DE3508251A1 - Dipeptides - Google Patents

Abstract

Dipeptides of the formula I <IMAGE> in which R<1>-R<5>, Ar and Z have the meaning indicated in Claim 1, and the salts thereof show a blood pressure-lowering effect.

Description

Dipeptides

Dipeptides The invention relates to new dipeptides of the formula I. wherein R1 is H, alkyl or Ar'-alkyl, R2 is H or alkyl, @ 3 CH3 or - (CH2) 4-NH2, R4 is H, alkyl, Ar'-alkyl or acyl, R5 is COOR6, CH2OH or PO (OR8) 2 , R6 H, alkyl, cycloalkyl or alkyl substituted by OH, alkoxy, Ar ', R7-SO2NH, 2-oxopyrrolidino or phthalimido, R7 alkyl, Ar' or Ar'-alkyl, Z CH2, CF2, S, one free or one Functionally modified CO group in the form of an alkylene ketal, alkylene hemithioketal or alkylene thioketal, in which the alkylene group contains 2-5 C atoms or CH-O-CO-Q, Q NHR8 or R8 alkyl, cycloalkyl, Ar ', Ar'-alkyl or -CHR9-COOR10, R9 H, alkyl, Ar'-alkyl, alkylthioalkyl or Ar', R10 H, alkyl or Ar'-alkyl, Ar and Ar 'each unsubstituted or Phenyl which is mono- or polysubstituted by alkyl, alkoxy, alkylthio, phenyl, CF3, 11 CH2OR and / or acyl and R11 denotes H, alkyl or Ar′-alkyl, in which the alkyl and alkoxy groups each denote 1-8, the cycloalkyl groups each denote 3 - 7, the acyl groups each contain 1 - 10 C atoms, in which Ar is only phenyl, alkylphenyl or alkoxyphenyl if (a) Z is CH-O-CO-NHR12 (in which R12 is alkyl with 5 -8 C atoms, Ar ', Ar'-alkyl or -CHR9-COOR10) or and / or (b) R4 is different from H and / or (c) R5 is different from COOH, COO-alkyl and COO-alkyl-Ar ', and salts thereof.

Similar compounds are known from EP-A-12 401, also from EP-A-50 800, EP-A-52 991 and EP-A-79 522.

The invention was based on the object of finding new compounds with valuable Find properties, especially those used in the manufacture of drugs can be used.

It has been found that the compounds of formula I and their salts have very valuable properties. Above all, they inhibit the activity of "angiotensin" converting enzyme "in human serum. This effect can, for example, according to the method of J.W. Ryan et al., Biochem. J. 167, 501 ff.

(1977). With various forms of heightened Blood pressure, the compounds mentioned show a blood pressure lowering effect. in the In some cases, the compounds lower blood pressure in those who wear catheters, spontaneously hypertensive rats (SHR / NIA-Mo / CHB-EMD strain; method see Weeks and Jones, Proc.Soc.Exptl.Biol.Med.

104, 646 ff. (1960)) after intragastric administration of the compounds. Farther is the increase in blood pressure induced by intravenous injection of angiotensin I. in awake normotensive rats by intragastric pretreatment of the animals with the Compounds decreased (method of Sybertz et al., J. Cardiovascular Pharmacol. 5, 643 ff.

(1983)).

The compounds can be used as active pharmaceutical ingredients in human and Veterinary medicine are used, especially for prophylaxis and treatment of cardiovascular and vascular diseases, especially hypertension and heart failure. In addition, the compounds can be used for diagnostic purposes E.g. in patients with hypertension the contribution of the renin-angiotensin system to maintenance to determine the pathological condition.

In the formula I, the alkyl and alkoxy groups preferably have 1 or 2, but also 3, 4, 5, 6, 7 or 8 carbon atoms.

Alkyl is preferably methyl, in the second place ethyl, propyl, Isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, Hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or l, 2,2-trimethylpropyl, heptyl, 1-, 2-, 3-, 4- or 5-methylhexyl, octyl, 1-, 2-, 3-, 4-, 5- or 6-methylheptyl, 1-, 2-, 3- or 4-ethylhexyl. Preferably means alkoxy Methoxy, but also ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec. -Butoxy or tert-butoxy, also pentoxy, 1-, 2- or 3-methylbutoxy, l-ethylpropoxy, hexoxy, 1-, 2-, 3- or 4-methylpentoxy, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutoxy, 1- or 2-ethylbutoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropxy, 1,1,2- or 1,2,2-trimethylpropoxy, heptoxy, 1-, 2-, 3-, 4- or 5-methylhexoxy, octoxy, 1-, 2-, 3-, 4-, 5- or 6-methylheptoxy, 1-, 2-, 3- or 4-ethylhexoxy.

Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl or cycloheptyl, but also e.g.

1- or 2-methylcyclopropyl, 1-, 2- or 3-methylcyclobutyl, 1-, 2- or 3-methylcyclopentyl, 1-, 2-, 3- or 4-methylcyclohexyl.

Acyl is preferably alkanoyl with 1 - 10, in particular 1, 2, 3, 4 or 5 carbon atoms like formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, Isovaleryl, trimethylacetyl, hexanoyl, 4-methylpentanoyl, tert. -Butylacetyl, heptanoyl, Octanoyl, nonanoyl or decanoyl, also aroyl with 7-10 carbon atoms such as benzoyl, o-, m- or p-methylbenzoyl, o-, m- or p-methoxybenzoyl, 1- or 2-naphthoyl; Arylalkanoyl with 8-10 carbon atoms such as phenylacetyl, 1- or 2-phenylpropionyl; Alkoxycarbonyl with preferably 2 - 7 carbon atoms such as tert. -Butoxycarbonyl (BOC); Ar'-alkoxycarbonyl with preferably 8-12 carbon atoms such as benzyloxycarbonyl (CBZ).

Ar and Ar ', which can be the same or different, preferably denote Phenyl or 3,4- or 2,5-dimethoxyphenyl, furthermore preferably o-, m- or p-toyl, o-, m- or p-ethylphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-methylthiophenyl, o-, m- or p-phenylphenyl (= 2-, 3- or 4-biphenylyl), o-, m- or p-trifluoromethylphenyl, o-, m- or p-hydroxymethylphenyl, o-, m- or p-methoxymethylphenyl, o-, m- or p-Benzyloxymethylphenyl, o-, m- or p-formylphenyl, o-, m- or p-acetylphenyl, o-, m- or p-benzoylphenyl, 2,3-, 2,4-, 2,6- or 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl.

Specifically, R¹ preferably denotes H, methyl, ethyl, tert-butyl or benzyl, also propyl, isopropyl, isobutyl or sec-butyl.

R2 preferably denotes H or methyl, furthermore ethyl, propyl, isopropyl, Butyl, isobutyl, tert-butyl, pentyl, isopentyl or hexyl.

R3 preferably denotes methyl, furthermore 4-aminobutyl.

R4 preferably denotes H, furthermore preferably methyl, furthermore preferably ethyl, benzyl, formyl, acetyl, benzoyl or CBZ.

R7 is preferably methyl, ethyl, phenyl or benzyl.

Accordingly, R6 is preferably H; Alkyl, especially with 1-4 Carbon atoms, such as methyl or ethyl; Cycloalkyl, especially cyclopropyl, cyclobutyl, Cyclopentyl or cyclohexyl; Hydroxyalkyl, in particular with 2 - 4 carbon atoms such as 2-hydroxyethyl, also l-hydroxyethyl, 1-, 2- or 3-hydroxypropyl, 1-, 2-, 3- or 4-hydroxybutyl; Alkoxyalkyl, in particular with 2 - 5 carbon atoms such as methoxymethyl, 1- or 2-methoxyethyl, ethoxymethyl, 1-, 2- or 3-methoxypropyl, 1- or 2-ethoxyethyl, Propoxymethyl, isopropoxymethyl, 1-, 2-, 3- or 4-methoxybutyl, 1-, 2- or 3-ethoxypropyl, 1- or 2-propoxyethyl, butoxymethyl, isobutoxymethyl; Ar'-alkyl, especially benzyl; R7-SO2NH-alkyl, in particular methylsulfonamidomethyl, 1- or 2-methylsulfonamidoethyl, Ethylsulfonamidomethyl, 1- or 2-ethylsulfonamidoethyl, phenylsulfonamidomethyl, 1- or 2-phenylsulfonamidoethyl, benzylsulfonamidomethyl, 1- or 2-benzylsulfonamidoethyl; 2-oxopyrrolidinoalkyl such as 2- (2-oxopyrrolidinoethyl); Phthalimidoalkyl such as 2-phthalimidoethyl.

R5 is preferably COOR6, where R6 is preferably one of those indicated above Has meanings; R5 is also preferably CH2OH, PO (OCH3) 2 or PO (OC2H5) 2.

Z is preferably CH2, CF, S, CO, CH-O-CO-NH-CH3, CH-O-CO-NH-C2H5, CH-O-CO-NH-C6Hll, CH-O-CO-NH-C6H5, CH-O-CO-NH-CH2C6H5, CH-O-CO-NH-CH (CH3) -C6H5, CH-O-CO-NH-CH2-COOH, CH-O-CO-NH-CH2-COOCH3, CH-O-CO-NH-C02-COOC2H5 , CH-O-CO-NH-CH2-COOC4Hg, CH-O-CO-NH-CH2-COOCH2C6H5, CH-O-CO-NH-CH (CH3) -COOH, CO-O-CO-NH-CH ( CH3) -COOCH3, CH-O-CO-NH-CH (CH3) -COOC2H5, CH-O-CO-NH-CH (CH3) -COOC4H97 CH-O-CO-NH-CH (CH3) -COOCH2C6H5, CH -O-CO-NH-CH (iso-C3H7) -COOH, CH-O-CO-NH-CH (iso-C3H7) -COOCH3, CH-O-CO-NH-CH (iso-C3H7) -COOC2H5, CH-O-CO-NH-CH (iso-C3H7) -COOC4H9, CH-O-CO-NH-CH (iso-C3H7) -COOCH2C6H5, CH-O-CO-NH-CH (iso-C4H9) -COOH , CH-O-CO-NH-CH (iso-C4H9) -COOCH3, CH-O-Co-NH-CH (iso-C4H9) -COOC2H5, CH-O-CO-NH-CH (iso-C4H9) - COOC4H9, CH-O-CO-NH-CH (iso-C4H9) -COOCH2C6H5, CH-O-CO-NH-CH (sec.-C4H9) -COOH, CH-O-CO-NH-CH (sec.- C4H9) -COOCH3, CH-O-CO-NH-CH (sec-C4H9) -COOC2H5, CH-O-CO-NH-CH (sec-C4H9) -COOC4H9, CH-O-CO-NH-CH (sec-C4H9) -COOCH2C6H5, CH-O-CO-NH-CH (CH2C6H5) -COOH, CH-O-CO-NH-CH (CH2C6H5) -COOCH3, CH-O-CO-NH-CH (CH2C6H5 ) -COOC2H5, CH-O-CO-NH-CH (CH2C6H5) -COOC4H9, CH- O-CO-NH-CH (CH2C6H5) -COOCH2C6H5, CH-O-CO-NH-CH (CH2CH2SCH3) -COOH, CH-O-CO-NH-CH (CH2CH2SCH3) -COOCH3, CH-O-CO-NH -CH (CH2CH2SCH3) -COOC2H5, CH-O-CO-NH-CH (CH2CH2SCH3) -COOC4H4, CH-O-CO-NH-CH (CH2CH2SCH3) -COOCH2C6H5, CH-O-CO-NH-CH (C6H5) -COOH, CH-O-CO-NH-CH (C6H5) -COOCH3, CH-O-CO-NH-CH (C6H5) -COOC2H5, CH-O-CO-NH-CH (C6H5) -COOC4Hg, CH- O-CO-NH-CH (C6H5) -COOCH2C6H5.

