CH676988A5 - - Google Patents

Abstract

A compound of formula <IMAGE> where A is an acyl group; B and C are bonds or represent amino-acids with at least one amino-acid being present; R2 is a side chain of an amino-acid; R3 is H, OH, acyloxy or NH2; D is a bond, O, >NR1, or> CH-R1; Y is >CO, >SO2 or >P(O) NR4 R5; R1 is H or alkyl; and NR4 R5 is an amino function, These compounds have renin-inhibiting activity and are for use against hypertension and cardiac insufficiency.

Description

       

  
 



  The invention relates to the subject-matter defined in claims 1 to 15.



  The C atoms substituted by R2 and R3 can have the R or S configuration. Preferred compounds of the formula I are those in which the C atoms substituted by R2 and R3 are those in the formula I. <y> have the specified configuration.



  Preferred compounds of the formula I have the formula I. <y>
EMI1.1
 



  wherein
 A <y> tert-butyloxycarbonyl, pivaloyl, bis (1-naphthylmethyl) acetyl, benzoyl or 1-adamantylcarbonyl,
 B <y> a bond, phenylalanine or beta cyclohexylalanine,
 C. <y> histidine, norleucine, phenylalanine or leucine,
EMI1.2
 



  R1 <y> hydrogen or methyl,
 R2 <y> isobutyl, benzyl, cyclohexylmethyl or 1-adamantylmethyl,
 R3 <y> hydroxy, amino or groups of the formulas OCOCH3 or OCOC (CH3) 3,
 R4 <y> hydrogen, methyl, i-propyl, i-butyl or n-butyl,
 R5 <y> methyl, i-propyl, i-butyl or n-butyl, or
 
EMI2.1
 a pyrrolidinyl, piperidinyl or morpholinyl group and
 
EMI2.2
 mean that the Y <y> stands for -SO2- if D <y> means the groups -CH2- or CH-isopropyl.



  Very particularly preferred compounds of the formula I have the formula Iz
EMI2.3
 



  wherein
 A <z> tert. Butyloxycarbonyl or bis (1-naphthylmethyl) acetyl,
 B <z> a bond, phenylalaninyl or beta-cyclohexylalaninyl,
 C. <z> histidine, leucine or norleucine
EMI3.1
 



  R1 <z> hydrogen
 R2 <z> cyclohexylmethyl or 1-adamantylmethyl,
 R3 <z> hydroxy or amino,
 R4 <z> hydrogen or methyl,
 R5 <z> methyl, isopropyl or isobutyl or
 
EMI3.2
 a pyrrolidinyl, piperidinyl or morpholinyl group and
EMI3.3
 



  mean that Y <z> stands for -SO2- if D <z> means the groups -CH2- or CH- isopropyl.



  In the formula I, R6 means, if it is a straight-chain or branched alkyl having 1 to 10 carbon atoms, in particular methyl, ethyl, propyl, isopropyl, butyl, tert. Butyl, 2,2-dimethylethyl, pentyl, hexyl etc., especially methyl, tert. Butyl and 2,2-dimethyl-ethyl, and if it is substituted by aryloxy, especially phenoxymethyl or 1- or 2-naphthyloxymethyl, preferably 1-naphthyloxymethyl, if it is cycloalkyl with 3-7 carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, if it stands for (C3-10) cycloalkyl- (C1-5) alkyl, cycloalkyl can have the above meanings and also mean adamantyl, in particular it stands for cyclohexylethyl- or (1-adamantyl) ethyl, if it (C6-10) aryl is especially phenyl or 1- or 2-naphthyl, preferably 1-naphthyl if it is a heteroaryl radical,

   it means in particular pyridyl, thienyl or furyl, if it represents a heteroarylalkyl radical, the heteroaryl part and the alkyl part preferably have the abovementioned meanings, if it represents a straight-chain or branched alkoxy radical, it means in particular ethoxy or tert. Butoxy and if it stands for (C6-10) aryl- (C1-5) alkoxy, it has in particular the meanings given above for aryl and alkyl and preferably stands for benzyloxy. A then stands for the corresponding carbonyl compounds of R6.



