FR2470767A1 - N-Acyl-2-carboxy fused ring heterocyclic cpds. - useful for inhibiting angiotensin converting enzyme and enkephalin(s) - Google Patents

Abstract

Imino acid derivs. of formula (I) in racemic or optically active form and their diastereoisomers are new: (A is a mono- or bi-cyclic, satd. or unsatd. ring system, opt. substd. one or more times, and opt. including heteroatoms m, n and q are each zero to 2. R is H, methyl or benzyl. R1 is H or up to 5C alkyl. R2 is hydroxy or lower alkoxy. Z is carboxy, cyano, hydroxy, mercapto or amino, but if it is mercapto, then A is not benzo). They are made from corresp. N-H cpds. by reaction with Z'.(CH2)q.CHR.COOH, then deprotection. (Z' is as Z but protected). N-Q-2(RS)-carboxyperhydroindole; 2-Q-3-(S)carbethoxy-cis- perhydroisoquinoline and N-Q-I-(RS)carboxy-perhydroisoindole; Q is 3-mercapto-2-(RS)methylpropionylene specifically claimed. (I) are inhibitors of angiotensin-converting enzyme and encephalins, and are useful for treating arterial hypertension and cardiac insufficiency. They are pref. administered orally at 100-500 mg per day.

Description

The present invention relates to new imino acids and to their methods of preparation.

 It relates more particularly to bi-cyclic imino acids whose nitrogen atom is substituted by a propionylated chain.

Specifically, it relates to Azabicycloalkane 2-carboxylic acids of general formula I

 in which A represents a cyclic, mono or bicyclic, saturated, unsaturated or aromatic structure, which can incorporate one or more heteroatoms, unsubstituted or substituted by one or more substituents.

n is equal to zero or is an integer varying from 1 to 3
X is a methylene radical of formula

dans laquelle R3 est de l'hydrogène, un radical alcoyle inférieur, phényle, phényl substitué, aralcoyle ou aralcoyle substitué
R1 est de l'hydrogène, un radical alcoyle inférieur, ou un atome d'halogène
R est de l'hydrogène, un radical méthyle, trifluorométhyle, pentafluoroéthyle, hydroxyméthyle ou alcoxy méthyle
Z est un radical carboxy, carbalcoxy, cyano, carboxamide, thiocarboxamide de la forme

(dans laquelle R5 représente de l'hydrogène, un radical alcoyle inférieur, un radical acy- le inférieur ou un radical aroyle) un radical thio de la forme -SR4 dans laquelle R4 est de l'hydrogène, un reste acyle d'acide alcoyl carboxylique, arylcarboxylique ou arylalcoyl carboxylique, ou un reste hydroxycarbamoyl
R6 est un hydroxyle, un alcoxy inférieur ou un groupe amino
L'invention se rapporte également aux sels de composes de formule générale I dans laquelle R6 est un hydroxyle. Ces compo sés peuvent être salifiés par une base minérale ou organique, de préférence thérapeutiquement compatible.(in which R8 is hydrogen, a hydroxyl or a host and rnest equal to zero, 1, 2 or 3), thioalkoylene of the form -S-CH2, oxyalkylene of the form -O-CH2 or iminoalkylene of shape

in which R3 is hydrogen, a lower alkyl, phenyl, substituted phenyl, aralkyl or substituted aralkyl radical
R1 is hydrogen, a lower alkyl radical, or a halogen atom
R is hydrogen, a methyl, trifluoromethyl, pentafluoroethyl, hydroxymethyl or alkoxy methyl radical
Z is a carboxy, carbalkoxy, cyano, carboxamide, thiocarboxamide radical of the form

(in which R5 represents hydrogen, a lower alkyl radical, a lower alkyl radical or an aroyl radical) a thio radical of the form -SR4 in which R4 is hydrogen, an acyl residue of alkyl acid carboxylic, arylcarboxylic or arylalkoyl carboxylic, or a hydroxycarbamoyl residue
R6 is a hydroxyl, lower alkoxy or an amino group
The invention also relates to the salts of compounds of general formula I in which R6 is a hydroxyl. These compounds can be salified with a mineral or organic base, preferably therapeutically compatible.

