HU198720B - Process for producing pyridazodiazepines and pharmaceutical compositions containing them - Google Patents

Abstract

Bicyclo-diaza-heterocycles of formula (I) and their salts are new (B is methylene, ethylene or vinylene. R1 is H or alkyl (opt. substd. by aryl; amino (itself opt. substd. by 1 or 2 alkyl); acylamino; phthalimido; alkoxy-, aryloxy- or aralkoxy-carbonylamino; alkyl-, aryl- or aralkyl- aminocarbonylamino; or alkyl- or aryl-sulphonylamino). R2 is carboxy, alkoxycarbonyl, aralkoxycarbonyl, -PO(OH)2 or -CONR6R7. R3 is carboxy, alkoxycarbonyl or aralkoxycarbonyl. R4 and R5 are both H or together form oxo. R6 and R7 are H, alkyl, aralkyl or together complete a satd., 5 or 6 membered heterocycle, opt. contg. an additional N, O or S atom. n is 0-2). (I) are antihypertensives (inhibitors of angistension-converting enzyme). They are formulated conventionally for oral or parenteral administration, pref. at daily doses of 1-50 mg per kg..

Description

The present invention relates to the preparation of novel bicyclic compounds and pharmaceutical compositions containing them.

More particularly, the present invention relates to a process for the preparation of a bicyclic compound of formula (I) and pharmaceutically acceptable salts thereof

B is ethylene (-CH 2 -CH 2 -);

R ¹ is phenyl (lower alkyl) ·

-group;

R ² and R ³ represents carboxy or lower alkoxy carbonyl;

R ⁴ and R ⁵ each independently represent a hydrogen atom or together form an oxo group and. n is 2;

with the proviso that at least one of R ² and R ³ represents a carboxyl group).

The compounds of formula (I) contain asymmetric carbon atoms and may therefore exist in the form of optically pure diastereoisomers, dicaster stereoisomeric racemates, or dic stereoisomeric mixtures. The present invention encompasses the preparation of all of the above forms of the compounds of formula (Ij). All of the asymmetric carbon atoms in the compounds of formula (I) are preferably of the (S) -configuration.

As used herein, the term "alkyl", alone or in combination, refers to straight or branched C 1 -C 4 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.). The phenyl-lower alkyl group is e.g. benzyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-renyl-butyl and the like. may. The term alkoxy, as used in alkoxycarbonyl, means straight or branched chain alkoxy having from 1 to 4 carbon atoms. Among the alkoxycarbonyl groups, e.g. methoxycarbonyl and ethoxycarbonyl.

R ^J preferably represents a carboxyl group.

Particularly advantageous properties of the following compounds of formula I are:

9- (l-carboxy-3-phenylpropyl-amino) octahydro-6,10-dioxo-6H-pyridazo [l, 2-a] [l, 2] diazepin-l-carboxylic acid;

9- (l-ethoxycarbonyl-3-phenyl-propylamino) octahydro-6.10-dioxo-6H-pyridazo [l, 2-a] [l, 2] diazepin-l-carboxylic acid:

9- (1-Carboxy-4-phenyl-butylamino) -octahydro-6,10-dioxo-6H-pyridazo [1,2-a] [1,2-diazepine-1-carboxylic acid:

9- (1-carboxy-2-phenylethylamino) -octahydro-6,10-dioxo-6H-pyridazo [1,2-a] [1,2] diazepine-1-carboxylic acid;

9-yl-ethoxycarbonyl-3-phenyl-propylamino) -octahiaro-10-dioxo-6H-pyridazo [1,2-a] (1,2-diazepine-1-carboxylic acid,

Further preferred compounds of general formula (I) have the following properties:

9- (l-carboxy-3-phenylpropyl-amino) octahydro-6,10-dioxo-6H-pyridazo [l, 2-a] [l, 2] diazepin-l-carboxylic acid; In accordance with the invention, the compounds of formula (I) and their pharmaceutically acceptable salts may be prepared as described above: R ^1T and R ³¹ are R ² , or phenyl (lower alkoxycarboyl). , provided that ·

That at least one of R and R is lower alkoxycarbonyl: and B is ethylene or vinylene / hydrogenolylated and optionally converted to a pharmaceutically acceptable salt of the resulting VB moiety. .

According to the process of the present invention, compounds of formula (I) wherein R ²¹ and / or R ^{31 are} phenylalkoxycarbonyl are hydrogenolysed by reacting R ² and / or R ³ with arboxyl and B with ethylene (11). The hydrogenation process may be carried out in a manner known per se by hydrogenolysis to reduce the vinylene group present at B * to ethylene.