  R7, if it is (C1-5) alkyl, has the meanings given above for alkyl and if it stands for aryl, in particular the meanings phenyl or 1- or 2-naphthyl, in particular 1-naphthyl.



  R8 and R9, if they are (C1-5) alkyl, have the meanings given above for alkyl and if they stand for aryl, the meanings phenyl, 1- or 2-naphthyl, preferably 1-naphthyl. The latter meaning is preferred for R8, while hydrogen is preferred for R9.



  In the group R10O (CH2CH2O) n (CH2) m-, R10 preferably has the meaning methyl, n is preferably an integer from 4 to 12, in particular 7 and m preferably 1.



  The hydrophilic or lipophilic amino acid side chain with the meaning of R11 can be, for example, an n-butyl, isobutyl, benzyl, 4-imidazolylmethyl, 2-methylthioethyl, cyclohexylmethyl or a pyridylmethyl radical.



  If R1 is (C1-5) alkyl, the alkyl radicals can be as defined above, in particular they are methyl.



  If R2 is (C1-10) alkyl, this can be straight-chain or branched and can mean the above alkyl radicals if it is an (C3-10) cycloalkyl (C1-5) alkyl which is optionally substituted in the cycloalkyl part , it preferably means cyclohexylmethyl, the cycloalkyl optionally being substituted by oxo, hydroxy, or by a radical of the formula
EMI5.1
 



  is di-substituted (spiro-fused), where o is 2 or 3, adamantyl, preferably 1-adamantylmethyl, if it is (C6-10) aryl- (C1-5) alkyl, it is preferably benzyl or naphthylmethyl and if it is represents a heteroaralkyl radical, the heteroaryl part means in particular pyridyl, thienyl or furyl radicals and the alkyl part is as defined above.



  If R4 and R5 represent a (C6-10) aryl- (C1-5-alkyl radical), these preferably mean a phenyl- (C1-5) -alkyl, in particular a benzyl radical, if they represent a heteroarylalkyl- When the radicals are, the heteroaryl part is in particular a pyridyl, thienyl or furyl radical and alkyl is the radicals given above If R4 and R5 are (C1-5) alkyl, alkyl has the meanings given above.



  If R12 is a (C1-5) alkyl radical, alkyl means the radicals indicated above, but especially isopropyl, n-butyl, isobutyl and 2-methyl-butyl. Hydroxyalkyl preferably means hydroxymethyl or hydroxyethyl. If R13 is aminomethylpyridyl, it is preferably aminomethyl-2-pyridyl.



  In R14 (C1-5) alkyl has the meanings given above.



  The processes for the preparation of compounds of the formula I described in claims 7 to 14 can be carried out in detail as follows:



  The process according to claim 7 for the preparation of compounds of the formula Ia is advantageously carried out in such a way that the compounds of the formula II are reacted with the compounds of the formula III by a method suitable for peptide couplings. For example, the reaction can be carried out in the presence of N, N min -dicyclohexylcarbodiimide or N-ethyl-N min - (dimethylaminopropyl) -carbodiimide and N-hydroxysuccinimide or 1-hydrobenzotriazole, the solvent being e.g. Dimethylformamide is used and the reaction takes place at temperatures from 0 ° to preferably room temperature.



   Alternatively, the reaction can also be carried out in the presence of 50% propane phosphoric anhydride in methylene chloride in the presence of a base, e.g. N-methylmorpholine in a suitable solvent, e.g. Dimethylformamide. The reaction is conveniently carried out at from 0 ° C. to room temperature, preferably at room temperature. In this process, a functional group, in particular a hydroxyl group of one of the reactants, is expediently protected beforehand by a protective group, for example a BOC group (tert. Butyloxycarbonyl group).