Among the compounds of the invention, the following subgroups, which are currently preferred, can be distinguished more particularly
10) tetrahydroisoquinoleine -carboxylic acids of general formula IA

in which the substituents R6, R, Z and R1 have the meanings previously supplied
R2 represents hydrogen, halogen or hydroxyl
D represents hydrogen, a lower alkyl radical, a lower alkoxy, a trifluoromethyl, a trifluoromethoxy, a trifluoromethylthio, an alkylenedioxy group or a sulfonamido group
and p is 1, 2, 3
2 ") decahydroisoquinolines of general formula 1B

in which the substituents R2, D, R1, R6, R, Z, n and p have the meanings provided previously 3) the B -carbol ibes of general formula I

in which the definition of the substituents R, R1, R6, Z,
D and p remains that previously provided
and R2 represents a hydroxyl, a lower alkyl, one or two halogens.

4) the tetrahydropyridine imidazolo of general formula

in which the definition of the substituents R, R1, R6, and
Z remains that previously provided
and R7 represents hydrogen or a lower alkyl radical.

5) indolines of structure 1e

in which the definition of the substituents R1, R2, R, Z,
D and p remain unchanged.

The compounds of general formula I contain at least one asymmetric carbon atom. Depending on the position of the substituents and the degree of hydrogenation there are two to seven centers of asymmetry. The racemic compounds can be split into their mixtures of diastereoisomers or epimers, or split into their enantiomers.

Preferably, the raw material chosen is (oxa) (Aza) (thia) Azacycloalkyl carboxylic acids or Azacycloalkylcarboxylic acids having the amino acid configuration of the animal kingdom.

The propionic chain can comprise an asymmetric carbon atom and it is preferred to use the configuration compounds
D.

It can be assumed that the pharmacological activity of the compounds of general formula I depends in part on the stereochemistry of the molecule. Only one optically active form carries the pharmacological activity. It can therefore be assumed that the non-split mixtures or the diastereoisomer mixtures have only half or a quarter of the activity of the optically-active molecular configuration responsible for the activity.

The compounds according to the invention and their salts are endowed with interesting pharmacological properties. They inhibit the transformation of the angiotensin I decapeptide into angiotensin II ltoctapeptide by a selective inhibition of the enzyme responsible for this conversion.

It is recognized that angiotensin exists in the circulation in the form of a precursor the Angiotensinogen that a specific enzyme, Renin, transforms into inactive Angiotensin I. The transformation of Angiotensin I into Angiotensin II gives rise to a very active biological substance on blood pressure, leading to hypertension. This is the reason why it has been considered that an excessively high level of Angiotensin II can be responsible for various forms of hypertension and in particular in essential hypertension. The compounds according to the invention have an inhibitory action on the carboxypolypepti dase responsible for the transformation of angiotensin I into angiotensin II. Their use in therapy therefore makes it possible to reduce or even suppress the formation of angiotensin II by acting on one of the mechanisms directly responsible for arterial hypertension in humans.

 The invention therefore relates to the therapeutic use of the compounds of general formula I and their salts, in particular for the treatment of arterial hypertension and heart failure.

 The invention also extends to pharmaceutical compositions containing as active principle at least one compound of general formula I or one of its addition salts, with an inorganic or organic base, in association with an inert non-toxic excipient which is pharmaceutically acceptable.

For the purpose of therapeutic use3 the compounds of general formula I or their salts are presented in pharmaceutical forms suitable for administration by the parenteral, buccal, perlingual or rectal route. The pharmaceutical compositions according to the invention contain, in addition to the active principle, one or more inert, non-toxic excipients suitable for pharmaceutical use and / or a binding agent, a flavoring agent, a disintegrating agent, a sweetening agent, an agent lubricant or else a liquid or solid vehicle suitable for parenteral or rectal administration.

 The pharmaceutical compositions according to the invention may also contain another active principle of complementary or synergistic action.

Among these latter active principles, mention may be made of a diuretic and in particular a saliuretic, such as for example a th-ia-vacuum, a dihydrothiazide, a chlorosulfamide, a benzol sulfamide acid, a benzo furan 2-carboxylic acid, a dihydrobenzofuran 2-carboxylic acid. or a derivative of phenoxy acetic acid. Examples of such compounds are N (3'-chloro 4'sulfamyl benzamido) 2-methyl indoline, ethacrynic acid, furosemide.

 We can also add a-adrenolytic substances like Prazosin.

The useful dosage can vary widely depending on the age, weight of the patient, the severity of the therapeutic indication and the route of administration. The preferred route of administration is the buccal route but the rectal or parenteral route are also perfectly suitable for the treatment of hypertension. In general, the unit dosage will range between 25 and 250 mg and the daily dosage between 100 and 500 mg.

