IE841386L

IE841386L - Isoindoles.

Info

Publication number: IE841386L
Application number: IE841386A
Authority: IE
Original assignee: Adir
Priority date: 1983-06-06
Filing date: 1984-06-05
Publication date: 1984-12-06
Also published as: IE57600B1; ES533174A0; NZ208386A; EP0129461B1; DE3462261D1; ZA844262B; ATE25258T1; FR2546886A2; JPS6011467A; EP0129461A1; OA07716A; ES8506623A1; PT78697A; CA1274347A; AU2915184A; AU566490B2; FR2546886B2

Abstract

1. Claims for the contracting states : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE Compounds corresponding to the general formula I : see diagramm : EP0129461,P7,F5 in which the ring A is saturated or, alternatively, benzenic, R represents a hydrogen atom or a lower alkyl group having from 1 to 4 carbon atoms, R' represents a linear alkyl radical having from 1 to 6 carbon atoms or a mono- or di-cycloalkyl-alkyl radical having from 4 to 7 carbon atoms, in their racemic form or in the form of optical isomers, and the salts thereof obtained with a therapeutically compatible mineral or organic base or the addition salts thereof obtained with a pharmaceutically compatible mineral or organic acid. 1. Claim for the contracting state : AT Process for the preparation of compounds corresponding to the general formula I : see diagramm : EP0129461,P7,F6 in which the ring A is saturated or, alternatively, benzenic, R represents a hydrogen atom or a lower alkyl group having from 1 to 4 carbon atoms, R' represents a linear alkyl radical having from 1 to 6 carbon atoms or a mono- or di-cycloalkyl-alkyl radical having from 4 to 7 carbon atoms, in their racemic form or in the form of optical isomers, and the salts thereof obtained with a therapeutically compatible mineral or organic base or the addition salts thereof obtained with a pharmaceutically compatible mineral or organic acid, characterised in that a carboxyisoindole derivative of the formula : see diagramm : EP0129461,P8,F1 in which A has the same meaning as in formula I and R" represents an alkyl group having from 1 to 6 carbon atoms, preferably a tert.-butyl group, or one of the addition salts thereof, is condensed with a functional derivative of a substituted amino acid of the formula III : see diagramm : EP0129461,P8,F2 in which R et R' have the same meanings as in formula I and the nitrogen atom is protected by a radical customarily used for protection in the synthesis of peptides, such as benzyloxycarbonyl or tert.-butoxycarbonyl, and the intermediate compound obtained is subjected to customary deprotecting processes, such as, for example, total or partial saponification, and/or hydrogenolysis, and in this manner is converted into a compound of the formula I.

Description

37600 - 1A- The present invention relates to substituted isoindoledicarboxylic acid derivatives, their preparation and pharmaceutical compositions containing them.

Various amino acids possessing an inhibiting action 5 on enzymes, like the carboxypolypeptidases, which are re- i sponsible for the transformation of angiotensine I into angiotensine II, or like the encephalinases are already ' known.

European Patent Application EP 31 741 describes 10 certain alcohols, acids, thiols, nitriles or primary amines derived from azabicycloalkanic carboxylic acids.

Other amino acids with an indoleic, isoquinoleic or azaalcanoylindoleic structure are described in European \ Patent Specifications EP 46 953 and EP 51 301. Mono-15 or bicyclic peptides are also already known (European Patent Specification EP 81 094). Surprisingly very few amino acids with an isoindoleic or perhydroisoindoleic structure having an inhibiting action on conversion enzymes are known from the literature. The only products 20 referred to are perhydroisoindoles (European Patent Specification EP 58 567) or isoindoles (European Patent Specification EP 50 800) comprising an aromatic radical » in the side chain. The applicant has now discovered that certain derivatives of isoindoleic carboxylic acids - 25 with a completely aliphatic side chain and only comprising a single secondary amine function, have a very powerful action as regards the angiotensine convertase.