Accordingly, the invention particularly features those Compounds of the formula I in which at least one of the radicals mentioned is one of the has preferred meanings given above. Some preferred groups of Compounds can be expressed by the following sub-formulas Ia to Ihf, which correspond to the formula I and in which the radicals unspecified in Formula I have given meaning, in which, however, in Ia R4 is alkyl, Ar'-alkyl or Means acyl; in Ib R5 COOR6 and R6 cycloalkyl or through OH, alkoxy, R7-SO2NH, 2-oxopyrrolidino or phthalimido is substituted alkyl; in Ic R5 CH2OH, or is PO (OR6) 2; in Id R5 is COOR6 and R6 is cycloalkyl; in Ie R5 is COOR6 and R6 is alkyl substituted by OH; in If R5 COOR6 and R6 denotes alkyl substituted by alkoxy; also Ig or Iga to Igf, which den Formulas I and Ia to If correspond, in which Ar is additionally 3,4- or 2,5-dimethoxyphenyl means; also Ih or Iha to Ihf, which correspond to the formulas I or Ia to If, in which Ar is additionally phenyl.

The compounds of the formula I have at least three chiral centers. You can therefore in their preparation in different racemic and / or optical active forms occur. All of these forms are included in the subject invention. The S, S, S-forms in which the stereochemistry of the three necessarily exist chiral centers corresponding to those of the natural L-amino acids are preferred.

The invention also relates to a process for the preparation of compounds of the formula I according to claim 1 and their salts, characterized in that a compound of the formula II EH II in which E is the remainder and R1, R2 and Z have the meaning given in claim 1 or one of their reactive derivatives with a dicarboxylic acid derivative of the formula III HOOC-CHR3-NR4-CHR5-CH2CH2-Ar III wherein R3, R4, R5 and Ar are those given in claim 1 Have meaning or reacts one of its reactive derivatives, or that a compound of the formula IV E-CO-CHR3X IV with a compound of the formula V Y-CHR5-CH2CH2-Ar V wherein one of the radicals X and Y is ONLY 4, the other Cl , Br, J or a reactive, functionally modified OH group and R3, R4, R5, E and Ar have the meanings given in claim 1 or above, or that a compound of the formula I in which Z is CH-O-CO -Q denotes a hydroxy compound otherwise corresponding to the formula I, but which contains the group -CHOH- in place of Z, with an isocyanate of the formula OCN-R8 or a carbamic acid chloride of the formula Cl-CO-Q or successively with a carbonic acid derivative and a Amin of Fo and / or that a compound of the formula I or another compound corresponding to the formula I, but which instead of one or more H atoms has one or more protective groups and / or reducible or hydrogen-replaceable group (s) and / or or contains CC multiple bond (s), treated with solvolyzing or reducing agents and / or that an acid of the formula I (R1 and / or R6 = H) is esterified and / or an ester of the (R1 6 formula 1 (R1 and / or R6 are different from H) converted into the corresponding acid of the formula I (R1 and / or R6 = H) and / or an NH group is alkylated or acylated and / or a compound of the formula I is in by treatment with an acid or base converts one of its salts.

The compounds of formula I and also the starting materials for their Production are also produced by methods known per se, like them in the literature (e.g. in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart; also EP-A-12 401, EP-A-48 159, EP-A-79 521, US Pat. No. 4,374,829), under reaction conditions which are known and suitable for the reactions mentioned. You can also use make use of variants known per se but not mentioned here in greater detail.

The starting materials can, if desired, also be formed in situ so that they are not isolated from the reaction mixture, but immediately further to the compounds of formula I.

The compounds of the formula I are preferably by reacting Compounds of the formula II obtained with dicarboxylic acid derivatives of the formula III. Included it is expedient to work according to the usual methods of peptide synthesis, such as those described e.g. in Houben-Weyl, l.c., Volume 15 / II, pages 1 to 806 (1974).

The reaction is preferably successful in the presence of a dehydrating agent, e.g. a carbodiimide such as dicyclohexylcarbodiimide (DCC) or dimethylaminopropylethyl carbodiimide, also propanephosphonic anhydride (cf. Angew.Chem. 92, 129 (1980)), diphenylphosphorylazide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran (THF) or dioxane, an amide such as dimethylformamide (DMF) or dimethylacetamide, a nitrile such as acetonitrile, at temperatures between about -10 and 40, preferably between 0 and 300.

Suitable reactive derivatives can also be used in place of II or III of these substances are used in the reaction, e.g. those in which reactive Groups are blocked intermediately by protecting groups. The amino acid derivatives III can be used, for example, in the form of their activated esters, which are expediently described in situ, e.g. by adding l-hydroxybenzotriazole or N-hydroxysuccinimide.

Most of the starting materials of the formula II are known. Carbamates of the formula II (Z = CH-O-CO-NHR8) can be obtained, for example, by reacting hydroxyproline derivatives according to formula II (Z = -CHOH-) with ent- speaking isocyanates of the formula R8-NCO, alkyl derivatives of the formula II (R2 = alkyl) also by alkylation of compounds of the formula II (R2 = H), in which the NH group is an intermediate in a customary manner is protected, ester (formula II, R1 = alkyl or Ar'-alkyl) also by esterification of carboxylic acids of the formula II (R1 = H).

The starting materials of the formula III can be obtained, for example, from N-alkylation of compounds of the formula HOOC-CHR³-NH2 with compounds of the formula V (Y = X ') or of amino compounds of the formula V (Y = NH2) with compounds of Formula HOOC-CHR3-X 'using one of the methods described below.

The compounds of the formula I can also be prepared by reaction of amino compounds of the formula IV (X = NH2) with compounds of the formula V (Y = X ') or of amino compounds of the formula V (Y = NH2) with compounds of the formula IV (X = X ').

The group X 'preferably represents C1, Br, J or an alkyl or arylsulfonyloxy group with 1 - 10 carbon atoms such as methane, ethane, benzene, p-toluene or 1- or 2-naphthalenesulfonyloxy. The implementation is expediently carried out in one the mentioned inert solvents or solvent mixtures, e.g. acetonitrile, at temperatures between about 0 and 1200, preferably between about 20 and 1000. It is advisable to add a base such as triethylamine or pyridine.

For the preparation of carbamates of the formula I, in which Z denotes CH-O-CO-Q, can be an I corresponding hydroxy compound, but instead of Z the group -CHOH- contains, with an isocyanate of the formula OCN-R8 or one Carbamic acid chloride of the formula C1-CO-Q or in succession with a carbonic acid derivative (e.g. COCl2, C1COOC2H5) and an amine of the formula H-Q are expedient in the presence of an inert solvent such as THF, ethyl acetate or chloroform and a base such as triethylamine, pyridine or diazabicycloundecene at temperatures between 0 and 500.

The compounds of formula I can also be obtained by they from their functional derivatives by solvolysis, especially hydrolysis, or sets free by hydrogenolysis.

Preferred starting materials for solvolysis or hydrogenolysis are those in place of one or more free amino and / or carboxy groups contain corresponding protected amino and / or carboxy groups, preferably those that have an amino protective group instead of an H atom that is connected to an N atom carry, especially those of the formula VI E-CO-CH ((CH2) 4-NHL) -NH-CHR5-CH2CH2Ar VI wherein L is an amino protecting group.

Furthermore, starting materials are preferred that instead of the H atom of a Carboxy group carry a carboxy protecting group.

It is also possible to use several - identical or different - protected amino and / or carboxy groups may be present in the molecule of the starting material. if the existing protecting groups are different from each other, they can in many cases be selectively split off.

The term "amino protecting group" is well known and related based on groups that are appropriate to an amino group before chemical reactions to protect (to block), but which are easily removable after the desired one chemical reaction has been carried out elsewhere on the molecule. Typical for such groups are in particular unsubstituted or substituted acyl groups, furthermore unsubstituted or substituted aryl (e.g. 2,4-dinitrophenyl) or aralkyl groups (e.g. benzyl, 4-nitrobenzyl, triphenylmethyl). Since the amino protecting groups according to the The type and size of the reaction (or sequence of reactions) desired to be removed otherwise not critical; however, those with 1 to 20 are preferred, in particular 1 - 8 carbon atoms. The term "acyl group" is used in connection with the present Process to be understood in the broadest sense. It encompasses aliphatic, araliphatic, acyl groups derived from aromatic or heterocyclic carboxylic acid or sulfonic acids and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.

Examples of such acyl groups are alkanoyl such as formyl, acetyl, Propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as phenoxyacetyl; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodoethoxycarbonyl; Aralkoxycarbonyl such as benzyloxycarbonyl (CBZ; "carbobenzoxy"), 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC). Preferred protecting groups are CBZ, FMOC, benzyl and acetyl.

The term "carboxy protecting group" is also well known and refers to groups that are apt to be a carboxy group before chemical Protect implementations, but which are easily removable after the desired chemical reaction has been carried out elsewhere on the molecule. Typical for such groups, the abovementioned are unsubstituted or substituted Aryl, aralkyl or acyl groups, and also alkyl groups. The nature and size The carboxy protecting group is not critical as it is according to the desired chemical Reaction or reaction sequence can be removed again.

The functional derivatives of the to be used as starting materials Compounds of the formula I can be prepared by customary methods of amino acid and peptide synthesis as they are e.g. in the mentioned standard works and patent applications are described.

The release of the compounds of the formula I from their functional Derivatives succeed - depending on the protective group used - e.g. with strong acids, useful with trifluoroacetic acid or perchloric acid, but also with other strong ones inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. the The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably the above also e.g. carboxylic acids such as acetic acid, also alcohols such as isopropanol or tert. -Butanol and water. Mixtures of the aforementioned solvents are also used Question. Trifluoroacetic acid will preferably in excess without addition Another solvent used, perchloric acid in the form of a mixture of Acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperatures for the cleavage are expediently between about 0 and about 500, preferably working between 15 and 300 (room temperature).