  The reduction of the compounds of formula IV according to claim 8 is carried out by processes known per se, for example by means of catalytic hydrogenation in the presence of a suitable catalyst, e.g. Palladium on activated carbon in a suitable solvent, e.g. Ethanol at temperatures from 0 ° to about 50 ° C., preferably at room temperature and at pressures from 1 to 5 atm, preferably 1 atm.



  The reaction of compounds of formula V described in claim 9 with compounds of formula VI, wherein X is preferably chlorine, is conveniently carried out in the presence of a base such as e.g. Triethylamine or dimethylformamide at temperatures from about 0 ° to about 50 ° C., preferably at room temperature. If Y is C = O, the reaction can also be carried out with the corresponding isocyanate R4N = C = O, to give compounds of the formula I in which R5 is hydrogen.



  The process according to claim 10 is carried out by the action of an oxidizing agent, in particular hydrogen peroxide, on compounds of the formula Ie) in an acidic solvent, such as 100% acetic acid, at temperatures below room temperature, preferably about 10 ° C.



  The process according to claim 11 is expediently carried out by the action of sodium in liquid ammonia at temperatures of approximately -40 ° C. on compounds of the formula Ig, the benzyl group being split off. The compound Ig used here as the starting compound can be prepared according to the above method according to claim 9 from corresponding starting compounds.



  The process according to claim 12 is an alkylation process, compounds of the formula If at about -40 ° C. in liquid ammonia first being reacted with sodium and the reaction product is then reacted with a (C1-4) alkyl halide, in particular (C1-4) alkyl bromide.



  The catalytic cleavage of a benzyl group from compounds of the formula Ij according to claim 13 is expediently carried out using palladium (10% on activated carbon) as a catalyst in a suitable solvent, such as e.g. Ethanol, at a hydrogen pressure of 1 to 5 atmospheres at temperatures from room temperature to about 60 ° C., preferably at room temperature.



  The reaction of an azlactone of formula IX with compounds of formula X according to claim 14 is carried out using methods known from the literature, e.g. in a suitable solvent, e.g. Tetrahydrofuran or chloroform, optionally with the addition of an acylation catalyst, e.g. 4-Dimethylaminopyridine at temperatures from 0 ° to about 80 ° C., preferably at room temperature or the reflux temperature of tetrahydrofuran or chloroform.



  The starting compounds used in the above processes are either known (see, for example, E. Wünsch in: Houben-Weyl, "Methods of Organic Chemistry", Vol. XV / 1 and XV / 2, "Synthesis of Peptides", Georg Thieme, Stuttgart, 1974) or can be prepared in a manner known per se, for example as described in the examples below.



  The compounds of the formula I prepared according to the invention can be isolated and purified in a manner known per se. Racemic and / or diastereomeric mixtures can be separated in a manner known per se.



  If the compounds of the formula I contain acidic or basic groups, these can optionally also form salts, for example metal salts such as sodium salts or acid addition salts such as hydrochlorides.



  In the following examples, all temperatures are given in DEG C and have not been corrected.


 Example 1:
 


 (2R, 3S) -3- (tert-Butyloxycarbonylamino) -4-cyclohexyl-2-hydroxybutanesulfonic acid dimethylamide
 



  4 g of methanesulfonic acid dimethylamide are dissolved in 50 ml of tetrahydrofuran and 20 ml of n-butyllithium (1.6 M in hexane) are added at 0-5 °. To <1> / 2 h, 3.7 g of N-tert-Boc-cyclohexylalaninal are added all at once. To <1> / 2 h, the reaction mixture is poured onto ether / 2N aqueous tartaric acid, the org. Phase, dries with magnesium sulfate and evaporates the solvent in vacuo. The crude product is chromatographed on silica gel with ether / hexane 30-70%. The main product is obtained as a colorless oil which solidifies on standing. M.p. 86-87 DEG. The (2R, 3R) isomer is obtained as a by-product.