Specifically, the invention relates to compounds corresponding to the general formula - IB - r^r/ /R' I 0 - CH - NH- CH I I ch3 coor in which the ring A is saturated or, alternatively, benzenic, R represents a hydrogen atom or a lower alkyl group having 5 from 1 to 4 carbon atoms, and R' represents a linear alkyl radical having from 1 to 6 carbon atoms or a mono- or di-cycloalkyl-alkyl radical having from 4 to 7 carbon atoms, in racemic form or in the form of optical isomers, 10 and the salts thereof obtained with a therapeutically acceptable mineral or organic base or the addition salts thereof obtained with a therapeutically acceptable mineral or organic acid.

The compounds of the formula (I) have 3 asymmetric 15 carbon atoms (possibly 4 when R = 2-methylpropyl), 2 being in the side chain and the 3rd being the ring carbon atom carrying the carboxy group. - 2 - When A is saturated, the corresponding perhvdroiso-indole ring exists virtually only in the cis-form.

The racemic compounds can be resolved into their f diastereoisomeric or epimeric mixtures or into their ^ enantiomers in known manner. These various isomers form ^ part of the invention as do the racemic compounds. The (S)-isomers are, however, more active and are therefore "preferred.

The compounds according to the invention and the 10 salts thereof have valuable pharmacological properties.

They have, especially, an inhibiting action on certain enzymes, such as the carboxypolypeptidases, the encephalinases or kininase II. In particular, they inhibit the transformation of the decapeptide angiotensin 15 i into the octapeptide angiotensin II, which is responsible, in some cases, for arterial hypertension, by acting on the converting enzyme.

The therapeutic use of these compounds makes it possible, therefore, to reduce or even suppress the activity of those enzymes which cause hypertensive disorders and cardiac insufficiency. The action on kininase II results ^ in an increase in the circulating bradykinin and also in a decrease in blood pressure.

The invention relates also to pharmaceutical compo-25 sitions containing as active ingredient at least one compound of the general formula I, or one of the addition salts thereof with a mineral or organic base or acid, in association with a pharmaceutically acceptable, nontoxic, inert excipient.

For therapeutic use, the compounds of the general formula I or the salts thereof are presented in pharmaceutical forms suitable for administration by the intravenous or oral route- In addition to the active ingredient, the pharmaceutical compositions according to the invention contain one or more inert, non-toxic excipients that are suitable for pharmaceutical use and/or a binder, a flavouring agent, a disintegrating agent, a sweetener, a lubricant or, alternatively, a liquid carrier adapted to administration by the intravenous route.

The pharmaceutical compositions according to the invention may contain additionally a further active ingredient having a synergistic or complementary action.

Amongst these latter active ingredients there may be mentioned a diuretic and, especially, a saluretic such as, for example, a thiazide, a dihydrotniazide, a chlorosulphamide, a dihydrobenzofuran-2-carboxylic acid or a phenoxyacetic acid derivative. Examples of such compounds are N-(3'-chloro-4'-sulphamoylbenzamido)-2-methylindoline, ethacrynic acid and furosemide.

The useful dosage may vary widely depending on the age and weight of the patient, the severity of the therapeutic indication and the route of administration. - 4 - The preferred route of administration is the oral route but the intravenous route is also perfectly suitable for the treatment of hypertension. Generally, the unit dosage P is preferably within the range of from 1 to 100 mg.

The compounds of the invention can be prepared by 4 condensing a carboxyisoindole derivative of the formula COOR" in which A has the same meaning as given under formula I, and 10 R" represents an alkyl group having from 1 to 6 carbon atoms, preferably a tert.-butyl group, or an addition salt thereof, with a functional derivative of a substituted amino acid of the formula HOCO-CH-NH-CH-R' I l 15 CH, COOR III I in which R and R' have the same meanings as given under formula I and the nitrogen atom is protected by a protecting radical customary in the synthesis of peptides, for example benzyloxycarbonyl or tert.-butoxycarbonyl, and 20 the intermediate compound obtained is subjected to - 5 - customary deprotecting processes such as, for example, complete or partial saponification and/or hyarogenolysis, and is thus converted into a compound of the formula I.

The functional derivative of the amino acid (III) can i ^ be prepared in situ with an agent such as dicyclohexyl carbodiimide alone or in the presence of 1-hydroxy-benzotriazole in an aprotic solvent, for example dimethyl-formamide.