For example, the BOC group can preferably be mixed with 40% trifluoroacetic acid split off in methylene chloride or with about 3 to 5 N HC1 in dioxane at 15-300 the FMOC group with an approximately 5 to 20% solution of dimethylamine, Diethylamine or piperidine in DMF at 15-300.

Compounds of the formula I are also more appropriate by reduction Compounds available, but instead of one or more H atoms, one or several reducible or hydrogen-replaceable group (s) and / or C-C multiple bonds contain.

Preferred starting materials for the reduction correspond to the formula VII E-CO-G-CH2CH2Ar VII where G -CR3 = N-CHR5-, -CHR3 -N = CR5-, -CHR3-NL'-CHR5 or -CH ((CH2) 4-NHL ') - NH-CHR5- and L' is a hydrogenolytically removable amino protective group mean and E, Ar and R3 to R5 have the meanings given.

Hydrogenolytically removable protective groups L '(e.g. CBZ or benzyl) can e.g. by treating with hydrogen in the presence of a catalyst (e.g. a noble metal catalyst such as palladium, expediently on a carrier such as carbon) be split off. The solvents indicated above are particularly suitable as solvents e.g. alcohols such as methanol or ethanol or amides such as DMF. Hydrogenolysis will usually at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-300 and 1-10 bar. Hydrogenolysis The CBZ group, for example, works well on 5- to 10% Pd-C in methanol at 20 - 300.

Schiff bases of the formula VII (G = -CR3 = N-CHR5- resp.

-CHR3-N = CR5-) are expediently prepared by corresponding Carbonyl compounds of the formulas E-Co-co-R3 or R5-COCH2CH2Ar with the corresponding Amines of the formulas 5 H2N-CHR -CH2CH2-Ar or E-CO-CHR3 or converts. Here you can corresponding aminols or enamines are also formed. All of these connections can e.g. be reduced to compounds of formula I with NaBH3CN, expedient in one of the inert solvents mentioned, e.g. an alcohol such as ethanol, a Nitrile such as acetonitrile, in water or in mixtures of these solvents at temperatures between about 0 and about 800, preferably between 10 and 400. Particularly useful is an in situ reaction by bringing the carbonyl compound and the amine together converts, but the reaction product is not isolated, but the reaction mixture treated with the reducing agent. A catalytic hydrogenation of these starting materials, e.g. under the specified conditions is also possible.

If desired, an acid of the formula I (R¹ and / or R6 = H) be esterified by methods known per se, e.g. by reaction with the appropriate Alcohol in the presence of an acid or by reaction with a corresponding diazoalkane.

It is also possible, for example, to use an ester of the formula I in which R¹ and / or R6 are different from H, into the corresponding acid of the formula I (R¹ and / or R6 = H), e.g. with aqueous-dioxanic sodium hydroxide solution at room temperature. tert-Butyl esters can be selectively produced by treating with HCl in dioxane at about 15 - 250 are converted into carboxylic acids; others are present in the molecule Alkyl ester groups not attacked. Benzyl esters can according to the above Methods are split hydrogenolytically.

It is also possible to use known methods in one connection of the formula I (R4 = H) to alkylate or acylate an NH group. In the term By "alkylating" is included an "ar'-alkylation" (e.g., benzylation). Man can, for example, with corresponding alkyl or ar'-alkyl halides among the above for the implementation of IV with V specified conditions work, but also with aldehydes under reducing conditions.

An N-acylation succeeds e.g. with an appropriate acyl halide or anhydride in the presence of a base between about 0 and about 100 °, but also with the free acid under the conditions given above for the reaction of II with III.

A base of the formula I can be converted into the associated acid addition salt with an acid be transferred. For this implementation in particular acids come into question, which Deliver physiologically harmless salts. Inorganic acids can be used e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acid such as orthophosphoric acid, sulfamic acid, also organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, e.g.

Formic acid, acetic acid, propionic acid, pivalic acid, diethylene acetic acid, Malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, Malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, citric acid, Gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulphonic acid, Ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Naphthalene mono- and disulphonic acids, laurylsulphuric acid. Salts with physiological Acids that are not harmless, e.g. picrates, can be used for isolation and / or purification of the compounds of the formula I can be used.

An acid of the formula I can by reaction with a base in a their physiologically harmless metal or. Ammonium salts are transferred. The salts are in particular the sodium, potassium, magnesium, calcium and ammonium salts considered, further substituted ammonium salts, e.g. the dimethyl, diethyl or Diisopropylammonium, monoethanol, diethanol and triethanolammonium, cyclohexylammonium, Dicyclohexylammonium and dibenzylethylenediammonium salts, furthermore, for example, salts with N-methyl-D-glucamine or with basic amino acids such as arginine or lysine.

The new compounds of the formula I and their physiologically harmless ones Salts can be used in the manufacture of pharmaceutical preparations by they are used together with at least one carrier or auxiliary substance and, if desired, together with one or more other active ingredient (s) in a suitable dosage form brings. The preparations obtained in this way can be used as medicaments in the human or Veterinary medicine can be used. The carrier substances are organic or inorganic substances in question, which are suitable for enteral (e.g. oral) or parenteral Application are suitable and do not react with the new compounds, for example Water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatin, soy lecithin, carbohydrates such as lactose or Starch, magnesium stearate, talc, cellulose.

For oral use in particular tablets, coated tablets, capsules, Syrups, juices or drops, for rectal use suppositories, for parenteral use Application solutions, preferably oily or aqueous solutions, also suspensions, Emulsions or implants. The new compounds can also be lyophilized and the lyophilizates obtained are used, for example, for the production of injection preparations will. The specified preparations can be sterilized and / or auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, Salts to influence the osmotic pressure, buffer substances, color, taste and / or contain flavorings. You can also use one or more, if desired contain other active ingredients, e.g.

one or more vitamins and / or diuretics and / or antihypertensive agents.

The substances according to the invention are usually analogous to other known, commercially available peptides or to captopril, in particular but in analogy to the compounds described in EP-A-12 401 such as enalapril administered, preferably in doses between about 1 mg and 1 g, in particular between 5 mg and 200 mg per dosage unit. The daily dosage is preferably between about 0.07 and 3 mg / kg body weight. The specific dose for everyone However, the patient depends on a wide variety of factors, such as the Effectiveness of the specific compound used, based on age, body weight, general Health status, gender, diet, time and route of administration, on the rate of elimination, drug combination and severity of each Disease to which the therapy applies. Oral application is preferred.

Above and below, all temperatures are given in ° C. In the The following examples mean "customary work-up": If necessary, Add water, extract with ether or dichloromethane, separate, dry the organic Phase over sodium sulfate, filtered, evaporated and purified by chromatography on silica gel and / or crystallization.

Example 1 A mixture of 2.56 g of 2-methyl-L-proline benzyl ester hydrochloride, 3.09 g of 1-N- (1S- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanine, 1.23 ml of triethylamine, 1.53 g of l-hydroxybenzotriazole, 2.06 g of DCC and 40 ml of DMF are added for 1 hour.

stirred at 0 °. Customary work-up gives oily 1-N- (IS- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L-proline benzyl ester.