The invention also includes a process for obtaining the compounds of formula I

in which the definition of the substituents X, R1, R, Z and n remains that provided previously
A represents a cyclic structure, mono or bicyclic, its size, unsaturated or of aromatic character, which can incorporate one or more heteroatoms, unsubstituted or substituted by one or more substituents
and R6 is a lower alkoxy or amino radical
in which an alkyl ester of Azabicycloalkane 2-carboxylic acid of general formula II is subjected

dans laquelle Z' représente un radical carbalcoxy, cyano, carboxamide, thiocarboxamide de la forme

(dans laquelle
R5 représente un radical alcoyle inférieur , un radical acyle in rieur ou un radical aroyle) un radical thio de la forme -SR4 dans laquelle R4 est un reste acyle d'acide alcoyl carboxylique ou arylcarboxylique, ou un reste hydroxycarbamoyl
ou un de ses dérivés fonctionnels) pour obtenir un amide de formule générale IV

in which the definition of the substituents remains that mentioned above
and R6 represents a lower alkoxy
to the action of a substituted propionic acid of general formula III

in which Z 'represents a carbalkoxy, cyano, carboxamide, thiocarboxamide radical of the form

(in which
R5 represents a lower alkyl radical, an inner acyl radical or an aroyl radical) a thio radical of the form -SR4 in which R4 is an acyl residue of alkyl carboxylic or arylcarboxylic acid, or a hydroxycarbamoyl residue
or one of its functional derivatives) to obtain an amide of general formula IV

in which Z 'has the definitions provided above
R6 represents a lower alkoxy radical
and the substituents R1, X, A and n keep the meanings provided previously
which can, if desired, be partially hydrolyzed to the thiol derivative of formula V

in which Z 'represents a thiol radical
R6 represents a lower alkoxy radical
and the substituents R, X, A and n keep the meanings provided previously or completely saponify to form a carboxylic derivative of formula VI

in which Z 'represents a thiol, carboxy, cyano, carboxamide, thiocarboxamide group
R6 represents a hydroxyl
and the substituents A, X, R1 and n have the definitions previously provided.

The process according to the invention also comprises the optional amidation phase which consists in subjecting a compound of formula IV to the action of concentrated ammonia to form a compound of formula I

in which R6 is an amino group
Z is a thiol3 carboxy, cyanothiocarboxamide, hydroxycarbamoyl, carboxamide or carboxy radical
and the substituents X, R1, R, A and n have the same meanings as above.

 The compounds of general formula I for which R6 is a hydroxyl, give salts with mineral or organic bases such as for example the sodium, potassium, lithium, ammonium, calcium, magnesium, aluminum salts; alkyl amine such as methylamine, dimethylamine, methyl ethylamine, di-iso propylamine or triethylamine; cycloalkyl amine such as, for example, cyclopropylamine or dicyclohexyl amine; (cycloalkyl) alkyl amine such as, for example, cyclopropyl ethyl amine; amino sugars such as, for example, glucosamine, mannosamine, N-methylglucamine; amino acids like glycine or arginine.

According to preferred procedures, the process can be further defined as follows
the condensation between the substituted propionic acid of general formula III and the ester of azabicycloalkane carboxylic acid of general formula II is carried out, in the presence or in the absence of solvent, at a temperature close to 00.

 the condensation between the propionic acid of general formula III and the ester of Azacycloalkane carboxylic acid of general formula II takes place in the presence of a carboxyl activator such as for example a di-alkyl or di-cycloalkylcarbodi-imide, ethoxyacetylene or carbonyl di-imidazole.

the condensation of the azabicycloalkane carboxylic acid ester of general formula II with the substituted propionic acid of general formula III is carried out using a functional derivative of propionic acid of general formula III such as for example an acid halide , an anhydride; a mixed anhydride with ethyl chloroformate or a lower alkyl ester.

 - the partial saponification is carried out in a weak basic medium, for example in the presence of dilute ammonia, calcium hydroxide or barium hydroxide.

 - total hydrolysis is carried out in an acid medium, for example in the presence of hydrochloric acid, sulfuric acid or perchloric acid in an aqueous medium.

 the separation of the diastereoisomers from the compounds of general formula I is preferably carried out by physical methods using chromatography in vapor phase, chromatography in high pressure liquid phase or entrainment by reciprocal saturation.

 the splitting of the diastereoisomers into their optical antipodes is preferably carried out by salification of the compounds of general formula I for which R6 is a hydroxyl using an optically active base such as, for example, brucine, strychnine, sparteine, ephedrine, d-threo 1-paranitrophenyl 2-dimethylamino propane 1,3-diol, d-glucosamine or 1streptamine.