 Example 2:
 


 (2R, 3S) -3- (tert-Butyloxycarbonylamino) -4- (1,4-dioxaspiro [4,5] dec-8-yl) -2-hydroxybutanesulfonic acid dimethylamide
 



  Analogously to Example 1, the title compound is obtained from 5.2 g of methanesulfonic acid dimethylamide, 26 ml of n-butyllithium and 6 g of the corresponding aldehyde. Mp 48-50 DEG.


 Example 3:
 


 (2R, 3S) -3- (tert-Butyloxycarbonylamino) -4-cyclohexyl-2-azido-butanesulfonic acid dimethylamide
 (Interconnection)
 



  1 g of the by-product from Example 1 (2R, 3R isomer) is dissolved in 10 ml of toluene and at -30 ° C. with 1.5 g of triphenylphosphine, 30 ml of HN3 (approx. 1N solution in benzene) and 0.9 ml of azodicarboxylic acid. added diethyl ester. The mixture is stirred at room temperature overnight and then the reaction mixture is filtered off over silica gel. An inseparable mixture of the title compound and (3S) - (tert-butyloxycarbonyl) -4-cyclohexyl-1-butenesulfonic acid dimethyl amide is obtained.


 Example 4:
 


 (2R, 3S) -3- (tert-Butyloxycarbonylamino) -2-hydroxy-4- (2-naphthyl) butanesulfonic acid dimethylamide
 



  Analogously to Example 1, 1.7 g of methanesulfonic acid dimethylamide, 8.5 ml of butyllithium and 2 g of the corresponding aldehyde give the title compound as a colorless oil.


 Example 5:
 


 (2R, 3S) -3- (tert-Butyloxycarbonylamino) -2-hydroxy-5-methyl-hexanesulfonic acid dimethylamide
 



   Analogously to Example 1, 4 g of methanesulfonic acid dimethylamide, 60 ml of n-butyllithium and 4 g of N-tert-Boc-leucinal give the title compound as a mixture of diastereomers (approx. 2: 1).


 Example 6:
 


 (3S, 4S) -4- (tert-Butyloxycarbonylamino) -5-cyclohexyl-3-hydroxy-pentanesulfonic acid dimethylamide
 



  1 g of methanesulfonic acid dimethylamide are dissolved in 10 ml of tetrahydrofuran. At 0-5 ° 5.1 ml of n-butyllithium are added dropwise. To <1> / 2 h, 1 g of (2S) -2 - ((1S) -tert-butyloxycarbonylamino-2-cyclohexyl-ethyl) oxirane is added. After 20 min, partition between ether and 2N aqueous tartaric acid, the org. Phase, dries and evaporates. The crude product is recrystallized from methylene chloride / hexane. M.p. 110-111 DEG.


 Example 7:
 


 (1S, 3S, 4S) -4- (tert-Butyloxycarbonylamino) -5-cyclohexyl-3-hydroxy-1-isopropyl-pentanesulfonic acid dimethylamide
 



  Analogously to Example 6, 0.4 g of isobutanesulfonic acid dimethylamide, 1.5 ml of n-butyllithium and 200 mg of epoxide give the title compound as a mixture of diastereomers (approx. 1: 5).


 Example 8:
 


 (2R, 3S) -3- (N-BOC-phenylalanyl-phenylalanyl)) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide
 



  330 mg of the sulfonic acid amide from Example 1 are dissolved in 1 ml of methylene chloride and 1 ml of trifluoroacetic acid is added. After 1 hour is partitioned between 2N aqueous sodium carbonate solution and methylene chloride, the org. Phase separated, dried with potassium carbonate and evaporated. Then 230 mg BocPhePheOH, 225 mg HOBT and approx. 5 ml methylene chloride are added. It is cooled to 0-5 °, 170 mg of dicyclohexylcarbodiimide are added and the mixture is stirred for about 15 hours at room temperature. The precipitated dicyclohexylurea is filtered off and the crude product is chromatographed on silica gel with ether / methylene chloride 50-90%. [alpha] D <2> <0> = -29.1 ° (c = 0.6 in CH2CH2).