1-N- (IS- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-L-proline benzyl ester is obtained analogously 1-N- (IS- (2-Ethoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-L-proline benzyl ester 1-N- (IS-Cyclopentoxycarbonyl-3-phenylpropyl) -L-alanyl-L-proline benzyl ester 1-N- (IS-Cyclohexoxycarbonyl-3-phenylpropyl) -L-alanyl-L-proline benzyl ester 1-N- (IS- (2-Hydroxyethoxycarbonyl-3-phenylpropyl) -L-alanyl-L-proline benzyl ester 1-N- (IS- (2-methylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-L-proline benzyl ester 1-N- (IS- (2-Phenylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-L-proline benzyl ester 1-N- (IS- (2-Benzylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-L-proline benzyl ester 1-N- (IS- (2- (2-Oxopyrrolidino) ethoxycarbonyl) -3-phenylpropyl) -L-alanyl-L-proline benzyl ester 1-N- (IS- (2-phthalimidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-L-proline benzyl ester 1-N- (IS- (2-Ethoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L-proline benzyl ester 1-N- (IS-Cyclopentoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L-proline-benzyl ester 1-N- (IS-Cyclohexoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L-proline benzyl ester 1-N- (IS- (2-Hydroxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L-proline benzyl ester 1-N- (IS- (2-Methylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L-proline-benzyl ester 1-N- (IS- (2-Phenylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L-proline-benzyl ester 1-N- (IS- (2-Benzylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L-proline-benzyl ester 1-N- (IS- (2- (2-Oxopyrrolidino) -ethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L-proline-benzyl ester 1-N- (IS- (2-phthalimidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L-proline benzyl ester 1-N- (IS- (2-methoxyethoxycarbonyl) -3-p-methylthiophenylpropyl) -L-alanyl-L-proline benzyl ester 1-N- (IS- (2-methoxyethoxycarbonyl) -3- (4-biphenylyl) propyl) -L-alanyl-L-proline benzyl ester 1-N- (IS- (2-methoxyethoxycarbonyl) -3-m-trifluoromethylphenylpropyl) -L-alanyl-L-proline benzyl ester 1-N- (IS- (2-methoxyethoxycarbonyl) -3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-L-proline benzyl ester 1-N- (IS- (2-methoxyethoxycarbonyl) -3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-L-proline benzyl ester l-N- (1S- (2-Methoxyethoxycarbonyl) -3-p-methylthiophenylpropyl) -L-alanyl-2-methyl-L-proline benzyl ester 1-N- (IS- (2-methoxyethoxycarbonyl) -3- (4-biphenylyl) propyl) -L-alanyl-2-methyl-L-proline benzyl ester 1-N- (IS- (2-methoxyethoxycarbonyl) -3-m-trifluoromethylphenylpropyl) -L-alanyl-2-methyl-L-proline benzyl ester 1-N- (IS- (2-methoxyethoxycarbonyl) -3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-L-proline benzyl ester 1-N- (IS- (2-methoxyethoxycarbonyl) -3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-L-proline benzyl ester 1-N- (IS-Cyclohexoxycarbonyl-3-p-methylthiophenylpropyl) -L-alanyl-L-proline-benzyl ester 1-N- (IS-Cyclohexoxycarbonyl-3- (4-biphenylyl) propyl) -L-alanyl-L-proline benzyl ester l-N- (lS-Cyclohexoxycarbonyl-3-m-trifluoromethylphenylpropyl) -L-alanyl-L-proline benzyl ester 1-N- (IS-Cyclohexoxycarbonyl-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-L-proline benzyl ester 1-N- (IS-Cyclohexoxycarbonyl-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-L-proline benzyl ester 1-N- (IS-Cyclohexoxycarbonyl-3-p-methylthiophenylpropyl) -L-alanyl-2-methyl-L-proline benzyl ester 1- N- (IS-Cyclohexoxycarbonyl-3- (4-biphenylyl) propyl) -L-alanyl-2-methyl-L-proline-benzyl ester 1-N- (IS-Cyclohexoxycarbonyl-3-m-trifluoromethylphenylpropyl) -L-alanyl-2-methyl-L-proline-benzyl ester 1- N- (IS-Cyclohexoxycarbonyl-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-L-proline-benzyl ester 1-N- (IS-Cyclohexoxycarbonyl-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-L-proline-benzyl ester 1-N- (IS-carbethoxy-3-p-methylthiophenylpropyl) -L-alanyl-L-proline benzyl ester 1-N- (IS-Carbethoxy-3- (4-biphenylyl) -propyl) -L-alanyl-L-proline-benzyl ester 1-N- (IS-Carbethoxy-3-m-trifluoromethylphenylpropyl) -L-alanyl-L -proline benzyl ester 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-L-proline benzyl ester 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-L-proline benzyl ester 1-N- (IS-carbethoxy-3-p-methylthiophenylpropyl) -L-alanyl-2-methyl-L-proline benzyl ester 1-N- (IS-carbethoxy-3- (4-biphenylyl) propyl) -L-alanyl-2-methyl-L-proline benzyl ester 1-N- (IS-carbethoxy-3-m-trifluoromethylphenylpropyl) -L-alanyl-2-methyl-L-proline benzyl ester 1- N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-L-proline benzyl ester 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-L-proline benzyl ester 1-N- (IS- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (IS- (2-ethoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (IS-Cyclopentoxycarbonyl-3-phenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS-Cyclohexoxycarbonyl-3-phenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (IS- (2-Hydroxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester l-N- (lS- (2-methylsulfonamidoethoxycarbonyl) -3-phenylpropyl ) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS- (2-phenylsulfonamidoethoxycarbonyl) -3-phenylpropyl ) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (IS- (2-benzylsulfonamidoethoxycarbonyl) -3-phenylpropyl ) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (IS- (2- (2-oxopyrrolidino) ethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-ethylenedioxy -L-proline benzyl ester 1-N- (IS- (2-phthalimidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (IS- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (1S- (2-ethoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (IS-Cyclopentoxycarbonyl-3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (IS-Cyclohexoxycarbonyl-3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS- (2-Hydroxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS- (2-methylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS- (2-phenylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (IS- (2-Benzylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (IS- (2- (2-Oxopyrrolidino) ethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS- (2-phthalimidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS-carbethoxy-3-p-methylthiophenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (IS-carbethoxy-3- (4-biphenylyl) propyl) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (IS-carbethoxy-3-m-trifluoromethylphenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (IS-carbethoxy-3-p-methylthiophenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS-carbethoxy-3- (4-biphenylyl) propyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS-carbethoxy-3-m-trifluoromethylphenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (1S- (2-methoxyethoxycarbonyl) -3-p-methylthiophenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (IS- (2-Methoxyethoxycarbonyl) -3- (4-biphenylyl) -propyl) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (IS- (2-methoxyethoxycarbonyl) -3-m-trifluoromethylphenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester 1-N- (IS- (2-methoxyethoxycarbonyl) -3- (2,5-dimethOxyphenyl) propyl) -L-alanyl-4, 4-ethylenedioxy-L-proline benzyl ester 1-N- (IS- (2-methoxyethoxycarbonyl) -3- (3,4-dimethoxyphenyl) propyl) ) -L-alanyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS- (2-methoxyethoxycarbonyl) -3-p-methylthiophenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS- (2-methoxyethoxycarbonyl) -3- (4-biphenylyl) propyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS- (2-methoxyethoxycarbonyl) -3-m-trifluoromethylphenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS- (2-methoxyethoxycarbonyl) -3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS- (2-methoxyethoxycarbonyl) -3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline benzyl ester 1- N- (IS- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline benzyl ester 1- N- (IS- (2-ethoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline benzyl ester 1- N- (IS-Cyclopentoxycarbonyl-3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline benzyl ester 1- N- (IS-Cyclohexoxycarbonyl-3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline benzyl ester 1- N- (IS- (2-Hydroxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline benzyl ester 1- N- (IS- (2-methylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS- (2-Phenylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline-benzyl ester 1- N- (IS- (2-Benzylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline benzyl ester l-N- (lS- (2- (2-oxopyrrolidino) ethoxycarbonyl) -3-phenylpropyl ) -L-alanyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS- (2-phthalimidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS- (2-Methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline benzyl ester 1- N- (IS- (2-ethoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS-Cyclopentoxycarbonyl-3-phenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS-Cyclohexoxycarbonyl-3-phenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS- (2-Hydroxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS- (2-methylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS- (2-Phenylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS- (2-Benzylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS- (2- (2-Oxopyrrolidino) ethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS- (2-phthalimidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS-carbethoxy-3-p-methylthiophenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS-carbethoxy-3- (4-biphenylyl) propyl) -L-alanyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS-carbethoxy-3-m-trifluoromethylphenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS-carbethoxy-3-p-methylthiophenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS-carbethoxy-3- (4-biphenylyl) propyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS-carbethoxy-3-m-trifluoromethylphenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline benzyl ester 1-N- (IS-Dimethylphosphono-3-phenylpropyl) -L-alanyl-L-proline benzyl ester 1-N- (IS-Diethylphosphono-3-phenylpropyl) -L-alanyl-L-proline benzyl ester 1-N- (IS- (2-Methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-difluoro-L-proline benzyl ester Benzyl l-N- (lS- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-L-thiazolidine-2-carboxylate 1-N- (IS- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-al anyl -4-oxo-L-proline-ethylene hemithioketal benzyl ester 1-N- (IS- (2-Methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-ethylenedithio-L-proline benzyl ester 1-N- (IS- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-propylenedithio-L-proline benzyl ester 1-N- (IS-Carbethoxy-3- (2,5-dimethoxyphenyl) -propyl) -L-alanyl-4,4-difluoro-L-proline-benzyl ester 1-N- (IS-Carbethoxy-3- (2,5-dimethoxyphenyl) -propyl) -L-alanyl-L-thiazolidine-2-carboxylic acid benzyl ester 1- N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4-oxo-L-proline-ethylene hemithioketal-benzyl ester 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4,4-ethylenedithio-L-proline benzyl ester 1-N- (IS-Carbethoxy-3- (2,5-dimethoxyphenyl) -propyl) -L-alanyl-4,4-propylenedithio-L-proline-benzyl ester.

Example 2 To a mixture of 3.01 g of 4R-N-phenylcarbamoyloxy-L-proline methyl ester hydrochloride (oily; obtainable by reaction of 1-benzyloxycarbonyl-4R-hydroxy-L-proline methyl ester with phenyl isocyanate and subsequent hydrogenolytic cleavage of the CBZ group) 3.16 g of N- (1S-carbethoxy-3-phenylpropyl) -L-alanine hydrochloride, 1.8 ml of N-methylmorpholine, 1.32 g of 1-hydroxybenzotriazole and 120 ml of CH2C12 are added dropwise at -5 "with stirring Solution of 1.8 g of DCC in 60 ml of CH2Cl2, stirs for another 12 hours at 20 °, cools to -700, filtered, the filtrate was washed successively with 1N hydrochloric acid and saturated NaHCO3 solution and evaporates. After purification by chromatography (silica gel; toluene / ethyl acetate 1: 1) 1-N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-phenylcarbamoyloxy) -L-proline methyl ester is obtained. Maleate, F. 1410.