 As far as the invention is concerned, the term lower alkyl denotes a saturated hydrocarbon radical having 1 to 6 carbon atoms in a straight or branched chain. Such radicals are, for example, the methyl, ethyl, isopropyl, terbutyl, dry pentyl and n hexyl radicals.

The term aryl denotes a benzene or naphthalene ring which is unsubstituted or substituted by one or more substituents chosen from the group consisting of halogens, a lower alkoxy radical, such as, for example, 3,4-dimethoxy phenyl, 2,4-dichlorophenyl, m.trifluoromethyl phenyl, 3,4,5-trimethoxy phenyl, 2,6dimethylphenyl, 3,5-dimethoxy phenyl, 6,7-dimethoxynaphtyl or 4hydroxy phenyl, it can also be substituted by an alkyl, a hydroxyl or a trifluoromethyl
The term aryl (lower alkyl) is defined in the same way. It includes, for example, the 3,4-dimethoxy benzyl, m.trifluoromethyl benzyl, -methyl benzyl, phenyl ethyl, phenyl propyl, 8-methyl phenylethyl, p.chlorobenzyl, methylene dioxy benzyl and benzyl radicals.

The invention also includes another method for obtaining Azabicycloalkane carboxylic acids of general formula I which consists in subjecting an amino acid of general formula

in which A and R6 have the definitions previously provided
to the action of substituted propionic acid of general formula III

in which Z 'and R are defined as above
or a functional derivative of this acid to obtain a peptide of general formula

in which the definition of the substituents X, A, R6, R and
Z remains unchanged
and subjects it to the action of formalin in an acid medium to obtain a bicycloalkane carboxylic acid derivative of general formula

in which the definition of the substituents A, X, R6, R and
Z 'remains that provided previously.

 Among the different meanings of the cyclic structure A, mention may be made of homocycles such as benzene, naphtha lene or indene; heterocycles including one or more oxygen, sulfur and / or nitrogen atoms such as, for example, pyridine, pyrimidine, tetrahydropyrimi dine, pyrrole, i, midazole, imidazoline, thiophene, thiachromanne, benzofuran, indole, indoline, ltoxazole, azepine, pyrazine or quinoxaline.

The following examples illustrate the invention. They do not limit it in any way.

EXAMPLE I
Acid 2- (3-mercapto 2-methyl propionyl) 1,2,3,4-tetrahydro-isoquinoline 3-carboxylic (mixture of diastereoisomepes)
Stage A
Tetrahydroisoquinoline (levorotatory) 3-carboxylic acid.

 15 g of l-phenylalanine are introduced into a three-tube flask surmounted by a condenser, followed by 34 ml of a formalin solution containing 40.0 and 105 ml of concentrated hydrochloric acid.

 It is heated for 30 minutes in a boiling water bath. A clear solution is thus obtained, the reaction medium is allowed to return to ambient temperature and then 15 ml of formalin and 30 ml of concentrated hydrochloric acid are added. Then heated 3 hours at reflux of the solvent. The mixture is allowed to cool and then the precipitate is separated by filtration. After spinning, it is taken up in 200 ml of boiling water and 400 ml of hot ethanol. The solutions are combined and neutralized by adding 10% ammonia.

 Tetrahydroisoquinoline 3 ~ carboxylic acid crystallizes.

The crystalline mixture is left to stand overnight in a cooler and then separates the precipitate which is drained and washed with ethanol. 1793 of raw product are thus collected. A sample is taken for analytical purposes. The product is dried under phosphoric vacuum.

Analysis: C10 H1l 2 N = 177
CH
Calculated 67.78 6.26 7.90
Found 66.87 6.20 7.96
IR spectrum
NH2 + band at 2800-2400 cm -1
COO carbonyl strip at 1630 cm 1
Rotating power
a D = - 108 (c = 2.2 NaOH normal)
Stage B
Methyl tetrahydroisoquinoline hydrochloride 3-carboxylate.

 5 g of a tetrahydroisoquinoline 3-carboxylic acid and 30 ml of methanol are successively charged into a three-tube flask. To this suspension is added by pouring while avoiding that the temperature does not exceed 0, + 5.6 g of thionyl chloride.

The addition takes about 10 minutes. After this addition is complete, stirring is continued for 2 hours at ambient temperature, then the solvent is refluxed for 1 hour and a half.

