NO160780B - ANALOGY PROCEDURE FOR THE PREPARATION OF SUBSTITUTED IMINODIC ACIDS. - Google Patents

Description

The present invention relates to an analogous process for the production of new substituted iminodiacids and more particularly substituted azabicycloalkanedicarboxylic acids.

The invention relates in particular to the production of compounds

with the general formula

in which

the ring A is saturated,

R± means a lower alkyl group with 1-4 carbon atoms,

R2 means hydrogen or an alkyl group with 1-4 carbon atoms,

R 3 means a straight or branched alkyl group, a mono- or dicycloalkylalkyl group with no more than 9 carbon atoms in total, or a substituted alkyl group with the formula:

wherein R 4 = H, a lower C 1 - 4 alkyl group or a C 3 - 8 cycloalkyl group, R 5 = a C 3 - 6 cycloalkyl group or an alkoxycarbonyl group,

, where Q = H or an acetyl or

benzyloxycarbonyl group.

The compounds produced contain at least one carboxyl

sewing group: two in the case where R2 = H. and at least one salt-forming amino group: two when Y-NH or R-j^NrL^alk. The invention also relates to salts of compounds of the general formula (I), obtained by therapeutically compatible inorganic or organic bases.

The invention also relates to addition salts of the compounds

of formula (I), obtained with therapeutically compatible inorganic or organic acids.

The compounds of formula (Il contain at least 3 asymmetric carbon atoms. Depending on the position of the substituents and the degree of hydrogenation, there will be 3-6 asymmetric centers. The racemic mixtures can be divided into their diastereoisomeric or epimeric mixtures or resolved into their enantiomers in a known manner. The various isomers form part of the invention as well as the racemic compounds.

The invention thus encompasses the production of derivatives

of perhydroindole correspondingly

the general formula:

in which the symbols R-^, R 2 and R^ have the previously indicated meanings, (formula I) in their racemic form or as optical isomers, as well as salts thereof obtained with therapeutically compatible acids or bases.

In addition, preferred compounds are those corresponding to formula (I ) wherein R 3 is a straight or branched (C 3 -1 alkyl group, a C 1 -6 )-cycloalkylalkyl group, or a substituted alkyl group -CH 2 -S-CHR 4 R 5 wherein R 4 = H or an alkyl group and R,- = an alkoxycarbonyl group, and where the alkyl^ and alkoxy groups contain 1-4 carbon atoms. In addition, R 1 can advantageously be a methyl group.

The compounds produced according to the invention, as well as their salts, exhibit interesting pharmacological properties - More particularly, they exhibit an inhibitory effect on certain enzymes, such as carboxypolypeptidases, encephalinases and kininase II. In particular, they inhibit the conversion of decapeptide angiotensin I to octapeptide angiotensin II, which in certain cases causes arterial hypertension, by acting on the converting enzyme.

The therapeutic use of these compounds makes it possible to reduce or even eliminate the activity of these enzymes that cause hypertension or heart failure. The effect on kininase II leads to an increase in the circulating bradykinin and also in this way a reduction of species in the blood pressure.

For therapeutic use, the compounds of the general formula I or salts thereof are prepared in the form of pharmaceutical preparations suitable for intravenous or oral administration. In addition to the active ingredients, the pharmaceutical mixtures may contain one or more inert, non-toxic carriers suitable for pharmaceutical use, and/or a binder, a flavoring agent, dispersing agent, sweetener and lubricant or a liquid excipient. -ent suitable for intravenous administration, Such pharmaceutical mixtures may also contain other active ingredients with a synergistic or complementary effect.

Among the latter active ingredients that can be mentioned are

a diuretic and especially a saliuretic, for example a thiazide, a dihydrothiazide, a chlorsulfamide, a dihydrobenzofuran 2-carboxylic acid or derivatives of phenoxyacetic acid. Examples of such compounds are N-(3'-chloro-4'-sulfamoyl-benzamido)-2-methylindoline, ethacrynic acid and furosemide.

It is also possible to add α-adrenolytic ingredients such as prazosin or other anti-hypertensive ingredients.

