HU194278B - Process for production of medical compounds containing as active substance bicyclic dipeptides and of the active substance - Google Patents

Abstract

The invention relates to cis, exo- and trans-compounds of the formula I <IMAGE> in which n denotes 0, 1 or 2, R1 denotes hydrogen, alkyl which can optionally be substituted by amino, acylamino or benzoylamino, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl or partially hydrogenated aryl, which in each case can be substituted by alkyl, alkoxy or halogen, arylalkyl which can be substituted in the aryl radical as defined above, a mono- or bicyclic S- or O- and/or N-heterocycle radical or a side chain of a naturally occurring amino acid, R2 denotes hydrogen, alkyl, alkenyl or arylalkyl, Y denotes hydrogen or hydroxyl, Z denotes hydrogen or Y and Z together denote oxygen and X denotes alkyl, alkenyl, cycloalkyl, aryl which can be mono-, di- or trisubstituted by alkyl, alkoxy, hydroxyl, halogen, nitro, amino, alkylamino, dialkylamino or methylenedioxy, or indol-3-yl, and their physiologically acceptable salts, a process for their preparation, compositions containing them and their use, and also novel bicyclic amino acids as intermediates and a process for their preparation.

Description

The present invention relates to pharmaceutical compositions containing novel bicyclic dipeptides of the formula I and their physiologically acceptable acid addition salts.

In the formula (I), the carbon atoms in the 3a and (6 + n) positions may be in either cis or trans configuration; in the cis configuration, the carboxyl group at position 2 is exo with respect to the bicyclic ring.

In the formula n is 0, 1 or 2,

Rj is methyl, para-benzyl substituted with C 1-2 alkoxy,

R ₃ is hydrogen, C 1-6 alkyl,

Y is hydrogen or hydroxy,

Z is hydrogen or

Y and Z together represent an oxygen atom,

X is phenyl, the asterisk represents an asymmetric carbon atom; the carbon atom to which R 1 is attached is S, to which CO ₂ R _{2 is} attached in the S configuration.

Physiologically acceptable inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, maleic acid, fumaric acid are used to form the physiologically acceptable acid addition salts of the compounds of formula (I).

For the trans configuration of the 3a and 6 (n) hydrogen atoms on the carbon atoms, two configurations can be calculated on the double ring, such as the 2β, 3aoc (6 + n) a / 3 configurations, the compound of formula Ib /, and a 2/3, 3aft (6 + n) aconfirugation (compound of formula Ic); in the case of hydrogen atoms in the cis configuration, the carboxy group is in the exo position (β position).

The exo position (position β) of the carboxy group at the 2-position carbon atom can be defined so that the carboxy group is oriented toward the corresponding hydrogen atom, i.e., towards the concave side of the double ring. This configuration can be represented by the formula (Ia). (The positions a and β are defined by Fieser / see Fieser and Fieser; Steroids, 2, (1962)).

The compounds of formula (I) contain asymmetric carbon atoms in the 2, 3a, (6 + n) position, and the carbon atoms in the side chain marked with an asterisk are also asymmetric. The present invention relates to compounds of the R and S configurations. The compounds of formula I may exist as optical isomers such as diastereomers, racemates or mixtures thereof. Particularly preferred are compounds of formula I wherein the carbon at position 2 and the asterisked carbon atoms in the side chain are of the S configuration;

Particular preference is given to compounds of formula I wherein R 1 is metM or benzyl,

R _a is hydrogen, C 1-4 alkyl,

X is phenyl.

Especially preferred are those compounds of formula (I), wherein R is methyl, X is phenyl, and wherein R ₂ is hydrogen or methyl.

Among the compounds of formula I, the following are preferred:

N- (1S-Carbethoxy-3-phenylpropyl) -S-alanQ-2S, 3aR, 6aRoctahydrocyclopenta (b) pyrid-2-carboxylic acid, N- (1S-carboxy-3-phenylpropyl) -S-alanyl- 2S, 3aR, 7aR-octahydro-indole-2-carboxylic acid,

N- (1S-carboxy-3-phenylpropyl) -S-alanyl-2S, 3aR, 6aR-octahydrocyclopenta (b) pyrid-2-carboxylic acid, N-O-S-carboxy-3-phenylpropyl) -S- alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid and N-OS-carboxy-e-phenylpropyl) -S-alanyl-2S, 3aS, 7aR-octahydroindole-2-carboxylic acid is particularly preferred.

N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl-2S, 3aR, 7aR-octahydroindole-2-carboxylic acid,

N (1S-Carbetoxy-3-phenylpropyl) -S-alanyl -2S, 3aR, 7aSoctahydroindole-2-carboxylic acid and N (1S-carbethoxy-3-phenylpropyl) -S-alanyl-2S, 3aS, 7aRoctahydroin l-2-carboxylic acid.

Compounds of formula (I) and salts thereof are prepared by reacting a compound of formula (Π): wherein R 1, R ₂ , X and Y and 2 are as defined above.

- a compound of general formula (III) - in which the hydrogen atoms on the carbon atoms 3 and 6 + n are in cis or trans configuration with each other, in which case the -COOW group is exo to the bicyclic ring in the cis configuration and r is 0, 1 or 2,

W is hydrogenolytically or acidically cleavable group, preferably benzyl or tert-butyl group, by reaction of the peptide with amide formation known in the chemical art, followed by catalytic hydrogenation or acid treatment of the resulting W group and optionally cleavage of the resulting compound. by treatment with an acid or a base, the R ₂ group is cleaved and, if desired, the resulting compound is converted to a salt.

Compounds of formula (I) wherein Y and Z together represent an oxygen atom may also be prepared by reacting a compound of formula (IV) - wherein the hydrogen atoms attached to the 3a and (6 + n) carbon atoms are either cis or trans wherein, in the configuration, the -COOW group is exo with respect to the bicyclic ring and wherein n and Rj are as defined in formula (I) and W is as defined in formula (III) - in one of formula (V) with a compound of formula wherein R ₂ and X are as defined for formula (I) in a known manner, by the reaction of Michael + Organic / Organic, 6th Edition, 492 (1967), followed by reaction of the W and R _{2 is} cleaved as described above, or a compound of formula IV can be cleaved by a chemical of formula VI yülettel - wherein R ₂ is as defined in formula (I) - or (VII) a compound of the formula: - wherein X is as described in Formula (I) - known as a Mannich reaction / Bull. Soc. Chim. Francé, 625 (1973), and the resulting compound is then cleaved with the W group and optionally the R ₂ group as described above.

Compounds of formula (I) wherein Y and Z are hydrogen may also be prepared by reacting a compound of formula (IV)

194.278, J. Amer. Chem. Soc., 93, 2897 (197Γ)], in a known manner, reacting a compound of formula (VIII) wherein R ₂ and X are as defined in formula (I), and reducing the resulting Schiff base; followed by catalytic reduction of the group W and optionally the group R ₂ as described above or the compound of formula (I), wherein Y and X together represent an oxygen atom, as above, are catalytically reduced with hydrogen. The reduction of Schiff bases can be effected catalytically, electrolytically, or with the aid of a reducing agent such as sodium borohydride or sodium cyanoborohydride.

Compounds of formula (I) wherein Y is hydroxy and Z is hydrogen may also be prepared by reducing a compound of formula (I) wherein Y and Z are each substituted with oxygen. The reduction may be carried out using hydrogen _; in the presence of a catalyst, or other reducing agents such as sodium borohydride.

Starting materials are compounds of formula (ΠΓ) wherein n is an integer from 0 to 10,

W 'is hydrogen, C1-18 alkyl, or C7-10 aralkyl group, and R _3, R ₄ and / or R _s is hydrogen, or _R3 and R4 or R4 and _R5 together represent a bond.

Preferably, compounds of formula (ΠΓ) are prepared wherein the carbon atoms of the 2, 3a and (6 + n) positions have the same configuration as the compounds of formula (III), n being 0, 1 or 2, W 'is as defined for formula (IH), W is the same or hydrogen. These compounds can be used as starting materials for the preparation of compounds of formula I and can be prepared as follows.

The starting materials of formula (III) are prepared from a compound of formula (IX); wherein the hydrogen atoms on the carbon atoms 3a and (6 + n) may be in cis or trans configuration with respect to each other; n is 0, 1 or 2.

Compounds of formula IX wherein n = 0 Booth et al., J. Chem. Soc., 1050 (1959), the compounds of n 1, King et al., J. Chem. Soc., 250, 253 (1953)], and n = 2 Ayerst et al. Chem. Soc .: 3445 1960).

The compounds of formula (IX) are acylated in a known manner; an aliphatic or aromatic acyl group, preferably an acetyl or benzoyl group, attached to the anitrogen atom; converting the resulting compounds acylated on the nitrogen atom into an aliphatic alcohol, preferably in a C 1 -C 4 alkanol, preferably in methanol, in the presence of a conductive salt, preferably at a temperature of 0 to 40 ° C. in the resulting compound of formula X, n is 0, 1 or 2; R _{3 is C} 1 -C 4 alkyl / Liebigs Ann. Chem., 1719, (1978).

The compounds of formula (X) thus obtained with trimethylsilyl cyanide (Tetrahedron Letters (1981)) in a proton-free organic solvent such as a hydrocarbon or halogenated hydrocarbon, ether or tetrahydrofuran are preferably -60 and 20 ° C, preferably -40 and 0 ° C. At a temperature in the range of C, a Lewis acid such as zinc chloride, SnCl ₂ , SnCl ₄ , TiCl ₄ , BF ₃ ether, preferably in the presence of BF ₃ , is reacted to give compounds of formula XI, wherein 3a and ( 6m) the hydrogen atoms on the carbon at the position may be cis or trans configuration relative to one another; in the case where the substituents are in the cis configuration, the CN group is in an exo position with respect to the double ring, and n is as defined above, and the resulting compounds are purified by recrystallization and column chromatography and separated from the by-products. The resulting purified compounds are treated with an acid or a base to give a compound of formula (III) wherein W 'is hydrogen, which may be optionally esterified. Acidic hydrolysis of the nitrile group is conveniently carried out using hydrochloric acid or hydrobromic acid, and the esterification is carried out in a manner known per se, according to the procedures for amino acids.

Compounds of formula (IH ') may also be prepared by reacting a compound of formula (XIII), wherein the hydrogen atoms at the 3-position and the 6m-position carbon atoms are in the cis or trans configuration, with the same value as given above. in a known manner / Helv. Chim. Acta: 46, 1190 (1963) / Beckmann rearrangement to give compound (XHI) wherein n is as defined above. The resulting compounds are then converted to compounds of formula (XIV) wherein n is as defined above, Hal is halogen, preferably chlorine or bromine. As the halogenating agent, an inorganic halide such as PCL ₅ , SO ₂ Cl, POCl ₃ , SOCl ₂ , PBr ₃ or halogens such as bromine may be used.

It is preferred to use PCl ₅ or POCl ₃ in combination with SO ₂ Cl ₂ . The intermediate is first formed into an imide halide which is treated with one of the aforementioned halogenating agents and subsequently hydrolyzed under basic conditions (preferably aqueous alkali carbonate) to give a compound of formula XIV.