The resulting compound of formula (I) may be converted, if desired, into a salt with pharmaceutically acceptable acids or bases. For the formation of salts, inorganic acids (e.g., hydrogen halides such as hydrobromic acid or hydrochloric acid; or sulfuric acid, phosphoric acid, nitric acid, etc.) or organic acids (e.g., acetic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, etc.) may be used. As a pharmaceutically acceptable base for salt formation, e.g. alkali metal hydroxides (e.g. sodium hydroxide or potassium hydroxide), alkaline earth metal hydroxides (e.g. calcium hydroxide or magnesium hydroxide), ammonium hydroxide or organic bases (e.g. dicyclohexylcarbodiimide) are used.

The starting materials of formula (II) used in the present invention are novel compounds and may be prepared by reacting a compound of formula (III), wherein B 1 R ⁴ , R ⁵ and n are as defined above, with Hal; R ³² is carboxyl, altoxycarbonyl or phenylalkoxycarbonyl) with a compound of formula IV wherein R ¹ is as defined above and R ²² is carboxyl, alkoxycarbonyl or phenylalkoxycarbonyl; provided that at least one of R ²² and R ³² is phenylalkoxycarbonyl).

The reaction of the compounds of formula (III) and (IV) may be carried out in a manner known per se. The reaction is preferably carried out in the presence of an acid acceptor in an inert organic solvent. Suitable organic solvents are aromatic hydrocarbons (e.g. benzene, toluene, etc.), dimethylformamide, etc. It can be used. The acid scavenger is preferably an organic base and particularly preferably a tertiary organic base (e.g. triethylamine, etc.). However, an excess of the compound of formula (IV) may also serve as an acid scavenger. The reaction may be preferably elevated temperatures (eg. 60 C and ⁴ to 21,

HU 198720 Β at the boiling point of the action mixture)

The compounds of the general formula (ΠΙ) are new and these compounds are, for example, compounds of formula (.). can be prepared by cyclizing a compound of formula (V) wherein R ⁴ , R, η, B 'and Hal are as defined above; X is halogen and R ³⁰ is alkoxycarbonyl to another carboxyl group; or aralkoxycarbonyl group.

The ring closure of the compound of formula (V) may be carried out in a manner known per se. The reaction may be carried out in a suitable inert organic solvent (e.g. dimethylformamide or tetrahydrofuran), optionally in the presence of a base (e.g. triethylamine, N-ethylmorpholine, etc.) at a temperature of 0 to 80 ° C. The ring closure is preferably carried out in situ without isolation of the compound of formula (V).

In the resulting products, the alkoxycarbonyl group at R ³⁰ , i.e. the alkoxycarbonyl group at R ³² in the compound of formula (111), may be converted to the carboxyl group by treatment with an acid or base. The reaction may be carried out in a manner known per se, e.g. such that the alkyl ester is treated with an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide), preferably at a temperature between room temperature and the reflux temperature of the reaction mixture, or a tertiary butoxycarbonyl group is cleaved by treatment with anhydrous acid.

The compound of formula (HI) thus obtained, wherein R ³² is a carboxy group, may be esterified if desired. so e.g. reacting a compound of formula (111) containing a carboxyl group at R ³² with the appropriate alkanol (e.g. methanol, ethanol, etc.) in the presence of an acid (e.g. mineral acid such as hydrochloric acid, etc.) or the corresponding diazoalkane (e.g.

by treatment with thionyl chloride, phosphorus trichloride or phosphorus pentachloride, etc., to the corresponding acid chloride and reacting the product with the appropriate alkanol in a manner known per se. Reaction of the carboxylic acid of formula (III) wherein R ³² is carboxylic acid with sulfuric acid in the presence of sulfuric acid affords the corresponding compound of formula (III) wherein R ³² is tertiary butoxycarbonyl.

Transesterification of a compound of formula R ³² NELY containing alkoxycarbonyl group (III) are known per se NELY R ³² may be converted to other formula yegyüktté alkoxycarbonyl or aralkoxycarbonyl group (III).

Compounds of formula (V) wherein R ⁴ and R ^{5 are} hydrogen are e.g. may be prepared by reacting a compound of formula (VI) with a compound of formula (VII) and then removing the benzyloxycarbonyl group (B ', R ³⁰ , η, X and Hal) from the resulting compound of formula (VIII) is as defined above and Z is benzyloxycarbonyl).

