3 7.2? 11

DK 15701 1 B

The intermediate product ethyl 4- [N- (benzyloxycarbonyl) -dicyclopropylamino] -2-oxobutyrate is prepared in 6 steps as follows:

Stage 1: Condensation of bromoacetaldehyde diethyl acetal with 5 ethyl 2-dithianyl carboxylate as described by E. D. Eliel in J.

Org. Chem. (1972) Volume 37 2 pages 505-506.

Yield 57%, boiling point0.07 = 130-135 ° C.

Stage 2; the prepared 2- (2,2-diethoxy-1-ethyl) -2-ethoxy-carbonyl-1,3-dithian is converted to a semicarbazone of 2- (2-oxo-1-ethyl) -2-ethoxycarbonyl-1 , 3-dithian by stirring with a solution of semicarbazide hydrochloride in water at room temperature for 24 hours. The produced semicarbazone is obtained in a yield of 88% and has a melting point (Kofler) at 183 ° C.

15

Stage 3: the produced semicarbazone is converted to the corresponding aldehyde by stirring with pyruvic acid in an aqueous acetic acid solution by R. E. Beyler and co-workers (J. Ann.

Chem. Soc. (1960) 82, page 175). Boiling point0 / 8 = 140-145 ° C. Out-20 swap 50%.

Stage 4; this aldehyde is condensed with dicyclopropylmethylamine and the imine produced is subjected to reduction according to the procedure described by JW Lown and S. Itoh 25 (Can. J. Chem. (1975) 53, p. 960) to give 2- [ 2- (dicyclopropylmethylamino) ethyl] -2-ethoxycarbonyl-1,3-dithian in a yield of 65%. Its hydrochloride melts at 150 ° C (K).

Stage 5; the derivative produced is subjected to the action of 30 benzyl chloroformate according to the procedure described in "Chemistry of the amino acids" Volume 2p 895 by Greenstein and Winitz (Wiley stands as publisher). 2- {2- [N- (benzylic oxycarbonyl) -dicyclopropylmethylamino] -1-ethyl} -2-ethoxycarbonyl-1,3-dithian is a viscous oil obtained in a yield of 93%.

Stage 6; This product is subjected to the action of N-bromosuccinimide in an aqueous acetone solution and converted to ethyl 4- [N- (benzyloxycarbonyl) -dicyclopropylamino] -2-oxobutyrate in a 12

DK 15701 1 B

yield of 70% following the procedure described by E. J.

Corey (J. Org. Chem. (1971) 36, 3553-60).

The compounds prepared in the above examples and other compounds of formula I prepared in similar ways are discussed in the following table.

The table lists characteristic values for the infrared (IR) and nuclear magnetic resonance 10 (NMR) connections: p. Stands for single d "" double ç "" quadruple m "" multiple dual 15 20 25 30 35 13

DK 15701 1 B

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17

DK 15701 1 B

Pharmacological investigations of the compounds prepared according to the process according to the invention.

The compounds prepared according to the method according to the invention were investigated as well by intravenous oral administration to dogs by consciousness.

The blood pressure of the dogs was measured by a pressure measuring apparatus (Statham P 23 Db) after catheterization of the aorta through the femoral artery. The results were recorded using a recording apparatus (Brush 400).

Angiotensin I and angiotensin II were given to the animals intravenously at a dose of 0.3 γ / kg. Then, the compounds prepared according to the method of the invention were given orally or intravenously in doses of 1 to 5 mg / kg.

An inhibition of the hypertensive effect of angiotensin I of 50 to 100% was observed, occurring 30 to 90 minutes.

20 after the administration and lasted for 40 to 80% more than 6 hours after the administration. Some compounds remained active after 24 hours, which is not the case with any known compound, other than captopril, which has the formula 25

HS - CH. - CH - CO - N-1-COOH

J I

CH3 30

In addition, the compounds prepared according to the process according to the invention do not appear to have any toxic effect. LD50> 500 mg / kg i.p. in mice.

The results are presented in Table I.

18

DK 15701 1 B

Table I

Inhibition of angiotensin converting enzyme by the compounds of the invention. . . . Irlhibition Inhibition

Connect Dose Admini-% after1% after · 6 partition (mg.kg-1) strations ·· {hour: hours _nr, _ road___

Captopril 5 I.V. 76 30

Captoprii 5 P.O. 87 · 30 2 5 I.V. 67 43 3 S I.V. 73 38 4 5 I.V. 65 35 6 5 I.V. 77 47 7 5 I.V. 67 25 8 (ex n32) 5 I.V. 83 62 9 2 I.V. 100 48 1 P.O. 52 48 10 5 I.V. 92 67 5 P.O. 71 56 12 (ex n33) 5 I.V. 65 40 13 5 I.V. 60 25 14 5 I.V. 100 83 1 I.V. 94 53 15 5 I.V. 100 68 1 P.O. 91 72 16 1 I.V. 84 46 19 1 I.V. 79 41 1 I.V. 90 38 20 1 I.V. 84 52 22 1 P.O. 90 65

Claims (1)

R 1 wherein R 1 represents an alkyl group of 1 to 4 carbon atoms or an amino alkyl group of 1 to 4 carbon atoms, wherein the amino function 20 is protected in a manner known per se and R 'represents a lower alkoxy group or hydroxy group, a reductive alkylation reaction by a compound of the general formula III: 25 0. c> w (III) + COOR 2 wherein the substituents R 2 and R 3 have the meanings given above to give an amine of the general formula IV: 35 DK 15701 1 B 5 - CO - CH - NH - CH - RII 3 R, COOR '2 10 where R' and R '' have the meanings set forth above for Formula II and the symbols R 2 and R 3 have the meanings given above wherein the compound thus obtained is, if necessary, subjected to the usual deprotection processes in the form of full or partial saponification and / or hydrogenolysis to form a compound of formula (I) as if desired converted to a site with an inorganic or organic base or to an addi-t ion salt with an inorganic or organic acid. 20 25 30 35