Once the mixture is completely dissolved, the heating is stopped and then evaporated to dryness. The residue is taken up in methanol three times and then brought to dryness. Finally collected 8 g of colorless crystals which are purified by trituration with ether. The crystals are separated by filtration, drained, washed with ether and dried. This gives 694 of methyl tetrahydroisoquinoline hydrochloride 3-carboxylate.
Analysis C10 H13 N02 ClH = 227.69
CHN Cl%
Calculated 58.03 6.20 6.15 15.57
Found 57.79 6.46 6.38 15.67
IR spectrum
carbonyl band at 1735 cm 1
NH2 band at 2800-2400 cm 1
Stage C
2- (3 acetylthio 2-methyl propionyl) 3-methoxy carbonyl 1,2, 3,4-tetrahydroisouinoline.

6 g of tetrahydroisoquinoline hydrochloride 3-methyl carboxylate, 1.4 ml of triethyl amine and 200 ml of methylene chloride are introduced into a container provided with mechanical stirring. The solution is cooled in an ice-water bath and then 3g96 of dicyclohexyl carbodimide, 1g47 of hydroxybenzotriazole and 196 of 2-methyl 3-acetylthiopropionic acid dl are added. Stirring is continued for 12 hours at room temperature. The precipitate of dicyclohexyl urea is filtered and then the filtrate is evaporated to dryness. The dry residue is taken up in 100 ml of ethyl acetate and the insoluble material is filtered, then the filtrate is washed with a saturated sodium chloride solution, then with a 10% citric acid solution and finally with a saturated solution of sodium chloride. The ethyl acetate is dried and then evaporated to dryness. 3 g of an oily product are thus obtained, practically homogeneous in thin layer chromatography.

 The product is purified by chromatography on silica and elution with a benzene-ethyl acetate mixture. The head fractions are eliminated. The middle fractions provide by evaporation 198 of 2- (3-acetylthio 2-methylpropionyl) 3-methoxy carbonyl 1,2,3,4-tetrahydroisoquinolene.

NMR spectrum
compatible with structure
triplet 5.45 ppm
4 phenyl protons at 7.25 ppm
3 acetyl protons at 3.65 ppm
5 protons of saturated carbon between 3 and 3.5 ppm.

in CPV
presence of a single main peak approximately 98% pure under the operating conditions used.

Stage D
2- (3-Mercapto 2-methyl propionyl) 1,2,3,4-tetrahydroisoquinoline 3-L carboxylic acid.

 1.7 g of 2- (3-acetylthio 2-methyl propionyl) 3-methoxycarbonyl 1,2,3,4tetrahydro isoquinoline are introduced into a three-tube flask provided with magnetic stirring and a bubbling of inert gas. 11 ml of normal potash and 30 ml of ethanol. Stirred for 24 hours at room temperature and then neutralized exactly by adding hydrochloric acid. The ethanolic solution is concentrated which is exhausted with ethyl acetate. The solution in ethyl acetate. The ethyl acetate solution is washed with water, dried over calcium sulphate and evaporated to dryness. The residue is taken up in 20 ml of isopropyl ether and the insoluble material is filtered. The filtrate is brought to dryness, thus obtaining 1 g 2 of pure product, presenting in CCM a very largely dominant spot.

Analysis C14 H17 N03S L 279.36
CHN
Calculate 60.19 6.13 5.01 11.48
Found 60.48 6.49 4.62 11.00
This acid is soluble in dilute soda solutions.

By evaporation under reduced pressure, the sodium salt of 2 (3-mercapto 2-methyl propionyl) 1,2,3,4-tetrahydroisoquinoline 3-L.carboxylic acid is isolated.

EXAMPLE II
2- (3-Mercapto 2-methylpropionyl) cis decahydroisoqui noline 3-carboxylic acid.

Using the procedure of Example I starting from cis decahydro-isoquinoline 3-carboxylic acid obtained according to the hydrogenation method described by Rapala J. of Am. Chem. Soc.

79 (1957) 3770, and 3-acetylthio 2-methyl propionic acid, successively obtained
- the methyl ester of cis decahydroisoquinoline 3-carboxylic acid
- 2- (3-acetylthio 2-methyl propionyl) cis decahydroisoquinoline 3-methyl carboxylate
- 2- (3-acetylthio 2-methyl propionyl) cis decahydroisoquinoline 3-carboxylic acid.

The product consists of a mixture of diastereomers.

IR spectrum: conforms to the structure
RMV spectrum: integration of protons in agreement with the structure.

