DD287512A5 - AMINOMETHYL-PEPTIDES, METHOD FOR THE PREPARATION AND THEIR USE IN MEDICINAL PRODUCTS - Google Patents

Abstract

The invention relates to a process for the preparation of aminomethyl peptides having reninihibitorischen properties. According to the invention, compounds of the general formula are prepared in which A, B, D, E, F, R 1, R 2, R 3 and R 4 have the meaning given in the description, processes for their preparation and their use in medicaments, in particular in circulation-influencing medicaments. Formula {New Aminomethyl-peptides; renin-inhibitory activity; Application of circulatory drugs; Treatment of hypertension, heart failure}

Description

The invention relates to a process for the preparation of renininhibitorischer Aminomethyl-peptides and their use in medicaments, in particular in Kreislauflaufbaanflussenden drugs.

Characteristic of the known state of the art

Renin is a proteolytic enzyme that is mainly produced by the kidneys and secreted into the plasma. It is known that renin cleaves the decapoptide angiotensin I in vivo from the angiotensinogen. Angiotensin I in turn is broken down in the lungs, kidneys or other tissues to the blood pressure-effective octapeptide angiotensin II. The various effects of angiotensin II such as vasoconstriction, Na ⁺ retention in the kidney, aldosterone release in the fog, and increase in tone

of the sympathetic nervous system are synergistic in the sense of a blood drip increase.

The activity of the renin-angiotensin system can be manipulated iacharmonically by inhibiting the activity of renin or the angiotensin conversion system (ACE) and by blocking angiotensin II receptors. The development of orally usable ACE inhibitors has thus led to new antihypertensive agents (cf DE-OS 3628650, Am.

Med. 77,690, 1984)

A more recent approach is to intervene in the renin-angiotensin cascade at an earlier stage, namely by inhibitors

the highly specific peptidase renin.

To date, various types of renin inhibitors have been developed: renin-specific antibodies, phospholipids, peptides with the N-terminal sequence of prorenin, synthetic peptides as substrate analogs, and modified peptides.

Object of the invention

The aim of the invention is to provide novel compounds having a purely inhibitory effect which can be used in anticancer drugs for the treatment of hypertension and cardiac insufficiency.

Explanation of the essence of the invention

The invention has for its object to provide new compounds with the desired properties and methods for their

To find production.

New renin inhibitors have now been found which are derived from the amino acid (3S, 4S) -4-amino-3-hydroxy-6-methylheptanecarboxylic acid (statin) (see DH Rich, J. Med. Chem., 28, 263-273 [1985], Boger, J .; Lohr, N. S .; Ulm. E.H .; Poe, M .; Blaine,

E.H .; Fanelli, G.M .; Lin, T.-Y .; Payne, L. S .; Schorn, T.W .; LaMont, B.I .; Vassil, T.C .; Stabilito, 1.1 .; Veber, D.F .; Rich, D.H .; Boparai,

A.S .; Nature (London) 1983, 30381.

The introduction of an aminomethyl side chain, in addition to a high selectivity towards human renin a high stability to enzymatic degradation and good water solubility. According to the invention

Aminomethyl-peptides of the general formula (I) prepared.

HR ¹ / NR ³

abden- ^ y / ^ co-fr ⁴ '

H OR ²

in which

A - hydrogen means or

- is C ₁ -C ₈ -alkyl, C ₁ -C 4 -alkylsulfonyl, phenylsulfonyl or tolylsulfonyl or

- is a group of the formula COR ⁶ or COOR ⁸ in which

R ^{6 represents} straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by hydroxy, aryl, amino, alkylamino having up to 8 carbon atoms per alkyl group or dialkylamino having up to 8 carbon atoms per alkyl group and

R ^e - represents straight-chain or branched alkyl having up to 8 carbon atoms or.

A - represents an amino protecting group B - represents a direct bond or

- for a group of the formula

p7 iru-i

Ϊ NFT, -NH- (CH ₂ ) -C

Il

I Il ο ο

H O

R ⁷

1 or R ⁸ -S (O) _1n -CH ₂ - ^ they are not ₍

O in which

ρ - a number 1,2 or 3 means m - a number 0,1 or 2 means η - a number O, 1,2,3 or 4 means R ⁷ - hydrogen, C 1 -C 12 -alkyl, hydroxymethyl, hydroxystryl, carboxy, C 1 -C ₈ - Alkoxycarbonyl or mercaptomethyl or - is a group of the formula -CHj-NH-R ⁸ wherein R ⁸ - is hydrogen, Ct-Ca-alkyl, phenylsulfonyl. Ct-Ca-alkylsulfonyl or - represents an amino group

R ⁷ - guanidinomethyl, methylthiomethyl, halogen, indolyl, imidazolyl, pyridyl, triazolyl or pyrazolyl, which is optionally substituted by R ⁸ wherein R ⁸ has the above-defined meaning or

- represents cycloalkyl having 3 to 8 carbon atoms

- is aryl which may be substituted identically or differently up to 3 times by C 1 -C ₆ -alkyl, C 1 -C ₆ -alkoxy, C 1 -C ₆ -alkylbenzyloxy, trifluoromethyl, halogen, hydroxyl, nitro or by a group of the formula

-N

wherein

R ⁹ and R ¹⁰ are identical or different and represent hydrogen, C | -C _e alkyl, Ct-Ce-alkylsulfonyl, aryl, aralkyl,

Tolylsulfonyl, acetyl, benzoy I or

- stand for an amino protecting group or B - for a group of the formula

stands

worm

X - represents methylene, hydroxymethylene, ethylene, sulfur or oxygen,

and

A is the meaning given above Nat

D - has the abovementioned meaning of B and is the same or different, E - has the abovementioned coverage of B and is the same or different, F - has the meaning given above of B and is identical or different with this , R ¹ - represents straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by halogen,

Hydroxy, cycloalkyl of 3 to 8 carbon atoms, amino, alkylamino of up to 8 carbon atoms, dialkylamino with

up to 8 carbon atoms per alkyl group or phenyl, which in turn is represented by C ₁ -C ₈ -alkyl, amino,

Nitro, cyano or halogen may be substituted or - is aryl having 6 to 10 carbon atoms, which is up to ₄ times the same or different by C, -C ₆ alkyl,

C ₁ -C ₈ -alkoxy, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, phenyl or

through the group of the formula

-N

may be substituted ₍ wherein

R ⁹ and R ^{10 are the} same or different and have the abovementioned meaning, R ² - is hydrogen or

- stands for straight-chain or branched alkyl having up to 10 hydrocarbon atoms or

- for the group of the formula

- COR ⁵ is in which

R ^{5 has} the abovementioned meaning, R ^{3 is} hydrogen or

represents straight-chain or branched alkyl having up to 10 carbon atoms, which may be substituted by halogen, hydroxyl, aryl, aralkyl or heteroaryl or

- for a group of the formula

-COR ⁵ stands.

wherein

R ^{5 has the} meaning given above, R ³ - is aryl which may be substituted identically or differently up to 4 times by halogen, hydroxy, nitro,

Cyano C 1 -C ₈ -alkoxy, C 1 -C ₈ -alkyl or amino R ⁴ - is straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by hydroxyl,

Cycloalkyl having 3 to 8 carbon atoms, halogen, Ci-Cg-alkoxy, Ci-Cg-alkoxycarbonyl or aryl is substituted or

- is C, -C ₈ alkoxy or

- is aryl which may be substituted by halogen, hydroxy, nitro, cyano, amino or C 1 -C 6 -alkoxy up to and including 3 ', or

- for a rest

-HN-R "stands

wherein

R "- means hydrogen or

- represents straight-chain or branched alkyl having up to 10 carbon atoms stsht, which is optionally substituted by hydroxyl, halogen, Ci-C ₈ -alkoxy, Ci-Ce-alkoxycarbonyl, cycloalkyl having 3 to 8 carbon atoms, aryl or heteroaryl or

- represents cycloalkyl having 3 to 8 carbon atoms or

- is phenyl which may be substituted by hydroxy, halogen, nitro, cyatio, C 1 -C ₈ -alkyl, C 1 -C ₆ -alkoxycarbonyl or by amino,

and their physiologically acceptable salts.