The administration can vary within wide limits, depending

of the patient's age and weight, symptoms and administration method. Oral administration is preferred, but intravenous administration is also suitable for the treatment of hypertension. In general, the unit doses will preferably be in the range of 5-100 mg.

The invention includes a process for the preparation of compounds of the general formula I, which process comprises subjecting an alkyl ester of azabicycloalkanedicarboxylic acid of the general formula II;

in which the meanings of the symbols A and R^ are as previously indicated,

R<1> means a lower alkoxy or hydroxy group f

which compound is subjected to a reductive alkylation reaction by means of a compound of the general formula III:

wherein the meanings of the substituents R2 and R3 are as previously indicated to provide an amine of the general formula IV:

in which R<1> and have the meanings indicated for compound II and the substituents R2, R^ and A have the previously indicated meanings,

and after the reductive alkylation, the intermediate product obtained can, if necessary, be subjected to usual deprotection processes such as total or partial saponification and/or hydrogenolysis and thus converted into a compound of the formula

IN.

The compounds of formula II are described in or can be prepared according to European patent application published under the number 0031741. The above-mentioned reductive alkylation used in the process is described by R.F. BORCK, M.D. BERNSTEIN, and H. DUPONT DURST, JACS 93, 289J (13711. The reaction is preferably carried out in an alcoholic medium and in the presence of a neutral dehydrating agent and in the presence of an organic or inorganic cyanoborohydride.

The following examples illustrate the invention.

Example' 1

1- {(S)-N-[(IRS)-1-carboxyethyl]-alanyl]-2-carboxyperhydro-indole.

Trirm_A

(2RS).-2-carboxy indole in.

31.5 g of the above-mentioned indoline (86%1) was obtained by saponification in 250 ml of IN sodium hydroxide solution and 150 ml of ethanol for 18 h at room temperature of 43 g (0.224 mol) of the corresponding ethyl ester prepared according to E.J. COREY et al.(J. Amer. Chem. Soc. 1970 92, p. 2476).

The aqueous alcoholic solution was concentrated to half the volume, neutralized with 25 ml of ION hydrochloric acid and the precipitate formed was filtered, washed with water and dried.

The crude acid was purified by passing it through an ion exchange resin ("Dowex 50 W" x 8 H<+>) and washing with 2N aqueous ammonia solution. The ammonium salt obtained was dissolved in the minimum amount of water and the acid precipitated by adding the theoretical amount of HC1 and then dried, washed with water and air dried.

Step_B.

(2S)-2-Carboxyindoline.

60.5 g (0.37 mol) of (DL)^2-carboxyindoline prepared in step A was added to a solution of 44.9 g (0.37 mol) of ( + )-ti-methylbenzylamine in 400 ml of anhydrous ethanol . The precipitate obtained was filtered and dissolved in 350 ml of anhydrous isopropanol under reflux. After cooling, the suspension was filtered and the precipitate washed with a little isopropanol and dried.

The weight of the (L)-2-carboxyindoline-(+γ-α-methyl-benzylamine salt) obtained was 29.8 g.

(2S)-^2-Carboxyindoline was prepared in the theoretical amount by dissolving 10 g of the above-mentioned salt (0.029 mol), in 50

ml of water followed by acidification with 29. ml IN hydrochloric acid.

The precipitate formed was filtered and washed with water, distilled and dried. Optical purity: 96% (VPC after conversion to the form of (-)-camphanic acid amide.

(2R)-2^-carboxyindoline was obtained by the same procedure starting from (RS)-carboxyindoline and (•*■■)-cf-methylbenzylamine.

The absolute configurations of the (S) and (R) acids were determined

as follows:

Analytical quantities (approx. 0.5 g). of each of the acids was converted

to ethyl esters by treatment with thionyl chloride and ethanol according to the procedure described in step C.

The esters were reduced with lithium aluminum hydride according to 1

E. J. COREY (loe.eit.) to the corresponding primary alcohols,

which were identified by their optical activity with the alcohols described by E. J. COREY, whose respective absolute configurations are known.

Step_C

(2S)-2^-Ethoxycarbonylperhydroindole.