The compounds of formula (VI) and (VII) are known substances or analogs with known compounds. The reaction of the compounds of formula (VI) and (VII) may be carried out in a manner known per se. so e.g. in an inert organic solvent medium (e.g., halogenated hydrocarbons, such as dichloromethane), an acid scavenger (e.g., alkali metal carbonates such as sodium carbonate; or alkali metal bicarbonates such as sodium bicarbonate, etc.). in the presence of room temperature.

From the resulting compound of formula (VIII), the benzifoxycarboml group may be cleaved in a manner known per se, e.g. hydrobromic acid in glacial acetic acid at room temperature or by catalytic hydrogenation.

R ⁴ and R ⁵ together represent an oxo group of formula V

[) First may be prepared by reacting a compound of general formula (VI) with a compound of formula (IX) (wherein n and Hal are as defined above and Bz is benzyl), from the compound of formula (X) wherein B ' , R, n, fish, Bz and Z are as defined above), the benzyl and benzyloxycarbonyl groups are removed and the resulting acid of formula XI (wherein B ', R, .n and Hal are as defined above) is to the corresponding acid halide.

Compounds of formula (IX) are known substances or are analogous to known compounds. The reaction of the compounds of the formulas VI and IX can be carried out in an analogous manner to the reaction of the compounds of the formulas VI and VII.

The benzyl and benzyloxycarbonyl groups of the compounds of formula (X) may be cleaved by methods known per se, e.g. by catalytic hydrogenation in the presence of a noble metal catalyst (e.g. palladium on carbon). The group other than the tertiary butoxycarbonyl group at R ³⁰ may be cleaved with hydrogen bromide in glacial acetic acid.

The conversion of the acid of formula XI to the corresponding acid halide of formula V can be accomplished by methods known per se, vol. a suitable halogenating agent, e.g. thionyl chloride, phosphorus pentachloride, etc.).

The compounds of formula IV used as starting materials are known or analogous to known compounds and may be prepared by similar methods.

Alternatively, compounds of formula (II) may be prepared by reacting a compound of formula (XII) (wherein B 1 R ³² R ⁴ R ³ and n are as defined above) with a compound of formula (XIII) wherein R ¹ and R ²² are as defined above). _

A (XlT) is a compound of general formula a

The reductive alkylation of HU 198720 with compounds of formula (XIII) may be carried out in a manner known per se. This may be achieved by carrying out the reaction in the presence of sodium cyanoborohydride in a suitable solvent (e.g. water or a mixture of water and an alkanol such as aqueous ethanol). The reaction is preferably carried out in a neutral medium at room temperature. Alternatively, the compound of formula (XII) is reacted with the compound of formula (XIII), whereupon the resulting Schiff base is hydrogenated in situ. During the catalytic hydrogenation, the vinylene group at the B site is reduced to the ethylene group. The catalytic hydrogenation is carried out under conventional conditions, e.g. in the presence of a noble metal catalyst (e.g. palladium / carbon) or Raney nickel in an inert organic solvent (e.g. an alkanol such as ethanol) at room temperature and from 1 to 10 atm. under pressure.

Compounds of formula (XIf) are, e.g. it can be prepared by reacting the corresponding compound of formula (III) with an alkali metal azide and reducing the resulting azide of formula (XIV) (wherein B ', R ³ , R ⁴ , R ⁵ and na are as defined above).

The reaction of the compound of formula (III) with an alkali metal azide (preferably sodium azide) can be carried out in a manner known per se. Thus, it is possible to work in the presence of an inert organic solvent (e.g. ketones, such as acetone) at elevated temperatures (e.g., the boiling point of the reaction mixture).

Compounds of formula (XIV) can be converted into compounds of formula (XII) by known reduction methods. Preferably, the azide of formula (XIV) is reacted with triphenylphosphine in a suitable inert organic solvent (e.g., dioxane) at room temperature and then subjected to acid hydrolysis (e.g., hydrochloric acid).

The compounds of formula (XII) may also be prepared by cyclizing a compound of formula (XV) (wherein B ', R, R ⁴ , R, n and X are as defined above and R ⁸ is phthaloylamino). and then removing the phthaloyl group (in which B ', R, ^{R4, R8} and n are as defined above) of the resulting (XVI) with a compound of formula: and alkoxycarbonyl at the ^N3 where R SETB desired carboxy group, of an alkoxycarbonyl group or is converted to an aralkoxycarbonyl group before or after cleavage of the phthaloyl group.

The ring closure of compounds of formula XV may be carried out by methods known per se, e.g. under the conditions specified for the cyclization of the compounds of formula (V). The cyclization of the compounds of formula (XV) is preferably carried out in situ.