The compounds of formula (XIV) are then converted to a compound of formula (XV) in a polar protonic solvent such as an alcohol, preferably ethanol or a carboxylic acid such as acetic acid, after the addition of an acid acceptor (such as sodium acetate or triethylamine). n and Hal are as defined above. Catalysts include Raney-nickel or activated carbon containing palladium or platinum.

Compounds of formula (XV) may also be prepared directly by halogenation of compounds of formula (ΧΠΙ) using a small amount of the aforementioned halogenating agent.

Compounds of formula (XV) can be converted into compounds of formula (ΙΠ ') wherein W' is hydrogen in the presence of a base by the known Favorskii reaction, and the resulting compounds may optionally be case-centered. The aforementioned Favorskii reaction is conveniently carried out in an alcoholic solvent such as methanol, ethanol or tert-butanol or water or a mixture thereof at 20-140 ° C, preferably 60-100 ° C.

194,278 performed. Suitable bases are preferably an alkali or lower alkali hydroxide, such as sodium, potassium or barium hydroxide, or an alkali alcoholate such as sodium methylate or potassium tert-butanolate.

Compounds of formula (ΠΓ) wherein the hydrogen atoms at the 3a and (6 + n) carbon atoms are in the cis configuration may also be derived from compounds of general formula (XVI) wherein n is 0, 1 or 2, / J. Org. Chem., 29, 2780 (1964). The starting materials are reduced to the compound of formula XIII in the presence of platinum oxide / acetic acid and the resulting compound is further reacted as described above. Compounds of formula XVI are known / J. Org. Chem., 29, 2780 (1964).

Compounds of formula (ΗΓ), wherein the hydrogen atoms in the 3a and (6 * n) carbon atoms are in the trans configuration, can also be prepared from compounds of formula (XVI) if these compounds are + Bull. Soc. Chim. Belg. 85 11 (1976)) in the presence of sodium formic acid and formic acid to form a compound of formula XIII, and the resulting compounds are further reacted as described above.

The (III ') 2-azabicycloalkane-3-carboxylic acid derivatives wherein n is 0 to 10 and W' is hydrogen, and the alkyl or aralkyl esters of these compounds are prepared by either An enamine derivative of Formula XVII wherein n is as defined above and Xj is a C2-C10 dialkylamino group or a group of Formula XVHa wherein m and o are 1.2 or 3, (m + o)> 3 further A is CH _? , NH group, oxygen or sulfur atom (Organikunr, 6th edition, 370, (1967)), with an N-acylated β-haloaminopropionic acid ester of formula (XVIII) + the free amino compounds in place. Chim. Acta 40, 1541 (1957), wherein X ₂ is halogen, preferably chlorine or bromine, Y 1 is C 1 -C 5 alkanoyl, C 7 -C 9 aroyl or any other acidic preparation customary in peptide sulfur. a cleavable protecting group and R 4 'represents C 1-5 alkyl or C 7-9 aralkyl, or a compound of formula XVII above with an acrylic ester of formula XIX (Chem. Beer 91 2427 (1958)). wherein Y ¹ and R ₄ 'are as defined above, to give a compound of formula XX, wherein R 4' and Y are as defined above, and then treating the resulting compounds with strong acids to afford the acylamide and These compounds may also exist in the tautomeric form (XXlb) wherein n is as defined above. The resulting compounds of formulas XXIa and XXlb, optionally converted to C 1 -C 18 or C 7 -C 10 aralkyl esters by catalytic hydration, are either transition metal catalysts or boramine complexes or complexes. using borohydrides, they can be converted to the compound of formula (III ') wherein n is as defined above, W' is hydrogen, (C 1 -C 18) alkyl or (C 7 -C 10) aralkyl. Optionally, the ester group of the resulting compound is saponified to give compounds of formula (1ΙΓ) wherein W 'is hydrogen, wherein n is saponified, or compounds containing W1 (C1-C18) alkyl or (C7-C10) aralkyl are saponified. .

Soc., 81, 2596 (1956) describes the reaction of 3-bromopropylamine with the cyclohexanone enamine. It is also known that alkylation requires the presence of a free NH ₂ group. Surprisingly, it has been found that halo-propionic acid derivatives of acylated amino groups, such as the aforementioned compounds of formula (XVIII), are capable of alkylating enamine compounds. The amines of cyclohexanone and cycloheptanone are conveniently used for this step. Examples of the ami101 component include diethylamine, pyrrolidine, piperidine or morpholine. In addition, other secondary deamines may be contemplated, preferably pyrrolidinocycloalkylenes.

Cleavable protecting groups include, but are not limited to, formyl, acetyl, propionyl or benzoyl, and tert-butyloxycarbonyl, which may also be cleaved under acidic conditions. These groups are used as the Y ¹ substituent of the chloro-caminocarboxylic acid esters of the formula (XVHI). Suitably, C 1-3 alkyl or benzyl esters are contemplated.

The acrylic acid derivatives of formula (XIX) may also be used as starting materials. These compounds are prepared by treating the haloaminopropionic acid derivatives or analogous o-tosylserine derivatives with a base. Preferably, a terrier organic base such as triethylamine is used for this operation.

It is preferable to add a small amount of a polymerization inhibitor such as hydroquinone dissolved in an organic solvent to the reaction. The acrylic acid derivatives of formula (XIX) may also be used instead of the halo-propionic acid derivatives under the same reaction conditions.

Suitable solvents for the synthesis of enamine compounds include solvents which are not alkylated, such as dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, or toluene. Dimethylformamide is particularly preferred.

Excessive use of the enamine derivatives of formula (XVII) is desirable to avoid contamination of the N-acrylacrylic ester in the final product.

Hydrolysis of the N-acyl groups generally involves the use of strong aqueous inorganic acids such as sulfuric acid or preferably hydrochloric acid. At the same time, the ester groups are ruptured. When the N-tert-butyloxycarbonyl derivatives of formula XVIII are used in dioxane hydrochloric acid medium or anhydrous trifluoroacetic acid medium, the ester groups of the dehydrocarboxylic acid esters of formula XXIa or XXlb can be protected from cleavage. These compounds may be hydrated or treated with borohydride in the presence of boramine amine complexes to form the azabicyclo carboxylic acid esters of formula (III).

Compounds of formula (XXIa) or (XXlb) wherein n is as defined above can be catalytically converted to the compound of formula (III) in the presence of transition metal catalysts. In this formula, n is 0 or an integer from 1 to 10, and W 'is hydrogen. The product obtained is largely of the formula (IIFa)

Contains 194,278 cis isomers, where n is as defined above.

When used as the metal catalyst for hydrogenation using platinum or Raney nickel, 70-90% endocis and 10-30% trans azabiacloalkane-2-carboxylic acid are obtained. However, other noble metal or nickel catalysts may also be used. The ratio of isomers formed by catalytic hydrogenation depends on the reaction conditions and the catalyst used. In addition to Rh / Al ₂ O ₃ , Pt / C can be used for the reduction, but in this case the proportion of trans isomers increases. The reduction time can be reduced by increasing the hydrogen pressure. However, it is advisable to keep the reduction temperature low. Suitable solvents for the catalytic hydrogenation are ethanol, methanol, ethyl ester, dioxane, acetic acid or a mixture of these solvents.

Compounds of formula (IIP) wherein n is 0 or an integer from 1 to 10, and W 'is hydrogen and wherein the gold of the trans isomers of formula (IH'b) is greater than 50% - wherein n is The above compounds of formula (XXIa) or (XXIb) may be prepared by reduction of the value of n above. The reduction of these compounds using boramine amine complexes or complex borohydrides is carried out in lower alcohols.

It is particularly advantageous to use sodium borohydride as a reducing agent in an alcohol such as methanol, ethanol or isopropanol, and especially glacial acetic acid solution of the amine boron complexes is particularly preferred.

The isolation of pure endocis and trans compounds of formula (IIIa) and (1H'b) is carried out by chromatography or crystallization.

Particularly advantageous in the preparation of pure endo cis compounds of formula (IIIa) is the fractional crystallization of a mixture of diastereoisomers formed by catalytic hydrogenation.

The pure trans (III'b) compounds are conveniently isolated by fractional crystallization from the diastereomeric mixture resulting from the reduction with the amine-boron complex.

Compounds of formula (IH'a) or (IH'b), or mixtures thereof, are known in the art / such as Houben-Weyl VIII. (1952) / C 1 -C 18 alkyl or C 7 -C 10 aralkyl ester.

Compounds of formula II used in the preparation of compounds of formula I wherein Y and Z are hydrogen, R 1 = methyl, R ₂ = methyl or ethyl, X is phenyl. (European Patent No. 37,231) The compounds of formula (Π) may be prepared by a variety of methods. In one embodiment, they are derived from a ketone of formula (VII), known in the art, using a Mannich reactor, a compound of formula (VI), and a compound of formula (XXII) wherein R 1 and W are as defined above ( XXIII) wherein R 1, R ₂ , X and W are as defined above, with the proviso that when W is a hydrogenation group, preferably a benzyl group, then it must be different from R ₂ . In the case where the W group is cleaved by hydrogenation, for example, with palladium, compounds of formula II wherein Y and Z are hydrogen are obtained. When the W group is cleaved with an acid such as trifluoroacetic acid or hydrochloric acid in an inert organic solvent such as dioxane, the compounds of formula II wherein Y and Z together are an oxygen atom are obtained.

Compounds of formula (ΧΧΙΠ) may also be prepared by subjecting a compound of formula (V) to a compound of formula (XXII) in a known manner by Michael addition. This process is particularly useful for the preparation of compounds of formula XXIII wherein R 1 is methyl, R ₂ is ethyl and X is aryl.

The compounds of formula (ΧΧΠΙ) are formed as a mixture of diastereoisomers. Preferred diastereomers of formula (ΧΧΙΠ) are those wherein the asterisked carbon atoms have the S configuration. These compounds can be isolated by recrystallization or chromatography (e.g., silica gel). In the next step, the configuration of the asymmetric carbon atoms is no longer changed during the cleavage of the W group.

Compounds of formula (IV) used as starting materials for the preparation of compounds of formula (I) are prepared starting from compounds of formula (III). These compounds are prepared from 2-aminocarboxylic acids of formula (XXIV) containing a nitrogen protecting group. In the formula V is a protecting group, R 1 is as defined above. The reaction is carried out in a manner known per se, the protecting group V being cleaved after completion of the reaction, the protecting group being benzyloxycarbonyl or tert-butoxycarbonyl.

The reaction of a compound of formula (II) with a compound of formula (III) yields a compound of formula (I). This reaction is carried out according to known condensation reactions in peptide chemistry, using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole as condensing agents. Palladium is preferably used as the catalyst for the hydrogenolytic cleavage of the W group, and trifluoroacetic acid or hydrochloric acid may be used as the acid for the acid cleavage of the W group.