Amino Schutzgruppa is within the scope of the invention for the usual amino-protecting groups used in peptide chemistry. Preferred for this purpose are benzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, dichlorobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitroboncyloxycarbonyl, 2- Nitrobenzyloxycarbonyl, 2-nitro-4,5-d-methoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarboyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, hexoxycarbonyl, cyclohexoxycarbonyl, octoxycarbonyl, 2- Ethylhexoxycarbonyl, 2-iodohexoxycarbonyl, 2-bromoethoxycarbonyl, 2-chloroethoxycarbonyl, 2,2,2-trichlorotrioxycarbonyl, 2,2,2-trichloro-tert-butoxycarbonyl, benzhydryloxycarbonyl, bis (4-methoxyphenyl) methoxycarbonyl, phenacyloxycarbonyl, 2-trimethylsilylethoxycarbonyl , 2- (di-n-butyl-methylsilyl) ethoxycarbonyl, 2-triphenylsilylethoxycarbonyl, 2- (dimethyl-tert-butylsilyl) ethoxycar bonyl, menthylyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, phenoxycarbonyl, tolyloxycarbonyl, 2,4-dinitrophenoxycarbonyl, 4-nitrophenoxycarbonyl, 2,4,5-trichlorophenoxycarbonyl, naphthyloxycarbonyl, fluorenyl-9-methoxycarbonyl, ethylthiocarbonyl, methylthiocarbonyl, butylthiocarbonyl, tert-butylthiocarbonyl, phenylthiocarbonyl , Benzylthiocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, methylthiocarboxylic, butylthiocarbonyl, tert-butylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, iso -propylaminocarbonyl, formyl, acetyl, propionyl, pivaloyl, 2-chloroacetyl, 2-bromoacetyl, 2-iodoacetyl, 2 , 2,2-trifluoroacetyl, 2,2,2-trichloroacetyl, benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl, 4-nitrobenzyl, 4-nitrobenzoyl, naphthylcarbonyl, phenoxyacotyl, adamantylcarbonyl, dicyclohexylphosphoryl, diphenylphosphoryl, dibenzylphosphoryl, di- (4- nitrobenzyl) phosphoryl, phenoxyphenylphosphoryl, diethylphosphinyl, diphenylphosphinyl, phthalo yl or phthalimido. Particularly preferred amino-protecting groups are benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, cyclohexoxycarbonyl, hexoxycarbonyl, octoxycarbonyl, 2-bromoethoxycarbonyl, 2-chloroethoxycarbonyl, phenoxyacetyl, naphthylcarbonyl, adamantylcarbonyl, phthaloyl, 2,2, β-trichloroethoxycarbonyl, 2,2,2-trichloro-tert-butoxycarbonyl, menthyloxycarbonyl, vinyloxycarbonyl, Allyloxycarbonyl, phosphonoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, formyl, acetyl, propionyl, pivaloyl, 2-chloroacetyl, 2-benzoacetyl, 2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido or isovaleroyl.

The compounds of the general formula (I) according to the invention have several asymmetric carbon atoms. SL may independently exist in the D or the L form. The invention includes the optical antipodes as well as the isomeric mixtures or racemates.

Preferably, the groups B, D, E and F are independently in the optically pure, preferably in the L-form. The group of the formula

-NR ³

H OR ^

For example, depending on the definition of the radicals, it may have up to 3 asymmetric carbon atoms which may be independently in the R or S configuration. Preferably this group is in the 1S, 2S, 3R configuration, 1R, 2S, 3R-

Configuration, 1S, 2R, 3S configuration or in the 1R, 2R, 3S configuration.

Particularly preferred are the 1S, 2S, 3R configuration and the 1S, 2R, 3S configuration.

The compounds of the general formula (I) according to the invention can be present in the form of their salts. These may be salts of the compounds according to the invention with inorganic or organic acids or bases. The acid addition products preferably include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or with carboxylic acids such as acetic acid, propionic acid, oxalic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, adipic acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, Lactic acid, ascorbic acid, salicylic acid, 2-acetoxybenzoic acid, nicotinic acid, isonicotinic acid, or sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalene-2-sulfonic acid or

Naphthalenedisulfonic.

Preferred compounds of general formula (I) are those in which A is hydrogen or

- is C ₁ -Ce-AIkYl, Ci-Ce-alkylsulfonyl ^ henylsulfonyl or tolylsulfonyl or

- represents a group of the formula COh ⁵ or COOR 'in which

R ⁵ - represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxy, phenyl, amino, alkylamino having up to 6 carbon atoms or dialkylamino having up to 6 carbon atoms per alkyl group, and

R ^e - represents straight-chain or branched alkyl having up to 6 carbon atoms or

A - for an amino protecting group is B - stands for direct attachment or

- for a remainder of the formula

CH ₃ O

NH

NH-

-NH ^^ s ^ »-NH- χ-, OO

NR ^c

(CHO) O-SCH ₃

JL

HO

X.

, -NH

t ^{2) 4} - ^no

-NH-

NH

SH

COOH

NH

COOCH-

COOCH ₃

(CH _{2) 2} -C00H

NH

(CH ₂ ) O-COOCH-

NH

(O) O-COOCHo,

CONHR

-NH-

(CHO) o-C0NHR ^f

I Ct Ct

NH

NH

NH

R ⁸ -S (0) _m -CH ₂

R ⁸ -S (0) _m -CH ₂

R ⁸ -S (O) _m -CH ₂

-N

Il

C-

(CH ₂ ) ₃ -NHR ^f

NO-

CH-

-ΝΗ- ^ γ-, -NH

O

or

NH

in their D-form, L-form or as D.L isomer mixture, preferably in the L-form,

m - a number 0,1 or 2 means

R ^{8 is} hydrogen or

- for C ^ -Co -alkyl.phenylsulforiyl.lVCVAalkylsulfonyl or

- represents an amino protecting group, B - represents a group of the formula

Stehl,

wherein X is - methylene, Schv / IfeJ or oxygen and A has the abovementioned meaning in its L-form, D-form or as a mixture of D, L isomers,

D, E and F are the same or different and have the same meaning as B and are the same or different R '- geradgeradkettiges or branched alkyl having up to 8 carbon atoms, dds optionally by fluorine, chlorine, bromine, hydroxy, cycloalkyl with 3 to 8 carbon atoms, A.nino, alkylamino having up to 6 carbon atoms, dialkylamino having up to 6 carbon atoms per Alkylgruppo or phenyl is substituted, which in turn by

C ₁ -C ₆ -A ^ yl, amino, nitro, cyano or halogen may be substituted or - stand phenyl ', up to 3 times the same or different by Ci-CrAlkyl, Ci-C4-alkoxy, hydroxy, cyano, nitro , Trifluoromethyl, trifluoromethoxy, Trifluormethyltl.io, phenyl or by a group of the formula

/ R

-N

may be substituted

wherein R ⁹ and R ^{10 are the} same or different and

- are hydrogen, C) -C ₆ alkyl, Ci-Ci-alkylsulfonyl, phenyl, benzyl, Tnlylsiilfonyl, acetyl or benzoyl or

an amino protecting group, R * is hydrogen, or

- represents straight-chain or branched alkyl having up to 8 carbon atoms or

- represents the group of the formula COR ⁵ , in which

R ^{5 has the} meaning given above, R ^J - is hydrogen or

represents straight-chain or branched alkyl having up to 8 carbon atoms, which may be substituted by fluorine, chlorine, bromine, hydroxyl, phenyl, benzyl, pyridyl or pyrimidyl or

- for a group of forms! COR ⁵ , wherein R ^{5 has} dioobon angogebano meaning or

R ³ - represents phenyl which may be substituted identically or differently up to 3 times by fluorine, chlorine, bromine, hydroxyl, nitro, cyano, C 1 -C 6 -alkoxy, C 1 -C ₄ -alkyl or amino

R ^{4 is} straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxyl, cyclopropyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, C ₁ -C ₆ -alkoxy, C 1 -C ₆ -alkoxycarbonyl or phenyl or

- for C 1 -C 4 alkoxy or

- is phenyl, which may be the same or different substituted by fluorine, chlorine, bromine, hydroxyl, nitro, cyano, amino or C ₁ -Ce-AIkOXy up to twice, or

- for sine rest

-HN-R ",

R ¹¹ - Wauserstoff means or

- represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxyl, fluorine, chlorine, bromine, Ci-Cg-alkoxy, Ci-Ce-alkoxycarbonyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyridyl or pyrimidyl or

- represents cyciopropyl, cyclopentyl or cyclohexyl or

- is phenyl, which may be substituted by hydroxyl, fluorine, chlorine, bromine, nitro, cyano, Ci-C _e alkyl, C, -C _e -Aikoxycarbonyl or by amino,

and their physiologically acceptable salts.

Particularly preferred compounds of the general formula (I) are those in which A - hydrogen means or

- represents C 1 -C ₄ -alkyl, C 1 -C ₄ -alkylsulfonyl-phenylsulfone or -olylsulfonyl or

- a group of the formula

-COR ⁵ or COOR ⁶ is ₍

wherein

R ⁵ - represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxy, Phonyί, amino, alkylamino having up to 4 carbon atoms or by dialkylamino having up to 4 carbon atoms per alkyl group

R ^s - is a branched or branched alkyl having up to 4 carbon atoms or A - is an amino protecting group, B - is a direct bond or

for glycyl (Gly), alanyl (Ala), arginyl (Arg), histidyl (His), leucyl (Leu), isoloucyl (lie), seryl (Ser), threonyl (Thr), tryptophyi (Trp), tyrosyl (Tyr ), VaIyI (VaI), lysyl (Lys), asparagyl (Asp), asparagine amido (Asn), glutam / I (Glu), glutaminamido (GIn), cystyl (Cys), methionyl (Met), phenylalanyl (Phe), 2 -, 3- or 4-Nitrophenylalanyl, 2-, 3- or 4-aminophenylalanyl or pyridylalanyl, optionally with amino protecting group, or Prolyl (Pro), wherein the protein groups in each case in their L-form or D-form vorlieger

or

- for a group of the formula

NH

N (R ⁸ -S (0) _m -CH ₂ ^'A N _r ^ rder -NH- (CH ₂ J ₂ -C-,

A H O ö

O stands

wherein

A has the meaning given above and R 'is C ₁ -C ₄ alkyl

D, E and F are the same or different and have the same meaning as B and are the same or different, R '- for straight-chain or branched alkyl with up to 6 carbonates, ". optionally substituted by fluorine, chlorine,