The phthaloyl group may be removed from the compounds of formula XVI by methods known per se. The reaction is carried out e.g. hydrazine, preferably in an inert organic solvent (e.g., alkanol, such as ethanol) at room temperature or higher (e.g., the boiling point of the reaction mixture).

Conversion of the alkoxycarbonyl group at R ^{30 to} a carboxyl group, other alkoxycarbonyl group or an aralkoxycarbonyl group is known in the art, e.g. may be carried out as described for the preparation of starting materials of formula (III).

Compounds of formula (XV) wherein R ⁴ and R ^{5 are} hydrogen may be prepared by reacting a compound of formula (VI) with a compound of formula (XVII) (wherein R ⁸ , n and X are as defined above), followed by removal of the benzyloxycarbonyl group (B ', R, R, η, X and Z as defined above) from the resulting compound of formula XVIII.

The compounds of formula (XVII) are known substances or are analogous to known compounds. The reaction of the compounds of the formulas VI and XVII is carried out in a manner analogous to the reaction of the compounds of the formulas VI and VII.

The benzyloxycarbonyl group can be cleaved from the compounds of formula XVIII by appropriate conversion of the compounds of formula VIII, in a manner analogous to that described above.

Compounds of formula XV wherein R ⁴ and R ^{5 are taken} together to form an oxo group are e.g. may be prepared by reacting a compound of formula (VI) with a compound of general formula (XIX) (wherein R, n and Bz are as defined above), the resulting compound of formula (XX), the benzyloxycarbonyl group is removed and the resulting acid of formula XXI (wherein B ', R ⁸ , R ³⁰ and n are as defined above) is converted to the corresponding acid halide.

Compounds of formula XIX are known substances or are analogous to known compounds. The reaction of compounds of formula (VI) and (XIX) may be carried out in a manner known per se, as described previously for the reaction of compounds of formula (VI) and (VII).

The benzyl and benzyloxycarbonyl groups of the compound of formula (XX) may be cleaved as described previously for similar conversion of compounds of formula (X).

The conversion of the acid of formula (XXI) to the corresponding acid halide of formula (XV) can be carried out analogously to the conversion of the compound of formula (XI) into the corresponding acid halide.

Compounds of formula XIII are known compounds or analogs of known compounds and can be prepared in a similar manner.

Alternatively, the compounds of formula (II) may be prepared by reacting a compound of formula (XII) (wherein R ³ is alkoxycarbonyl or tem 1 -alkoxycarbonyl) with a compound of formula (XXII)

GB 198,720 Β talános alkileziink cyclooctadienone compound of formula wherein R ^l is as defined above; R ¹⁰ is alkoxycarbonyl or phenylalkoxycarbonyl and Q is a leaving atom or group).

R ^3Z appropriate alkoxycarbonyl or phenyl-containing alkoxycarbonyl group (H) reaction of compound of formula and the compound of formula (XXII), preferably in an inert organic solvent (eg. DMF, dimethyl sulfoxide, acetonitrile, etc.) About 0 At -100 ° C, in the presence of an acid scavenger (e.g., alkali metal carbonates such as sodium carbonate; tertiary organic bases such as triethylamine; or basic ion exchange resins). In the starting materials of formula (XXII), the leaving group at Q is e.g. a halogen atom (such as a bromine atom) or a sulfonate group of the formula -O-SO6Y (where Y is methyl, trifluoromethyl or p-tolyl).

Compounds of formula (XXII) are known or analogous to known compounds and can be prepared by methods known per se.

The compounds of formula (I) and their pharmaceutically acceptable salts possess valuable antihyperlensing properties. These compounds inhibit the action of the angiotensin converting enzyme (ACE), which causes the conversion of angiotensin I to angiotensin II, and can therefore be used to reduce or alleviate angiotensin-related hypertension.

The angiotensin converting enzyme inhibitory activity of the compounds of formula (I) is demonstrated by the following in vitro assay.

The assay was performed according to the method of Cushman and Cneung [Biochem. Pharmacol. 20, 1637-1648) using the modifications of Hayakari et al. (Anal. Biochem. 84, 361-369)]. in sodium potassium phosphate buffer (pH 8.3; 100 mmol) for 24 hours at 37 ° C (500 μ on volume). A control solution containing no test compound was used for control. (If an ester is used as the test compound, the ester is preferably cleaved with porcine liver esterase prior to the assay.) The reaction is terminated by the addition of 3 ml of potassium phosphate buffer, pH 8.3 '200 mM at 0' C. A solution of 2,4,6-trichloro-triazine in dioxane (3%, 1.5 mL) was then added and the mixture was stirred until the yellow chromophore was formed. Precipitate was removed from the samples by centrifugation. The yellow chromophore formed by the reaction of 2,4,6-trichloro-triazine with free hippuric acid is measured spectrophotometrically at 382 nm. The IC50 value is defined as the dose of test compound which, under the above conditions, reduces the cleavage of hippuryl nystidyl leucine angiotensin by 50%.