In the process for the preparation of the compounds of formula (III '), (IV) and (I), the configuration of the intermediates with respect to the carbon atoms in position 3a and (6 + n) remains unchanged. In the case where the configuration of the hydrogen atoms on the 3a and (6 + n) positions on the carbon atoms is trans, the compounds are obtained in part as a pure diastereomer and in part as a mixture of diastereomers. The diastereomers show 2/3, 3aa, (6 + n) a / 3 and 2/3, 3 a / 3, (6 + n) aoconfirugation. These isomers may be separated by recrystallization or chromatography. In the preparation of compounds of formula (ΙΙΓ), (IV) or (I), the starting materials are those in which the hydrogen atoms on the carbon atoms of 3a and (6 + n) are in a cis configuration, almost exclusively exo ( iii) β) isomers are obtained. The resulting material can be recrystallized or chromatographically liberated from small amounts of other isomers,

The compounds of formula (ΙΙΓ) obtained by the above processes are available as racemic mixtures and can be used as such for further reaction steps. However, it is also possible for the resulting raemate to be optically active by salt formation in a known manner

194,278 by separation with optical bases or acids, into optical antipodes, pure enantiomers.

When the compounds of formula (I) are obtained as racemates, they can be resolved into enantiomers by conventional means, for example by salt formation, optical active bases or acids.

The compounds of formula (I) form an inner salt. These amphoteric compounds may form salts with acids or bases. The salts may be prepared by the addition of an equivalent amount of acid or base in a known manner.

The compounds of the formula I and their salts have an intense antihypertensive effect. Compositions containing these compounds can be used for the treatment of hypertensive conditions of various origins, and the compositions of the invention may contain, in addition to the compounds of formula I, other antihypertensive, vasodilating or diuretic agents. These compounds are described in Erhardt-Ruschig, Arzneimittel, 2nd edition, Weinheim (1972). The compositions of the invention may be administered intravenously subcutaneously or orally.

For oral administration, the dose is in the range of 1-100 mg, preferably 1-40 mg, depending on the average adult patient. In severe cases, the dose may be increased, as the compounds have so far shown no toxic properties. The dose may also be reduced, especially if the patient is concomitantly receiving diuretic therapy.

The compounds of the invention may be formulated into compositions for oral or parenteral administration. Known excipients, carriers, stabilizers, inert diluents are added to the active ingredients in a known manner, for example in the form of tablets, dragees, capsules, aqueous, alcoholic or oily suspensions, solutions. Among the inert carriers are gum arabic, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. Dry or wet granules are prepared by tabletting. Oily carriers include, for example, vegetable or animal oils, such as sunflower seed oil or cod liver oil.

In the case of formulations for subcutaneous or intravenous use, the active compounds, and their physiologically acceptable salts, are formulated into solutions, suspensions, or emulsions with known substances, diluents, emulsifiers, or other excipients. Suitable solvents are, for example, water, physiological saline solution or alcohols such as ethanol, propanol or glycerol, in addition to sugar solutions such as glucose or mannitol solution, and mixtures of the abovementioned solvents.

The compounds of the present invention are extremely potent, as shown in Table 1. The results in the table are for studies in which anesthetized I of 310 mg administered anesthetized rats intraduodenally 30 minutes after administration of test drugs. Inhibition of hypertension was measured. The 50% inhibition is ED _{50 :} Pancake-finished pond.

Table 1

3a and (6 + n) are cis configurations of hydrogen atoms on carbon

n X Y Z R ₂ ^R 1 ED _S0 (µg / kg) 0 H H -c ₂ h ₅ -ch ₃ 40 0 H H H -ch ₃ 700 1 H H —C ₂ Hs -ch ₃ 50 1 H H H -ch ₃ 600 2 H H —C ₂ I5 -ch ₃ 230 2 H H H -ch ₃ 840 1 -SHE - -c ₂ h _s -ch ₃ 390

The terms in the table header refer to the compound of formula (I).

Hydrogen atoms in position 3a and (6 + n) at the carbon atoms are transconfirmed, X »phenyl, Rj methyl)

194 278 '

n Y Z Ra the configuration of the double ring ED _S0 0 H H H 2S, 3aR, 6aS 700 0 H H -C ₂ H _s 2S, 3aR, 6aS 40 1 H H H 2S, 3aR, 7aS 800 1 H H -CjHj 2S, 3aR, 7aS 55 1 H H H 2S, 3aS, 7aR 850 1 H H -CjHj 2S, 3aS, 7aR 65 2 H H Η 2S, 3aR, 8aS 1080 2 H H -C ₂ Hj 2S, 3aR, 8aS 110 1 -SHE- -CjHj 2S, 3aR, 7aS 180

The notations in the table header refer to formula (I).

The following examples illustrate the present invention:

Preparation of starting materials

Example

2 (3, 3a, 3, 7a, 3-octahydro-indole-2-carboxylic acid)

a) N-acetyl-3a / 3,7a / 3-octahydroindole g indole is dissolved in 700 ml glacial acetic acid and 3.5 g platinum oxide is added. The mixture was hydrogenated for 16 hours at 20-25 ° C, 100 atm and then at 20-25 ° C under normal pressure until hydrogen uptake ceased. The catalyst was filtered off and the solvent was evaporated in vacuo. The residue was taken up in water, basified with saturated potassium carbonate solution, saturated with sodium chloride, extracted four times with methylene chloride and dried over the organic phase.

The residue is taken up in 250 ml of pyridine, taken up in 93 ml of acetic anhydride and reacted at 20-25 ° C for 12 hours. After distilling off the pyridine, the residue is taken up in water and made basic with concentrated aqueous sodium hydroxide. The aqueous layer was extracted with methylene chloride, and the combined organic layer was washed with 2N hydrochloric acid and water. The solution was dried, evaporated and the residue was distilled. Yield: 85 g, b.p. 91-95 ° C / 0.5 mmHg.

b) N-Acetyl-2-methoxy-3a / 3,7a / 3-octahydro-indole g N-acetyl-3a / 3,7a / 3-octahydro-indole is dissolved in methanol, mtgd tetramethylammonium tetrafluoroborate is added, / Liebigs Ann Chem., 1719 (1978)] and then distilled, the residue was filtered through 500 g of silica gel using ethyl acetate as the eluent. Concentration of the ethyl acetate solution gave 53.6 g of the title compound, Rf (thin layer chromatography): 0.33 (silica, ethyl acetate).

c) Acid nitrile of N-acetyl-2/3, 3a, 3, 7a, 7a-octahydroindole-2-carbonyl

49.8 g of N-acetyl-2-methoxy-3a / 3,7a / 3-octahydroindole are dissolved in 250 ml of methylene chloride and 25 g of trimethylsilyl cyanide in 50 ml of methylene chloride are dissolved at -40 ° C. solution is added dropwise. 35.90 g of boron trifluoride etherate are then added dropwise so that the temperature of the reaction mixture is not above -20 ° C. After 2 hours at -20 ° C, the reaction mixture was allowed to warm slowly to 0 ° C and stirred overnight at 0 ° C and then for an additional hour at 20-25 ° C. Water was added and the mixture was stirred for a further 10 minutes. The aqueous phase is extracted three times with methylene chloride, the combined organic extracts are dried, evaporated and the residue is triturated with diisopropyl ether. Yield: 47 g, mp 128-130 ° C.

d) 2/3 3a / 3, 7a) 3-octahydro-indole-2-carboxylic acid g N-acetyl-2/3, 3,3,3,7a / 3-octahydro-indole-2-carboxylic acid nitrile and 30 ml concentrated 'hydrobromic acid the mixture is refluxed for 2 hours. The hydrobromic acid is then distilled off, the residue is triturated with a little acetone and filtered. The product obtained is dissolved in water and the aqueous solution is adjusted to pH 6.0 with a weakly basic ion exchanger. After filtration, the solution was evaporated and the residue was filtered through silica gel with methylene chloride / methanol / acetic acid / water (20:10: 0.5: 0.5). The eluate was concentrated and the residue was triturated with diisopropyl ether. Yield: 7.6g ¹ H-NMR spectrum * 1.0-2.5 (m, 11H), 3.4-3.9 (m, IH), 4.0-4.5 (m, IH ), 7.5-8.3 (s-wide, interchangeable with D ₂ O) * H-MMR spectral analyzes were performed in CDCl ₃ , the results refer to ppm.

194 278

Examples

Example 1

N 1 S -carbetoxy-3-phenylpiperidine) -S-alanyl-2S, 3 a R,

7aR-octahydroindole -2-carboxylic acid benzyl ester (=

Diastereomer A11) and N- (1S-Carbethoxy-3-phenylpropyl) -S-alanyl-2R, 3aS, 7aS-octahydroindole-2-carboxylic acid benzyl ester (= Diesteromer B 11).

2.5 g of N < 1 &gt; S-carbethoxy-3-phenylpropyl) -S-alanine, 1.22 g of 1-hydroxybenzotriazole, 2.5 g of (d, l) -2p, 3a / J, 7a-octahydroindole -2-Carboxylic acid benzyl ester hydrochloride, 1.25 ml of N-ethylmorpholine and 2 g of dicylhexylcarbodiimide were added to 20 ml of dimethylformamide at 0 ° C. After stirring for 1 hour at 0 ° C, the mixture was allowed to warm slowly to room temperature and then stirred overnight at 20-25 ° C.

The reaction mixture was combined with 25 ml of glacial acetic acid and the precipitated urea was removed by filtration. The solution is evaporated and the residue is taken up in 50 ml of ether, the ethereal solution is washed with a saturated aqueous sodium bicarbonate solution and then with water, dried and evaporated. A mixture of diastereomers A11 and B11 is obtained, which is eluted on a silica gel eluting with a 4: 1 mixture of cyclohexane and ethyl acetate to separate the diastereomers.

Rfaz for the A11 stereomer: 0.36

Rf for stereoisomer B11: 0.34.

The compounds of Example 26 can be prepared as described in Example 1.

Example 2

N- (1-S-carbethoxy-3-phenylpropyl) -S-alanyl-2S, 3aR,

7H-octahydroindole-2-carboxylic acid tert-butyl ester (= diastereomer A 12) ¹ H-MMR: 1.25 (d * t, 6H), 1.35 (s, 9H), 1.3 - 3.6 (m, 18H), 4.2 (q, 2H), 4.4 (m, 1H), 7.3 (s, 5H).

Example 3

N- (1- S -carbethoxy-3-phenylpropyl) -S-alanyl-2S, 3aR,

6aR-Octahydrocyclopenta (b) Pyrrole-2-carboxylic acid benzyl ester (= Diastereomer A 13).

1 H-MMR: 1.1 (d, 3H), 1.3 (t, 3H), 1.3 -

2.4 (m, 10H), 2.3-3.4 (m, 6H), 4.1 (q, 2H), 4.55 (d 1H), 5.2 (s, 2H), 7, 2 (s, 5H); 7.4 (s, 5H).

Example 6

N-1- S -carbetoxy-3-phenylpropyl) -S-alanyl-2S, 3aR,

8H-decahydrocyclohepta (b) pyrrole-2-carboxylic acid tert-butyl ester (= diastereomer A 16) 1 H-MMR: 1.1 (d, 3H), 1.3 (t, 3H), 1.4 ( s, 9H), 1.4-2.5 (m, 14H), 2.3-3.4 (m, 6H), 4.1 (q, 2H)

4.7 (m, 1H), 7.3 (s, 5H).