Hydroxy, cyciopropyl, cyclopentyl, cyclohexyl, amino, alkylamino of up to 4 carbon atoms, di-alkylamino with

up to 4 carbon atoms per alkyl group, or phenyl which in turn is substituted by C ₁ -C ₃ -alkyl, amino,

Nitro, cyano, fluorine or chlorine may be substituted or

- is phenyl which is up to twice the same or different by C ₁ -C ₃ -Alkyl, C ₁ -C ₂ -alkoxy, hydroxy, cyano, nitro, trifluoromethoxy, Trifluormethyithio, phenyl or by a Gruppo of the formula

/ -R ⁹

-N

in which can be substituted

R ⁹ and R ^{10 are the} same or different and

- represent hydrogen, C ₁ -C ₃ -alkyl, C _t -C ₃ -alkyloyl, phenyl, benzyl, tolylsulfonyl, acetyl or benzoyl or

- an amino-protecting group, R * - hydrogen or

- represents straight-chain or branched alkyl having up to 6 carbon atoms or

- for the group of the formula

-COR ⁶ is _t

wherein

R ^{5 has} the abovementioned meaning R ^J - is hydrogen or

represents straight-chain or unsaturated alkyl having up to 6 carbon atoms, which may be substituted by fluorine, chlorine, hydroxyl, phenyl, pyridyl or pyrimidyl o Jer

- for a group of the formula

-COR ⁵ stands,

wherein

R ^{6 has} the abovementioned meaning or R * - is phenyl which may be substituted identically or differently up to twice by fluorine, chlorine, hydroxyl,

Nitro, cyano, C ₁ -C ₂ -alkoxy, C ₁ -C ₃ -alkyl or amino R ⁴ - is straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxy, cyclopropyl, cyclopentyl, cyclohexyl, fluorine, chlorine Is C ₁ -C ₄ -alkoxy, CHV alkoxycarbonyl or phenyl substituted or

- WrC ₁ -C ₄ -alkoxy-BrB

- is phenyl which may be substituted by fluorine, chlorine, hydroxyl, nitro, cyano, amino or C ₁ -C ₄ -alkoxy or

- for a rest

H-N-R ",

wherein

R "- hydrogen means or

is straight-chain or branched alkyl having up to 6 carbon atoms, optionally substituted by hydroxy, fluorine, chlorine, bromine, C ₁ -C ₄ -alkoxy, C) -C ₄ alkoxycarbonyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyridyl or Pyrimidyl is substituted or

- Door cyclopropyl, cyclopentyl or cycloh vl is or

- is phenyl which may be substituted by fluorine, chlorine, bromine, nitro, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxycarbonyl or by amino,

and their physiologically acceptable salts.

Salts of the compounds according to the invention having salt-forming groups can be prepared in a manner known per se, for example by reacting the compounds according to the invention which contain acidic groups with corresponding bases or by reacting the compounds according to the invention which contain basic groups with corresponding acids, preferably with jewel the abovementioned bases or acids.

Stereoisomer mixtures, in particular mixtures of oli stereomers, can be prepared in a manner known per se, e.g. be separated by fractional crystallization or chromatography in the individual isomers.

Racemates can in a known per se ^We: e, for example, cleaved by converting the optical antipodes into diastereomers

become.

The compounds of the general formula (I) according to the invention

R ¹ / NR ³ ABDEI

H OR ²

(I)

in which A, B, D, E, F, R ¹ , R ² , R ³ and R ^{4 have} the abovementioned meaning, is obtained by reacting compounds of the general formula (II)

R ¹ CO-FR ⁴

H 0 NR ³ ,

in which R ', R ³ , R ⁴ , A and F have the abovementioned meaning,

first deblocked by cleaving the group A by the usual method, and in a second step with

Compounds of the general formula (III)

ABDE-OH ₍ (III)

in which A, B, D and E have the abovementioned meaning, to the compounds of general formula (Ha)

R ¹ CO-FR ⁴

HO NR ³ ι

in which A, B, D, E, F, R ¹ , R ³ and R ^{4 have} the abovementioned meaning,

and subsequently reducing the compounds of the general formula (Ha) by hydrogenolysis with ring opening.

The compounds of general formula (II) are novel and can be prepared by reacting compounds of the

general formula (Hb)

R ¹ COR ¹²

(Lib)

HO NR ³ ι

in which A, R 'and R ^{3 have} the abovementioned meaning and R "- is C ₁ -C ₄ -alkoxy,

first saponified by customary methods and then with compounds of the general formula (IV)

HFR ⁴ , (IV)

in which F and R ^{4 have} the abovementioned meaning, converts.

The compounds of the general formula (Hb) are novel and can be prepared by reacting compounds of the

general formula (V)

R ¹

H '

in which A, R ¹ and R ^{12 have} the abovementioned meaning, with compounds of the general formula (VI)

C) U

3 Il "θ < ^{V |} )

F ³ -NO ι

in which

R ^{3 has} the abovementioned meaning, in a nitrone cycloaddition reaction,

The synthesis can be exemplified by the following reaction scheme.

BOC-N H

CH-

4C / Hc'-CHo-N-O]

COOCoHc

Δ 60 ⁰ C

BOC-N

HoN

BOC-N

H 0

/ COOCoHc

NaOH

- ^ COOH

BOC-N

H 0

H O

+ 1Ie-OCH ₃

HCl

+ BOC-Phe-His-OH

BOC-Pha-His-HN

CO-IIe-Ocho

Pd / C / NH ₄ HCOO

r ^ | -NH ₂

BOC-Phe-His-N / VVCO-Ie-OCHr ₁ HT ³

OH

Suitable solvents for the additions of the compounds of the general formula (III) and (IV) are the customary inert solvents which do not change under the particular reaction conditions chosen. These include water or organic solvents such as diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride or acetone, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, ethyl acetate, Pyridine, triethylamine or picoline. It is also possible to use mixtures of said solvents

 Preference is given to tetrahydrofuran, methylene chloride, dimethylformamide and ethyl acetate.

Usually, the process is carried out in the presence of suitable solvents or diluents, if appropriate in the presence of an adjuvant or catalyst in a temperature range from -8O ⁰ C to 300 ⁰ C, preferably from -3O ⁰ C to +30 ⁰ C under normal pressure. It is also possible to work at elevated or reduced pressure. As auxiliaries condensing agents are preferably used, which may also be bases, in particular when the carboxyl group is activated as anhydride. Preference is given here, the usual condensing agents such as Cat bodiimide z. B. Ν, Ν'-diethyl, N, N'-dipropyl, Ν, Ν'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride, or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1 -ethoxycarbonyl-1,2-dihydro-quinoline, or propanephosphonic anhydride, or isobutylchloroformate, or benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate, and as bases, alkali metal carbonates ζ. Β. Sodium or potassium carbonate or bicarbonate, or organic bases such as trialkylamines such as triethylamine, N-ethylmorpholine or N-methylpiperidine used.

The compounds of general formula (III) may be prepared by reacting a corresponding fragment consisting of one or more amino acid groups with a free carboxy group optionally present in activated form with a complementing fragment consisting of one or more amino acid groups having an amino group, optionally in activated form, and this process optionally repeated as many times with appropriate fragments until the desired peptides of the general formula (III) has been prepared, then optionally cleaves off protective groups or exchanged for other protective groups. In this case, additional reactive groups, such as. As amino or hydroxy groups, optionally protected in the side chains of the fragments by conventional protecting groups.

Activated carboxyl groups are preferred here:

Carboxylic acid azides (obtainable, for example, by reaction of protected or unprotected carboxylic acid hydrazides with nitrous acid, their salts or alkyl nitrites (e.g., isoamyl nitrite),

or unsaturated esters, in particular vinyl esters, (obtainable, for example, by reacting a corresponding ester with vinyl acetate), carbamoylvinyl esters (obtainable, for example, by reacting a corresponding acid with an isoxazolium reagent), alkoxyvinyl esters (obtainable, for example, by reacting the corresponding acids with alkoxyacetylenes , preferably ethoxyacetylene), or amidinoester z. B. N ₁ N'or Ν, Ν-disubstituted amidino esters (obtainable, for. Example, by reacting the corresponding acid with an Ν, Ν'-disubstituted carbodiimide (preferably dicyclohexylcarbodiimide, diisopropylcarbodiimide od.v NP-N'-Dimethylaminopropyll ethyl-carbodiimide hydrochloride) or phenyl esters substituted with an N, N-disubstituted cyanamide, or aryl esters, especially electron-withdrawing substituents, for example 4-nitrophenyl, 4-methylsulfonylphenyl, 2,4,5-trichlorophenyl, 2,3 , 4,5,6-pentachlorophenyl, 4-phenyl-diazophenyl ester (obtainable, for example, by reacting the corresponding acid with an appropriately substituted phenol, if appropriate in the presence of a condensing agent such as, for example, N, N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide, X (3-dimethylaminopropyldN 'ethylcarbodiimide hydrochloride, isobutylchloroformate, propanephosphonic anhydride), benzotriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate, or cyanomethyl ester (available, for example, by reaction ng of the corresponding acid with chloroacetonitrile in the presence of a base),

or thioesters, in particular nitrophenyl thioesters (obtainable durch B. by reaction of the corresponding acid with