 Example 9:
 


 (2R, 3S) -3- (N-BOC-beta-cyclohexylalanyl-beta -cyclohexylalanyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide
 



  50 mg of the product from Example 8 are dissolved in 5 ml of ethanol and hydrogenated for 24 hours at 40 ° / 2 atm hydrogen over Rh-Alox (5%). The catalyst is filtered off and the product is lyophilized from benzene. [alpha] D <2> <0> = -46.1 ° (c = 0.6 in CH2Cl2).


 Example 10:
 


 (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide
 



  Analogously to Example 8, 160 mg of Boc-SO2-Chatin-NMe2 (Example 1) are reacted with 100 mg of BocPheNleOH, 100 mg of HOBT and 80 mg of DCC. [alpha] D <2> <0> = -32.4 ° (c = 0.2 in CH2Cl2).


 Example 11:
 


 (2R, 3S) -3- (N-BOC-beta-Cyclohexylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide
 



  20 mg of the product from Example 10 are hydrogenated in the same way as in Example 9. [alpha] D <2> <0> = 38.2 ° (c = 0.1 in CH2Cl2).


 Example 12:
 


 (2R, 3S) -3- (N-BOC-phenylalanyl-histidyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide
 



  Analogously to Example 8, 225 mg of Boc-SO2-Chatin-NMe2 (Example 1) are reacted with 236 mg of BocPheHisOH, 160 mg of hydroxybenzotriazole and 120 mg of dicyclohexylcarbodiimide. Dimethylformamide is used instead of methylene chloride for the peptide coupling. Chromatography MeOH / CH2Cl2, 0-10% gives two diastereomers: Diastereomer A: [alpha] D <2> <0> = 32.2 ° (c = 0.2 in CH2Cl2 / MeOH 9: 1; diastereomer B: [alpha] D <2> <0> = 26.0 ° (c = 0.6 in CH2Cl2 / MeOH 9: 1).


 Example 13:
 


 (2R, 3S) -3- [N- (bis- (1-Naphthylmethyl) acetyl) norleucyl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide
 



  Analogously to Example 8, 200 mg of Boc-SO2-ChatinNMe2 (Example 1) are reacted with 240 mg of N- (bis- (1-naphthylmethyl) acetyl) -Nle-OH, 140 mg of hydroxybenzotriazole and 110 mg of dicyclohexylcarbodiimide. [alpha] D <2> <0> = -43.9 ° (c = 0.2 in CH2Cl2).


 Example 14:
 


 (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-amino-4-cyclohexyl-butanesulfonic acid dimethylamide
 



  Analogously to Example 8, 150 mg of the sulfonic acid amide mixture from Example 3 are reacted with 100 mg BocPheNleOH, 700 mg hydroxybenzotriazole and 80 mg dicycloxylcarbodiimide. The crude product is dissolved in ethanol and hydrogenated for 4 hours at 20 ° C./1 atm hydrogen over Pd / C (10%). Chromatography on silica gel with MeOH / CH2Cl2 0-5% gives the title compound [alpha] D <2> <0> = -37.1 DEG (c = 0.2 in CH2Cl2) and Boc-Phe-Nle-SO2-deoxychatineNMe2 [alpha] D <2> <0> = -26.4 ° (c = 0.2 in CH2Cl2).