Example 7

N- (1- S -carbetoxy-3-phenylpropyl) -S-alanyl-2S, 3aR,

7aR-octahydroindole-2-carboxylic acid hydrochloride

Method A:

The diastereomer A11 of Example 1 (0.7 g) was dissolved in ethanol (25 mL) and hydrogen (100 mg, 10% palladium on charcoal) was added at 20-25 ° C under normal pressure. The catalyst was separated and 0.5N ethanolic hydrochloric acid was added until the reaction mixture was acidic. The solution was concentrated in vacuo and the residue was triturated with diisopropyl ether. 400 mg of the title compound are obtained, m.p. 198-200 ° C.

1 H-MMR data (free base: 1.0-3.0 (m, 19H), 3.0-30 (t, 1H), 30-3.9 (m, 3H), 30-4.4 (q, 2H), 4.4-4.7 (bs, 4H), 7.2 (s, 5H).

Method B:

3.8 g of diastereomer A12 of Example 2 are dissolved in 5 ml of methylene chloride and the solution is saturated with anhydrous hydrogen chloride gas and allowed to stand for 16 hours at 20-25 ° C. The solution was concentrated in vacuo. The residue was triturated with diisopropyl ether and filtered. Yield: 550 mg.

Example 3

N- (1- S -carbetoxy-3-phenylpropyl) -S-alanyl-2S, 3aR, 6a-octahydrocyclopenta (b) ρϊσο123ί3Λοη88ν hydrochloride

Example 7 Using the method A and starting with the diastereoisomeric compound 13 of Example 3, the title compound was obtained.

1 H-MMR Data: 10 (d, 3H), 1.3 (t, 3H), 1.23.8 (m, 16H), 4.15 (q, 2H), 4.2-4.6 (m , 4H), 70 (s, 5H).

Example 4

N- (1- S -carbethoxy-3-phenylpropyl) -S-alanyl-2S, 3aR,

8aR) -Decahydrocyclohepta (b) Pyrrole-2-carboxylic acid benzyl ester (= Diastereomer A 14).

¹ H-MMR data: 1.2 (d * t, 6H), 10-2.4 (m, 14H), 2.3-3.4 (m, 6H), 4.2 (q, 2H), 4.6 (m, 1H), 5.2 (s, 2H) 7.25 (2.5H), 7.4 (s, 5H).

Example 5

N- (1- S -carbetoxy-3-phenylpropyl) -S-alanyl-2S, 3aR,

6aR, tert-Butyl ester of octahydrocyclopenta (b) pyrrole-carboxylic acid (= diastereomer A15) 1 H NMR data: 1.1 (d, 3H), 1.3 (t, 3H), 102.4 (m, 10H) , 1.4 (s, 9H), 2.3-3.4 (m, 6H), 4.2 (q, 211), 4.6 (m, 111). 7.2 (s, 5H).

Example 9

N- (1- S -carbetoxy-3-phenylpropyl) -S-alanyl-2S, 3aR,

8aR-decahydrocyclohepta (b) pyrrc-carboxylic acid hydrochloride

Example 7 Using the method A and starting with diastereoisomer 4 of Example 4, the title compound was obtained.

1 H-MMR data: 1.2 (d, 3H), 10 (t, 3H), 1.23.8 (m, 20H), 4.2 (q, 2H), 4.0-4.7 (m, 4H), 7.2 (s, 5H).

The compounds of Examples 8 and 9 can also be prepared from diastereomers A5 and A6 according to Method B of Example 7.

194 278

Example 10

N- (1- S -carboxy-3-phenylpropyl) -S-alanyl -2S, 3aR,

7aR-octahydroindole-2-carboxylic acid g of N- (1S-carbethoxy-3-phenylpropyl) -S-alanine-2S, 3aR, 7aR-octahydroindole-2-carboxylic acid 4mydrochloride is dissolved in 10 ml of water and 2 molar equivalents are obtained. potassium hydroxide and 10% excess 4N potassium hydroxide solution were added. After stirring for 8 hours, the reaction mixture was adjusted to pH 4 with 2N hydrochloric acid and concentrated in vacuo. The residue is taken up in ethyl acetate, the precipitated salt is removed by filtration, the ethyl acetate solution is evaporated and the residue is triturated with diisopropyl ether and filtered. Yield: 0.6 g.

¹ H-MMR: 1.2 (d, 3H), 1.2-3.8 (m, 18H), 4.0-4.6 (m, 4H), 7.2 (s, 5H) .

Example 11

N- (1- S -carboxy-3-phenylpropyl) -S-alanyl-2S, 3aR,

6aR-octahydrocyclopenta (b) red · 2-carboxylic acid

Following the procedure of Example 10 and starting from the compound of Example 8, the title compound is obtained.

¹ H-MMR: 1.2 (d, 3H), 1/2 to 3.8.8 (m, 16H), 4.05-4.7 (m, 4H), 7.2 (s, 5H) .

Example 12

N-O-S-carboxy-3-phenylpropyl) -S-alanyl-2S, 3aR,

8Ar-decahydrocyclohepta (b) pyrrole-2-carboxylic acid

Example 10 was carried out using the compound of Example 9 as starting material.

1 H-MMR: 1.2 (d, 3H), 1.3-3.9 (m, 20H), 4.0-4.7 (m, 4H), 7.2 (s, 5H) .

Example 13

N- (1-S-Carbethoxy-3-phenyl-3-oxo-propyl) -5-alanyl20,3a-7α-octahydro-indole-2-carboxylic acid tert-butyl ester

2.5 g of N- (1S-carbethoxy-3-phenyl-3-oxopropyl) -S-alanine, 1.2 g of 1-hydroxybenzotriazole, 2.5 g of 20-3a0, 7a-octahydroindole-2-carboxylic acid tert -Butyl ethyl ester hydrochloride (d, 1) Dissolve 1.25 ml N-ethylmorpholine and 2 g didclohexylcarbodiimide in 20 ml dimethylformamide. The mixture was stirred at 0 ° C for 1 hour and then at 20-25 ° C for 12 hours. The reaction mixture was diluted with ethyl acetate (25 mL). The precipitated urea was removed by filtration and the solution concentrated in vacuo. The resulting residue was taken up in ether and the ether solution was washed with saturated aqueous sodium bicarbonate solution and water, dried and then concentrated to give 3 g of the title compound as a diastereomeric mixture.

14-28. examples

Example 13 was prepared as described in the following Examples. .

Example 14

N-β-S-carbetoxy-3-phenyl-3-oxopropyl) -S-alanyl-20

3ap, 6α-octahydrocyclopenta (b) pyrrole-2-carboxylic acid tert-butyl ester ¹ H-MMR: 1.2 (s, 9H), 0.9-2.5 (m, 16H),

3.5-5.1 (m, 6H); 7.2-8.2 (m, 5H).

Example 15

N- (1- S -carbethoxy-3-phenyl-3-oxopropyl) -S-alanyl-2S,

1 H-NMR data of 3aR, 8aR-decahydrocyclohepta- (b) pyrrole-2-carboxylic acid tert-butyl ester: 1.4 (s, 9H), 1.0-2.8 (m, 20H), 3 , 4-5.1 (m, 6H), 7.2-8.2 (m, 5H).

Example 16

N- (1- S -carbetoxy-3-phenyl-2-oxypropyl) -S-alanyl-20,

3ap, 7α-octahydroindole-2-carboxylic acid benzyl ester 'H-MMR data. 1.2 (d, 3H), 1.3 (t, 3H), 1.42.4 (m, 10H), 2.4-3.9 (m, 6H), 4.2 (q, 2H), 4 , 3-4.8 (m, 1H), 5.2 (s, 2H), 7.2 (s, 5H), 7.4-8.0 (m, 5H).

Example 17

N- (1- S -carbetoxy-3-phenyl-3-oxopropyl) -S-alanyl-20,

3ap, 6β-octahydrodclopenta (b) pyrrole-2-carboxylic acid benzyl ester 1 H-MMR: 1.25 (d + t, 6H), 1.4-2.4 (m, 8H), 2.4 -3.8 (m, 6H), 4.2 (q, 2H), 4.3-4.8 (ni, 1H),

5.2 (s, 2H), 7.2 (s, 5H), 7.4-8.0 (m, 5H).

Example 18

N- (1- S -carbetoxy-3-phenyl-3-oxopropyl) -S-alanyl-20,

3ap, 8α-octahydrodclohepta (b) pyrrole-2-carboxylic acid benzyl ester 1 H-MMR: 1.2 (d, 3H), 1.3 (t, 3H), 1,4-

2.5 (m, 12H), 2.4-3.8 (m, 6H), 4.2 (q, 2H), 4.3-4.8 (m, 1H), 5.2 (s, 2H) , 7.2 (s, 5H), 7.4-8.0 (m, 5H).

Example 19

N- (1- S -carbetoxy-3-phenyl-3-oxopropyl) -S-alanyl-20,

3ap, 7a-octahydroindole-2-carboxylic acid trifluoroacetate

2.6 g of the diastereomeric mixture of Example 13 are stirred in 15 ml of trifluoroacetic acid for 2 hours at 20-25 ° C. The solution was concentrated in vacuo and the residue was triturated with diisopropyl ether and filtered. Yield: 0.8 g.

1 H-MMR: 12 (d * t, 6H), 1.3-3.6 (m, 16H)

4.2 (q, 2H), 4.1-4.6 (m, 4H), 7.3-8.1 (m, 5H).

¹ H-MMR data: 1.2 (s, 9H), 0.9-2.6 (m, 18H),

3.5-5.1 (m, 6H); 7.2-8.2 (m, 5H).

The optically active compounds can be selected by passing the diastereomeric mixture through a column packed with silica gel, eluting with a mixture of cyclohexane-ethyl acetate.

Example 20

Α-β-S-carbethoxy-3-phenyl-3-oxopropyl) -S-alanyl-20,3α, 6α-octahydrodclopenta (b) pyrrole-2-carboxylic acid trifluoroacetate

194 278

The title compound was prepared as described in Example 19.

1 H-MMR data: 1.2 (d + t, 6H), 1.3-3.6 (m, 14H), 4.15 (q, 2H), 4.0-4.6 (m, 4H), 7.3-8.0 (m, 5H).

Example 21

N- (1- S -carbetoxy-3-phenyl-3-oxopropyl) -S-alanyl-2/3,

3ap, 8a, N-Decahydrocyclohepta (b) Pyrrole-2-carboxylic acid g N- (1S-Carbethoxy-3-phenyl-3-oxo-propyl) -S-alanyl-2β, 3a-bis [beta] -β-decahydrocyclohepta (b) The 2-carboxylic acid tert-butyl ester is dissolved in 10 ml of methylene chloride, saturated with hydrogen chloride gas and allowed to stand at 20-25 ° C for 16 hours. The solution was evaporated in vacuo, the residue was triturated with diisopropyl ether and filtered. Yield: 0.4 g.

1 H-MMR: 1.3 (d + t, 6H), 1.3-3.8 (m, 18H), 4.2 (q, 2H), 4.0-4.7 (m , 4H), 7.2-8.1 (m, 5H).

19-21. The carboxylic acids described in Examples 1 to 4 can also be prepared from the corresponding benzo esters by catalytic hydrogenation. (Activated carbon containing 10% palladium, 20-25 ° C, ethanol medium).

Example 22

N-yl-S-carboxy-3-phenyl-3-oxopropyl) -S-alanyl-2/3,

3ap, 7a-octahydroindole-2-carboxylic acid g N- (1S-carbethoxy-3-phenyl-3-oxopropyl) -S-alanyl-2β, 3β, 7a (3-octahydroindole-2-carboxylic acid according to Example 19 with potassium hydroxide as described.