The following is obtained analogously: 1-N- (lS-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-methylcarbamoyloxy) -L-proline benzyl ester 1-N- (lS-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-butylcarbamoyloxy) -L-proline benzyl ester, Maleate, F. 1200 1-N- (IS-Carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-cyclopentylcarbamoyloxy) -L-proline-benzyl ester 1-N- (IS-Carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-cyclohexylcarbamoyloxy) -L-proline benzyl ester 1-N- (lS-Carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-phenylcarbamoyloxy) -L-proline benzyl ester, Maleate, F. 1190 1-N- (lS-Carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-p-tolylcarbamoyloxy) -L-proline benzyl ester 1-N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-pmethoxyphenylcarbamoyloxy) -L-proline benzyl ester 1-N- (lS-Carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N- (3,4-dimethoxyphenyl) -carbamoyloxy) -L-proline benzyl ester 1-N- (lS-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-benzylcarbamoyloxy ) -L-proline benzyl ester 1-N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-pmethoxyphenylcarbamoyloxy) -L-proline benzyl ester 1-N- (lS-Carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N- (1-phenylethyl) -carbamoyloxy) -L-proline benzyl ester, Maleate, F. 1600 I-N- (IS-Carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-ethoxycarbonylmethyl-carbamoyloxy) -L-proline-benzyl ester 1-N- (IS-Carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-butoxycarbonylmethyl-carbamoyloxy) -L-proline-benzyl ester 1-N- (IS-Carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N- (1-carbethOxy-2-methylpropyl) -carbamoyloxy) -L-proline benzyl ester 1-N- (lS-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N- (1-carbethoxy-2-methylbutyl) -carbamoyloxy) -L-proline benzyl ester 1-N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N- (1-carbethOxy-3-methylbutyl) -carbamoyloxy) -L-proline benzyl ester 1-N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N- (1-carbethoxy-2-phenylethyl) -carbamoyloxy) -L-proline benzyl ester 1- N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N- (1-carbethoxy-3-methylthiopropyl) -carbamoyloxy) -L-proline benzyl ester 1-N- (lS-Carbethoxy-3-phenylpropyl) -L-alanyl-2-methyl-4R- (N-ethoxycarbonylmethyl-carbamoyloxy) -L-proline-benzyl ester 1-N- (lS-carbethoxy-3-phenylpropyl) -L-alanyl-2-methyl-4R- (N-butoxycarbonylmethyl-carbamoyloxy) -L-proline-benzyl ester 1-N- (1S-carbethoxy-3-phenylpropyl) -L-alanyl-2-methyl-4R- (N- (l-carbethoxy-2-methylpropyl) -carbamoyloxy) -L-proline benzyl ester 1-N- (lS-carbethoxy-3-phenylpropyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-2- methylbutyl) -carbamoyloxy) -L-proline benzyl ester 1-N- (1S-carbethoxy-3-phenylpropyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-3-methylbutyl) -carbamoyloxy) -L-proline benzyl ester 1-N- (1-S-carbethoxy-3-phenylpropyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-2-phenylethyl) -carbamoyloxy) -L-proline benzyl ester 1- N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-3-methylthiopropyl) -carbamoyl-oxy) -L-proline benzyl ester 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4R- (N-ethoxycarbonylmethyl-carbamoyloxy) -L-proline benzyl ester 1- N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4R- (N-butoxycarbonylmethyl-carbamoyloxy) -L-proline benzyl ester 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4R- (N- (1-carbethoxy-2-methylpropyl) -carbamoyl-oxy) -L-proline benzyl ester 1-N- (1S-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4R- (N- (1-carbethoxy-2-methylbutyl) -carbamoyloxy) -L-proline benzyl ester 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4R- (N- (1-carbethoxy-3-methylbutyl) -carbamoyl-oxy) -L-proline benzyl ester 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4R- (N- (1-carbethoxy-2-phenylethyl) -carbamoyl-oxy) -L-proline benzyl ester 1-N- (lS-Carbethoxy-3- (2,5-dimethoxyphenyl) -propyl) -L-alanyl-4R- (N- (1-carbethoxy-3-methylthiopropyl) -carbamoyloxy) -L-proline benzyl ester 1-N- (lS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N-ethoxycarbonylmethyl-carbamoylOxy) -L-proline- benzyl ester 1- N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N-butoxycarbonylmethyl-carbamoyl-oxy) -L-proline benzyl ester 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-2-methylpropyl) -carbamoyloxy ) -L-proline benzyl ester 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-2-methylbutyl) -carbamoyloxy ) -L-Proline Benzyl Ester 1-N- (IS-Carbethoxy-3- (2,5-dimethoxyphenyl) -propyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-3-methylbutyl ) -carbamoyloxy) -L-prol in-benzylester 1-N- (lS-carbethoxy-3- (2,5-dimethoxyphenyl) -propyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-2-phenylethyl) -carbamoyloxy) -L-proline-benzyl ester 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) -propyl) -L-alanyl-2-methyl -4R- (N- (1-carbethoxy-3-methylthiopropyl) carbamoyloxy ) -L-proline benzyl ester 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-4R- (N-ethoxycarbonylmethyl-carbamoyloxy) -L-proline benzyl ester 1-N- (IS-Carbethoxy-3- (3,4-dimethoxyphenyl) -propyl) -L-alanyl-4R- (N-butoxycarbonylmethyl-carbamoyloxy) -L-proline benzyl ester 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-4R- (N- (1-carbethoxy-2-methylpropyl) -carbamoyloxy) -L-proline benzyl ester 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-4R- (N- (1-carbethoxy-2-methylbutyl) -carbamoyl-oxy) -L-proline benzyl ester 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-4R- (N- (1-carbethoxy-3-methylbutyl) -carbamoyl-oxy) -L-proline benzyl ester 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-4R- (N- (1-carbethoxy-2-phenylethyl) -carbamoyloxy) -L-proline benzyl ester 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-4R- (N- (1-carbethoxy-3-methylthiopropyl) -carbamoyloxy ) -L-proline benzyl ester 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N-ethoxycarbonylmethyl-carbamoyl-oxy) -L-proline benzyl ester 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N-butoxycarbonylmethyl-carbamoyl-oxy) -L-proline benzyl ester 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-2-methylpropyl) -carbamoyloxy ) -L-Proline Benzyl Ester 1-N- (IS-Carbethoxy-3- (3,4-dimethoxyphenyl) -propyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-2-methylbutyl ) -carbamoyloxy) -L-proline-benzyl ester 1-N- (lS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-3-methylbutyl) -carbamoyloxy) -L-proline-benzyl ester 1-N- (lS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-2-phenylethyl) -carbamoyloxy) -L-proline-benzyl ester 1-N- (lS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-3-methylthiopropyl) -carbamoyloxy) -L-proline benzyl ester.

Example 3 To a mixture of 1.8 g of 2-methyl-L-proline methyl ester hydrochloride (DL form), 3.39 g of N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanine (available from L-alanine tert-butyl ester and 2-bromo-4- (2,5-dimethoxyphenyl) butyric acid ethyl ester and subsequent saponification and separation of diastereoisomers), 1.11 ml of N-methylmorpholine, A solution is added dropwise to 1.53 g of 1-hydroxybenzotriazole and 200 ml of CH2Cl2 at 0 ° under N2 of 2.06 g of DCC in 55 ml of CH2C12, stirred for 2 hours at 0 ° and 12 hours at 200 and cools to -700.

It is filtered and the filtrate is washed successively with 0.5N hydrochloric acid, saturated NaHCO3 solution and saturated NaC1 solution, dries, evaporates, takes in ether and receives 1-N- (IS-carbethoxy- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-L-proline methyl ester as an oily mixture of diastereoisomers, which is broken down into the two by chromatography on silica gel Forms (S, S, S) and (S, S, R) can be separated.

Example 4 a) To a mixture of 1.85 g of 2-methyl-L-proline tert-butyl ester, 4.11 g of N- (IS-carbethoxy-3-phenylpropyl) -N-benzyloxycarbonyl-L-alanine, 5 ml of 50% strength Propanephosphonic anhydride solution in CH2C12 and 20 ml CH2Cl2 are added with stirring 1.8 ml of N-methylmorpholine in portions so that the mixture remains neutral. To Stand for 24 hours, evaporate, work up as usual (ethyl acetate / 1N hydrochloric acid; Silica gel, toluene / ethyl acetate 7: 3) and receives 1-N- (IS-carbethoxy-3-phenylpropyl ) -N-benzyloxycarbonyl-L-alanyl-2-methyl-L-proline-tert-butyl ester.

b) 1 g of the tert-butyl ester is left with 50 ml of 4N HCl in dioxane Stand at 0 ° for 24 hours, evaporate, chromatograph on silica gel (CH2Cl2 / methanol 98: 2) and receives 1-N- (1S-carbethoxy-3-phenylpropyl) -N-benzyloxycarbonyl-L-alanyl-2-methyl-L-proline.

Example 5 A mixture of 3.35 g of 1-L-alanyl-4R-N-phenylcarbamoyloxy-L-proline methyl ester, 2.71 g of ethyl 2-bromo-4-phenylbutyrate and 1.01 g of triethylamine in 50 ml of acetonitrile is boiled for 12 hours, filtered and the filtrate is worked up as usual. You get l-N- (l-Carbethoxy-3-phenylpropyl) -L-alanyl-4R-N-phenylcarbamoyl-oxy-L-proline methyl ester as a mixture of diastereoisomers. Chromatographic separation yields the 1S-carbethoxy- (maleate, F. 1410) and IR-carbethoxy form.

Analogously are from 1-L-alanyl-2-methyl-L-proline tert-butyl ester and the corresponding ethyl 2-bromo-4-ar-butyrate available: 1-N- (1S- and 1-N- (1R-carbethoxy-3-p-formylphenylpropyl) -L-alanyl-2-methyl-L-proline-tert . -butyl ester 1-N- (1S- and 1-N- (1R-carbethoxy-3-p-acetylphenylpropyl) -L-alanyl-2-methyl-L-proline-tert. -butyl ester 1-N- (1S- and 1-N- (1R-carbethoxy-3-p-benzoylphenylpropyl) -L-alanyl-2-methyl-L-proline-tert. -butyl ester.

Example 6 A solution of 4.11 g of N-2-p-toluenesulfonyloxypropionyl-2 is stirred -methyl-L-proline-tert. -butyl ester (obtainable from 2-methyl-L-proline tert-butyl ester and 2-p-toluenesulfonyloxypropionyl chloride), 1.01 g of triethylamine and 2.37 g of 2-amino-4-phenylbutyric acid 2-methoxyethyl ester (S-form) in 15 ml of acetonitrile for 4 hours at 800, works up as usual and receives N- (1S - (2-methoxyethoxycarbonyl) -3 -phenylpropyl) -L-alanyl-2-methyl-L-proline tert-butyl ester.

Example 7 To a solution of 582 mg of 1- (N-tert-butoxycarbonyl-N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl) -4R-hydroxy-L-proline benzyl ester (available from 4R-hydroxy-L-proline benzyl ester and N-tert-butoxycarbonyl-N- (l-S-carbethoxy-3-phenylpropyl) -L-alanine) in 10 ml of THF, 140 mg of cyclohexyl isocyanate in 1 ml of THF are added at 200 with stirring and 1 drop of diazabicycloundecene. After 2 hours of stirring at 200 and the usual work-up one receives l- (N-tert-butoxycarbonyl-N- (lS-carbethoxy-3-phenylpropyl) -L-alanyl ) -4R- (N-cyclohexylcarbamoyloxy) -L-proline benzyl ester.

Example 8 A mixture of 540 mg of 1- (N- (lS-carbethoxy-3-phenylpropyl ) -N-benzyloxycarbonyl-L-alanyl) -4R-hydroxy-L-proline methyl ester (available from 4R-hydroxy-L-proline methyl ester and N- (1S-carbethoxy-3-phenylpropyl) -N-benzyloxycarbonyl -L-alanine), 192 mg l-chlorocarbonyl-L-proline methyl ester, 101 mg triethylamine and 15 ml of ethyl acetate is stirred for 3 hours at 20 °. Obtained after the usual work-up one l- (N- (lS-carbethoxy-3-phenylpropyl) -N-benzyloxycarbonyl-L-alanyl) -4R- (2S-carbomethoxypyrrolidinocarbonyloxy) -L-proline methyl ester.

Example 9 To a solution of 200 mg of phosgene in 10 ml of chloroform a solution of 548 mg of 1- (N- (IS-carbethoxy-3-phenylpropyl) -N-acetyl-L-alanyl) -4R-hydroxy-L-proline methyl ester is added dropwise at 0 ° with stirring and 200 mg of triethylamine in 15 ml of chloroform and evaporated. The crude acid chloride obtained is taken up in 20 ml of chloroform and with a solution of 205 mg of L-proline benzyl ester in 5 ml of chloroform were added. After standing overnight and Customary work-up gives 1- (N- (IS-carbethoxy-3-phenylpropyl) -N-acetyl-L-alanyl ) -4R- (2S-benzyloxycarbonylpyrrolidinocarbonyloxy) -L-proline methyl ester.

Example 10 A mixture of 1 g of 1- (N²- (1S-Cyclohexoxycarbonyl-3-phenylpropyl) -N6-BOC-L-lysyl) -tert-butyl ester (available from N²- (1S-Cyclohexoylcarbonyl-3-phenylpropyl) -N6-BOC-L-lysine and L-proline-tert-butyl ester), 10 ml of dioxane and 20 ml of 4N HCl in dioxane are stirred at 200 for 2 days.

It is evaporated, taken up several times with toluene and ether, evaporated again , dissolves in ethyl acetate / acetonitrile and precipitates 1- (N2-IS-cyclohexoxycarbonyl-3-phenylpropyl with ether ) -L-lysyl) -L-proline dihydrochloride.