 Example 15:
 


 (2R, 3S) -3- (N-BOC-Phenylalanylyl-norleucyl) -amido-4- (1,4-dioxaspiro [4.5] dec-8-yl) -2-hydroxy-butanesulfonic acid dimethylamide
 



  Analogously to Example 8, 335 mg of the sulfonamide from Example 2 are reacted with 290 mg Boc-Phe-NleOH, 200 mg hydroxybenzotriazole and 158 mg dicyclohexylcarbodiimide. [alpha] D <2> <0> = -32.6 ° (c = 0.2 in CH2Cl2).


 Example 16:
 


 (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) -amido-4- (4 min -oxocyclohexyl) -2-hydroxy-butanesulfonic acid dimethylamide
 



  200 mg of the product from Example 15 are dissolved in 10 ml of tetrahydrofuran / water and conc. With a few drops of hydrochloric acid. transferred. After 10 hours, partition between ethyl acetate and aqueous Na bicarbonate solution, the org. Phase separated, dried and evaporated. [alpha] D <2> <0> = -45.6 ° (c = 0.2 in CH2Cl2).


 Example 17:
 


 (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4- (4 min -hydroxy-cyclohexyl) -2-hydroxy-butanesulfonic acid dimethylamide
 



  70 mg of the product from Example 16 are dissolved in 5 ml of methanol. 10 mg of sodium borohydride are added, the mixture is stirred at room temperature for 15 min and then partitioned between ethyl acetate and 2N aqueous sodium carbonate solution. [alpha] D <2> <0> = -31.1 ° (c = 0.2 in CH2Cl2).


 Example 18:
 


 (3S, 4S) -4- (N-BOC-Phenylalanyl-norleucyl) amido-5-cyclohexyl-3-hydroxy-pentanesulfonic acid dimethylamide
 



  Analogously to Example 8, 135 mg of the sulfonamide from Example 6 are reacted with 75 mg of Boc-Phe-Nle-OH, 70 mg of hydroxybenzotriazole and 52 ml of dicyclohexylcarbodiimide. [alpha] D <2> <0> = -10 ° (c = 0.2 in CH2Cl2).


 Example 19:
 


 (2S, 3S, 4S) -4- (N-BOC-Phenylalanyl-norleucyl) amido-5-cyclohexyl-3-hydroxy-1-isopropyl-pentanesulfonic acid dimethylamide
 



   Analogously to Example 8, 47 mg of the diastereomer mixture from Example 7 are reacted with 40 mg BocPhe-Nle-OH, 28 mg hydroxybenzotriazole and 22 mg dicyclohexylcarbodiimide. Chromatography on silica gel with ether / hexane 50-100% gives two diastereomers: A: [alpha] D <2> <0> = -36.4 DEG, B: [alpha] D <2> <0> = -10.0 DEG (c = 0.1 in CH2Cl2).


 Example 20:
 


 (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-2-hydroxy-4 (2-naphthyl) butanesulfonic acid dimethylamide
 



  Analogously to Example 8, 130 mg of sulfonamide from Example 4 are reacted with 115 mg of Boc-PheNleOH, 85 mg of hydroxybenzotriazole and 65 mg of dicyclohexylcarbodiimide. [alpha] D <2> <0> = -43.7 ° (c = in CH2Cl2).


 Example 21:
 


 (2R, 3S) -3- [N- (BIS- (1-naphthylmethyl) acetyl) norleucyl] amido-2-hydroxy-5-methyl-hexanesulfonic acid dimethylamide
 



  Analogously to Example 8, 100 mg of the mixture of diastereomers from Example 5 are reacted with 70 mg of bis- (1-naphthylmethyl) acetyl-Nle-OH, 70 mg of hydroxybenzotriazole and 51 mg of dicyclohexylcarbodiimide. The product is obtained as an inseparable mixture of diastereomers (approx. 2: 1).