1 H-MMR: 1.2 (d, 3H), 1.3-3.6 (m, 16H),

4.1-4.7 (m, 4H); 7.2-8.1 (m, 5H).

Example 23

N- (1S-Carbetoxy-3-phenyl-3-hydroxypropyl) -S-alanyl

-2β, 3a / 3. 7a / 3-octahydroindole-2-carboxylic acid g N- (1S-carbethoxy-3-phenyl-3-oxo-propyl) -5-alanyl-2β, 3H-ol Tacho-droindole-2-carboxylic acid is dissolved in 50 ml of anhydrous ethanol, presence of activated carbon at 20-25 ^° C, hydrogenated at normal pressure and 1 mole equivalent of hydrogen. The catalyst is filtered off, the solution is evaporated and the residue is triturated with diisopropyl ether and filtered off. Yield: 0.7 g.

H-NMR-data; 1.2 (d, 3H), 1.3 (t, 3H), 1.33,8 (m, 16H), 4.2 (q, 2H), 4.1-4.6 (m, 4H) , 4.7 (d, 1H), 7.1-7.4 (m, 5H).

Example 24

N-yl-S-carbethoxy-3-phenyl-3-hydroxypropyl) -S-alanyl

-2p, 3a / 3, 6a / 3 octahydrocyclopenta (b) pyrrole-2-carboxylic acid

Starting from the compound prepared in Example 19, the procedure of Example 23 was followed. The title compound has the following characteristics:

1 H-MMR: 1.2 (d, 3H), 13 (t, 3H), 1.4 -

3.9 (m, 14H), 4.2 (q, 2H), 4.1-4.7 (m, 4H), 4.7 (d, 1H), 7.0-7.4 (m, 5H).

Example 25

N- (1- S -carbetoxy-3-phenyl-3-hydroxypropyl) -S-alanyl

-2β, 3αβ, 8β, 3decahydrodclohepta (b) pyrrole-2-carboxylic acid

The compound of Example 21 is converted to the title compound according to Example 23.

1 H-MMR: 1.25 (d + t, 6H), 1.3-4.0 (m, 18H), 4.2 (q, 2H), 4.1-4.6 (m, 4H), 4.8 (d, 1H), 7.0-7.5 (m, 5H).

Example 26 '

S-Alanyl-2S, 3aR, 7aR-octahydroindole -2-carboxylic acid benzyl ester

a) Dissolve Boc-Ala-OH in N-tert-butoxycarbonyl-S-alanyl-2S, 3aR, 7aR, 7-octahydro-indole-2-carboxylic acid in 100 ml of dimethylformamide, 13 ml of N-ethylmorpholine, 13.5 g of 1-hydroxybenzotriazole and 29.6 g of 2/3, 3a0, 7a / 3-octahydroindole-2-carboxylic acid benzyl ester hydrochloride are added. The mixture was cooled in an ice bath and treated with 21 g of dicyclohexylcarbodiimide. The mixture was stirred at 20-25 ° C for 15 hours. The precipitated urea was filtered off, the filtrate was concentrated in vacuo and taken up with ethyl acetate. The organic phase is extracted 3 times with aqueous potassium bisulfate solution, potassium bicarbonate solution and brine, and the organic phase is dried and evaporated. The residue is chromatographed on silica gel with a mixture of ethyl acetate and cyclohexane (1-3). The first fraction contains the title compound. Yield: 21 g.

1 H-MMR: 1.3 (d, 3H), 1.45 (s, 9H), 1.12.4 (m, 12H), 3.2-3.9 (m, 2H), δ , 3 (s, 2H), 7.4 (s, 5H;).

b) S-Alanyl) -2S, 3aR, 7aR-octahydro-2-carboxylic acid benzyl ester

20.5 g of N-tert-butoxycarbonyl-S-alanyl-2S, 3aR, 7aR-octahydroindole -2-carboxylic acid benzyl ester are dissolved in 50 ml of trifluoroacetic acid. After 10 minutes, the solution was concentrated in vacuo, the residue was triturated with diisopropyl ether and dried in vacuo. Yield: 14 g.

Examples 27 and 28

By following the procedure of Example 26 (a) and (b), the following compounds were prepared:

Example 27

1 H-MMR for S-Alanyl-2S, 3aR, 6aR-octahydrocyclopenta (b) pyrrole-2-carboxylate, b-ester: 1.3 (d, 3H), 1.1-2.4 (m). , 10H).

3.2-3.9 (m, 2H), 5.2 (s, 2H), 7.4 (s, 5H).

Example 28

S-alanyl-2S, 3aR, 8aR-decahydrocyclohepta (b) pyrrole-2-carboxylic acid-butylbenzyl ester, ¹ H NMR data: 1.3 (d, 3H), 1.1-2.4 (m, 14H);

3.2-3.9 (m, 2H), 5.2 (s, 2H), 7.4 (s, 5H).

-101

Example 29

N- (1- S -carbetoxy-3-phenylpropyl) -S-alanyl-2S, 3aR,

7aR-octah droin dl-2-carboxylic acid

a) N, N-1S-Carbethoxy-3-phenylpropyl) -S-alanyl-2S, 3aR, 7aR-octahydroindole-2-carboxylic acid benzyl ester moleS-Alanyl-2S, 3aR, 7aR-octahydro-dinol-2- Carboxylic acid benzyl ester is dissolved in 30 ml of anhydrous ethanol. The solution was adjusted to pH 7.0 with ethanolic potassium hydroxide, 1 g of the powdered molecular sieve (4A) and 10 mmol of ethyl 2-keto-4-phenylbutyric acid were added. A solution of 1 g of sodium cyanoborohydride in 10 ml of anhydrous ethanol is slowly added dropwise. After 20 hours, the reaction mixture was filtered at 20-25 ° C and the solvent was distilled off. The residue is taken up in a mixture of ethyl ester and water. The ethyl ester phase is evaporated and the residue is chromatographed on silica gel with ethyl acetate / cyclohexane (1: 4). The MMR data is the same as in Example 11.

b) The compound obtained above was converted according to the method of Example 7, Method A.

Example 30

N- (1-S-carbethoxy-3-oxo-3-phenylpropyl) -S-alanyl-20,

3ap, 6aO-octahydrocyclopenta (b) pyrrole-2-carboxylic acid benzyl ester, mmol of S-alanyl -2S, 3aR, 6aR-octahydrocyclopenta (b) pinole-2-carboxylic acid benzyl ester, 10 mmol of 3-benzoyl acrylic acid ethyl ester. triethylamine (100 mmol) was added in 100 mL of water-ethanol and the mixture was stirred for 24 hours at 20-25 ° C. The mixture was neutralized with n-hydrochloric acid solution, dried, and the residue was taken up in a mixture of ethyl ester and water. The ethyl ester phase was dried, concentrated and chromatographed on silica gel.

Example 31

N- (1- S -carbetoxy-3-oxo-3-phenylpropyl) -S-alanyl-20,

3ap, 8α, 3-decihydrocyclopenta (b) pyrrole-2-carboxylic acid benzyl ester, mmol of acetophenone, 10 mmol of ethyl glyoxylic acid, and 10 mmol of S-alanyl-2S, 3aR, 8aR-decahydrodclohepta (b) pyrrole-2-carboxylic acid; The benzyl ester was refluxed in 30 ml of acetic acid for 36 hours at 45 ° C. The mixture was concentrated in vacuo, basified with aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The organic phase was evaporated and chromatographed on silica gel.

Example 32

N- (1-S-carbethoxy-3-phenylpropyl) -S-alanyl -2S, 3aR,

7aS-octahydroindole-2-carboxylic acid

a) Benzyl-DL-2/3, 3a / 3, 7a-octahydro-indole-2-carboxylic acid steroid hydrochloride

Dissolve 1.4 ml of thionyl chloride in 14 ml of benzyl alcohol at -5 to 0 ° C and add to the solution at -10 to 0 ° C 1.4 g of DL-20, 3a / 3, 7a-octahydroindole-2-carboxylic acid . The mixture was stirred for 1 hour

Stir at 0 ° C and allow to stand overnight at 20-25 ° C. The benzyl alcohol was then distilled in vacuo at 50 ° C and the residue was triturated with diisopropyl ether. This gave 2.5 g of colorless crystals, m.p. 154 ° C.

b) N- (1- S -carbetoxy-3-phenylpropyl) -S-alanyl-20,3a, 7a-octahydroindole -2-carboxylic acid benzyl ester

2.16 g of N- (η 5 -carbetoxy-3-phenylpropyl) -S-alanine

It is suspended in 8.6 ml of anhydrous dimethylformamide to give 1.06 g of 1-hydroxybenzotriazole, 2.2 g of DL-20, 3a / 3, 7a-octahydroindole-2-carboxylic acid benzyl ester hydrochloride and 1080 ml of N- ethyl morpholine was added followed by dicyclohexylcarbodiimide (1.7 g) at 0 ° C. After stirring at 20-25 ° C for 3.5 hours, the reaction mixture was diluted with ethyl acetate (20 mL) and the precipitated dicyclohexylurea was filtered off. The filtrate was concentrated in vacuo, the residue taken up in ether, washed twice with saturated aqueous sodium bicarbonate, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel, eluting with a mixture of ethyl ester and cyclohexane, to give a pale yellow oily product containing the desired isomers in a ratio of 1-1.

¹ H-MMR data for the 2R, 3aR, 7aS configuration isomer: 7.35 (s, 5H), 7.2 (s, 5H), 5.18 (s, 2H), 4.55 id, 1H). , 4.1 (q, 2H), 3.4-2.3 (m, 6H), 2.4-1.3 (m, 2H), 1.3 (t, 3H), 1.1 (d) , 3H).

¹ H-MMR data for the 2S, 3aS, 7aR configuration isomer: 7.35 (s, 5H), 7.2 (s, 5H), 5.16 (s, 2H), 4.9 -4.2 (m, 1H), 4.2 (q, 2H), 3.9-2.4 (m, 6H), 2.4-1.4

12H), 1.25 (drt, 6H).

c) N- (1- S -Carbetoxy-3-phenylpropyl) -S-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid

1.7 g of the 2S, 3aS, 7aR isomer obtained under b) are dissolved in 60 ml of anhydrous ethanol and hydrogenated with 200 mg of 10% palladium on charcoal at 20-25 ° C for 2 hours at normal pressure. The catalyst was filtered off and the filtrate was concentrated. This gave 1.2 g of the title compound as a colorless foam.

¹ H-MMR: 7.2 (s, 5H), 4.4 (m, 4H), 4.2 (q, 2H), 3.6-1.3 (m, 18H), 1/28 (d, 6H).

The hydrochloride salt of the above compound is obtained as a colorless amorphous powder.

33-37. example

The compounds mentioned in these Examples can be prepared as described in Example 32.

Example 33

N- (1- S -carbetoxy-3-phenylpropyl) -S-alanD-2S, 3aS,

7aR-octahydroindole-2-carboxylic acid

The Π. The title compound is obtained from a mixture of the compounds prepared in Examples 1-8. Following the procedure of Example 32, the isomers were chromatographed on a silica gel column prior to hydrogenation according to Example 32 (c).