The compounds of the formula II are described in the 10 literature (G. CIGNARELLA et al., Gazz. Chim. Ital. 106, 65-75, 1976, and European Patent Application No. 31.741).

Some of the amino acids of the formula III (Rs^Ht-) are known (M. VINCENT et al_. , Tetr. Lett. 23 (16), 1677-1680, 1982) or can be synthesised in a similar 15 manner.

The following Examples illustrate the invention.

EXAMPLE I: 2-[N-(1 -(S)-ethoxycarbony1butyl)-(S)-alanyl]-1-(S)-carboxy isoindoline, tert.-butylamine salt 20 Stage A: 1-(R,S )-tert.-butoxycarbonvlisoindoline hydrochloride By reacting 30 c cf 1 -(R,S)-methoxycarbonyliso-indolir-e hydrochloride (prepared according to G.

CIGNARELLA et al., Gazz. Chirr:. Ital. 106, 65-75 , 1 97 6) - 6 - with 31 cm3 of benzyloxycarbony1 chloride according to the method described by J.P. GREENSTEIN and M. WINITZ in "Chemistry of the Amino Acids", vol. 2, page 887, 47.2 g F of N-benzyloxycarbony1-1 - (R, S)-methoxycarbonylisoindoline 5 are obtained which, on hydrolysis, yield 39.4 g of 4 N-benzyloxycarbonyl-I-(R,S)-carboxyisoindoiine. All of this acid is treated in 200 cm3 of methylene chloride with '100 mg of isobutylene in the presence of 1 cm3 of sulphuric acid according to the method described by G.W. 10 ANDERSON, F.M. CALLAHAN, J. Am. Cnem. Soc. 82, 3359, (1960). In this manner, 43.5 g of N-benzyloxy-carbonyl-1-(R,S)-tert.-butoxycarbonylisoir.doline are obtained which, after hydrogenolysis (ethanol, 10 % palladium-on-carbon; 2.5 kg/cm2) and precipitation of the 15 hydrochloride in ethyl acetate using the stoichiometric amount of hydrochloric acid, yields 27.6 c of 1-(R,S)-tert.-butoxycarbonvlisoindoline hydrochloride. m.p. = 152°C (decomposition) analysis : HCl 20 C H N CI calculated: 61 .05 7.09 5. 48 13. 86 found: 60.82 7.05 5. 42 13. 29 IR spectrum: NH2 : 2300 CO (ester) -2800 cm-1 : 17 30 cm 1 Stage B: 2-[N-(1-(S)-ethoxycarbonylbuty1)-(S)-alanyl]-1-(S)-tert.-butoxycarbonylisoindoline 6 g of' 1-(R,S)-tert.-butoxycarbonylisoindoline hydrochloride (obtained in stage A), 4 0 cm3 of anhydrous 5 dimethylformamide and 3.4 cm3 of triethylamine are introduced into a flask provided with a stirrer and a calcium chloride guard. There are added in succession 4.6 g of N-[1-(S)-ethoxycarbonylbutylHS)-alanine (prepared according to M. VINCENT et aK,• Tetrahedron Letters, vol. 10 23, No. 1b, page 1677-1680 (1982)) in solution in 5 0 cm3 of anhydrous dimethylformamide, a solution of 3.05 g of N-hydroxybenzotriazole in 8 0 cm3 of anhydrous dimethylformamide and then a solution of 4.82 g of dicyclohexyl carbodiimide in 4 0 cm3 of methylene chloride. 15 Stirring is carried out for 24 hours at room temperature, the dicyclohexylurea formed is filtered and the filtrate is evaporated iri vacuo. The residue is dissolved in 200 cm3 of ethyl acetate and the solution is washed twice with 5 0 cm3 of a saturated solution of sodium bicarbonate 20 each time and then three times with 50 cm3 of a saturated solution of sodium chloride each time. The whole is dried over calcium sulphate and evaporated to dryness. The residue (7.3 g) is chromatographed over silica gel (eluant ethyl acetate). In this manner, 2-[N-(1 - ( S )-ethoxy-25 carbonylbutyl)-(S)-alanyl]-1-(S ) - tert.-butoxycarbonylisoindoline (Rf = 0.45; 2.5 g) is separated from - 8 - 2-[N-(1 -(S)-ethoxycarbony1butyl) - (S) - alanyl]-1 -(R)-tert.-butoxycarbonylisoindoline (R^ = 0.30; 1.7 g).