Analysis C13 H21 N03S = - 271.38
CHN
Calculated 57.78 7.80 5.16 11.82
Found 57.94 7.12 5.24 11.66
EXAMPLE III
5 '- (3 "-mercapto 2" -methylpropionyl) acid 1', 2 ', 5', 6 'tetrahydro (pyridino 3', 4'-4,5-imidazolyl) 6-carboxylic
Using the same procedure as in Example I, starting with the acid 1 ', 2', 5 ', 6' tetrahydro (pyridino 3 ', 4' - 4,5 imidazolyl) 6'-carboxylic prepared according to the method described by
Ackermann HSZf Phys.Chem. 284 (1949) 131, and 3-acetylthio 2-methyl propionic acid, successively obtained
- 1 ', 2', 5 ', 6' tetrahydro (pyridino 3 ', 4'-4,5 imidazolyl) 6'-ethyl carboxylate
- 5 '- (, 3 "-acethylthio 2" -methyl propionyl) 1', 2 ', 5', 6 'tetrahydro (pyridino 3', 4 '- 4,5 imidazolyl) 6'-ethyl carboxylate
- 5 '- (3 "-thio 2" -methylpropionyl) acid 1', 2 ', 5', 6 'téerahydro (pyridino 3', 4'-4,5-imidazolyl) 6'-carboxylic
Analysis C10 H12 N3 03 S = 254.29
CHN
Calculation 47.23 4.76 16.52 12.61
Found 47.42 4.68 16.73 12.38
EXAMPLE IV
Acid 2- 0 (3 'mercapto 2'-trifluoromethylpropionyl) 1,2,3,4 tetrahydro 9H | pyrido- (3,4b) indole 3-carboxylic.

Using the procedure of Example I starting from the acid (1,2,3,4-tetrahydro [9H] pyrido (3,4-b) indole) 3-carboxylic, obtained according to the method described by A Brossi J. Med,
Chem. 16 (1973) 419 and 3-acetylthio 2-trifluoromethyl propionic acid (obtained according to the process described in Belgian patent 872,972), successively obtained
- methyl tetrahydro ho pyrido (3,4-b) indole) 3-carboxylate
- methyl 2- (3'-acetylthio 2'-trifluoromethyl propionyl) 1,2,3,4tetrahydro [9H] pyrido (3,4-b) indole 3-carboxylate
- 2 - [(3'-mercapto 2'-trifluoromethylpropionyl) 1,2,3,4-tetrahydro [9Hi pyrido (3,4-b) indoles 3-carboxylic acid.

- the dicyclohexylamine salt of 2-3'-mercapto 2'trifluoromethyl propionyl) 1,2,3,4-tetrahydro [9H] pyrido (3,4-b) indole] 3-carboxylic acid (mixture of diastereoisomers) .

Analysis C16 H14 F3 N2 02S + C12 H23N = 533.69
CHN
Calculated 63.02 6.99 8.06 6.01
Found 62.54 7.08 8.22 5.79
EXAMPLE V
2- (3'-cyano 2'-methylpropionyl) 3 xmethyl 6,7-dihydroxy 1,2,3,4-tetrahydro isoquinoline 3-carboxylic acid (mixture of diastereoisomers).

 By operating according to the procedure of Example I starting from 6,7-dShydroxy 3 a-methyl 1,2,3,4-tetrahydroisoquinoleine 3 (L) -carboxylic acid (described by Rachlin Scheur Tétrahedron Letters ( 1968), 39 4163), the methyl ester of 6,7-dihydroxy 3 -methyl 1,2,3,4-tetrahydro iso quinoleine 3 (L) -carboxylic acid is prepared which is condensed with the chloride of 3-cyano 2-methylpropionic acid in solution in dime-methyl formami.

 This gives the methyl ester of 2- (3'-cyano 2'-methylpropionyl) 3 a-methyl 6,7-dihydroxy 1,2,3,4-tetrahydroisoquinoline 3 (L) carboxylic acid.

 The methyl ester is saponified by stirring with a baryte solution at ordinary temperature. The solution is then saturated with carbon dioxide. The precipitate is separated by filtration, washed with water several times, the aqueous phases are combined and brought to dryness under vacuum.

The dry residue is taken up in ethyl acetate by hot and cold.

 1,2,3,4-tetrahydro 2- (3'-cyano 2'-methyl propionyl) 3 amethyl 6,7-dihydroxy isoquinoline 3 (L) -carboxylic acid is obtained in the form of slightly yellowish crystals.

Analysis C16 H18 O, N2 = 318.17
CH
Calculated 60.35 5.70 8.80
Found 59.84 5.79 8.97
EXAMPLE VI
Pharmacological study of the compounds of the invention.

The compounds according to the invention are tested by administration to batches of dogs of the Mongrel breed, not anesthetized, maintained in forced breathing using a respiratory device.
Mark VII Bird.