Nitrothiophenols, optionally in the presence of condensing agents such as N.N'-dicyclohexylcarbodiimide, Diisopropylcarbodiimide, N-O-dimethylaminoprcpyD-N'-ethyicarbodiimide hydrochloride, isobutylchloroformate, Propanphosphonsäureanhydrid, Benzotriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate), or amino or Amido esters (obtainable, for example, by reacting the corresponding acid with an N-hydroxyamino or N-hydroxyamido Compound, in particular N-hydroxy-succinimide, N-hydroxypiperidine, N-hydroxy-phthalimide, N-hydroxy-5-norbornene-2,3-

dicarboxylic acid amide or 1-hydroxybenzotriazole, optionally in the presence of condensing agents such as N ₁ N '

Dicyclohexylcarbodiimide, diisopropylcarbodiimide or N-O-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride, Isobutyl chloroformate or n-propanephosphonic anhydride), or anhydrides of acids, preferably symmetric or

unsymmetrical anhydrides of the corresponding acids, especially anhydrides with inorganic acids (available eg.

by reaction of the corresponding acid with thionyl chloride, phosphorus pentoxide or oxalyl chloride), or anhydrides with

Carbonic acid half derivatives e.g. Carbonic acid lower alkyl halide (obtainable, for example, by reaction of the corresponding acid

with haloformic acid lower alkyl esters, e.g. Methyl chloroformate, ethyl ester, propyl ester, isopropyl ester, butyl ester or isobutyl ester or with i-lower alkoxycarbonyl, lower alkoxy-i-dihydro-quinoline, e.g. 1-methoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), or anhydrides with dihalophosphoric acids (obtainable, for example, by reacting the corresponding acid with phosphorus oxychloride), or anhydrides with phosphoric acid derivatives or phosphorous acid derivatives (for example propanephosphonic anhydride, H. Wissmann and HJ Kleiner, Angew. Chem. Int Ed., 19, 133 [1980]) or anhydrides with organic carboxylic acids (obtainable, for example, by reaction of the corresponding acids with an optionally substituted lower alkane or phenylalkanecarboxylic acid halide, in particular phenylacetic acid, pivalic acid or

Trifluoroacetic acid chloride), or anhydrides with organic sulfonic acids (obtainable, for example, by reaction of an alkali metal salt

a corresponding acid with a sulfonic acid halide, in particular methane, ethane, benzene or

Toluenesulfonyl chloride), or symmetrical anhydrides (obtainable, for example, by condensation of appropriate acids,

optionally in the presence of condensing agents such as N, N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide, N- (3

Dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride isobutylchloroformate, propanephosphonic anhydride or Benzotriazolyloxy tris (dimethyfamino) phosphonium. Reactive cyclic amides are in particular amides with five-membered heterocycles having 2 nitrogen atoms and

optionally aromatic in nature, preferably amides with imidazoles or pyrazoles (obtainable, for example, by reacting the corresponding acid with Ν, Ν'-carbonyldiimidazole or optionally in the presence of condensing agents, such as e.g.

N.N'-dicyclohexylcarbodiimide, Ν, Ν'-diisopropylcarbodiimide, N-O-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride, Isobutyl chloroformate, propanephosphonic anhydride, benzotriazolyloxy-tris (dimethylamino) phosphonium

hexafluorophosphate with z. B. 3,5-dimethyl-pyrazole, 1,2,4-triazole or tetrazole.

The amino acids used in the definition B, D, E, F and thus also the compounds of general formula (IV) are on

are known or can be obtained by known methods or are naturally occurring amino acids (Houben-

Weyls, "Methods of Organic Chemistry", Volumes XV / 1 and 2). The reduction can be carried out either with catalysts such as palladium hydroxide or palladium / carbon or via a catalytic Transfer hydrogenation be carried out in a conventional manner (see Tetrahedron 41.3479 [1985], 3-463 (1985), Synthesis

1987.53).

For the nitrone cycloaddition, the usual organic solvents which are not suitable under the reaction conditions

change. These include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol diethyl ether or hydrocarbons such as

Benzene, toluene, xylene, mesitylene or petroleum fractions or n-butyl acetate. Preference is given to benzene, toluene, xylene or

Mesitylene.

The reaction may be in a temperature range from ⁰ ° C to 200 ° C, preferably at 3O ⁰ C to 9O ⁰ C and under elevated or normal Pressure to be performed. The compounds of the general formulas (V) and (VI) are known per se or can be prepared by conventional methods

become.

(Chem. Pharm. Bull.30, 1921 [1982], J. J. Tufariello in I.S Dipolar Cycloaddition Chemistry, Vol.2, id., Padwa, pp. 83-168, John

Wiloy [1984], R.Huisgen, H. Seidel, J.Brüning, Chem. Ber. 102.1102 [1969 ». The compounds of the invention have a circulation-influencing effect. You can therefore use in medicines for Treatment of hypertension and heart failure are used. In vitro test

The inhibitory potency of the peptides according to the invention against endogenous renin from the human plasma is determined in vitro. Pooled human plasma is obtained with the addition of ethylenediaminetetraacetic acid (EDTA) as an anticoagulant and stored at -2O ⁰ C. Plasma renin activity (PRA) is determined as the rate of formation of angiotensin I from endogenous angiotensinogen and renin after incubation at 37 ^° C. The reaction solution contains 150μΙ plasma, 3μΙ 6.6% 8-Hydroxychinolulfatulfatlösung, 3μΙ 10% ig * Uimercaprollösung and 144μ! Sodium phosphate buffer (0.2 M, 0.1% EDTA, pH 5.6) with or without the substances according to the invention in various concentrations. The angiotensin I formed per unit time is determined by radioimmunoassay. The percent inhibition of plasma renin activity is calculated by comparing the substances claimed herein. The co-concentration range, in which the substances claimed here show a 50% inhibition of the plasma renin activity, are between 10 ' ⁴ to 10 "' M.

-17- 287 512 application belsplele

Example no. % Lnhib. IC ₆₀ (M) 31 31 35 34 39 67 77 96 1,1 χ ΙΟ " ⁶ · 79 95 2.5x10 "* 82 89 1,4x10- * 84 100 9.2 x 10 " ⁸ '85 100 2.4x10 " ⁷ 86 92 9,0x10- " 94 100 3.7 x 10 "· 96 100 1.0x10 "· 97 100 2.2 x 10 "'

The new active ingredients can be converted into the customary formulations in known manner, such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. Here, the therapeutically active compound should be present in each case in a concentration of about 0.5 to 90 wt .-% of the total mixture, d. H. in amounts sufficient to achieve the stated dosage margin.

The formulations are prepared, for example, by stretching the active compounds with solvents and / or carriers, if appropriate using emulsifiers and / or dispersants, wherein z. For example, in the case of using water as a diluent, organic solvents may optionally be used as auxiliary solvents.

For example, listed as Hillsstorfe selen:

Water, non-toxic organic solvents, such as paraffins (e.g., petroleum fractions), vegetable oils (e.g., peanut / sesame oil), alcohols (e.g., ethyl alcohol, glycerin), carriers, e.g. B. ground natural minerals (eg kaolins, clays, talc, chalk), ground synthetic minerals {.t. Fumed silica, silicates), sugars (eg, tubular, lactic, and tri, benzougs), emulsifiers (eg, polyoxyethylene fatty acid esters), polyoxyethylene fatty alcohol ethers (e.g., lignin, sulfite bleed, Methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg, magnesium stearate, talc, stearic acid and sodium sulfate).

Dfi. Application is carried out in a customary manner, preferably orally or parenterally, in particular perlingually or intravenously. In the case of oral administration, of course, apart from the abovementioned excipients, tablets may also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various adjuvants such as starch, preferably potato starch, gelatin and the like. Further, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting. In the case of aqueous suspensions, the active ingredients can be crosslinked with the exception of the abovementioned excipients with various flavor enhancers or dyes. In the case of parenteral administration, solutions of the active ingredients may be employed using suitable liquid carrier materials.

In general, it has proved to be advantageous to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight to achieve effective results when administered intravenously, and for oral administration, the dosage is about 0.01 to 20mg / kg, preferably 0.1 to 10mg / kg of body weight. Nevertheless, it may be necessary to deviate from the stated amounts, depending on the body weight of the experimental animal or the type of application, but also due to the species and their individual behavior towards the drug or their nature of its formulation and the time or interval at which the administration takes place. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute them in several single doses throughout the day. For the application in human medicine, the same Dosierspiolraum is provided. Analogously, the above statements also apply here.