The results are summarized in the table below. It is used with the following test compounds:

Compound A 9? (S) - (1-Carboxy-3-phenylpropylamino) -octahydro-o, 10-dioxo-6H-pyridazo [1,2-a] [1,2] diazepine-1 (S) carboxylic acid; Isomer A,

Compound D = 9 (S) - [1 (R and S) -Carboxy-4-phenyl-butylamino-octahydro-6,10-dioxo-6H-pyridazo [1,2-a] [1,2] [diazepine -lfS) -carboxylic acid;

Compound E = 9 (S) - [1 (R and S) -carboxy-2-phenylethyl-Amino-octahydro-6.10-dioxo-6H- pyridazo * ^f - [l, 2-a] [1,2 diazepine-1 (S) -carboxylic acid.

Table I

Test compound IC ₅₀ THE 4,2xlO-'M D 1,1x10-®M E 2.6 x ^{10 8} M

The compounds of formula (I) and their pharmaceutically acceptable salts may be used in medicine in the form of compositions comprising nanomaterials and suitable pharmaceutical carriers. Suitable carriers include enteric (e.g., oral) or parenteral, organic or inorganic materials (e.g., water, gelatin, acacia, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, etc.). The pharmaceutical compositions may be solid (e.g., tablets, dragees, suppositories or capsules) or liquid (e.g., solutions, suspensions or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations (e.g., sterilization) and / or may contain adjuvants (e.g., preservatives, stabilizers, wetting or emulsifying agents, salts or buffers which may cause osmotic pressure changes). The pharmaceutical compositions may further contain pharmaceutically valuable additional substances.

The daily dosage for adults of the compounds of formula (I) and their pharmaceutically acceptable salts is generally about 1 mg / kg. 0.1 to 100 mg, preferably ca.

1-50 mg-kg body weight. The daily dose may be administered in one or more portions. However, the above dose ranges are provided for information only; the dosage used may vary depending on several factors (e.g., activity of the active ingredient, mode of administration, severity of the condition being treated, condition of the patient, etc.) and will depend on the prescribing physician's instructions.

The following examples further illustrate the process without limiting the invention to the examples.

Example 1 .......

170 mg of 9 (S) [1 (S) -benzyloxycarbonyl-Menyl-propylamino] -octahydro-6,10-dioxo-6H-pyridazo [1,2-a] [1,2] -azepine-1 (S) -carboxylic acid methyl The ester is dissolved in 5 ml of acetic acid and hydrogenated in 10% palladium-carbon at 20 DEG C. for 17 hours at atmospheric pressure, the catalyst is filtered off and the filtrate is evaporated.

The residue was taken up in ethyl acetate and hydrogen chloride in ethyl acetate was added. An excellent solid is born. 85 mg of 9 (S) -fl (S) -carboxy-3-phenylpropylamino] octanedro-6,10-aioxo-6H-pyridazo [12-a] (1,2-diazepine) as a white solid. -1 (S) -carboxylic acid methyl ester, diffuse melting point, MS: m / e 417 (M ⁺ ).

The starting material used was 9 (S) - [1 (S) -benzyloxycarbonyl-3-phenylpropylamino] octahydro-6,10-dioxo-6H-pyridazo [1,2-a] fl, 2] -diazepine. 1 (methyl carboxylic acid) is prepared as follows:

Analogous to the procedure described in paragraph B below is 5.34 g of 2-oxo-4-phenylbutanoic acid and 2.97 g of 9 (S) -aminooctahydro-6,10-dioxo-6H-pyridazoyl, 2-a]. 1.7 g of 9 (S) - [1 (R) -carboxy-3-phenylpropylaminoloctahydro-o, 10] diazepine-1 (S) -carboxylic acid tertiary ester). -dioxo-6H-pyridazo [1,2-a] [1,2] cfiazepine-1 (S) -carboxylic acid (tert-butyl ester) and 1.75 g of 9 (S) - [1 (S) -carboxy-3-phenyl-pronylamino-β-octahydro-6,10-dioxo-6H-pyridazof1,2-a] [1,2] -diazepine-1 (S) -carboxylic acid (tert-butyl ester) -t we produce. The two diastereomers are isolated after chromatography on silica gel.