Example 11 A solution of 185 mg of N- (2-oxopropionyl) -L-proline and 283 mg of ethyl 2-amino-4-p-biphenylyl-butyrate in 5 ml of ethanol is added for 1 hour stirred at 20 ° with 3 g molecular sieve type 4A. It is added in portions within 3 hours 75 mg NaBH3CN are added and the product is purified by adsorption on strong cation exchange resin and eluting with 2% pyridine in water. An epimer mixture of 1- (N- (1-carbethoxy-3-p-biphenylyl-propyl) -alanyl) -L-proline is obtained, which is separated by means of "reversed phase" HPLC.

Example 12 Analogously to Example 11, L-alanyl-L-proline and 2-oxo-4-phenylbutyric acid-2-methoxyethyl ester in the presence of NaBH3CN 1- (N- (1-2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl) -L-proline, Diastereoisomeric mixture of the 1S and IR forms.

Example 13 A mixture of 258 mg of 1-L-alanyl-L-proline-tert. -butyl ester, 236 mg of 2-oxo-4-phenylbutyric acid 2-methoxyethyl ester and 2 g of MgSO4 in 10 ml of ethanol is stirred for 16 hours at 20 °. The so obtained solution of the Schiff base is after Addition of 0.5 g of 5%. Pd-C hydrogenated to a standstill for 8 hours at 20 ° and 1 bar. It is filtered, evaporated and a mixture of diastereoisomers is obtained, from which one passes through HPLC the 1- (N- (1S- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl) -L-proline-tert-butyl ester receives.

Example 14 To a solution of 390 mg of l-N-fS-carbethoxy-3-phenylpropyl> -L-alanyl-2-methyl-L-proline 70 mg of LiAlH4 Man are added in portions at 0 ° with stirring to 14 ml of diethyl ether poured into ice-cold 1N hydrochloric acid, filtered through kieselguhr and subjected to the obtained hydrochloric acid aqueous solution of ion exchange chromatography (Dowex 50 W x 2, 50-100 mesh, H-shape); the ammoniacal phase obtained is evaporated, the residue purified by chromatography (silica gel; CH2Cl2 / CH3OH / CH3COOH 18: 2: 1). You get 1- N- (IS-hydroxymethyl-3-phenylpropyl) -L-alanyl-2-methyl-L-proline.

Analogously, reduction of the corresponding esters gives: 1-N- (1S-hydroxymethyl-3-phenylpropyl) -L-alanyl-L-proline-1-N- (IS-hydroxymethyl-3-p-tolylpropyl) -L-alanyl -L-proline 1- N- (IS-hydroxymethyl-3-methoxyphenylpropyl) -L-alanyl-L-proline 1-N- (IS-hydroxymethyl-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-L-proline 1-N- (IS-hydroxymethyl-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-L-proline 1-N- (IS-hydroxymethyl-3-phenylpropyl ) -L-alanyl-2-ethylproline 1-N- (IS-hydroxymethyl-3-p-tolylpropyl) -L-alanyn-2-methylproline 1-N- (IS-hydroxymethyl-3-methoxyphenylpropyl) -L-alanyl-2-methyl-proline 1-N- (IS-hydroxymethyl-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2 -methyl-prolir.

1-N- (IS-hydroxymethyl-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-proline.

Example 15 A solution of 0.5 g of 1- (N- (IS-carboxy-3-phenylpropyl) -L-alanyl) -4-N-phenylcarbamoyl-L-proline in 10 ml of dioxane is maintained with a solution of diazoethane in dioxane until it exists yellowing. It is evaporated and l- (N- (iS-Carbethoxy-3-phenylpropyl) -L-alanyl is obtained ) -4-N-phenylcarbamoyloxy-L-proilnethylester.

Example 16 A mixture of 1 g of 1- (N- (1S-Carbethoxy-3-phenylpropyl) -L-alanyl) -4-N-phenylcarbamoyloxy-L-proline-tert-butyl ester, 10 ml of dioxane and 20 ml of 4N HCl in dioxane are stirred at 200 for 2 days. One steams a, takes up several times with toluene and ether, evaporates again, dissolves in ethyl acetate / acetonitrile and precipitates with ether the 1- (N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl) -4-N-phenylcarbamoyloxy-L-proline hydrochloride.

Example 17 1 g of N- (1S-carbethoxy-3-phenylpropyl) -L-alanyl-4R-N-phenylcarbamoyloxy-L-proline methyl ester maleate is transferred into the base and stir it in a mixture of 9 ml of dioxane, 1 ml of water and 1.6 ml in aqueous NaOH for 12 hours at 20 °. It is neutralized with acetic acid and worked up as usual. N- (IS-carboxy-3-phenylpropyl) -L-alanyl-4R-N-p> .enylcarbamoylOxy-L-proline is obtained.

Example 18 1 g of 1-N- (IS- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L-proline benzyl ester is hydrogenated on 0.5 g of 5% Pd-C in 50 ml of methanol at 200 and 1 bar until the calculated Amount of hydrogen, filtered, evaporated and obtained 1-> X- (IS- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L-proline; Hydrochloride, m.p. 141-1430.