Stage C: 2-[N-(1-(S)-ethoxycarbonylbuty1)-(S)-alanyl]-1-(S)-carboxyisoindoline, tert.-butylamine salt. 5 1.2 g of 2-[N-(l-(S)-ethoxycarbonylbutyl-(S)- alanyl]-1-(S^)-tert.-butoxycarbonylisoindoline (obtained in the preceding stage) are dissolved in 100 cm3 of hydrochloric ethyl acetate (4N). The solution is left for 18 hours at room temperature and then evaporated to 10 dryness. The residue is taken up in 100 cm3 of water and extracted once with 100 cm3 of diethyl ether. The aqueous phase is adjusted to pH 4 by 1N sodium hydroxide and then evaporated to dryness. The residue is taken up in 50 cm3 of anhydrous ethanol, the sodium chloride is filtered and *5 the filtrate is evaporated to dryness. The residue is taken up in 50"cm3 of.anhydrous diethyl- ether. The whole is filtered over talc, 1.5 cm3 of tert.-butylamine are added to the filtrate and the salt precipitates immediately; the whole is filtered and washed twice with 20 20 cm3 of anhydrous diethyl ether each time. In this manner, 0.8 g of product are obtained. analysis: c-jgH26N2°5' C4H11N C H N calculated: 63.42 8.56 S.65 25 found: 63.05 8.49 9.47 - 9 - IR spectrum: NHt band: 2100-2800 cm 1 COO : 1580 cm CO (ester): 1725-1740 cm 1 _ 1 CO (amide): 164 5 cm -1 '4b 5 10 15 EXAMPLE II: 2-[N-(1-(S)-ethoxycarbonylbutyl)-(S)-alanyl]-1-(R)-carboxyisoindoline 1 g of 2—[N—(1-(S)-ethoxycarbonylbutyl)-(S)-alanyl]-1-(R)-tert.-butoxycarbonylisoindoline (obtained in stage B of Example I) is dissolved in 80 cm3 hydrochloric ethyl acetate (4N) and the solution is left for 18 hours at room temperature. The solution is evaporated to dryness and the residue is taken up in 100 cm3 of water and extracted with 100 cm3 of diethyl ether. The aqueous phase is adjusted to pH 4 by 1N sodium hydroxide and then evaporated to dryness. The residue is taken up in 50 cm3 of anhydrous ethanol, the sodium c.hloride is filtered and the filtrate is evaporated. The residue is taken up in 50 cm3 of methylene chloride, filtered over talc, brought to dryness, redissolved in 25 cm3 of water and lyophilised; in this manner 0.4 2 g of product is obtained. analysis: c-joH26N2°5 C H N calculated: 62.97 7.23 7.73 found: 62.93 7.03 7.56 - 10 - IR spectrum: OK and NH bands 2000-3700 cm 1 CO: 1655 and 1735 cm-1 EXAMPLE III 2-[N-(1-(S)-ethoxycarbonylbutyl)-(S)-alanyl]-1-{S)-5 carboxyperhydroisoindole, maleate Stage A: 1-(R,S)-tert.-butoxycarbonylpernydroisoindole hydrochloride 300 g of fused tert.-butanol, 20 g of 1-(R,S)-tert.-bytoxycarbonylisoindoline hydrochloride (stage A, Example I) and 4 g of rhodi.um-on-aluminium are introduced into a 1-litre autoclave. Hydrogenation is carried out for 24 hours at 40°C under a pressure of 60 kg/cm2. The whole is filtered, the catalyst is washed with 50 cm3 of anhydrous ethanol and the filtrate is evaporated to 15 dryness. The residue is taken up in 50 cm3 of anhydrous acetone and the precipitate is filtered and washed twice with 3 0 cm3 of anhydrous acetone each time; in this manner 7.7 g of 1-(R,S)-tert.-butoxycarbonylperhydro-isoindole hydrochloride is obtained. 20 m.p. = 171°C.