11 g of the (L)-2-carboxyndolin-( + )-α-methylbenzylamine salt (0.032 mol) prepared in step B was dissolved in 10.0 ml of water and converted to the corresponding acid by adding 32 ml of 1N HCl. The acid was dried, washed with water and dried in a desiccator over phosphorus pentoxide and then suspended in 50 ml of anhydrous ethanol. At a temperature of 0*-5°C, 3.9 ml of thionyl chloride were added during 10 minutes with stirring and the stirring continued for 1 h at 25°C and then for 1 h at 50°C.

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

The obtained (2S) ^2-ethoxycarbonylindoline hydrochloride was hydrogenated in a solution of 150 ml of water in the presence of 2 g of palladium on charcoal for 8 h at 45°C under a pressure of 50 kg/cm 2 .

After cooling and filtering the catalyst, the filtrate was evaporated to dryness. The remainder was the desired product in the form of the hydrochloride.

Weight 6.9 g (93*1

Step^D

(2S). -N- [ (S) -t^Boc. -alanyl] ^2-ethoxycarbonylperhydroindole.

A solution consisting of 3 g (0.0128 mol, (2S)^2-^ethoxycarbonylperhydroindole hydrochloride, prepared according to the previous step CO, 15 ml of dried dimethylformamide (DMF) and 1.8 ml of triethylamine is added to a solution consisting of of 2.42 g (0.0128 mol. L-t-Boc.-alanine in 15 mL DMF cooled to 5°C and stirred. The resulting mixture was then sequentially added to a solution of 1.7 g (0.0128 molL N -hydroxybenz-triazole in 20 ml of DMF, then a solution of 2.64 g (0.0128 mol) of dicyclohexylcarbodiimide in 15 ml of dry chloroform.

After 65 h of stirring at 25°C, the dicyclohexylurea formed was filtered off and washed with ethyl acetate. The combined filtrates were successively washed with 80 ml of a saturated aqueous solution of NaCl, 2 x 40 ml of concentrated acetic acid solution, 2 x 40 ml of a saturated aqueous solution of NaHCO 3 and then again with 2 x 40 ml of NaCl solution.

The organic solution was dried over CaSO 4 , filtered and concentrated to dryness under vacuum from a water jet pump and the residue taken up in 100 ml of ethyl acetate. The solution was filtered to remove the last traces of dicyclohexylurea and the filtrate concentrated to dryness to give a residue which was the desired product in

form of a very viscous oil.

Weight : 3.8 g (81%)

Analysis ci9H32N2°5

Step_E

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

3.6 g (0.0098 mol) of the ester obtained in step D was dissolved in 30 ml of methanol in the presence of 11 ml of 1N aqueous sodium hydroxide solution.

After 20 h at 25°C, the methanol was evaporated under vacuum from a water jet pump and 60 ml of water added. The solution was washed with 2 x 50 mL ethyl acetate to eliminate unsaponified material and then acidified with 11 mL 1N hydrochloric acid. The white precipitate formed was extracted with 2 x 50 mL ethyl acetate which was combined and washed with water, dried over CaSO 4 , filtered and concentrated to dryness. The rest was the desired product:

Weight: 1.9. g (57%).

Step_F

(2SX-1-[(S)-alanyl]-2-carboxyperhydroindole.

1.6 g (0.0047 mol), of the acid prepared in the previous step

(E) was stirred at a temperature in the range 0-5°C in a solution of 10 ml of trifluoroacetic acid for 1 h and then further

15 min. at room temperature.

After evaporation to dryness under vacuum by a rotary pump, the residue was dissolved in 15 ml of water and passed through an ion exchange resin column ("Dowex W" + 8H<+>). The column was washed out with 1 1 2N aqueous ammonia solution. The washings were concentrated to dryness under vacuum. The residue obtained was the desired product.

Weight: 0.90 g (95%).

Analysis ci2<H>20<N>2<C>'3

Step^G

(2S)-1-{(S)-N-[(IRS)-1-carboxyethyl]-alanyl-2-carboxyperhydroindole.