500 mg of 9 (S) - [1 (S) -carboxy-3; phenyl-prone (-amino] -octanidro-6,10-aioxo-6H-pyridazo [1,2-a] [1,2] diazepine-1 The (S) -carboxylic acid (tert-butyl ester) was dissolved in diethyl ether and treated with a solution of phenyl diazomethane in diethyl ether at 20 DEG C. The solution was washed with aqueous sodium bicarbonate solution and dried. The residue was chromatographed on silica gel eluting with 1: 1 ethyl acetate / n-hexane to give 9 (S) -1 L (S) -benzyloxycarbonyl-3-phenyl-propylamino] as a gum (430 mg). -octahydro-6,10-dioxo-6H-pyridazo [1,2-a] [1,2] diazepine-1 (S) -carboxylic acid (tert-butyl ester) is obtained.

410 mg of 9 (S) - [1 (S) -benzyloxycarbonyl-3-phenylpropylamino] -octahydro-6,10-dioxo-6H-pyridazor, 2-a] [1,2] diazepine-1 (S) ) -carboxylic acid (tert-butyl ester) and 3 ml of trifluoroacetic acid were allowed to stand at 20 ° C for 1.5 hours and then evaporated. The foamy residue was taken up in ethyl acetate and a solution of hydrogen chloride in ethyl acetate was added. The precipitated solid was filtered. White solid, m.p. 198-202 ° C

In its slag 330 mg of 9 (S) - [1- (S) -benzyloxycarbonyl-3-phenyl-propylaminol-octanidro-6,10-dioxo-6H-pyrazo [1.2-a] (l, z) diazepine-1 (S) Carboxylic acid hydrochloride is obtained.

260 mg of 9 (S) - [1 (S) -benzoyloxycarbonyl-3-phenylpropyl] -amino] octahydro-6,10-dioxo-6H-piddazole [1,2-a] [1,2] dlazepine 1 (S) -Carboxylic acid was dissolved in diethyl ether and treated with a solution of dichazomethane in diethyl ether at 20 ° C. After 10 minutes, the solution was washed with aqueous sodium bicarbonate solution, dried and evaporated. The gum was chromatographed on silica gel eluting with ethyl acetate-hexane (1: 1). 180 mg of 9 (S - [1 (S) -benzyloxycarbonyl-3-phenyl-propylamino] -octahydro-6,10-dioxo-6H-pyrrolazo [1,2-a] [1,2] diazepline as a colorless gum -1 (S) -carboxylic acid methyl ester is obtained.

B) 2.0 g of 9 (S) -amino-octahydro-6,10-dioxo-6H-pyridazo [1,2-a] [1,2-diazepine-1 (S) -carboxylic acid (tert-butyl ester) and 4 2 g of 2-oxo-4-phenylbutanoic acid ethyl ester are dissolved in a mixture of 50 ml of ethanol and 5 ml of acetic acid, 4 g of powdered molecular sieve are added in the presence of 10% palladium on carbon at 4 atm. The reaction mixture was filtered, the filtrate was evaporated and the residue was chromatographed on silica gel eluting with ethyl acetate / n-hexane 950 mg of 9 (S) -fl (R) -ethoxycarbonyl-3-phenylpropylaminol. octahydro-6,10-dioxo-6H-pyridazofl, 2-a] 1,2,2-diazepine-1 (S) -carboxylic acid (tertiary Dutyl ester) and 870 mg of 9 (S) · - [l ( S) -ethoxycarbonyl-3-phenyl-propylamino-octanidro-6,10-dioxo-6H-pyridazole 1,2-a] [1,21-diazepine-1 (S) -carboxylic acid (tert-butyl ester). we get

Example 2

1.35 g of 9 (S) -J (S) -ethoxycarbonyl-3-phenylpropylamino] -octahydro-10-oxo-6H-pyridazo] 1,2-a] [1,2] diazepin-lYS) The 6-carboxylic acid ester was dissolved in ethanol (200 ml) and hydrogenated at atmospheric pressure in the presence of 50 mg of 10% palladium on carbon until hydrogen uptake ceased. The catalyst was removed by filtration and the filtrate was evaporated. In the form of a colorless oil, 1.02 g of 9 (S) -N (S) -ethoxycarbonyl-3-phenylpropylamino-octahydro-10-oxo-1H-pyridazol-1,2-a [1,2] diazepine-1 (S) were obtained. ) -carboxylic acids are obtained. The resulting oil was dissolved in ethyl acetate (10 mL) and hydrogen chloride (2.5 N in ethyl acetate, 2 mL) was added. 100 ml of diethyl ether are then added and the mixture is stirred for one hour. The precipitated solid was filtered. In the form of a hygroscopic solid, 0.72 g (60% of J 9 (S) -J (S) -ethoxycarbonyl-3-phenylpropylamino-octahydro-10-oxo-6H-pyridazoyl, 2-a) [ , 2ldiazeoin-1 (S) -carboxylic acid hydroclonde is obtained.