 The dogs' blood pressure was measured by a Statham P23Db pressure sensor after catheterization of the aorta via the femoral artery. The recording is carried out by a Brush 400 recording device.

 Angiotensin I and angiotensin II are injected into animals intravenously at a dose of 0.3 1Kg. A dose / activated curve is established for each of these hormones. The compounds according to the invention are then administered by the oral route at a dose corresponding to 0.023 M / Kg of split product. A second dose / activity curve is then established for angiotensin I and for angiotensin II after administration of the trial products.

The following results were obtained in comparison with those obtained with captopril administered under the same conditions.

composed of the example time% inhibition
1 15 min 80
30 min 90
60 mins 60
90 44
2 hours 44
3:29
4:18
5:16 a.m.
6:20 a.m.
compounds of the example
2 15 min 75
30 min 89
60 min 94
90 min 58
2 hours 52
3 hours 41
4:28 a.m.
Captopril 15 mins 100%
(0.023 M / kg = 5 mg / kg)
30 min 92
60 min 88
90 min 80
2 hours 62
3 hours 51
4 hours 34
5:28 a.m.
6:26 a.m.
The products according to the invention are therefore practically as active as captopril by the oral route in equimolecular doses.

EXAMPLE VII
Solution for injection for venous infusion
2- (3'-mercapto 2'-methylpropionyl) tetrahydroisoquinoline 3-carboxylate dicyclohexyl ami ne Logo15
N- (3'-sulfamoyl 4'-chlorobenzamido) 2-methyl indoline 09075 p.hydroxybenzoate Og15 p.hydroxybenzoate propyl Ogl5 sodium chloride distilled water qs 1000 ml
EXAMPLE VIII
Solution for injection for venous infusion
2- (3'-mercapto 2'-methylpropionyl) tetrahydroisoquinoline dicyclohexylamine 3-carboxylate / Og015 acid 5- (aminosulfonyl) 4-chloro 2 (2-furanylmethyl) amino] benzolque 09045 p.hydroxybenzoate Og15
Propyl p. Hydroxybenzoate Og15 lithium chloride 6g5 distilled water qs 1000 ml
EXAMPLE IX
solution for injection for intravenous infusion
N- (3-mercapto 2-methyl propionyl) decahydro isoquinoline 3-carboxylate di cyclohexyl amine 09015
N- (3'sulfamoyl 4'-chlorobenzamido) 2-methyl indoline 09075 p.hydroxybenzoate Yoga5 p.propyl hydroxybenzoate Og15 lithium chloride 695 sterile water qs 1000 ml
EXAMPLE X
50 mg tablets of active ingredient
2- (3'-mercapto 2-methylpropionyl) tetrahydro isoquinoline 3-carboxylic acid 5-aminosulfonyl 50 g 4-chloro 2- (2-furanyl methylamino) benzoic 45 g wheat starch 80 g corn starch 70 g formalin casein 20 g magnesium stearate 15 g talc 20 g per 1000 tablets with an average weight of 09300
EXAMPLE XI
100 mg tablets of active ingredient
2- (3mercapto 2-methyl propionyl) decahydroisoquinoline 3-carboxylic acid 100 g tricalcium phosphate 125 g wheat starch 35 g carboxymethyl starch 25 g formalin casein 5g colloidal silica 5g magnesium silicate 25 g talc 20 g per 1000 tablets of average weight 0g25

Claims (2)

CLAIMS The subject of the invention is 1 ") Azabicycloalkane α-carboxylic acids and their derivatives, of general formula I in which A represents a cyclic structure, mono or bicyclic, saturated, unsaturated, or of aromatic character, which can incorporate one or more heteroatoms, unsubstituted or substituted by one or more substituents. n is zero or represents an integer varying from 1 to 3 X is a methylene radical of formula (in which R8 is hydrogen, hydroxyl or halogen and m is a number equal to zero, one, two or three) thialcoylene of the form-S-CH2-, oxaalcoylene of the form-OCH2or iminoalkylene of the form (in which R3 is hydrogen, a lower alkyl radical, phenyl , substituted phenyl, aralkyl or substituted aralkyl) R1 is hydrogen, a lower alkyl radical or a halogen atom R is hydrogen, a methyl, trifluoromethyl, pentafluoroethyl, hydroxymethyl, or alkoxymethyl radical Z is a ra dical carboxy, carbalkoxy, cyano, carboxamide, thiocarboxamide of the form (in which R5 represents hydrogen, a lower alkyl radical, lower acyl, or an aroyl radical); a thio radical of form -SR4 in which R4 is hydrogen, an acyl residue of alkylcarboxylic acid, arylcarboxylic or aryl alkylcarboxylic acid; or a hydroxycarbamoyl residue, and R6 is a hydroxyl, lower alkoxy or an amino group. 2 ") The addition salts with an inorganic or organic base of the compounds according to claim 1 for which R6 is a hydroxyl. 3) The tetrahydroisoquinoline compounds according to claim 1", corresponding to the general formula IA in which the substituents R6, R1, R and Z are defined as above R2 represents hydrogen, a halogen or a hydroxyl D represents hydrogen, a lower alkyl radical, a lower alkoxy, a trifluoromethyl, a trifluoromethoxy, a trifluoromethylthio, an alkylenedioxy group or a sul fonami group of, and p is equal to 1, 2 or 3. 4) The decahydroisoquinolinic compounds according to claim 1 ") corresponding to the general formula IR in which the definition of the substituents n, R, R1, R6, Z, D and p remains that supplied previously 5) The a-carbolinic compounds according to claim 10) corresponding to the general formula c in which the definition of the substituents -R, R1, R6, Z, D and p remains that supplied above emment and R2 represents a hydroxyl, a lower alkyl. or one or two halogens.  60) The imidazole compounds according to claim 1 of general formula Id