0.7 g (0.00291 mol) of (2S)-N-[(S)-alanylJ-2-carboxyperhydro-indole prepared in the previous step (F) and 1.67 g (0.0183 mol) of acetomauric acid were dissolved in 18 ml 1N aqueous sodium hydroxide solution and 40 ml pH 7 buffer and the resulting solution subjected to reduction with 0.400 g (0.0064 mol), sodium cyanoborohydride as described in Example 1, step F.

After treatment with concentrated hydrochloric acid and passed through an ion exchange resin ("Dowex 50" H+). the ammonia wash after evaporation left 0.76 g (79%). of a residue which was the desired product in the form of the monoammonium salt.

^ alYse C15H27<N>3°5

Example 2

(2S)-1-{n-[2-((1RS)-1-ethoxycarbonylethylthio)--(1RS).-1-ethoxycarbonylethyl]-(S)-alanyl]-2-carboxyperhydroindole.

1 g (4.17 mmol) (2S)-1-[ (S).-alanylJ-2-carboxy-perhydroindole prepared as described in Example 3, Step F and 4.72 g (19

m mol) ethyl [(IRS)-1-ethoxycarbonylethylthio]-pyruvate was dissolved in 50 ml of anhydrous ethanol in the presence of 15 g of a molecular sieve 4 Å. After 45 min. stirring at room temperature was 0.25

g of sodium cyanoborohydride in a solution of 2.25 ml of anhydrous ethanol added over the course of 6 h.

After the molecular sieve was separated by filtration, the filtrate was concentrated to dryness under reduced pressure and the residue dissolved in 100 ml of sulfuric ether. The solution was extracted with 2 x 100 ml distilled water and then dried over calcium phosphate, filtered and chromatographed over 200 g silica ("Merck F 254") and washed out with 180/20 methylene chloride/methanol mixture. 0.5 g (25%). of the desired product was obtained in the form of the sodium salt.

Analysis C22H35<N>2Na °7S

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

kr>., c = 165-170°C

Yield 67%

Example 3

(2S)-1-[N-(2-ethoxycarbonylmethylthio-(IRS)-1-ethoxycarbonylethyl)-(S)-alanyl]^2-carboxyperhydroindole.

Prepared as in example 4 starting from 1 g (4.17 mmol) (2S)-1-[(S)-alanyl]-2-carboxyperhydroindole, 4.45 g (1.9 mol) ethylethoxycarbonylmethylthiopyruvate and 0.25 g sodium cyanoborohydride .

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

The intermediate ethylethoxycarbonylmethylthiopyruvate is prepared by condensing ethylbromopyruvate with ethylthioglycolate according to the procedure described in the reference mentioned in example 4.

bp.15 = 165-175°C, Yield 50%

Example 4

(2S)-1-{n-[3-(N-benzyloxycarbonyl-N-dicyclopropylmethylamino)-(1RS)-1-ethoxycarbonylpropyl]-(S)-alanyl-2-carboxyhydroindole.

(2S)-1-[(S).-alanyl]^-2-carboxyperhydroindole, 4.3 g of ethyl 4-[N-(benzyloxycarbonyl)-dicyclopropylamino]-2-oxobutyrate and 0.15 g of sodium cyanoborohydride were prepared as in example 4 starting from 0.6 g.

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

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

Step 1: condensation of bromoacetaldehyde diethyl acetal with

ethyl 2-dithianyl carboxylate according to* E.D. ELIEL, J. Org. Chem. (1972) Vol. 37 2 pp. 505-506.

Dividend: 57% kp.Q Q? = 130-135°C.

Step 2: the obtained 2-(2,2-diethoxy-1-ethyl).-2-ethoxycarbonyl-1,3-dithiane was converted into a semicarbazone of 2-(2-oxo-1-3-ethyl)-2- ethoxycarbonyl-1,3-dithiane by stirring with a solution of semicarbazide hydrochloride in water at room temperature for 24 h. The semicarbazone was obtained with a yield of 88% and had a melting point (Kofler) of 183°C.