The starting material used was 9 (S) -yl (S) -ethoxycarbonyl-3-phenopropylamino] -octahydro-10-oxo-6H-pyridazo [1,2-a] 11,2] diazepine-1 (S). ) -carboxylic acid benzyl ester may be prepared as follows:

A) To a solution of 2 g of α- (S) - (3-bromopropyl) -1,3-dioxo-2-isoindoline acetic acid in 15 ml of anhydrous diethyl ether is added 1.34 g of phosphorus pentachloride, followed by stirring. the reaction mixture was stirred at room temperature for 1.5 hours. The solvent was removed and the residue was re-evaporated twice with toluene and dissolved in 25 ml of dichloromethane. While stirring, a solution of 1.64 g of 1-benzyloxycarbonylhexahydro-3-pyridazine-carboxylic acid (tert-butyl ester) in 10 ml of dichloromethane was added, followed by 25 ml of a saturated aqueous sodium bicarbonate solution. After stirring at room temperature for 3 hours, the layers were separated. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel eluting with 4: 1 aryl toluene / ethyl acetate. 2.4 g as an oil

HU 198720 Β (75%) 2- (5-bromo-2-phthalimido-valenyl) -1,3-pyridazine-dicarboxylic acid (1-benzyl-3-tert-butyl ester) is obtained (2 diastereomers).

B) 2.37 g of 2- (5-bromo-2-phthalimido-valeryl) -1,3-pyridazine-dicarboxylic acid (1-benzyl-3-tert-butyl ester) (2 diastereomers) are dissolved in 25 ml of ethanol. and hydrogenating the solution in the presence of 50 mg of 10% palladium on carbon at atmospheric pressure until hydrogen uptake stops. The catalyst was removed by filtration and the filtrate was evaporated. There was obtained 1.79 g (96%) of 2- (5-bromo-2-phthalimido valeryl) -3-pyridazine-carboxylic acid tert-butyl ester (2 diastereomers) as an oil.

C) 15 g of 2- (5-bromo-2-phthalimido valeryl) -3-pyridazine carboxylic acid (tert-butyl ester) (2 diastereomers) are dissolved in 200 ml of anhydrous dimethylformamide and the solution is stirred at 80 ° C. Stir for 60 hours. The solvent was removed and the residue was partitioned between water and dichloromethane. The organic solution was dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel eluting with 4: 1 toluene-acetic acid to give 3.6 g (33%) of octahydro as white crystals (ethyl acetate: n-hexane), m.p. -10-oxo-9 (S) -Phthalimido-6H-pyridazole-1,2-a] (1,2) = diazepine-1 (S) -carboxylic acid and white, m.p. 241-244 ° C (ethyl acetate and of n-hexane) as octahydro-10-oxo-9 (S) -phthalimido-6H-pyridazo [1,2-a] [1,2] dlazepine-1 (R) as crystals. 3.57 g of octahydro-10-oxo-9 (S1-phthalimido-6H-pyridazo] 1,2-al [1,2] diazepine-1 (S) -carboxylic acid are obtained in 25 ml of 0.4 A solution of 0.5 g of hydrazine hydrate in 25 ml of ethanol was added and the reaction mixture was stirred at room temperature for 4 hours and then concentrated to 80 ml of 2N acetic acid and stirred at room temperature for 3 hours. stir, Mayan filtrate, The filtrate is evaporated The column was applied to a column containing 40 g of Duolite C224 ion exchange resin (H ⁺ form), eluted with 2% pyridine in water, and the eluate was evaporated. 1.7 g (75%) of 9- (S-amino-octahydro-10-oxo-6H-pyridazo [1,2-a, 2] diazepine-1 (S) -carboxylic acid) are obtained as a white solid. crystallization from acetonitrile, m.p. 247-249 ° C: (α) ²⁰ D = -121.9 ° (c = O, 675, water).