Similarly, hydrogenolysis of the corresponding benzyl esters gives: 1-N- (IS- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-L-proline 1-N- (1S- (2-ethoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-L-proline 1-N- (IS-Cyclopentoxycarbonyl-3-phenylpropyl) -L-alanyl-L-proline 1-N- (IS-Cyclohexoxycarzonyl-3-phenylpropyl) -L-alanyl-L-proline 1-N- (IS- (2-Hydroxyethxycarbonyl) -3-phenylpropyl) -L-alanyl-L-proline 1-N- (IS- (2-methylsulfonamidoethoxycarbonyl) -3-phenylpropyl ) -L-alanyl-L-prclin 1-N- (IS- (2-phenylsulfonamidoethoxycarbonyl) -3-phenylpropyl ) -L-alanyl-L-proline l-N- (IS- (2-Benzylsulfonamidoethoxycarbonyl) -3-phenylpropyl3-L-alanyl-L-prcline 1-N- (IS- (2- (2-Oxopyrrolidino) ethoxycarbonyl) -3-phenylpropyl) -L-alanyl-L-proline IN- (IS- (2-Phthalimidcethoxycarbonyl) -3-phenylpropyl) -L-alanyl-L-proline 1-N- (1S- (2-ethoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L -proline 1-N- (IS-Cyclopentoxycarbonyl-3-phenylpropyl) -L-alanyl-2-methyl-L-proline 1-N- (IS-Cyclohexoxycarbonyl-3-phenylpropyl) -L-alanyl-2-methyl-L-proline , Hydrochloride, m.p. 179-1810 1-N- (1S- (2-Hydroxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L-proline 1-N- (IS- (2-methylsulfonamidoethoxycarbonyl) -3-phenylpropyl ) -L-alanyl-2-methyl-L-proline 1-N- (IS- (2-phenylsulfonamidoethoxycarbonyl) -3-phenylpropyl ) -L-alanyl-2-methyl-L-proline 1-N- (IS- (2-benzylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L-proline 1-N- (IS- (2- (2-Oxopyrrolidino) -ethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L-proline, Hydrochloride, m.p. 1450 (dec.) 1- N- (IS- (2-phthalimidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L-proline 1-N- (IS- (2-methoxyethoxycarbonyl) -3-p-methylthiophenylpropyl) -L-alanyl-L-proline 1-N- (1S- (2-methoxyethoxycarbonyl) -3- (4-biphenylyl) -propyl) -L-alanyl-L-proline 1-N- (1S- (2-methoxyethoxycarbonyl) -3-m-trifluoromethylphenylpropyl ) -L-alanyl-L-proline 1-N- (IS- (2-methoxyethoxycarbony) -3- (2,5-dimethOxyphenyi) -propyl ) -L-alanyl-L-proline 1-N- (IS- (2-methoxyethoxycarbonyl) -3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-L-proline 1-N- (IS- (2-methoxyethoxycarbonyl) -3-p-methylthiophenylpropyl) -L-alanyl-2-methyl-L-proline 1-N- (1S- (2-methoxyethoxycarbonyl) -3- (4-biphenylyl) propyl) -L-alanyl-2-methyl-L-proline 1-N- (1S- (2-methoxyethoxycarbonyl) -3-m-trifluoromethylphenylpropyl) -L-alanyl-2-methyl-L-proline 1- N- (IS- (2-methoxyethoxycarbonyl) -3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-L-proline 1-N- (IS- (2-methoxyethoxycarbonyl) -3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-L-proline 1-N- (IS-Cyclohexoxycarbonyl-3-p-methylthiophenylpropyl) -L-alanyl-L-proline 1-N- (1S-Cyclohexoxycarbonyl-3- (4-biphenylyl) -propyl) -L-alanyl-L-proline 1-N- (1S-Cyclohexoxycarbonyl-3-m-trifluoromethylphenylpropyl) -L-alanyl-L-proline 1-N- (IS-Cyclohexoxycarbonyl-3- (2,5-dimethoxyphenyl) -propyl) -L-alanyl-L-proline 1-N- (IS-Cyclchexoxycarbonyl-3- (3,4-dimethoxyphenyl) -propyl) -L-alanyl-L-proline 1-N- (1S-cyclohexoxycarbonyl-3-p-methylthiophenylpropyl) -L-alanyl-2-methyl-L-proline 1-N- (IS-Cyclohexoxycarbonyl-3- (4-biphenylyl) -propyl) -L-alanyl-2-methyl-L-proline 1-N- (IS-Cyclohexoxycarbonyl-3-m-trifluoromethylphenylpropyl) -L-alanyl-2-methyl-L-proline 1-N- (IS-CyclohexoxycarDonyl-3- (2,5-dimethoxyphenyl) -propyl) -L-alanyl-2-methyl-L-proline 1-N- (IS-Cyclohexoxycarbonyl-3- (3,4-dimethoxyphenyl) d propyl) -L-alanyl-2-methyl-L-proline 1-N- (IS-carbethoxy-3-y-methylthiophenylpropyl) -L-alanyl-L-proline 1-N- (IS-carbethoxy-3- (4-biphenylyl) propyl) -L-alanyl-L-proline , Maleate, F. 152C 1-N- (IS-Carbethoxy-3-m-trifluoromethylphenylpropyl) -L-alanyl-L-proin l-N- (lS-carbethoxy-3-s2,5-dimethoxyphenyl) -propyl) -L-alanyl-L-proline, hydrochloride, amorphous l-N- (lS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-L-proline 1-N- (IS-carbethoxy-3-p-methylthiophenylpropyl) -L-alanyl-2-methyl-L-proline 1-N- (IS-carbethoxy-3- (4-bipheny ~ yl) -propyl) -L-alanyl-2-methyl-L-proline, hydrochloride, F. 1830 (dec.) 1-N- (IS-carbethoxy-3-m-trifluoromethylphenylpropyl) -L-alanyl-2-methyl-L-proline 1-N- (IS-carbethoxy-3- (2,5-dimetnoxyphenyl) propyl) -L-alanyl-2-methyl-L-proline, hydrochloride, F. 172-1740 1-N- (IS-Carbethoxy-3- (3,4-dimethoxyphenyl) -propyl) -L-alanyl-2-methyl-L-proline 1-N- (IS- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1-N- (IS- (2-ethoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1-N- (IS-Cyclopentoxycarbonyl-3-phenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1-N- (IS-Cyclohexoxycarbonyl-3-phenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1-N- (IS- (2-hydroxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4 , 4-ethylenedioxy-L-proline 1-N- (IS- (2-methylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1-N- (IS- (2-phenylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1-N- (IS- (2-Benzylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1- N- (IS- (2- (2-Oxopyrrolidino) ethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1-N- (IS- (2-phthalimidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1-N- (IS- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4 , 4-ethylenedioxy-L-proline 1-N- (IS- (2-ethoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline 1-N- (IS-Cyclopentoxycarbonyl-3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline 1- N- (IS-Cyclohexoxycarbonyl-3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline 1-N- (1S- (2-Hydroxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline 1-N- (IS- (2-methylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4, 4-ethylenedioxy-L-proline 1- N- (IS- (2-phenylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline 1- N- (IS- (2-Benzylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline 1-N- (IS- (2- (2-Oxopyrrolidino) -ethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline Hydrochloride, m.p. 142-144C 1-N- (IS- (2-phthalimidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline 1- N- (IS-carbethoxy-3-p-methylthiophenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1-N- (IS-Carbethoxy-3- (4-biphenylyl) -propyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1-N- (IS-Carbethoxy-3-m-trifluoromethylphenylpropyl) -L -alanyl-4,4-ethylenedioxy-L-proline 1- N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1- N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1- N- (IS-carbethoxy-3-p-methylthlophenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline 1-N- (IS-carbethoxy-3- (4-biphenylyl) -propyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline 1-N- (IS-carbethoxy-3-m-trifluoromethylphenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline 1-N- (IS-2-methoxyethoxycarbonyl-3-p-methylthiophenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1-N- (IS-2-methoxyethoxycarbonyl-3- (4-biphenylyl) propyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1-N- (IS-2-methoxyethoxycarbonyl-3-m-trifluoromethylphenylpropyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1-N- (IS-2-methoxyethoxycarbonyl-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1-N- (IS-2-methoxyethoxycarbonyl-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-4,4-ethylenedioxy-L-proline 1-N- (IS-2-methoxyethoxycarbonyl-3-p-methylthiophenylpropyl-L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline 1-N- (IS-2-methoxyethoxycarbonyl-3- (4-biphenylyl) propyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline 1- N- <IS-2-methoxyethoxycarbonyl-3-m-trifluoromethylphenylpropyl-L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline 1-N- (IS-2-methoxyethoxycarbonyl-3- (2,5-dimethoxyphenyl) -propyl-L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline 1-N- (IS-2-methoxyethoxycarbonyl-3- (3,4-dimethoxyphenyl) -propyl-L-alanyl-2-methyl-4,4-ethylenedioxy-L-proline 1-N- (1S- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline 1-N- (IS- (2-ethoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline 1-N- (IS-Cyclopentoxycarbonyl-3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline 1-N- (IS-Cyclohexoxycarbonyl-3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline 1-N- (IS- (2-Hydroxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline 1-N- (IS- (2-methylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline 1-N- (IS- (2-phenylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline 1-N- (IS- (2-Benzylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline 1-N- (IS- (2- (2-Oxopyrrolidino) -ethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline 1-N- (IS- (2-phthalimidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline 1-N- (IS- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline 1-N- (IS- (2-ethoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline 1-N- (IS-Cyclopentoxycarbonyl-3-phenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline 1-N- (IS-Cyclohexoxycarbonyl-3-phenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline 1- N- (IS- (2-Hydroxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline 1-N- (IS- (2-methylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4, 4-propylenedioxy-L-proline 1-N- (IS- (2-phenylsulfonamidoethoxycarbonyl) -3-phenylpropyl ) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline 1-N- (IS- (2-benzylsulfonamidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-pzopylenedioxy -L-proline 1-N- (IS- (2- (2-Oxopyrrolidino) -ethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4, 4-propylenedioxy-L-proline 1-N- (IS- (2-phthalimidoethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4, 4-propylenedioxy-L-proline 1-N- (IS-carbethoxy-3-p-methylthiophenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline 1-N- (IS-carbethoxy-3- (4-biphenylyl) propyl) -L-alanyl-4,4-propylenedioxy-L-proline 1-N- (IS-carbethoxy-3-m-trifluoromethylphenylpropyl) -L-alanyl-4,4-propylenedioxy-L-proline 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4,4-propylenedioxy-L-proline 1- N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-4,4-propylenedioxy-L-proline 1-N- (IS-carbethoxy-3-p-methylthiophenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline 1- N- (IS-carbethoxy-3- (4-biphenylyl) propyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline 1- N- (IS-carbethoxy-3-m-trifluoromethylphenylpropyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyi) -propyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline 1- N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4,4-propylenedioxy-L-proline 1-N- (IS-Dimethylphosphono-3-phenylpropyl) -L-alanyl-proline. 1-N- (IS-Diethylphosphono-3-phenylpropyl) -L-alanyl-proline 1-N- (1S- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-4,4-difluoro-L-proline 1-N- (IS-Dimethylphosphono-3-phenylpropyl) -L-alanyl-L-thiazolidine-2-carboxylic acid 1-N- (IS-Dimethylphosphono-3-phenylpropyl) -L-alanyl-4-oxo-L-proline-ethylene hemithioketal 1-N- (IS-Dimethylphosphono-3-phenylpropyl) -L-alanyl-4,4-ethylenedithio-L-proline 1-N- (IS-Dimethylphosphono-3-phenylpropyl) -L-alanyl-4,4-propylenedithio -L-proline 1-N- (IS-carbethoxy-3- (9,5-dimethoxyphenyl) propyl) -L-alanyl-G, 4-dlfluoro-L-proline 1-N- (1S-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-L-thiazolidine-2-carboxylic acid 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4-oxo-L-proline-ethylene hemithioketal 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4,4-ethylenedithlo-L-proline 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4,4-propylenedithio-L-proline 1-N- (lS-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-methylcarbamoyloxy) -L-proline 1-N- (lS-carbethoxy-3-pnenylpropyl) -L-alanyl-4R- ( N-butylcarbamoyloxy) -L-proline, 173 ° 1-N- (IS-carbethoxy-3-; henylpropyl) -L-alanyl-4R- (N-cyclopentylcarbamoyloxy) -L-proline 1-N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-cyclohexylcarbamoyloxy) -L-proline 1-N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-phenylcarbamoyloxy) -L-prolira 1-N- (IS-carbethoxy-3-henylpropyl) -L-alanyl-4R- (N-p-tolylcarbamoyloxy! -L-prolira 1-N- (1S-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-p-methylphenylcarbamoyloxy) -L-proline 1-N- (15-Carbethoxy-3-phenylprop.yl) -L-alanyl-4R- (N- (3,4-dimethoxyphenyl) -carbamoyloxy) -; - proline 1-N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-benzy1.-carbamoyloxy) -L-proline 1-N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-pmethoxybenzylcarbamoyloxy) -L-proline 1-N- (15-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N- (1-phenylethyl) -carbamoyloxy) -L-proline, 171 ° 1-N- (IS-carbethoxy-3-phenylpropJl) -L-alanyl-4R- (N-ethoxycarbonylmethyl-carbamoyloxy) -L-proline 1-N- (lS-Carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N-butoxycarbonylmethyl-carbamoyloxy) -L-proline 1-N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N- (1-carbethoxy-2-methylpropyl) -carbamoyloxy) -L-proline 1-N- (IS-carbethoxy-3-phenylpropyl) -L-ala; .yl-4R- (N- (1-carbethoxy-2-methylbutyl) -carbamoyloxy) -L-proline 1-N- (1S-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N- (1-carbethoxy-3-methylbutyl) -carbamoyloxy) -L-proline 1-N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-4R- (N- (1-carbethoxy-2-phenylethyl) -carbamoyloxy) -L-proline 1-N- (IS-carbethoxy-3-phenylpropyl) -L-alarlyl-49- (N- (1-carbethoxy-3-methylthiopropyl ) -oarbamoyloxy) -L-proline 1-N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-2-methyl-4R- (N-ethoxycarbonylmethyl-carbamoyloxy) -L-proline 1-N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-2-methyl-4R- (N-butoxycarbonylmethyl-carbamoyloxy) -L-proline 1-N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-2-methylpropy ') -carbamoyloxy) -L-proline 1-N- (1S-carbethoxy-3-phenylpropyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-2-methylbutyl) -carbamoyloxy) -L-proline 1- N- (IS-carbethoxy-3-phenylproFyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-3-methylbutyl -carbamoyloxy) -n-proline 1-N- (1S-carbethoxy-3-phenylpropyi) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-2-phenylethyl) -carbamoyloxy) -L-proline 1- N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-3-methylthiopropyl) -carbamoyl-oxy) -L-proline 1-N- (lS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4R- (N-ethoxycarbonylmethyl-carbamoyloxy) -L-proline 1-N- (IS-carbethoxy-3- (~, 5-dimethoxyphenyl) -propyl) -L-alanyl-4R- (N-butoxycarnonylmethyl-carbamoyloxy) -L-proline 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4R- (N- (1-carbethoxy-2-methylpropyl) -carbamoyloxy) -L-proline 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4R- (N- (1-carbethoxy-2-methylbutyl) -carbamoyl-oxy) -L-proline 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4R- (N- (1-carbethoxy-3-methylbutyl) -carbamoyl-oxy) -L-proline 1-N- (1S-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-4R- (N- (1-carbetnoxy-2-phenylethyl) -carbamoyl-oxy) -L-proline 1-N- (lS-carbethoxy-3 - (- ', 5-dimethoxyphenyl) propyl) -L-alanyl-4R- (N- (1-carbetnoxy-3-methylthlopropyl) -carbamoyloxy ) -L-proline 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) -propyl) -L-alanyl-2-methyl-4R- (N-ethoxycarbonylmethyl-carbamoyl-oxy) -L-proline 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N-sutoxycarbonylmethyl-carbamoyl-oxy) -L-proline 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-2-methylpropyl) -carbamoyloxy ) -L-prolir 1-N- (1S-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-2-methylbutyl) -carbamoyloxy) -L- proline 1- N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-3-methylbutyl) -carbamoyloxy) -L-proline 1-N- (IS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-2-phenylethyl ) -carbamoyloxy) -L-proline 1-N- (lS-carbethoxy-3- (2,5-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-3- methylthiopropyl) carbamoyloxy) -L-proline 1-N- (Ib-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-4R- (N-ethoxycarbonylmethyl-carbamoyloxy) -L-prolir.