 Example 22:
 


 (2S, 3S) - and (2R, 3S) -3- (BOC-phenylalanyl-norleucyl) -amido-4-cyclohexyl-1-isobutyl-sulfamoylamino-
 2-butanol
 



  A mixture of 273 mg (2S, 3S) -3- (Boc-phenylalanyl-norleucinyl) amido-1-amino-4-cyclohexyl-2-butanol and 0.1 ml of triethylamine in 11 ml of dioxane is mixed with a solution of 94 mg Isobutylsulfamoyl chloride in 1 ml of dioxane is added and the mixture obtained is stirred for 20 hours at room temperature and then concentrated in vacuo. The residue is dissolved in ethyl acetate and the solution is washed with dilute hydrochloric acid, an aqueous sodium bicarbonate solution and aqueous sodium chloride solution. Drying over anhydrous sodium sulfate, evaporation in vacuo and chromatography (silica gel with dichloromethane-methanol 40: 1 as eluent) gives the compound mentioned in the title as an amorphous dye, [alpha] D = -7 ° (c = 0.5 in dichloromethane).



  Starting from (2R, 3S) -3- (Boc-Phenylalaninyl-norleucinyl) amido-1-amino-4-cyclohexyl-2-butanol, the same procedure gives (2R, 3S) -3- (Boc-Phenylalaninyl-norleucinyl) -amido-4-cyclohexyl-isobutyl-sulfamoylamino-2-butanol as an amorphous solid, [alpha] D <2> <0> = -3.2 ° (c = 0.5 in dichloromethane).



  The starting compounds used in this process are obtained as described below:


 a) (3S) -3-BOC-amido-4-cyclohexyl-1-nitro-2-butanone
 (Intermediate product)
 



  A solution of 32.6 ml of nitromethane in 160 ml of tetrahydrofuran and 160 ml of hexamethylphosphoric triamide are added to a suspension of 18.0 g of sodium hydride (80% in mineral oil) in 180 ml of tetrahydrofuran with ice cooling and vigorous stirring. The solution obtained is stirred at room temperature for 1 hour, then cooled to 0 ° and a solution of 69.9 g of N-BOC-L-beta -cyclohexylalanine-3,5-dimethylpyrazolide in 700 ml of tetrahydrofuran is added. After stirring for 20 hours, the mixture is mixed with 600 ml of 1N hydrochloric acid, extracted twice with ether, the combined organic extracts are washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo.

  Chromatography of the crude product on silica gel using toluene / ethyl acetate (6: 1) as the eluent gives the above intermediate 1 as colorless crystals of mp 97-98 °.


 b) (2S, 3R) - and (2R, 3S) -3-BOC-amino-4-cyclohexyl-1-nitro-2-butanol
 (Interconnects 2A and 2B)
 



  2.27 g of sodium borohydride are added in small portions to an ice-cooled solution of 18.9 g of intermediate 1 obtained above in 190 ml of ethanol. The mixture is then stirred for one hour without cooling, then the pH of the solution is adjusted to 3 by adding 10% aqueous tartaric acid with cooling, the solution is evaporated in vacuo, extracted twice with ether, the combined organic phases are washed with aqueous sodium chloride solution, Dried over anhydrous sodium sulfate and evaporated in vacuo. Treatment of the remaining oily mixture of two diastereoisomers with ether / hexane gives isomer 2A of mp 116-118 ° (decomp.). Chromatography of the mother solution on silica gel using hexane / ether (2: 1) as eluent gives the isomer 2B as \ l.



  Rf values (silica gel, hexane / ether 2: 1): 2A, 0.136; 2B, 0.106.


 c) (2S, 3SO) - and (2R, 3S) -1-amino-3-BOC-amino-4-cyclohexyl-2-butanol
 (Interconnects 3A and 3B)
 



  To a mixture of 7.5 g of the intermediate compounds 2A, which was obtained as described above, and 0.75 g of palladium (10% on animal charcoal) in 50 ml of methanol in an inert atmosphere, 5.96 g of ammonium formate are added in small proportions for 1 hour added. After stirring for 17 hours at room temperature, the suspension is filtered through Celite and the filtrate is evaporated in vacuo. The residue is taken up in 2N hydrochloric acid, washed twice with ether and the aqueous phase is made alkaline by adding sodium bicarbonate. The aqueous phase is extracted twice with ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate and evaporated in vacuo. The foamy residue is converted into the hydrogen oxalate and crystallized from ether. The hydrogen oxalate of intermediate compound 3A of mp 165-166 ° (dec.) Is obtained.