-111

194.278 ¹ H-MMR: 7.2 (s, 5H), 4.0-4.6 (m, 4H), 4.15 (q, 2H), 3.8-1.2 (m, 18H) ), 1.3 (t, 3H), 10 (d, 3H).

The hydrochloric acid salt is obtained as a colorless amorphous powder.

Example 34

N- (1- S -carbetoxy-3-phenylpropyl) -S-alanyl-2S, 3aR,

¹ H-MMR data for 6aS-octahydrocyclopenta (b) pyrrole-2-carboxylic acid: 7.25 (s, 5H), 4.35 (m, 4H), 4.2 (q, 2H), 3.9-1. , 4 (m, 16H), 1.35 (t, 3H), 1.15 (d, 3H)

The hydrochloride salt is obtained as a colorless amorphous powder.

Example 35

N- (1- S -carbetoxy-3-phenylpropyl) -S-alanyl-2S, 3aS,

¹ H-MMR data of 6aR-octahydrocyclopenta (b) pithiol-2-carboxylic acid: 7.3 (s, 5H), 4.3 (m, 4H), 4.2 (q, 2H), 3.8-1. , 3 (m, 16H), 1.3 (Vd, 6H).

Example 36 '

N- (1- S -carbetoxy-3-phenylpropyl) -S-alanyl-2S, 3aS,

¹ H-MMR data of 8aR-decahydrocyclohepta (b) pyrrole-2-carboxylic acid: 7.2 (s, 5H), 4.4 (m, 4H), 4.25 (q, 2H), 3.8-1. , 2 (m, 20H), 1.3 (t, 3H), 1.15 (d, 3H)

Preparation of starting compounds

II. example

2β, 3a0, 7afleoctahydroindole carboxylic acid

a) 3-Chloro-N-acyl-alanine-methyl-yl

181 g of 3-chloro-alanylmethyl ester hydrochloride were spun with a solution of 163.9 g of acetic acid chloride in 10 L of water-toluene at reflux for 5 hours until a clear solution was obtained. The resulting solution was dried and the residue was recrystallized from ethyl acetate / petroleum ether. 170 g of the title compound are obtained, m.p. 104 ° C.

b) 3- (2-Oxo-cyclohexyl) -N-acetylalanine methyl ester

160 g of 3-chloro-N-acetyl-alanine methyl ester and 171.9 g of 1-pyrrolidinocyclohexene are dissolved in 1.2 L of absolute dimethylformamide and allowed to stand for 3 days at 20-25 ° C. The solution was concentrated in vacuo and the resulting residue was taken up in water (600 mL) and adjusted to pH 2.0 with concentrated hydrochloric acid. The aqueous solution was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and evaporated. A yellow oil is obtained.

c) 3,3a, 4,5,6,7-2H-hexahydroindole-2-carboxylic acid hydrochloride

220 g of the product obtained under b) are heated at reflux for 2 hours in 1 liter of 2L hydrochloric acid. The mixture is then extracted with ethyl ester and the aqueous phase is concentrated. The remainder of the water was removed by addition of toluene by evaporation three times under vacuum. 210 g of product are obtained in the form of a yellow oil which crystallizes on standing.

d) 2β, 3α, 7α-octahydroindole-2-carboxylic acid

128 g of 3,3a, 4,5,6,7-2H-hexahydroindole-2-carboxylic acid are combined with 700 ml of glacial acetic acid and hydrogenated under normal pressure at room temperature in the presence of 4 g of activated carbon containing 10% platinum. After filtration, the filtrate is concentrated, the residue is taken up in 500 ml of hot ethanol and the solution is cooled to -20 ° C. The title compound precipitates in the form of 2β, 3αβ, 7 & β isomers. The product in solution is recovered by evaporation and addition of isopropyl. Colorless crystals: mp 280 ° C;

III. example

Αβ, 3aa, 7α-octahydroindole-2-carboxylic acid

a) 3,4,5,6,7,8-octahro-1H-quinolin-2-one

A mixture of 392 g of cyclohexanone, 212 g of acrylonitrile, 20 g of cyclohexflamine, 4 g of glacial acetic acid and 0.4 g of hydroquinone is heated under reflux for 4 hours until the temperature reaches 200 ° C. After distillation at 100-150 ° C at 0.5 mm Hg, the distillate was heated at 200 ° C for 10 days with 10 ml of 50% glacial acetic acid. After cooling, the reaction mixture was recrystallized from methanol / water. The resulting distillation residue was recrystallized from n-hexane to give a total of 460 g of product, m.p. 143-144 ° C.

b) Trans-octahydro-1H-quinolin-2-one The product prepared in (a) is mixed with a solution of 70 g of formic sodium in 120 ml of formic acid and refluxed for 18 hours. The mixture was basified with 20% aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated. The residue was recrystallized from cyclohexane, m.p. 15-2 ° C.

c) 3,3-dichloro-trans-octahydro-1H-quinolin-2-one

A solution of 19.4 g of the compound prepared in b) is added dropwise to a solution of 24.3 g of phosphorus tetrachloride in 300 ml of anhydrous chloroform and a solution of 36.4 g of sulfuryl chloride in 40 ml of chloroform is added dropwise at 30 ° C to 30 ° C. across. The mixture is refluxed for 6 hours and then allowed to stand overnight at 20-25 ° C.

After neutralization with ice-cold saturated aqueous potassium carbonate solution, the mixture was extracted with methylene chloride, and the organic phase was dried over sodium sulfate and evaporated. The residue was recrystallized from ethanol after addition of activated carbon. 25 g of product are obtained, m.p. 190-198 ° C.

d) 3-Chloro-trans-octahro dro-1H-quinolin-2-one

15.6 g of compound (c) in 1 liter of ethanol and

9.7 ml of triethylamine are added. After the addition of Raney nickel, the mixture is hydrogenated at 20-25 ° C under normal pressure to 1 molar equivalent of hydrogen. The catalyst was filtered off and filtered

-121

After drying at 194,278, the residue is taken up in ethyl acetate.

The organic layer was washed twice with water, dried over sodium sulfate and evaporated. The residue was triturated with diisopropyl ether, filtered and dried. The title compound is obtained in the form of colorless crystals, m.p. 115-120 ^° C.

e) 2ft 3ac <7α-octahydroindole-2-carboxylic acid

6.63g base-as sodium hydroxide octahydrate obtained according to compound 3.75 g, d) is added to 120 ml of water "in the boiling solution of ^u. After refluxing for 4 hours, sulfuric acid (0.9 ml) was added, the mixture was refluxed for an additional hour, and the reaction mixture was filtered and the filtrate was washed with brine (6 g). After adjusting to pH 5, the solution is evaporated, the residue is taken up in ethanol, refluxed, then filtered again, and the filtrate is concentrated to a small volume to give a crystalline mixture of the title compound and Example II in a 1 to 1 ratio. Mp: 275-276 ° C

ARC. example·

2/3, 3a / 3, 6α-octahydrocyclopenta (b) pyrrole-2-carboxylic acid

a) 1,2,3,4,6,7-hexahydro-5H-1-pyrid-2-one 25 moles cyclopentanone, 1 mole acrylonitrile, 0.05 moles ammonium acetate and 3 ml 30% ammonia under pressure boil in a pressure vessel for 3 hours at 220 ° C. The mixture was filtered through silica gel, eluting with ethyl acetate / cyclohexane (1-1), the filtrate was evaporated and the residue was recrystallized from cyclohexane. 118-120 ° C.

1 H-MMR: 9.4 (s-broad, 1H), 3.2-2.0 (m,

12H). 35

b) Octahydro-trans-5H-1-pyridine-2-οη

In III. Example 1 (b).

^1H-NMR data: 7.8 (8s br, IH), 2.9 (br s,

1H), 2.6-2.2 (m, 2H), 2.1-1.0 (m, 8H). 40

c) 3,3-dichlorooctahydro-trans-5H-1-pyrid-2-οη

In III. Example 1c can be used to prepare this compound.

1 H-MMR: 7.9 (s-broad, 1H), 3/8 (s-broad, 45 1H), 3.2-2.0 (m, 2H), 2.1-1.0 (m, 6H).

d) 3-chlorooctahydro-trans-5H-1-pyrid-2-οη

By following the procedure of Example 111 (d), this compound can be prepared.

1 H-MMR: 7.8 (s broad, 1H), 4.6-4.3 (m,

IH). 3.3-3.0 (m, 1H), 2.1 (d, J = 6Hz, 2H), 1.8-1.1 (m, 6H).

e) 2β, 3a0, ocaoctahydrocyclopenta (bj pyrrole-2-55 carboxylic acid

This compound can be prepared according to Example I (e).

* H-MMR data: 4.7-4.4 (m, 1H), 3.0-0.9 (m,

10H). 60

Example V

2/3, 3a / 3, 8aunfecahydrocyclohepta (b) from red-2-carboxylic acid

a) 1,2,3,4,5,6,7,8-octahydrocyclohepta (b) pyrid-2-one

The ΠΙ. The title compound was prepared according to Example 1 a). Cycloheptanone is used as starting material.

^1H-NMR data: 9.4 (s, br, IH), 3.2 to 2.0 (m, 14H).

b) trans-decahydrodclohepta (b) pyrid-2-οη

The ΙΠ. Example 1 (b): Starting with the compound of (a).

1 H-MMR: 7.9 (s-broad, 1H), 2.9 (s-broad, 1H), 2.6-2.2 (m, 2H), 2.1-1.0 ( m, 12H).

c) 3,3-dichloro-trans-decahydrocyclohepta (b) pyrid-2-one

In III. Example 1c.

1 H-MMR: 7.9 (s-broad, 1H), 3.8 (s-broad, 1H), 3.2-2.0 (m, 2H), 2.1-1.0 ( m, 10H).

d) 3-chloro-trans-decahydro-cyclohepta (b) pyrid-2-one

In III. Example 1 (d).

^1H-NMR data: 7.8 (s, br, IH), 4.6-4.3 (m, IH), 3.3-3.0 (m, IH), 2.1 (d, J = 6 Hz, 2H), 1.8-1.1 (m, 10H).

e) 2/3, 3a / 3, 8aodecahydrocyclohepta (b) pyrrole-2-carboxylic acid

The ΙΠ. Example 1 (e).

1 H-MMR: 4.7-4.4 (m, 1H), 3.2-1.1 (m, 1H).

Example 37

N- (S-Alanyl) -2S, 3aR, 7aS-octahydroindole -2-carboxylic acid tert-butyl ester hydrochloride

a) N- (N'-Benzyloxycarbonyl-5-alanyl) -2S, 3aR, 7aS-octahydroindole-2-carboxylic acid tert-butyl ester

The title compound can be prepared using Z-alanine according to the procedure of Example 26 (a). The resulting isomers are separated as described there.

¹ H-MMR: 7.4 (s, 5H), 5.3-4.8 (m, 1H),

4.2-3.7 (m, 2H), 3.1-1.4 (m, 11H), 1.3 (d, J = 7Hz, 3H), 1.2 (s, 9H).

b) The compound obtained under a) is hydrogenated in the presence of palladium and barium sulfate in a solution of hydrochloric acid in n-ethanol to give the title compound.