The following eluent systems were used:

(A) 10: 1 Methylene chloride / methanol (B) 20: 1 Methylene chloride / Methanoj (C) 40: 1 Methylene chloride / methanol (D) 2: 1 n-hexane / ether (E) 9: 1: 0.1 Methylene chloride / methanol / formic acid (F) 20: 1 Chloroform / acetone (G) 15: 1 Methylene chloride / methanol (H) 20: 1 Chloroform / methanol (I) 9: 1: 0.1 Methylene chloride / methanol / conc. ammonia (J) 1: 1 n-hexane / Essigester (K) 30: 1 Methylene chloride / methanol

Abbreviations ι: leucine Leu tert-butyloxycarbonyl Boc isoleucine Ue N-ethylmorpholine NEM 1-hydroxy-1H-benzotriazole HOBT dicyclohexylcarbodiimide DCC 2-aminomethylpyridine AMP phenylalanine Phe histidine His proline Per . 3-cyclohexylalanine CHxAIa embodiment

The invention is explained in more detail below by some examples. The following embodiments of Tables 1 to 3 (Ex 1 to 76) show precursors and intermediates and the embodiments of Tables 4 to 6 (Ex77 to 109) describe compounds of formula (I).

Example 1 L-phenylalanine methyl ester hydrochloride

χ HCl

OCH

99 g (0.83 mol) of thionyl chloride were added dropwise at -10 ° C to 600 ml of absolute methanol. Subsequently, 100 g (0.605 mol) of L-phenylalanine were added and the reaction mixture was heated under reflux for two hours. The solution was concentrated, the residue dissolved in just sufficient amount of absolute methanol and the product precipitated by the addition of absolute ether.

Yield: 119 g = 91% of theory. Mp 159 ⁰ C.

Example 2 L-leucine ethyl ester hydrochloride

^HC1

Example 2 is prepared analogously to the procedure of Example 1. Yield: 118.4f _; = 86% of the tenth Mp 148 ° C

Example 3 tort-butoxycarbonyl-L-phenylalanine methyl ester

116 g (0.343 mol) of triethylamine and 146 g (0.669 mol) of di-tert-butylpyrocarbonate were added successively at 5 ° C. to 119 g (0.553 mol) of the compound from Example 1 in 750 ml of DMF, and the mixture was stirred overnight at room temperature. The mixture was filtered, the filtrate. concentrated, the residue taken up in 1: 1 water / ethyl acetate and washed with dilute

Hydrochloric acid adjusted to pH 3. The aqueous phase was extracted three times with ethyl acetate, the combined org. Live twice with sat. Washed brine, dried over sodium sulfate and concentrated.

Yield: 154g = 100% d. Th. R _F (i): 0.86

Example 4 tert-butoxycarbonyl-L-leucine methyl ester

\ _f 3 H II O

Example 4 is prepared analogously to the procedure of Example 3.

Yield: 69 g = 100% of theory Rf (a): 0.90

Example 5 Tert-butoxycarbonyl-L-phenylalaninol

To a suspension of 31.22 g (0.828 mol) of sodium borohydride in 200 ml abs. Tetrahydrofuran was added in portions of 110.8 g (0.828 mol) of lithium iodide. Subsequently, a solution of 190.2 g (0.552 mol) of the compound from Example 3 in 320mol abs. Dropped tetrahydrofuran and the suspension stirred at 40 ° C overnight. The mixture was poured cautiously into 10% citric acid solution, extracted four times with ethyl acetate, the combined org. Phases twice a day

 Washed brine, dried over sodium sulfate and concentrated. The crude product was recrystallized from Essigoster / nHoxan.

Yield: 118g = 85% d. Th.

M.p. 95 ^° C. Rf (a): 0.61

Example 6 Tert-butoxycarbonyl-L-S-cyclohexylalaninol

Example 6 is prepared analogously to the instructions of Example 5.

Yield: 123.7 g = 89% d. Th. Rf (b): 0.44

Example 7 Tert-butoxycarbonyl-L-leucinol

Example 7 is prepared analogously to the procedure of Example 5.

Yield: 33.2 g = 87.5% of theory R _F (b): 0.37

Example 8 tert-Butoxycarbonyl-L-phenylalaninal

57.9 g (0.23 mol) of Boc-phenylalaninol (Example 5) in 700 ml of DMSO were admixed under ice-cooling with 96 ml (0.69 mol) of triethylamine and 114 g (0.69 mol) of pyridine-SOj complex and the mixture was stirred at room temperature for one hour touched. The solution was poured onto ice, extracted four times with ether, the combined org. Washed twice with 10% citric acid, twice with 5% sodium bicarbonate and twice with semisaturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was processed directly.

Yield: 52.6 g = 91.9% of theory Rf (a): 0.71

Example 9 tert-Butoxycarbonyl-L-cyclohexylalaninal

BOC-N - ^^ CHO

Example 9 is prepared analogously to the procedure of Example 8.

Yield: 65 g = 95% of theory Rf (b): 0.57

Example 10 Tert-butoxycarbonyl-L-leucinal

BOC-N

H Example 10 is prepared analogously to the procedure of Example 8.

Yield: 56 g = 94% of theory Rf (a): 0.71

Example 11 4- (S) -Boc-amino-5-phenyl-2-pentenoic acid ethylestor

To a solution of 32.8 g (0.147 mol) of triethyl phosphonoacetate in 220 ml of absolute 1,2-dimethoxyethane, 6.2 g (0.147 mol) of lithium chloride were added and then added dropwise at ^{0 0} C slowly 18.0 g (0.140 mol) of diisopropylethylamine. After stirring for 15 minutes at ⁰ ° C., a solution of 36.43 g (0.139 mol) of Boc-phenylalaninal (Example 8) in 200 ml of abs. Added 1,2-dimethoxyethane and the mixture stirred for two days at room temperature. The resulting suspension was stirred into ice-cold 10% citric acid solution, extracted four times with ether, the combined org. Phases with sat

 Washed brine, dried over sodium sulfate, concentrated and the crude product via silica gel in 30: 1 methylene chloride / methanol column filtered.

Yield: 36.3 g = 77.6% of theory Rf (k): 0.67

Example 12 4- (S) -Boc-amino-5-cyclohexyl-2-pentenoic acid ethyl ester

BOC -

Example 12 is prepared analogously to the procedure of example 11.

Yield: 14.9 g = 70.6% of theory, M.p .: 49-5O ⁰ C. Rf (d): 0.39

Example 13 4- (S) -Boc-amino-6-methyl-2-heptenoic acid, ethyl ester

Beispiol 13 is prepared analogously to the procedure of Example 11.

Yield: 23 g = 72.9% of theory Wax. Rf (c): 0.58

Example 14

tert-butoxycarbonyl-L-phenylalanine

BOC-N - ^ - COOH

50 g (0.30 mol) of L-phenylaianine in 900 ml 2: 1 dioxane / V / asser were mixed with 151 ml of 2 N sodium hydroxide solution and 88.7 g (0.366 mol) of 90% di-tert-butylpyrocarbonate. The mixture was stirred overnight at room temperature, then to about one third of the

The residue was diluted with water and extracted at pH 9 twice with ether. The aqueous phase was acidified with dilute hydrochloric acid to pH 3, extracted six times with ethyl acetate, the combined ethyl acetate Phasnn with sat. Washed brine, dried over sodium sulfate and concentrated. The residue was triturated with n-hexane until crystallization and the product was filtered off with suction.

Yield: 77 g = 95.5% of theory Mp 84 ^° C.

Example 15 Tert-butoxycarbonyl-L-3-cyclohexylalanine

0OH

299 g (1.126 mol) of the compound from Example 14 in 1.11 methanol were hydrogenated with the addition of 30 ml of glacial acetic acid bai 30-4O ⁰ C with 30 g of 5% RH / C catalyst and a hydrogen pressure of 40-50 bar. After completion of the reaction, the catalyst was filtered off and the solution was concentrated.

Yield: 306 g = 100% of theory

Example 16 Tert-butoxycarbonyl-L-S-cyclohexylalanine methyl ester

To 242.7 g (0.856 mol) of the compound from Example 15 in 1.21 DMF was added 177.4 g (1.283 mol) of potassium carbonate and 56 mL (0.898 mol) of methyl iodide. After adding a further 500 ml of DMF, the mixture was stirred vigorously overnight at room temperature, then filtered, the filtrate was concentrated, the residue taken up in water and extracted four times with ether. The combined organic phases were washed with sat. Washed brine, dried over sodium sulfate and concentrated.

Yield: 232g = 95% of theory. R _f (b): 0.82

Example 17 Tert-butoxycarbonyl-L-isoleucine

Example 17 is prepared analogously to the procedure of Example 14.

Yield: 168.4 g = 95.5% d. Th. Mp. 70 ⁰ C

Example 18 N-Methylenebenzylamine N-oxide

Θ Θ

65 g (0.313 mol) of N-benzylhydroxylamir. in 630 ml of ether with vigorous stirring with 125 ml (1.585 mol) of 35% aqueous formaldehyde solution were used. Stirring was continued for one hour, then the organic phase was purged, dried over sodium sulfate and concentrated. The crude product was processed directly.

Yield: 65.7 g = 92% of theory

Example 19 Ethyl 2-benzyl-5- (1- (S) -boc-amino-2-phenylethyl) -isoxazolidine-4-carboxylate

COOEt

20 g (0.063 mol) of the compound from Example 11 and 16.9 g (0.125 mol) of the compound from Example 18 in 30 mmol of toluene were stirred at 60 ° C. for seven hours and then at room temperature overnight. After addition of another 4.16 g (0.031 mol) of the compound from Example 18 in 25 ml of toluene was heated again to 6 ° C for two hours, then the reaction mixture washed twice with half-saturated brine, dried over sodium sulfate and concentrated. Column chromatography of the crude product on silica gel in 2: 1 hexane / ether gave 12.65 g (44.5% of theory) of the nonpolar and 4.26 g (15.0% of theory) of the polar isomer.