Step 3: the semicarbazone obtained above was converted into

a corresponding aldehyde by stirring with aetomauric acid in an aqueous acetic acid solution according to R.E. BEYLER et al. (J. Ann. Chem. Soc. (1960). 82 p. 175). bp.Q Q = 14Q - 145°C. Yield: 50%.

Step 4: the aldehyde obtained above was condensed with di-cyclopropylmethylamine and the imine obtained was subjected to reduction according to the procedure described by J. W. LOWN and S. ITOH (Can. J. Chem. (1975). 53 p. 960), to give give 2-[2-(dicyclopropyl-methylamino)-ethyl]-2-ethoxycarbonyl-1,3-dithiane in 65% yield. Its hydrochloride melted at 150°C (Kofler).

Step 5: the derivative obtained in the previous step was treated with benzyl chloroformate according to the method described in "Chemistry of the amino acids" vol. 2 p. 895 by GREENSTEIN and WINITZ (Wiley Editor).. 2-{2-[N-(benzyloxycarbonyl)-dicyclo-propylmethylaminoj-1-ethylj-2-ethoxycarbonyl'-1,3-dithiane was obtained in the form of a viscous oil with a yield of 9.3%.

Step 6; by treatment with N-bromosuccinic acid imide in aqueous acetone solution, the derivative obtained in the previous step was converted into ethyl 4-[N-(benzyloxycarbonyl)-dicyclopropylamino]-2-

oxobutyrate by the method according to E.J. COREY

(J. Org. Chem. (1971) 36, 3553-60) with a yield of 70%.

The compounds prepared in the preceding examples, as well as other compounds of formula (I) prepared in a similar manner, are shown in the following table.

The table also gives characteristic properties of the compounds with respect to (IR) spectra and nuclear magnetic resonance (NMR): s for singlet,

d for doublet,

q for quadruple,

m for the multiplet.

Pharmacological investigations of the manufactured compounds.

The compounds prepared according to the invention were investigated by i.v. or p.o. administration to unconscious dogs.

The dogs' blood pressure was measured using a pressure sensor ("Sta-tham P 23 Db") after introducing a catheter into the aorta via the femoral artery. The measurements were recorded using a writing device ("Brush 400").

Angiotensin I and angiotensin II were injected intravenously in doses of 0.3 U/kg. Then the compounds prepared according to the invention were administered orally or intravenously in doses of 1-5 mg/kg.

An inhibition of the hypertensive effect for angiotensin I of the order of 50-100% was observed, which occurred 30-

90 min. after administration and which remained at 40-80% more than

6 hours after administration. Certain compounds remained active after 24 h which is not the case for any previously known compound (notably "captopril" which is the only commercially available compound). Furthermore, the compounds produced according to the invention do not seem to have any toxic effect (LD0^5QQ mg/kg i.p. in mice).

Claims (1)

Analogous procedure for the preparation of a therapeutically active compound of the general formula: in which ring A is saturated, R-L means a lower alkyl group with 1-4 carbon atoms, R2 means hydrogen or an alkyl group with 1-4 carbon atoms, R3 means a straight or branched alkyl group, a mono- or dicycloalkylalkyl group with not more than a total of 9 carbon atoms, or a substituted alkyl group with the formula: wherein R4 = H, a lower C1-4 alkyl group or a C3_<g >cycloalkyl group, R5 = a C3-6 cycloalkyl group or an alkoxycarbonyl group, , where Q = H or an acetyl or benzyloxycarbonyl group, p = 1 or 2, in racemic form or as optical isomers, as well as salts thereof obtained with therapeutically compatible inorganic or organic bases, or acid addition salts obtained with pharmaceutically acceptable inorganic and organic acids, characterized by subjecting to an alkyl ester of an azabicycloalkanedicarboxylic acid of the general formula II wherein A and R-^ have the meanings given above, and R<1> means a lower alkoxy or hydroxy group, a reductive alkylation reaction with a compound of the general formula III: wherein R„ and R_, have the previously indicated meanings, to give an amine of the general formula IV: wherein R<1>, R^, R^ and A have the above eight meanings dg if necessary subject the compound of formula IV to a deprotection treatment, such as for example total or partial saponification and/or hydrogenolysis to give a compound of formula (I). .