ⁿ H-MMR: 5.2-4.8 (m, 1H), 4.2-3.7 (m, 2H), 3.1-1.4 (m, 11H), 1.3 ( d, J = 7fe, 3H), 12 (s, 9H).

38 to 42 below. Examples a

Example 37 Prepared according to a) and b).

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194 278

Example 38

¹ H-MMR data for N- (S-alanyl) -2S, 3aS, 7aR-octahydroindole-2-carboxylic acid tert-butyl ester: 5.2-4.7 (m, 1H), 4.4-3.8 (m, 2H), 3.1-1.4 (m, 11H), 1.25 (d, J = 7Hz, 3H), 1.2 (s, 9H).

Example 39

¹ H-NMR data of N- (S-alanyl) -2S, 3aR, 6aS-octahydrocyclopenta (b) pyrid-2-carboxylic acid tert-butyl ester hydrochloride: 5.3-4.7 (m, 1H) , 4.4-3.8 (m, 2H), 3.1-1.4 (m, 9H), 1.3 (d, J = 7Hz, 3H), 12 (s, 9H).

Example 40

1 H-NMR data of N- (Sa) alu] -2S, 3aS, 8aR-octahydrocyclopenta (b) pyrid-2-carboxylic acid tert-butyl ester hydrochloride 5.3-4.7 (m, 1H) , 4.4-3.8 (m, 2H), 3.1-1.4 (m, 9H), 1.3 (d, J = 7Hz, 3H), 1.2 (s, 9H).

Example 41

¹ H-NMR Spectrum of N- (S-Alanyl) -2S, 3aR-8aS-decahydrocyclohepta (b) pyrrole-2-carboxylic acid tert-butyl ester hydrochloride: 5.1-4.6 (m, 1H), 4 , 5-3.7 (m, 2H), 3.1-1.4 (m, 13H), 1.3 (d, J = 7Hz, 3H), 1.2 (s, 9H).

Example 42

1 H-NMR of N- (S-Alanyl) -2S, 3aS, 8aR-decahydrocyclohepta (b) pyrrole-2-carboxylic acid tert-butyl ester hydrochloride: 5.1-4.6 (m, 1H) , 4.5-3.7 (m, 2H), 3.1-1.4 (m, 13H), 1.3 (d, J = 7Hz, 3H), 1.2 (s, 9H).

Example 43

N- (1S-Carbethoxy-3-phenylpropyl) -S-alanyl-2S, 3aR,

7aS-octahydroindole-2-carboxylic acid

These compounds are prepared according to Example 29 (a). . The starting material used is N- (S-alanyl) -2S, 3aR, 7aS-octahydroindole-2-carboxylic acid tert-butyl ester. The tert-butyl group is cleaved with trifluoroacetic acid.

Example 44

N- (1S-carbetoxy-3-keto-3-phenylpropyl) -S-alanyl-2S,

3aR, 7aS-octahydroindole-2-carboxylic acid

By the procedure described in Example 30; Starting from N- (S-alanyl) -2S, 3aR, 7aS-octahydroindole-2-carboxylic acid tert-butyl ester, the title compound can be prepared. The tert-butyl group is cleaved with trifluoroacetic acid).

1 H-MMR: 1.2 (d + t, 6H), 1.3-3.6 (m, 16H)

4.2 (q, 2H), 4.1-4.6 (m, 4H), 7.3-8.1 (m, 5H).

Example 45

N- (1S-Carbethoxy-3-keto-3-phenylpropyl) -S-alanyl-2S,

3aS, 7aR-octahydroindl-1-2-carboxylic acid

This compound can be prepared by the method of Example 30 starting from N- (S-alanyl) -2S, 3aS, 7aR-octahydroindole-2-carboxylic acid tert-butyl ester. The tert-butyl group is cleaved with trifluoroacetic acid.

Example 46

N 1S-carbetoxy-3-keto-3-phenylpropyl) -S-alanyl-2S,

3aR, 6aS-octahydrocyclopenta (b) pyrrole-2-carboxylic acid

These compounds can be prepared as described in Example 30 starting from N-(S-a) anil) -2S, 3aR, 6aS-octahydrocyclopenta (b) pyrrole-2-carboxylic acid tert-butyl ester. The tert-butyl group is cleaved with trifluoroacetic acid.

1 H-MMR: 1.1 (d, 3H), 1.35 (t, 3H), 1.03.7 (m, 14H), 4.2 (q, 2H), 4.0-4.7 (m, 4H), 7.3-8.0 (m, 5H).

4 ⁷ . example

N (1S-carbetoxy-3-keto-3-phenylpropyl) -S-alanyl-2S,

3aS, 6aR-Octahydrocyclopenta (b) -pyrrole-2-carbonic acid

The title compounds can be prepared as described in Example 31. The tert-butyl group may be cleaved with trifluoroacetic acid.

1 H-MMR: 1.1 (d, 3H), 1.35 (t, 3H), 1.03.8 (m, 14H), 4.2 (q, 2H), 4.0-4.7 (m, 4H), 7.2-8.1 (m, 5H).

Example 48

N- (1S-carbetoxy-3-keto-3-phenyl-propyl) -S-alanyl-2S,

3aR, 8aS-decahydrocyclohepta (b) pyrrole-2-carboxylic acid

This compound can be prepared as described in Example 31 and the tert-butyl group is cleaved with trifluoroacetic acid.

1 H-MMR data: 1.2 (d, 3H), 1.4 (t, 3H), 1.23.8 (m, 18H), 4.1 (q, 2H), 4.0-4 , 6 (m, 4H), 7.2-8.2 (m, 5H).

Example 49

N- (1S-carbetoxy-3-keto-3-phenylpropyl) -s-alanyl-2S,

3aS, 8aR-Decahydrocyclohepta (b) pyrrole-2-carboxylic acid

The title compound can be prepared as described in Example 31. The tert-butyl group is cleaved with trifluoroacetic acid.

1 H-MMR: 12 (d * t, 6H), 12-33 (m, 18H), 4.2 (q, 2H), 4.0-4.6 (m, 4H), 7.1 -8.1 (m, 5H)

Example 50

N <1 S -carbetoxy-3-hydroxy-3-phenylpropyl) -S-alanine 2S-3aR-7aS-octahydroindoh2-carboxylic acid

The title compound can be prepared as described in Example 23.

1 H-MMR data: 1.2 (d, 3H), 1.3 (t, 3H), 1.33.8 (m, 16H), 4.2 (q, 2H), 4.0-4 , 6 (m, 4H), 4.7 (d, 1H) 7.1-7.4 (m, 5H).

Example 51

N- (1S-Carbetoxyl-3-hydroxy-3-phenylpropyl) -S-alanyl2S, 3aS, δR-octahydrocyclopenta (b) pyrrole-2-carboxylic acid

-141

This compound can be prepared according to Example 23.

¹ H-MMR: 1.2 (d, t, 3H), 1.1-3.9 (m, 14H)

4.2 (q, 2H), 4.0-4.7 (m, 4H), 4.8 (d, 1H), 7.1-7; 4 (m, 5H).

52-57th example

The compounds described in this Example were prepared according to the procedure described in Example 10.

Example 52

1 H-NMR data for N- (1S-carboxy-3-phenylpropyl) -S-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid: 1.2 (d, 3H), 1.2-3 , Δ (m, 18H), 4.0-4.6 (m, 4H), 7.2 (s, 5H).

Example 53

¹ H-NMR Spectrum of N- (1S-Carboxy-3-phenylpropyl) -S-alanyl-2S, 3aS, 7aR, -octahydroindole-2-carboxylic acid: 1.2 (d, 3H), 1,2- 3.8 (m, 18H) 4.0-4.6 (m, 4H), 7.2 (s, 5H).

Example 54

1 H-NMR data of N- (1S-carboxy-3-phenylpropyl) -S-alanyl-2S, 3aR, 6aSoctahydrocyclopenta (b) pyrid-2-carboxylic acid: 1.2 (d, 3H), 1.1 -3.7 (m, 16H), 4.0-4.6 (m, 4H), 7.2 (s, 5H).

Example 55

1 H-MMR of N- (1S-Carboxy-3-phenylpropyl) -S-alanyl-2S, 3aS, 6aR-octahydrodclopenta (b) pyrrole-2-carboxylic acid: 12 (d, 3H), 1.1 -3.8 (m, 16H) 4.0-4.6 (m, 4H), 7.2 (s, 5H).

Example 56

1 H-MMR for N- (1S-Carboxy-3-phenyl-propyl) -S-alanyl-2S, 3aR, 6a-octahydrocyclohepta (b) ρίιτοί-2-carboxylic acid: 1.2 (d, 3H), 0.9 -3.6 (m, 20H), 4.0-4.6 (m, 4H), 7.2 (s, 5H).

Example 57

1 H-NMR data of N- (1S-carboxy-3-phenylpropyl) -S-alanyl-2S, 3aS, 8aR-decahydrocyclohepta (b) pyrrole-2-carboxylic acid: 1.2 (d, 3H), 0.8 -3.6 (m, 20H), 4.0-4.6 (m, 4H), 7.2 (s, 5H).

Example 58

1 H-NMR data of N- (JS-carboxy-3-keto-3-phenylpropyl) -5-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid: 1.2 (d, 3H), 0 , 9-3.6 (m, 16H),

3.9-4.7 (m, 4H), 7.1-8.2 (m, 5H).

Example 59

1 H-NMR data of NX1S-carboxy-3-keto-3-phenylpropyl) -S-alanyl-2S, 3aS, 7aR-octahydroindole-2-carboxylic acid: 1.2 (d, 3H), 0.9- 3.6 (ni, 16H),

3.9-4.7 (m, 4H), 7.2-8.1 (m, 5H).

Example 60

1 H-MMR data for N- (1S-carboxy-3-keto-3-phenylpropyl) -5-alanyl-2S, 3aR, 6aS-octahydrocyclopenta (b) pyrrole-2-carboxylic acid; 1.2 (d, 3H), 1.1-3.7 (m, 14H), 3.9-4.6 (m, 4H), 7.2-8.1 (m, 5H).

Example 61

1 H-NMR data of N- (1S-carboxy-3-keto-3-phenylpropyl) -S-alanyl-2S, 3aS, 6aR-octahydrocyclopenta (b) pyrrole-2-carboxylic acid: 1.2 (d, 3H) , 1.1-3.7 (m, 14H),

3.9-4.6 (m, 4H), 7.2-8.1 (m, 5H).

Example 62

N- (1S-Carboxy-3-keto-3-phenyl-propyl) -S-alanyl-2S,

3 H, MMR data for 3aR, 8aS-decahydrocyclohepta (b) pyrrole-2-carboxylic acid: 1.2 (d, 3H), 1.1-3.7 (m, 18H),

3.9-4.6 (m, 4H), 7.3-8.2 (m, 5H).

Example 63

1 H-NMR of N- (1S-carboxy-3-keto-3-phenyl) -anyl-2S, 3aS, 8aR, decahydrocyclohepta (b) pyrrole-2-carboxylic acid: 12 (d, 3H), 1,1- 3.7 (m, 18H),

3.9-4.6 (m, 4H), 7.3-8.2 (m, 5H).