Total yield: 16.91g = 59.5% d.Th. Rf (d): 0.25 and 0.17 respectively

Example 20 Ethyl 2-8-Cyl-5- (1- (S) -boc-amino-2-cyclohexylethyl) -soxazolidine-4-carboxylate

^ 'COOEL BOC-N''"

Example 20 is prepared analogously to the procedure of Example 19.

Yield: 16.12g = 57% d. Th. Rf (d): 0.32 and 0, k5, respectively

Example 21 2-Benzo-1- (S- (S) -Boc-amino-3-methylbutyl) -isoxazolidine-4-carboxylic acid ethyl ester

BOC-I

H 0 "Example 21 is prepared analogously to the procedure of Example 19.

Yield: 18.55 g = 63.1% of theory Rf (d): 0.33 and 0.25 respectively

Example 22 2-Benkyl-5- (1- (S) -Boc-amino-3-methyl-butyl) -isoxazolidine-4-carboxylic acid

• k

5.4 g (12.9 mmol) of the compound from Example 21 (mixture of isomers) in 60 ml of 2: 1 dioxane / water were stirred for three cionclene long with 14.1 ml of 1N sodium hydroxide solution at room temperature and then allowed to stand overnight in the refrigerator. The solution was concentrated to an oil volume of the original volume, diluted with water and extracted twice with ether at pH 12.

The aqueous phase was brought to pH 5 with dilute hydrochloric acid, extracted four times with ethyl acetate, the combined ethyl acetate phases with sat. Washed brine, dried over sodium sulfate and concentrated.

Yield: 4.75 g = 94.4% of theory R _F (e): 0.45

Example 23 2-Benzyl-5- (1- (S) -Boc-amino-2-phenylet'iyl) -isoxazolidine-4-carboxylic acid

Example 23 is prepared analogously to the procedure of Example 22.

Yield: 12.74 g = 92.1% of theory R _F (e): 0.46

Example 24 2-Benzyl-5- (1- (S) -Boc-amino-2-cyclohexylethyl) -isoxazolidine-4-carboxylic acid

Example 24 is prepared analogously to the procedure of Example 22.

Yield: 3.9 g = 94% of theory. Rf (e): 0.40 and 0.31 respectively

Example 25 Boc-1-isoleucine-2-aminomethylpyridylamide

30g (0.13 mol) of the compound from Example 17 in 250 ml of methylene chloride at ⁰ ° C sequentially with 14,75g (0, '36rnol) 2-Picolyfamin, 123ml (0,886mol) of triethylamine and 116inl of a 50% solution of propane phosphonic acid anhydride in igeti Methylene chloride added. The solution was stirred at room temperature overnight, then poured into ice cold sodium bicarbonate solution, org. Phase again with 5% sodium bicarbonate and once with sat. Washed brine, dried over sodium sulfate, concentrated and the crude product via silica gel in 15: 1 methylene chloride / Mothanol filtered column.

Yield: 35.33 g = 84.6% of theory. Rf (g): 0.52

Example 26 L-isoleucine-2-aminomethylpyridylamide dihydrochloride

χ 2HCl

35.33 g (0.11 mol) of the compound from Example 25 were stirred with 15 ml of 4N HCl / dioxane and 40 ml of absolute methanol for 75 minutes at 0 ° C. and for three hours at room temperature. The solution was concentrated by evaporation, the residue was added several times with absolute ether, in each case concentrated again and the product was dried under high vacuum.

Yield: 33 g = 100% of theory

Example 27 N - ^ - Benzyl-S-d-ISJ-Boc-amino-phenyl-phenyl-isoxazolidine-1-carbonyl-L-isoleucine methyl ester

12.7 g (29.77 mmol) of the compound from Example 23 (mixture of isomers) in 100 ml of methylene chloride were added successively with 5.95 g (32.75 mmol) of L-IIe-OCH ₃ × HCl, 3.45 g (34 , 24mmol) triethylamine, 5.47g (35.73mmol) HOBt, and 7.06g (34.24mmol) OCC and the reaction mixture stirred overnight at room temperature. The resulting precipitate was filtered off, the filtrate twice with 5% sodium bicarbonate · and once with gas. Washed brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel in 40: 1 methylene chloride / methanol.

Yield: 14g = 85% d. Th.

Rf (c): 0.39 and 0.23 respectively

The examples listed in Table 1 were prepared analogously to the procedure of Example 27.

N (Λ ΙΛ cn » cn co cn ΙΛ ΙΛ O cn co O • ♦ cc O O O O O

CC

CQ

O)

• Η

α ·

U) U

• η 2

Ο) CQ

cn / X (M U X O U I Z I ΙΛ ΙΛ X X vO vX> O U I I (M (M X X U υ

ΙΛ ΙΛ χ X U U I ι (M (M χ X U U

O O CQ

(M SC U

ι X

ΙΛ

νθ

(NJ

XO

ΙΛ X

νθ U

CM

η η / X X (M U U X ο ο U ι X 2 ι ιη ΙΛ ΙΛ X X X νθ νθ -Ω U α U I ι ι (M (M (M X X X U U U

ΙΛ ΙΛ ΙΛ X X X νθ ^ o νθ U U α I I ι CM (M (M X X X U O U

ΓΜ

X o

X Z

ΙΛ

νΟ U

CM

X U

ΙΛ X

νβ

(M X U

U) U) U) U) * ri X X Ti X * ri X Phe Phe Phe Phe I Per I Per DOS DOS DOS DOS

00 CO

(M

τΗ CM

Example 35 N- [2-Benzyl-5- (1- (S) -Boc-amino-2-cyclohexylethyl) -isoxazolidine-4-carbonyl-L-isoleucine methyl ester

COOCH ₃

3.0 g (6.94 mmol) of the compound from Example 24 (mixture of isomers) in 35 ml methylene chloride at ⁰ ° C successively with 1.38 g (7,63mmol) _L-IIe-OCH3 x HCl, 0.92 g (7, 98%) N-ethylmorpholine, 1.27 g (8.32 mmol) HOBt and 1.72 g (8.32 mmol) DCC were added and the reaction mixture was stirred at room temperature overnight. The resulting precipitate was filtered off, the filtrate twice with 5% sodium bicarbonate and once with gas. Washed brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel in 1: 1 n-hexane / ethyl acetate.

Yield: 3.5 g = 90% of theory.

Rf (J): 0.60 and 0.49 respectively

The examples listed in Table 2 were prepared analogously to the procedure of Example 35.

CQ

Q) JQ (O

Q)

• rl

α ·

Ul U

• η Z Q) CQ

• JZ • Η (0   Η • Η O ΙΛ ιΛ N ΙΛ ΙΛ ΙΛ ·. jQ * ♦ · " ο ο O O O O

Cl

ac υ

ο ΙΛ υ ΙΛ ac I • ζ. ac νθ X U I υ ΙΛ ι ι X CM CM νθ X X U ο α I CM ac υ

\ η π η (M X ac X χ υ ο υ ι ο ο ο

ac ac νθ υ ο ι ι CM (M ac X υ O

O O CQ

ΙΛ

ac

νθ

CM

a: o

CO Cl

ο ή

ΙΛ ΙΛ ΙΛ ΙΛ ac ac X X υ υ U U I ι ι I CM CM CM ac ac X X υ υ U O

O ο U υ ι ι ι ι CM (NJ CM CM ac X ac X U U υ υ

ul U) U) ul X • Η X • Η X • rl X Phe Phe Phe Phe ι , Per ι BOC X BOC BOC

CM

Table 2 (continued)

R ¹ CO-FR ⁴

¹ '' 3 H 0 NR ³

Game No.

BOC Pro Phe His

^CH 2 " ^C 6 ^H 5

-HN-CH

0.38 (i)

44 BOC 45 H 46 BOC 47 BOC 48 H 49 BOC

Phe His

Phenomenology

His

- + SOo-CH ₇ -NHV ^ C- He

CH ₂ -C ₆ H _{1 l} CH ₂ -C ₆ H ₁₁

^CH 2 ~ ^C 6 ^H 11 CH ₂ -C ₆ H ₁₁

CH ₂ -C ₆ H ₁₁

CH ₂ -C ₆ H ₅ ^CH 2 " ^C 6 ^H 5

^CH 2 " ^C 6 ^H 5 ^CH 2" ^C 6 ^H 5 CH ₂ -C ₆ H ₅

CH ₂ -C ₆ H ₅

NH-IC ₄ H ₉ NH-IC ₄ H ₉

NH-IC ₄ H ₉

0.39 and 0.31 (c)

0.48 (i)

NH-C ₂ H ₄ -C ₆ H ₅ 0.43 or

0.34 (c) NH-C ₂ H ₄ -C ₆ H ₅

NH-C ₂ H ₄ -C ₆ H ₅ 0.47 (i)

NH-CH ₂

0.36 (b)

ro co I

Table 2 (continued)

R ¹ CO-FR ⁴

-R ³

Example A B no.