1-N- (IS-carbethoxy-3- (3,4-dimetnoxyphenyl) propyl) -L-alanyl-4R- (N-butoxycarbonylmet-1-carbam 1-N- (IS-carbethoxy-3- (3,4-dimethoxypheny) propyl) -L-alanyl-4R- (N- (1-carbethoxy-2-methylpropyl ) -carbamoyioxy -L-prol1n 1-N- (IS-carbethoxy-3- (3,4-dimetnoxypheny;) -propyl) -L-alanyl-4R- (N- (1-carbethoxy-2-methylbutyl> -carbamoyl-oxy ) -L-proline 1-N- (IS-Carbethoxy-3- (3,4-dimetnoxypheny) -propyl) -L-alanyl-4R- (N- (1-carbethoxy-3-methylbutyl) -carbamoyloxy) -L-proline 1- N- (IS-carbethoxy-3- (3,4-dimetnoxyphenyl) propyl) -L-alanyl-4R- (N- (1-carbethoxy-2-phenylethyl) -carbamoyl-oxy) -L-proline 1-N- (IS-Carbethoxy-3- (3,4-dimethoxyphenyl) -propyl) -L-alanyl-4R- (N- (1-carbethoxy-3-methylthiopropyl) -carbamoyL-oxy) -L-proline 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N-ethoxycarbonylmethyl-carbamoyl-oxy) -L-proline 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N-butoxycarbonylmethyl-carbamoyl-oxy) -L-proline 1- N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-2-methylpropyl) -carbamoyloxy-L-proline 1-N- (lS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N- (l-carbethoxy-2-methylbutyl) -carbamoyloxy) -L-proline 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N- (1-carbethoxy-3-methylbutyl) -carbamoyloxy ) -L-proline 1- N- (IS-Carbethoxy -3- (3,4-dimethoxyphenyl) propyl) -L-alanyl-2-methyl-4R- (N-1-carbethoxy-2-phenylethyl ) -carbamoyloxy -L-proline 1-N- (IS-carbethoxy-3- (3,4-dimethoxyphenyl-propyl) -L-alanyl-2-methyl-4R- (N-il-carbethoxy-3-methylth opropyl) -carbamoyloxy) -L-proline Example 19 a) To a mixture of 446 mg of 1-N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-2-methyl-L-proline tert-butyl ester, 360 mg of acetaldehyde, 1.6 g of crushed molecular sieve and 16 ml of ethanol are added dropwise a solution of 82 mg of sodium cyanoborohydride in 4 ml of ethanol with stirring. After 1 Hours are added again 360 mg of acetaldehyde and approximately mg of sodium cyanoborohydride in 4 ml of ethanol added. Customary work-up gives 1-N- (1S-carbethoxy-3-phenylpropyl) -N-ethyl-L-alanyl-2-methyl-L-proline tert-butyl ester.

Analogously, by N-alkylation, the following is obtained: l-N- (lS-carbethoxy-3-phenylpropyl) -N-methyl-L-alanyl-2-methyl-L-proline-tert-butyl ester 1-N- (IS-Carbethoxy-3-phenylpropyl) -N-butyl-L-alanyl-2-methyl-L-proline tert-butyl ester l-N- (lS-carbethoxy-3-phenylpropyl) -N-benzyl-L-alanyl-2-methyl-L-proline tert-butyl ester.

b) Cleavage of the tert-butyl ester with HCl in the dioxane analogous to the example 4b) gives 1-N- (1S-carbethoxy-3-phenylpropyl) -N-ethyl-L-alanyl-2-methyl-L-proline, 111 ° F.

1-N- (IS-carbethoxy-3-phenyipropyl) -N-methyl-L-alanyl-2-methyl-L-proline is obtained analogously 1-N- (IS-Carbethoxy-3-phenylpropyl) -N-butyl-L-alanyi-2-methyl-L-proline 1-N- (IS-Carbethoxy-3-phenylpropyl ) -N-benzyl-L-alanyl-2-methyl-L-proline.

Example 20 a) Analogously to Example 4, tert-butyl ester of 1-N- (IS-carbethoxy-3-phenylpropyl) -L-alanyl-2-methyl-L-proline is obtained and acetic acid in the presence of propanephosphonic anhydride in DMF denotes 1-N- (IS-carbethoxy-3-phenylpropyl ) -N-acetyl-L-alanyl-2-methyl-L-prolintert. -butyl ester.

b) By standing for 4 hours with five times the amount of trifluoroacetic anhydride (40% strength in methylene chloride) at 20 ° and evaporation gives 1-N- (IS-carbethoxy-3-phenylpropyl ) -N-acetyl-L-alanyl-2-methyl-L-proline.

The following examples relate to pharmaceutical preparations, the compounds of the formula I or their physiologically acceptable salts contain: Example A: Tablets A mixture of 0.1 kg of l-N- (lS-carbethoxy-3-phenylpropyl) L-alanyl-4R- (N-phenylcarbamoyloxy) -L-proline methyl ester maleate, 0.4 kg lactose, 0.12 kg of potato starch, 0.02 kg of talc and 0.01 kg of magnesium stearate is used in the usual way compressed into tablets in such a way that each tablet contains 5 mg of active ingredient.

Example B: Dragees Analogously to Example A, tablets are pressed which then in the usual way with a coating of sucrose, potato starch, Talc, tragacanth and dye are coated.

Example C: Capsules 0.1 kg of 1-N- (IS- (2-methoxyethoxycarbonyl) -3-phenylpropyl) are filled ) -L-alanyl-2-methyl-L-proline hydrochloride in the usual way in hard gelatin capsules, so that each capsule contains 10 mg of active ingredient.

Example D: Ampoules A solution of 0.25 kg of 1-N- (IS- (2- (2-Oxopyrrolidino) -ethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-4,4-ethylenedioxy-L -proline hydrochloride in 10 1 double distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions.

Each ampoule contains 2.5 mg of active ingredient.

Similarly, tablets, coated tablets, capsules or ampoules are available, the one or more of the other active ingredients of the formula I and / or their physiological contain harmless salts.

Claims (8)

Claims: Dipeptides of the formula I. wherein R1 is H, alkyl or Ar'-alkyl, R2 is H or alkyl, R3 is CH3 or - (CH2) 4-NH2 R4 is H, alkyl, Ar'-alkyl or acyl, R5 is COOR6, CH2OH or PD (OR6) 2, R6 H, alkyl, cycloalkyl or alkyl substituted by OH, alkoxy, Ar ', R7-SO2NH, 2-oxopyrrolidino or phthalimido, R7 alkyl, Ar' or Ar'-alkyl, Z CH2, CF2, S, one free or one in the form of an alkylene metal, alkylene hemithioketais or alkylene thioketal functionally modified CO group, in which the alkylene group contains 2-5 C atoms or CH-O-CO-Q, Q NHR8 or Rc8 alkyl, cycloalkyl, Ar ', Ar'-alkyl or -CH39-COOR10 R9 H, alkyl, Ar'-alkyl, alkylthioalkyl or Ar', 10 H, H, alkyl or Ar'-alkyl, Ar and Ar 'are each unsubstituted or phenyl which is mono- or polysubstituted by alkyl, alkoxy, alkylthio, phenyl, CF3, CH-OR11 and / or acyl and R11 is H, alkyl or ar'-alkyl, in which the alkyl and alkoxy groups are each 1-8, the cycloalkyl groups 3 - 7 each, the acyl groups each contain 1 - 10 carbon atoms, in which Ar is only phenyl, alkylphenyl or alkoxyphenyl if (a) Z is CH-O-CO-NHR12 (where R12 is alkyl with 5 - 8 E- Atoms, Ar ', Ar'-alkyl or -CHR9-CSOR10) or and / or (b) R4 is different from H and / or (c) R5 is different from COOH, COO-alkyl and COO-alkyl-Ar ', and salts thereof. 2.a) 1-N- (1S- (2-methoxyethoxycarbonyl) -3-phenylpropyl) -L-alanyl-2-methyl-L-proline; b) l-N- (lS-carbethoxy-3-phenylpropyl) -L-alany1-4R- (N-phenylcarbamoyloxy) -L-proline. 3. A process for the preparation of compound n of the formula I according to claim 1 and its salts, characterized in that one is a compound of the formula II EH II wherein E is the remainder and R1, R2 and Z have the meaning given in claim 1 or one of their reactive derivatives with a dicarboxylic acid derivative of the formula III HOOC-CHR3-NR4-CHR5-CH2CH2-Ar III in which R3, R4, R5 and Ar are as defined in claim 1 Have meaning or reacts one of its reactive derivatives, or that a compound of the formula IV E-C0-CHR3X IV with a compound of the formula V Y-CHR5-CH2CH2-Ar V in which one of the radicals X and Y NHR4, the other X ' C1, Br, J or a reactive, functionally modified OH group and R³, R4, R5, and Ar have the meanings given in claim 1 or above, or that a compound of the formula I in which Z is CH- O-CO-Q denotes a hydroxy compound otherwise corresponding to the formula I, but which contains the group -CHOH- in place of Z, with an isocyanate d [Formula OCN-R8 or a carbamic acid chloride of the formula Cl-CO-Q or in succession with a carbonic acid derivative and an amine of For mel HQ and / or that a compound of the formula I or another compound corresponding to the formula I, but which instead of one or more H atoms has one or more protective groups and / or reducible or hydrogen-replaceable group (s) and / or contains CC multiple bond (s), treated with solvolyzing or reducing agents and / or that an acid of the formula I (R1 and / or R6 = H) and / or an ester of the formula I (R1 and / or R 6 are different from H) converted into the corresponding acid of the formula I (R1 and / or R6 = H) and / or an NH group is alkylated or acylated and / or a compound of the formula I is converted into one by treatment with an acid or base converts their salts. 4. Process for the production of pharmaceutical preparations, thereby characterized in that a compound of the formula I and / or one of its physiologically harmless salts together with at least one solid, liquid or semi-liquid Carrier or adjuvant and optionally in combination with one or more brings further active ingredient (s) into a suitable dosage form. 5. Pharmaceutical preparation, characterized by a content on at least one compound of the formula I and / or one of its physiologically acceptable compounds Salts. 6. Compounds of the formula I according to claim 1 for combating from diseases in which there is an increase in blood pressure. 7. Use of compounds of the formula I in lowering blood pressure. 8. Use of compounds of formula I for the preparation of a Medicinal product.