Stage B: 2-[N-(1-(S)-ethoxycarbonylbuty1)-(S )-alany1)-1-(S)-tert.-butoxycarbonylperhydroisoindole Using the method described in Example I, stage B, starting from 6.2 g of 1-(R,S)-tert.-butoxycarbonyl-' perhydroisoindole (obtained in stage A) and after chromatography over silica gel (eluant ethyl acetate), 3 g of 2— [N— (1-(S)'-ethoxycar bony 1 butyl )-(S)-alanyl ]-1-(S) -tert.-butoxycarbonylperhydroisoindole (= 0.42) and 2.1 g of 2-[N-(1-(S)-ethoxycarbonylbuty1)-(S)-alanyl] -1 -(R)-tert.-butoxycarbonylperhydroisoindole (R^ = 0.30) are obtained.

Stage C: 2-[N-(1-{S)-ethoxycarbonylbutyl)-(S)-alanyl]-1-(S)-carboxyperhydroisoindole maleate 1.5 g of 2-[N-(1-(S)-ethoxycarbonylbuty1)-(S)-alanyl]-1 -(S)-tert.-butoxycarbonylperhydroisoindole obtained in stage B are dissolved in 100 cm3 of hydrochloric ethyl acetate (4N) and the solution is left for 24 hours at. room temperature.. The solution is evaporated to dryness and the residue is taken up in 100 cm3 of water and 100 cm3 of diethyl ether. The aqueous phase is adjusted to pH 4 with IN sodium hydroxide and then saturated with sodium chloride. Extraction is carried out 4 times with 100 cm3 of methylene chloride each time and the organic phases are combined and washed once with 50 cm3 of a saturated solution of sodium chloride. The whole is dried over calcium sulphate and evaporated to dryness. The residue is taken up in 100 cm3 of diethyl ether, any turbidity is filtered over talc and a solution of 2 g of maleic acid in 100 cm3 of diethyl ether is added to the - 12 - 10 solution; the (hygroscopic) maleate precipitates. The ether is decanted and the residue is washed twice with 100 cm3 of diethyl ether each time. It is redissolved in 25 cm3 of water and lyophilised and in this manner 1 g of product is obtained. analysis: C19H32N205' C4H4°4 C H N calculated: 57.01 7.49 5.78 found: 56.84 7.20 5.80 IR spectrum: OH and NH^ bands : 2200-3600 cm 1 _ ^ CO (amide and ester) 1740 cm COO" 1620-1660 cm"1 EXAMPLE IV : 2-[N-(1-(S)-ethoxycarbonylbutyl)-(S)-alanyl]-1-(R)-15 carboxyperhydroisoindole By using, in the process described above for Example II, 1.1 g of the 2-[N-(1-(S)-ethoxycarbonylbutyl)-(£>)-alanyl]-1-(R)-tert.-butoxycarbonylperhydroisoindole obtained in Example III, stage B, in place of 2-[N-(1-(S )-ethoxycarbonylbuty1)-(Sj-alanyl]-1-(R)-tert.-butoxycarbonylisoindoline there is obtained, after lyophilisation, 0.7 g of 2-[N-(1-(S)-ethoxvcarbonyl-butvl)-(S)-alanyl]-1-(R)-carboxyperhydroisoindole. analysis: Ct9H32N2°5 20 - 13 - C H N calculated: 61.93 8.75 7.60 found: 61.79 8.54 7.60 IR spectrum: OH and NH^ bands : 2300-3600 cm""1 CO ester : 1730 cm 1 COO and amide : 1600-1650 cm-1 In an identical manner, the following compounds are prepared: 2-[N-(1-(S)-ethoxycarbonylpropyl}-(S)-alanyl]-1-(S)-carb-oxyisoindoline 2-[N-(1-(S)-ethoxycarbonylpropyl)-(S)-alanyl]-1-(SJ-carb-oxyperhydroisoindole 2-[N-(1 -.(S )-ethoxycarbonylpentyl )-(S)-alanyl ]-1-(S )-carb-oxyperhydroisoindole 2-[N-(1-(S)-ethoxy.carbonylpentyl-(S)-alanyl]-1-(S)- carb-oxyisoindoline 2-[N-(1 -(S)-ethoxycarbonyl-2-cyclopropylethyl) - (S) -alanyl]-1-(S)-carboxyisoindoline 2-[N-(1-(S)-ethoxycarbonyl-2-cyclopropylethyl)-(S)- alanyl]-1-(S)-carboxyperhydroisoindole 2-[N-(1-(S)-ethoxycarbonyl-2,2-dicyclopropylethyl}- (S)-alanyl]~1-(S)-carboxyisoindoline 2-[N-(1-(S)-ethoxycarbony1-2,2-dicyclopropylethyl)- (S)-alanyl]-1-(S)-carboxyperhydroisoindole.