E) To a solution of 1.6 g of 9 (S) -amino-octahydro-10-oxo-6H-pyridazo (1,2-aH1,2J) diazepine-1 (S) -carboxylic acid in 5 ml of methanol was added a solution of phenyl diazomethane in diethyl ether. The reaction mixture is added and the reaction mixture is stirred until starting material is removed, the solvents are removed and the residue is partitioned between dichloromethane and 2N hydrochloric acid, the aqueous solution is made alkaline with potassium carbonate solution and the organic solution is extracted with sodium hydroxide. washed with brine, dried over magnesium sulfate and evaporated to give crude 9 (S) -amino-octahydro-10-oxo-6H-pyridazo [1,2-a] [1,2] as an oil. Diazepine-1 (S) -carboxylic acid benzyl ester was obtained and the product was used without further purification.

²⁷ λ ^1.27 7 9 (S) -amino-octahydro-10-oxo-6H-pindazo] 1,2-a] [1,2] diazepine-1 (S) -carboxylic acid 5-benzyl ester, 36g 2 ( A mixture of R) -trifluoromethanesulfonylpxy-4-phenylbutyric acid ethyl ester, 0.4a -triethylamine and 10 ml acetonitrile was stirred at room temperature for 16 hours. The solvent was removed and the residue was partitioned between water and ethyl acetate. The organic solution was dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate / n-hexane (1: 1). In the form of a colorless oil

1.55 g of 9S) - [1 (S) -ethoxycarbonyl-3-phenylpropylamino] -octahydro-10-oxo-6H-pyridazo [1,2-a] -] 1,2] diazepine-1 The (S) -carboxylic acid benzyl ester is obtained.

20 25 Example 3 The pharmaceutical formulations according to the known methods of preparation of the tablets have the following composition: we: component . --- 4 Quantity, mg / tablet An active ingredient of the formula (I) 10.0 Lactose 125.0 corn starch 75.0 30 talc 4.0 Magnesium stearate 1.0 Total weight: 213.0 mg

Example 4

Capsules of the following pharmaceutical formulations are known:

Component Amount, mg / capsule 25.0 of active ingredient

Lactose 150.0

Maize starch 20.0

Talkum___5 * Q—

Total weight: 200.0 mg

Claims (6)

PATENT CLAIMS .50 A process for the preparation of a compound of formula (I) B is ethylene (I-CH ₂ -CH ₂ -); R ¹ is phenyl (lower alkyl) V -group: R ² and R ³ are carboxyl or lower alkoxycarbonyl; R ⁴ and R ⁵ is hydrogen, separately or together form an oxo group and n is 2; with the proviso that at least one of R ² and R ³ represents a carboxyl group) and pharmaceutically acceptable salts thereof, wherein a compound of formula II (wherein R ¹ , R ⁴ , R ⁵ and n are R ²¹ and R ³¹ are κ, 11-71 GB 198,720 Β lice R ^J is of the same or phenyl- (lower alknxikarbpnil) alkyl, with the proviso that 'at least one phenyl (lower alkonkarbonil) is the alkylation of: and B' R ^2r and R ³ is ethylene, or vinylene group), and optionally converting the resulting compound of formula I into a pharmaceutically acceptable salt. 2. A process according to claim 1 for the preparation of compounds of formula (I) wherein R ³ is a carboxyl group, using the appropriate starting materials. The process according to claim 1, which is 9- (1-carboxy-3-phenylpropylamino) -octahydro-6,10-dioxo-6H-pyridazo [1,2-a] [1,2] diazepine-1-carboxylic acid. characterized in that the appropriate starting materials are used. 4. A process according to claim 1 for the preparation of 9- (1-ethoxycarbonyl-3-phenylpropylamino) -Ptahydro-10-oxo-6H-pyridazo [1,2-a] yl, 21-diazepine-1-carboxylic acid and its hydrochloride, to use the appropriate starting materials. 5. Process for the preparation of compounds of formula (I) having the (S) -configuration on all carbon atoms according to any one of claims 1 to 3, characterized in that the appropriate starting materials are used. 6. A process for the preparation of a pharmaceutical composition, in particular an antihypertensive agent, comprising the process of claim 1. or a pharmaceutically acceptable salt thereof as an active ingredient in an inhaled, non-toxic, solid or liquid pharmaceutical form; a compound of formula (I) wherein R ¹ R ² , R ³ , R *, R * ₍ and n are as defined in claim 1); carriers, and, if desired, one or more other pharmaceutically acceptable compounds which are not synergistic with the compounds of formula (ij) and are formulated in a pharmaceutically acceptable form.