Example 64

N- (1S-Carboxy-3-hydroxy-3-phenylpropyl) -S-alanyl-2S

3 H, 7aS, 7aS-octahydroindole-2-carboxylic acid 1 H-MMR: 12 (d, 3H), 1.1-3.7 (m, 16H), 3.8-4.6 (ni, 4H), 4 , 7 (ni, 1H), 7.1-7.4 (m, 5H)

Example 65

1 H-NMR of N- (1S-Carboxy-3-hydroxy-3-phenyl-propyl) -5-alanine-2S, 3aS, 6aR-octahydocyclopenta (b) pyrrole-2-carboxylic acid: 1.2 (d, 3H) , 1.1-3.7 (m, 14H),

3.9-4.5 (m, 4H), 4.7 (d, 1H), 7.1-7.4 (m, 5H).

Example 66 Endocis-octahydroindole-2-carboxylic acid

290 g. the acetylamino derivative prepared in Example I was refluxed with 1.5 L of 2N hydrochloric acid for 45 minutes. The mixture was then concentrated in vacuo, the residue taken up in ethyl acetate, and then 5 g of Rh / Al ₂ O ₃ (5% Rh) was added and the mixture was hydrogenated under 5 bar of hydrogen. The reduction is carried out at normal pressure, however, the reduction occurs more rapidly under pressure and at higher batches. After uptake of hydrogen, the mixture was filtered, concentrated, and the residue was inoculated with crystals and recrystallized from chloroform (diisopropyl ether), m.p.

An additional 10 g of mother liquor can be recovered, but the resulting material is trans-octahydroindole-215.

-151

It is contaminated with 194.278 carboxylic acids. 10-20 g of material is crystallized from the last mother liquor, consisting of slightly impure trans-octahydroindole carboxylic acid, m.p. 225-230 ° C (dec.) (Solid crystals).

The above can be used to prepare endocis-2-azabicyclo (5.3.0) decan-3-carboxylic acid and endocis-2-azabicyclo (6.3.0) undecan-3-carboxylic acid.

EXAMPLE 67 tran-octahro droin dol-2-carboxylic acid

290 g of the acylamino derivative prepared in Example I are mixed with 2N hydrochloric acid and then heated to reflux. The reaction mixture was concentrated in vacuo, the residue taken up in isopropanol (1 L), reduced with NaBH 4 (about 35 g), and sodium borohydride added portionwise over 30 minutes. The reaction temperature was maintained at 40-50 ° C. After 4 hours, the reaction mixture was concentrated in vacuo, diluted hydrochloric acid was adjusted to pH 6.5, saturated with solid sodium chloride, and the amino acids extracted several times with n-butanol. The organic phase is concentrated and the residue is recrystallized from chloroform / diisopropyl ether fractionally. Yield: 40-60 g of cis compound, 20 g of mixed fraction, 100-130 g of trans compound. 230 ° C (dec.).

Thus, trans-2-azabicyclo (5.3.0) decane-3-carboxylic acid and trans-2-azabicyclo (6.3.0) un decane-3-carboxylic acid can be prepared.

Example 68

N- (1S-carbetoxy-3-phenyl] -propyl) -O-ethyl-S-tyrosyl-2S,

3aR, 7a S-octah droin dol-2-carboxylic acid

a) N-O-R, S-carbetoxy-3-phenylpropyl) -O-ethyl-S-tyrosylbenzyl ester g of benzoyl acrylic acid ethyl ester in 100 ml of ethanol are dissolved in 30 g of O-ethyl -S-triosine benzyl ester was added and reacted in the presence of 0.5 ml triethylamine. The mixture was concentrated and the residue was triturated with diethyl ether / petroleum ether (1-1) and dried in vacuo to give 42 g of the title compound.

b) N- (1-R, S-carbetoxy-3-phenylpropyl) -O-ethyl-S-tyrosine g, the compound obtained according to example 68a) a) in 800 ml glacial acetic acid, 4 g, 10%. hydrogenated at 100 bar at room temperature.

The resulting mixture was chromatographed on silica gel, eluting with ethyl acetate / cyclohexane (1: 3). The organic base was stripped and dried to give 25 g of thin layer chromatography to give the title compound as a nearly uniform product. Mp 205-213 ° C. C ₂₃ H ₂₉ NO _S (399.5) Found: C 69.15%, H 7.31%, N 3.50%.

Found: C 69.5%, H 7.4%, N 3.3%.

c) N- (1- S -Carbetoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid

In the same manner as in Example 32 b), 1.5 g of the benzyl ester described in Example 32 a) are reacted with 2.5 g of N (1 R, 5-carbethoxy-3-phenylpropyl) -O-ethyl-S-tyrosine. , 1.3 dicyclohexylcarbodiimide and 0.8 g of 1-hydroxybenzotriazole. The crude product was chromatographed on silica gel using cyclohexane / ethyl acetate 2: 1 as the eluent. The title compound is obtained as a colorless oil.

The MMR data and mass spectrum data are consistent with the expected structure.

The resulting benzyl ester was hydrogenated as in Example 32c). 0.6 g of the title compound is obtained as a colorless amorphous powder.

¹ H-MMR: 7.3 (s, 5H), 7.1-6.5 (2d, 4H),

4.4-4.0 (m, 4H), 3.9-3.0 (m, 4H), 2.9-1.2 (m, 17H)

1.4 (t, 3H); 1.25 (t, 3H).

Example 69

N- (1-S-Carbetoxy-3-phenyl-propyl) -O-methyl-S-tyrosyl

-23,3aR, 7aS-octahydroindole-2-carboxylic acid

Example 68 was repeated using O-methyl tyrosine benzyl ester as starting material. In the A's spleen.

¹ H-MMR: 7.2 (s, 5H), 7.1-6.5 (2d, 4H),

4.4-4.0 (m, 3H), 3.9-3.0 (m, 3H), 3.5 (s, 3H), 2.91.2 (m, 17H), 1.3 ( t, 3H).

Example 73

N- (1- S -carbethoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl-2S

3aS, 7aR-Octahydroindole-2-carboxylic acid

The starting material was prepared according to the procedure described in Example 68, starting from III. The amino acid described in Example 1b is used. The resulting MMR data are consistent with the expected structure.

Example 71

N- (1- S -carbethoxy-3-phenylpropyl) -O-methyl-S-tyrosyl 2S, 3aS, 7aR-octahydroindole-2-carboxylic acid

The procedure of Example 69 was followed, starting from the compound of Example III. The MMR data are consistent with the expected structure.

Example 72

N- (1- S -carbetoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl 2S, 3aR, 2S-octahydrocyclopenta (b) ρΐσοΙ-2-carboxylic acid

The starting material was prepared as described in Example 68 starting from IV. alkdljTidzzuk amino acid described in example ¹ H-NMR-data: 7.3 (s, 5H), 7.2-6.6 (2d, 4H);

4.4-3.9 (m, 4H), 3.9-3.0 (m, 4H), 2.9-1.2 (m, 15H), 1.35 (t, 3H), 1.25 (t, 3H).

Example 73

N- (1- S -carbethoxy-3-phenylpropyl) -O-methyl-S-tyrosyl 2S, 3aR, 6aS-octahydrocyclopenta (b) 2-carboxylic acid

The procedure of Example 69 was followed, starting from IV. The amino acid described in Example 1b is used. The MMR data are consistent with the assumed structure.

-161

194 278

Example 74

N / 1-S-carbethoxy-3-phenylpropyl) -O-ethyl-5-tyrosyl-2S,

3aS, 6aR-octahydrocyclopenta (b) pyrrole / 2-carboxylic acid

Proceed as in Example 68, and the analytical data are consistent with the structure given.

Example 75

N- (1- S -carbethoxy-3-phenylpropyl) -O-methyl-S-tyrosyl 2S, 3aS, 6aR-octahydrocyclopenta (b) -2-carboxylic acid

Proceed as described in Example 69, and the analytical data are consistent with the structure given.

Claims (2)

CLAIMS 1. A process for the preparation of the bicyclic dipeptides of the formula I and their physiologically acceptable acid addition salts, wherein the hydrogen atoms on the carbon atoms 3a and 6 ⁺ n can be in cis or trans configuration with each other in the cis configuration. the carboxyl group on the carbon atom is in the oxo position relative to the bicyclic ring, wherein n is 0,1 or 2, Rj is methyl, benzyl substituted with 1 to 2 carbon atoms in the para position, R ₂ is hydrogen, a C 1-6 lower alpha sport, Y is hydrogen or hydroxy, Z is hydrogen or Y and Z together represent an oxygen atom, X is phenyl, the asterisk represents the symmetric carbon atom, the carbon atom to which R _{t is} attached to S, to which CO ₂ R _{2 is} attached in the S configuration, a) a compound of the formula II in which R 1, R ₂ , X, Y and Z are as defined above, a compound of the formula III in the formula 3a and the hydrogen atoms of the carbon atoms (6 + n) are in the ds or trans position, in the cis configuration the CO ₂ W group is exo with respect to the bicyclic ring, n is 0.1 or 2, W is C 1 -C 18 alkyl or C 7 -C 10 aryl group, and then cleavage of the W group and optionally the R ₂ group by hydrolysis or hydrogenolysis, or b) Y and Z are taken together to form an oxygen atom to form compounds of formula (I) wherein n, R 1, R _{2 and} X are as defined above, B) ₂ ) a compound of formula IV wherein the hydrogen atoms of 3a and 6 + n are in either cis or trans configuration with each other and in the cis configuration the CO ₂ W group is exo to the bicyclic ring .. and n and Rj are as defined above for ^{1 u} , W is for C 1 -C 18 ali or A group having from 7 to 10 carbon atoms is reacted with a compound of formula (V) wherein R ₂ and X are as defined in formula (I), followed by hydrolysis or hydrogenolysis of W and optionally R ₂ or b ₂ ) a compound of formula IV wherein the substituents are as defined above for a compound of formula VI wherein R ₂ is as defined for the compound of formula I and a compound of formula VII; reacting a compound of formula (X) as defined above, then cleaving the group and optionally R ₂ , or c) for the preparation of compounds of formula I wherein Y and Z are each hydrogen 25 - wherein n, R 1, R ₂ and X are as defined above, a compound of formula IV described in a) bj with a compound of formula VII, wherein R ₂ and X are as defined in formula I and then reducing the resulting Schiff __ base, followed by reduction of W - W is C 1 -C 18 -alkyl or C 7 -C 10 -alkyl - and optionally R _{2 is} cleaved by hydrolysis or hydrogenolysis, or c) for the preparation of a compound of formula I wherein Y is hydroxy and Z is hydrogen _; n is R _1; Formula (I) compound - - wherein Y and Z together represent an oxygen atom - catalytically with hydrogen or with a reducing agent such as sodium borohydride reduction and the compound obtained in the above eljá40 variances any of converting a physiologically acceptable acid addition salts of the above R _2, and X is . 2. A process for the preparation of a pharmaceutical composition having a diuretic effect, comprising the preparation of a compound of formula 0) or a physiologically acceptable acid addition salt thereof according to claim 1, wherein n, R 1, R ₂ , Υ, Ζ, X and the asterisk has the same meaning as in claim 1, further comprising admixing a pharmaceutically acceptable carrier and excipient into a pharmaceutical composition.