in which the definition of the substituents R, R1, R6 and Z remains that previously provided and R7 represents hydrogen or a lower alkyl radical 70) The indolinic compounds according to claim 1 ") corresponding to the general formula

in which the definition of the substituents R, R1, R2, D, Z and p remain unchanged.  8) A compound according to claim 1 "), namely dl 2- (3-mercapto 2-methylpropionyl) 1,2,3,4-tetrahydro isoquino leinyl-3 carboxylic acid. 9 =) A compound according to claim 1 ", namely dl 2- (3-mercapto 2-methyl propionyl) decahydro lsoquinoleinyl-3 carboxylic acid.  10) The pharmaceutical compositions containing as active principle at least one compound according to claim 10 or claim 20 in association with an excipient or an inert non-toxic vehicle which is therapeutically compatible.  11) A pharmaceutical composition according to claim 10) in which the excipient or the vehicle are those which are suitable for parenteral, buccal, rectal or sublingual administration. 12 ") A pharmaceutical composition according to claim 10 characterized in that it contains another active principle of complementary or synergistic action.  13) A pharmaceutical composition according to one of claims 100 and 120 in which the active principle of complementary or synergistic action is a sulfonamide or a benzothiadiazine of diuretic action. 14 ") A pharmaceutical composition according to one of claims 100 and 120 in which the active principle of complementary or synergistic action is an alpha-adrenolytic substance. 15) A process for obtaining the compounds of general formula I according to claim 1 "

in which the definition of the substituents X, R1, R, Z and n remains that provided previously A represents a cyclic, mono or bicyclic saturated, unsaturated or aromatic structure, which can incorporate one or more heteroatoms, unsubstituted or substituted by one or more substituents  and R6 is a lower alkoxy or amino radical  in which an alkyl ester of azabicycloalkane c-carboxylic acid of general formula II is subjected

in which the definition of the substituents remains that mentioned above  and R6 represents a lower alkoxy  to the action of a substituted propionic acid of general formula III

in which Z 'represents a carbalkoxy, cyano3 carboxamide, thiocarboxamide radical, the form

(in which R represents a lower alkyl radical, a lower acyl radical or an aroyl radical, a thio radical of the form SR4 in which R4 is an acyl residue of alkyl carboxylic or arylcarboxylic acid, or a hydroxycarbamoyl residue  or one of its functional derivatives to obtain an amide of general formula IV

 in which Z 'has the definitions provided above  R6 represents a lower alkoxy radical  and the substituents R1, X, A and n keep the meanings provided previously  which can, if desired, be partially hydrolyzed to the thiol derivative of formula V

 in which Z 'represents a thiol radical R6 represents a lower alkoxy radical  and the substituents Ri, X, A and n keep the meanings provided previously  or completely saponify to form a carboxylic derivative of formula VI

 in which Z 'represents a thio, carboxy, cyano, carboxamide, thiocarboxamide group R6 represents a hydroxyl  and the substituents A, X, R1 and n have the definitions provided previously  16) A process according to claim 15 which comprises the additional amidation phase characterized in that an ester of Azabicycloalkane a -carboxylic acid of general formula IV is subjected to the action of concentrated ammonia to form a carboxamide of general formula I

 in which R6 is an amino group  Z 'is a thiol, carboxy, cyano3 thiocarbamoyl, hydroxycarbamoyl, carboxamide or carboxy radical.