51 BOC -

Phe

CO- He CH, -

-HN-CH ₂

0.33 (b)

52 BOC -

His He CH ₂ -C ₆ H ₁₁ CH ₂ -C ₆ H ₅

HN-CH

0.42 (i

Phe He CH ₂ -C ₆ H ₁₁ CH ₃ -C ₆ H ₅

-HN-CH ₂

0.38 (b)

+ SO ₂ -CH ₂ ^ M: 0-

His he

CH ₂ -C ₆ H ₁₁ CH ₂ -C ₆ H ₅

HN-CH

0,53 resp

 0.51 (i)

55 Boc

CO

His He CH ₂ -C ₆ H ₁₁ CH ₂ -C ₆ H ₅

-HN-CH ₂

0.50 (i)

Example 56 N- [2-Benzyl-5- (1- (S) -Boc-amino-3-methylbutyl) -isoxazolidine-4-carbonyl] -L-isoleucine methyl ester

COOCH ₃

Ph

2.76 g (7.01 mmol) of the compound from Example 22 (mixture of isomers) in 30 ml of methylene chloride were dissolved successively at ⁰ ° C. with 1.4 g (7.71 mmol) of L-IIe-OCH ₃ × HCl, 0.928 g (8, 06mmol) of N-ethylmorpholine, 1.29g (8.41mmol) of HOBt and 1.73g (8.41mmol) of OCC, and the reaction was stirred at room temperature overnight. The resulting precipitate was filtered off, the filtrate twice with 5% sodium bicarbonate and once with sat. Washed brine, dried over sodium sulfate and concentrated. Column chromatography of the crude product on silica gel in 20: 1 chloroform / acetone gave 1.83 g (50.3% of theory) of the nonpolar and 1.11 g (30.5% of theory) of the polar isomer.

Total yield: 2.94g = 80.8% d.Th.

Rf (f): 0.42 and 0.25 respectively

The examples listed in Table 3 were prepared analogously to the procedure of Example 56.

CQ

(O

N £ X) ~ ro ^ * (0 ω (m • Η N (D N (0X) w N * r co t-i νθ O in (η (M (O vO N (M * π O O O ο O O O

υ ο

\ X π U (M υ X O ο U U ι O

in in X X U U ι ι (M (M X X U O

ιη

νθ

IN THE

X O

ιη

ac

ν £ U I (M

SC

(M X U

• Η

PC

• Η

υ ο

O O CQ

ιη X

νθ U

(M S U

ιη X

νθ

(M DC U

ιη X

(M X o

σ * X

• Η

σ »ο

• Η (U

σ X

ιη X

(M X U

U) U) U) V) U) J • Η • Η • rt • Η • Η O = CJ X X X X X > X ^ (U Ο) O) (U (U I X! χ; χ: χ: X! 0 < OU OU OU 0η ο O ι U U ι ι OU ι ie I O υ U O υ O ο O O ο CQ X CQ CQ CQ CQ

0) ΙΛ ω ch ο (M 0) α · ιη ιη t ~ H ι-I U) U (U • Η 2 X) (U Π) CQ H

νθ

ιη

Table 3 (continued)

R ¹ CO-FR ⁴

H 0 N-R '

Example A no.

B D

C ₂ H ₅ OC- - Phe

His He IC ₄ H ₉

Phe His He 1C ₄ H ₉ CH ₂ -C ₆ H ₅

HN-CH

-HN-CH ₂

0.38 (i)

0.33 (i)

Bcc

O H H

C-

Il ο

He iC ₄ H ₉ CH ₂ -C ₆ H ₅

HN-CH

0.33 (b)

- + SC ₂ -CH ₂ His He

^CH 2 " ^C 6 ^H 5

HN-CH

0,46 resp

 0.42 (i)

Table 3 (continued)

R ¹ CO-FR ⁴

H 0 NR ³

Example A BD

Boc

Boc

H

His he

His He iC ₄ H ₉

CH ₂ -C ₆ H ₅

HN-CH

CH ₂ -C ₆ H ₅

HN-CH

0 »49 (i)

0.41 (i)

UI IS »

Table 3 (continued)

Example AB D no.

H 0 "E F

R ¹ CO-FR ⁴

NR ³

^RJ

Boc - Phe

Phe He 1C ₄ H ₉

He 1C ₄ H ₉

-HN -'- CO- Hey

His

Hey iC "H

4, "9

He 1C ₄ H ₉

CH ₂ -C ₆ H ₅

~ ^CH 2 ^C 6 ^H 5

^CH 2 " ^C 6 ^H 5

-HN-CH ₂ -

HN-CH

-HN- ^ H-

HN-CH

0.32 and Ij 0.28 (b)

0.40 brw. I 0.36 (b)

.0,23 or I 0,18 (b)

0.39 and I 0.36 (i)

C, 32 (b)

CO CJI I

VS IS)

Example 77 N - ^ - Aminomethyl-tSl-Boc-L-phanylalanyl-L-histidylamino-S-hydroxy-R-phenylpentanoyl-L-isoleucine methyl ester

BOC-Phe-His-HN

CO-IIe-OCH ₃

300mg of 10% Pd / C catalyst was added to a solution of 500 mg (0.6 mmol) of the compound from Example 31 and 189 mg (3 mmol) of ammonium formate in 25 ml of methanol and the mixture refluxed under argon for one hour. The catalyst was filtered off, the filtrate was concentrated, the residue taken up in methylene chloride, once with half the total. Washed brine, dried over sodium sulfate, concentrated, and the crude product by column chromatography on kieselge! in 9: 1: 0.1 methylene chloride / methanol / conc. aq. Cleaned ammonia solution.

Yield: 380 mg = 84.7% of theory

The examples listed in Table 4 were prepared analogously to the procedure of Example 77.

Table 4

Example A no.

) _jt_r4

OH

BOC Pro Phe His He CH ₃ -C ₆ H ₅

OCH--

0.28 or 0.21 (i)

BOC

Phe His He CH ₃ -C ₆ H ₅

HN-CH

0.21 (i)

BOC Pro Phe His He CH ₃ -C ₆ H ₅

HN-CH

0.28 and 0.19 respectively (i)

Example 81 N - ^ - Acetamidomethyl-ISI-Boc-L-phenylalanyl-L-histidyl-amino-S-hydroxy-B-phenylpentanoyl-L-isoleucine methyl ester

BOC-Phe-His-HN

110 mg (0.15 mmol) of the compound from Example 77 In 6 ml of methylene chloride were added at ^{0 0} C with 14μΙ (0.15 mmol) of acetic anhydride and 21 .mu.Ι (0.15 mmol) of triethylamine and the mixture 30min. stirred long at ^{0 0} C. The solution was added twice with gas. Washed brine, dried over sodium sulfate, concentrated, and the crude product purified by column chromatography on silica gel in 10: 1 methylene chloride / methanol.

Yield: 88 mg = 74% of theory Rf (a): 0.27

Example 82 N- [2-Aminomethyl-4- (S) -Boc-L-phenylalanyl-2-histidylamino-5-cyclohexyl-3-hydroxypentanoyl] -2-isoleucine methyl ester

300mg of 10% Pd / C catalyst was added to a solution of 500mg (0.59mmol) of the compound of Example 39 (unpolaros isomer) and 186mg (2.95mmol) of ammonium formate in 20ml of methanol and the mixture was placed under argon for one hour Reflux heated. The catalyst was filtered off, the filtrate was concentrated, the residue taken up in methylene chloride, once with half the total. Brine, dried over sodium sulfate, concentrated, and the crude product by column chromatography on silica gel in 9: 1: 0.1 methylene chloride / methanol / conc. aq. Cleaned ammonia solution.

Yield: 259 mg = 58% of theory

Rf (i): 0.12 and 0.09, respectively

The examples listed in Table 5 were prepared analogously to the procedure of Example 82. table

R ¹ / NH-R

-R ³

Example A no.

OH

BOC Pro Phe His

BOC

BOC BOC

Phe His

BOC Pro Phe His

Phe His Phe His

+ SO ₂ -CH ₂ -N ^ / ^

89 Boc

Phe

He CH ₂ -C ₆ H ₁₁ H

He CH ₂ -C ₆ H ₁₁ H

lie CH ₂ -C ₆ H ₁₁ H

^CH 2 ~ ^C 6 ^H 11 ^CH 2 ~ ^C 6 ^H 11

He CH ₂ -C ₆ H ₁₁ H

OCH

HN-CH

HN-CH

-NH-IC ₄ H ₉ -NH-C ₂ H ₄ -C ₆ H ₅

HN-CH

0.14 (i)

0.26 (i)

0.25 (i)

0-13 (i)

0.14 (i)

0.48 or, Ij 0.41 (i)

He CH ₂ -C ₆ H ₁₁ H

-HN-CH ₂

0.49 (i)

ω to I

Table 5 (continued)

i-ir-p4

I H

Example A no.