The compounds of the invention were subjected to a - 14 - pharmacological study in anaesthetised rats according to the procedure described by D.M. GROSS et aK (J. Pharmacol, and Exp. Ther. 216, 552-557. (1981)).

The intravenous dose capable of inhibiting 50 % of the activity of the angiotensin convertase present in the circulation (ED^g) was determined. The following results were obtained: COMPOUND OF EXAMPLE ED5Q (mg/kg) I 0.022 10 II 0.170 III 0.020 IV >300 FORMULATION EXAMPLE 2-[N-(1-(S)-ethoxycarbonylbuty1)-(S)-alanyl]-1-(S) 15 carboxyperhydroisoindole (maleate) wheat starch corn starch casein treated with formaldehyde magnesium stearate 20 talc for 1 tablet. 10 mg 1 20 mg 115 mg 20 mg 15 mg 20 mg - 15 -

Claims

1. Compounds corresponding to the general formula I COOH V CO - CH - NH - CH - R' I I CH3 COOR in which 5 the ring A is saturated or, alternatively, benzenic, R represents a hydrogen atom or a lower alkyl group having from 1 to 4 carbon atoms, R' represents a linear alkyl radical having from 1 to 6 carbon atoms or a mono- or di-cycloalkyl-alkyl radical 10 having from 4 to 7 carbon atoms, in their racemic form or in the form of optical isomers, and the salts thereof obtained with a therapeutically acceptable mineral or organic base or the addition salts thereof obtained with a therapeutically acceptable mineral *5 or organic acid.

2. 2-[N-(1-(S)-ethoxycarbonylbutyl)-(S)-alanylj-1-(R,S)-carboxyperhydroisoindole, its (S)-isomer and their salts.

3. 2-[N-(1-(S)-ethoxycarbonylbutyl)—(S)—alanyl]-1- 20 {R,S)-carboxyisoindoline, its (S)-isomer and their salts.

4. Pharmaceutical composition containing a compound - 16 - N according to any one of claims 1 to 3 as active ingredient together with a pharmaceutically acceptable excipient. 5. Process for the preparation of the compounds according to claim 1, characterised in that a carboxy-5 isoindole derivative of the formula COOR"

5. A N NH 11 in which A has the same meaning as given under formula I and R" represents an alkyl group having from 1 to 6 carbon 10 atoms, preferably a tert.-butyl group, or one of the addition salts thereof, is condensed with a functional derivative of a substituted amino acid of the formula III HOCO-CH-NH-CH-R' I I HI CH3 COOR 15 in which R and R' have the same meanings as given under the formula I and the nitrogen atom is protected by a protecting radical customary in the synthesis of peptides, such as benzyloxycarbonvl or tert.-butoxycarbonyl, and the intermediate compound obtained is subjected to customary deprotecting processes, such as, for example, total or partial saponification and/or hydrogenolysis, and in this manner is converted into a compound of the formula I.

6. A compound substantially as hereinbefore described with reference to the Examples.

7. A composition substantially as hereinbefore described with reference to the Examples.

8. A process substantially as hereinbefore described with reference to the Examples. Dated this 5th day of June 1984 CRUICKSHANK & CO., Agents for the Applicants, 1, Hoiles Street, Dublin 2.