B DE

OH F

Boc

C-His He CH ₂ C ₆ H ₁₁ H

HN-CH

0.23 (i)

Il] Il Phe »N> H

He CH ₂ -C ₆ H ₁₁ H-HN-CH-

0,53 resp

 0.39 (i)

- + SO-

His He CH ₂ -C ₆ H ₁₁ H

HN-CH

0,29 resp

 0.16 (i)

Boc -

His He CH ₂ -C ₆ H ₁₁ H

C-

Il 0 -HN-CH ₂ -

0.20 (i)

Example 94 N-ia-Aminomethyl-iSJ-Boc-L-phenylalanyl-L-histidylamino-S-hydroxy-e-methylheptanoyl-L-isoleucine methyl ester

BOC Phs-His-HN

300mg of 10% Pd / C catalyst was added to a solution of 500 mg (0.62 mmol) of the compound of Example 60 (non-polar isomer) and 196 mg (3.1 mmol) of ammonium formate in 20 mL of methanol and the mixture was stirred under argon for one hour heated to reflux. The catalyst was filtered off, the filtrate was concentrated, the residue taken up in methylene chloride, once with half the total. Brine, dried over sodium sulfate, concentrated, and the crude product by column chromatography on silica gel in 9: 1.0.1 methylene chloride / methanol / conc. aq. Cleaned ammonia solution.

Yield: 336 mg = 75.7% of theory (Lyophilisate)

Rf (O: 0.20

The examples listed in Table 6 were prepared analogously to the procedure of Example 94. table

Example λ Β No.

R ¹ r I oh ^ NH-R ³ A-B-D-E-N'I -CO-FR ⁴ I H e F

BOC Pro

Phe

His

He 1C ₄ H ₉ H OCH ₃

0.21 and 0.16 respectively (i)

BOC

Phe His

He 1C ₄ H ₉ H

HN-CH

0.15 or 0.09 (i)

BOC Pro

Phe His

He 1C ₄ H ₉ H

HN-CH

0.13 or 0.09 (i)

Phe His

He 1C ₄ H ₉ H

-HN-CH ₂ -

0.17 or 0.08 (i)

-N- (CH ₂ ) ₂ -C- He 1C ₄ H ₉ HHI!

HN-CH

He iC ₄ H ₉ H

-HN-CH ₂

0.20 or 0.17 (i)

0.14 or 0.08 (i)

Table 6 (continued)

A-B-D-E-I

HR ³ 0-FR ⁴

Example A B no.

HEIGHT

R ³ R ⁴

101 BOC

C-

Il

Ph e

HN-CH

0.47 (i)

He IC ₄ H ₉

-HN-CH ₂

0.40 and 0.29, respectively (i)

103 BOC

Ph e

"X

He IC ₄ H ₉

HN-CH

0.43 (i)

104 BOC

NH

He IC ₄ H ₉

-HN-CH ₂

0.40 and 0.37, respectively (i)

He iC ₄ H ₉

HN-CH

0.39 (i)

Table 6 (continued)

Example A no.

A-B-D-E-I

HR ³ 0-FR ⁴

OH

106 C ₂ H ₅ -OC-

Ph e

He iC ₄ H ₉

HN-CH

0.29 and 0.14 respectively (i)

He iC ₄ H ₉

HN-CH

0.35 or I 0.20 (i)

108 BOC

109 BOC

CO

O-

His His He IC ₄ H ₉ H

-HN-CH ₂ ·

0.29 (i)

He IC ₄ H ₉ H

HN-CH

0.40 (i)

Claims (2)

claims: 1. Process for the preparation of aminomethyl peptides of the general formula (I) Third .NO A-B-D-E-N ' ; O-f-r OR ' in which A is hydrogen or - represents C 1 -C 6 -alkyl, C 1 -C 4 -alkylsulfonyl, phenylsulfonyl or tolylsulfonyl or - for a group of the formula COR ⁵ or COOR ⁶ is in which R ⁵ - represents straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by hydroxy, aryl, amino, alkylamino having up to 8 carbon atoms per alkyl group or dialkylamino having up to 8 carbon atoms per alkyl group, and R ⁶ - represents straight-chain or branched alkyl having up to 8 carbon atoms or A - for an amino group stands for B - stands for a direct bond or - for a group of the formula R ' ^(CH 2> n -N -NH- (CHO) _n -C-2P, j H ⁽ <f ^H 2> n or R ⁸ -S (O) _m -CH _i stands wherein ρ - a number M, 2 or 3 means m - a number 0,1 or 2 means η - a number O _/ 1,2,3 or 4 bags R ^{7 is} hydrogen, C 1 -C ₈ -alkyl, hydroxymethyl, hydroxyethyl, carboxy, C 1 -C 4 -alkoxycarbonyl or mercaptomethyl or - is a group of the formula ## STR9 ## is CH ₂ -NH-R ⁸ wherein R ⁸ - is hydrogen, C ₁ -C ₈ alkyl, phenylsulfonyl, C ₁ -C ₆ alkylsulfonyl or - stands for an amino protecting group R ^{7 is} guanidinomethyl, methylthiomethyl, halogen, indolyl, imidazolyl, pyridyl, triazolyl or pyrazolyl optionally substituted by R ⁸
R ^{8 has} the meaning just given or - represents cycloalkyl having 3 to 8 carbon atoms - is aryl, which may be substituted up to 3-fold, identically or differently, by C ₁ -Ce-AlCl yI, C ₁ -C ₆ -alkoxy, C ₁ -C 10 -alkyl-benzyloxy, trifluoromethyl, halogen, hydroxy, nitro or by a group of the formula -N \ _R 10 I wherein R ⁹ and R ^{10 are the} same or different and - is hydrogen, C ₁ -C ₈ -alkyl, C ₁ -C -alkylsulfinyl, aryl, aralkyl, tolylsulfonyl, acetyl, benzoyl or - stand for an amino protecting group or B - for a group of the formula or wherein X - represents methylene, hydroxymethylene, ethylene, sulfur or oxygen, and A - has the meaning given above D - has the abovementioned meaning of B and is identical or different, E - has the abovementioned meaning of B and is identical or different, F - has the abovementioned meaning of B and is identical or different with this R ^{1 is} straight chain or branched alkyl having up to 10 carbon atoms optionally substituted by halogen, hydroxy, cycloalkyl of 3 to 8 carbon atoms, amino, alkylamino of up to 8 carbon atoms, dialkylamino of up to 8 carbon atoms per alkyl group or phenyl which in turn is substituted by C ₁ -C ₈ -Alkyl, amino, nitro, cyano or halogen may be substituted or - is aryl having 6 to 10 carbon atoms, which are up to ₄ times the same or different by C ₁ -C ₆ -Alkyl, C ₁ -C ₆ Alkoxy, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, Trifluoromethylthio, phenyl or by the group of the formula may be substituted
wherein R ⁹ and R ^{10 are the} same or different and have the abovementioned meaning, R ^{2 is} hydrogen or - represents straight-chain or branched alkyl having up to 10 hydrocarbon atoms or - for the group of the formula -COR ⁵ stands wherein R ^{6 has} the meaning given above,
R ^{3 is} hydrogen or
"- represents straight-chain or branched alkyl having up to 10 carbon atoms, which may be substituted by halogen, hydroxy, aryl or heteroaryl or - for a group of formula -COR ⁵ stands ₍ wherein R ^{5 has} the meaning given above
R ³ ~ is aryl which may be substituted identically or differently up to 4 times by Halogen, hydroxy, nitro, cyano, C ₁ -C ₈ -alkoxy, C, -C ₈ alkyl or amino R ⁴ - represents straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by hydroxyl, cycloalkyl having 3 to 8 Carbon atoms, halogen, C 1 -C ₈ alkoxy, C 1 -C ₆ alkoxycarbonyl or aryl is substituted or - stands for C ₁ -C ₈ -alkoxy or - is aryl which may be substituted by halogen, hydroxyl, nitro, cyano, amino or C ₁ -C ₈ -alkoxy up to 3-fold, identically or differently, or - for a rest -HN-R ¹¹ , wherein R ^{11 is} hydrogen or - represents straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by hydroxyl, halogen, C ₁ -C ₈ -alkoxy, C ₁ -C 4 -alkoxycarbonyl, cycloalkyl having 3 to 8 carbon atoms, aryl or heteroaryl or - represents cycloalkyl having 3 to 8 carbon atoms or - represents phenyl which is represented by hydroxy, halogen, nitro, cyano, Q-Ce-alkyl, Cr-Ce-alkoxycarbony! or may be substituted by amino, and their physiologically acceptable salts and optionally their pharmaceutical administration form, characterized in that compounds of the general formula (II) CQ-FR ⁴ (ID in which R ¹ , R ³ , R ⁴ , A and F have the abovementioned meaning, first deblocked by the group A is cleaved by the usual method, and in a second step with compounds of the general formula (III) A-B-D-E-OH, (III) in which A, B, D and E have the abovementioned meaning, to the compounds of general formula (Ha) CO-F-R H O - in which A, B, D, E, F, R ¹ , R ³ and R ^{4 have} the abovementioned meaning, and the compounds of general formula (Ha) then reduced by hydrogenolysis with ring opening and optionally the compounds prepared by this process under Use of customary excipients and carriers converted into a suitable application form. 2. Use of compounds of the general formula (I) according to claim 1, characterized in that they are used in the manufacture of medicaments with circulation-influencing action for the treatment of hypertension and cardiac insufficiency. Field of application of the invention