  The hydrogen oxalate of the intermediate 3B, which is obtained in an analogous manner from the intermediate 2B, melts at 137-138 ° (dec.).


 d) (2S, 3S) - and (2R, 3S) -3-BOC-amino-1-Cbz.-amino-4-cyclohexyl-2-butanol
 (Interconnections 4A and 4B)
 



  4.18 ml of benzyl chloroformate are added to a solution of 5.28 ml of triethylamine and 6.3 g of intermediate 3A obtained in accordance with the above method in 120 ml of dichloromethane at a temperature of 2 to 5 ° and the solution obtained Room temperature stirred for 30 minutes. The mixture is then diluted with dichloromethane and washed with 0.25N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water. The organic phase is dried over sodium sulfate and evaporated in vacuo. Chromatography of the residue on silica gel using toluene / ethyl acetate (3: 1) as eluent gives intermediate 4A as a slightly yellowish \ l.



   Using the same procedure, starting from interconnect 3B, interconnect 4B is obtained as \ l.


 e) (2S, 3S) - and (2R, 3S) -3-amino-1-Cbz-amino-4-cyclohexyl-2-butanol
 (Interconnects 5A and 5B)
 



  8.06 g of the intermediate 4A are cooled in 80 ml of the mixture of acetic acid / conc. Hydrochloric acid (9: 1) entered and the solution obtained stirred at room temperature for 1 hour and then evaporated to dryness. The hydrochloride of intermediate 5A is obtained as a colorless foam.



  Using the same method, the intermediate compound 4B gives the hydrochloride of the intermediate compound 5B.


 f) (2S, 3S) - and (2R, 3S) -3- (BOC-phenylalaninyl-norleucinyl) amino-1-Cbz-amino-4-cyclohexyl-2-butanol
 (Interconnections 6A and 6B)
 



  4.06 ml of diphenylphosphoryl azide and 4.94 ml of triethylamine are gradually added to an ice-cooled solution of 6.68 g of BOC-Phe-Nle-OH and 6.3 g of crude hydrochloride of the intermediate 5A in dimethylformamide and the clear solution obtained at room temperature Stirred overnight, then concentrated in vacuo, taken up in dichloromethane and the dichloromethane solution washed with 0.25N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water and dried over anhydrous sodium sulfate. After evaporation in vacuo, the residue is chromatographed on silica gel (dichloromethane / ethanol 49: 1 as eluent) and the product obtained is crystallized from dichloromethane / hexane. The intermediate 6A thus obtained melts at 167-168 ° (dec.).



  Using the same procedure, starting from the intermediate compound 5B, the intermediate compound 6B with the mp. 150-151 DEG (dec.) Is obtained.


 g) (2S, 3S) - and (2R, 3S) -1-amino-3- (BOC-phenylalaninyl-norleucinyl) -amino-4-cyclohexyl-2-butanol
 (Interconnections 7A and 7B)
 



  7.0 g of the intermediate compound 6A and 0.7 g of palladium on activated carbon (10%) in 140 ml of methanol are hydrogenated at room temperature in a hydrogen atmosphere at atmospheric pressure for 1.5 hours and then the mixture is diluted with dichloromethane and filtered through celite. After evaporating the filtrate in vacuo and crystallizing the residue from methanol / ether, the intermediate compound 7A is obtained as colorless crystals of mp 140-141 °, [alpha] D <2> <0> = -38.5 ° (c = 1 in methanol).



  Using the same method, starting from the intermediate compound 6B, the intermediate compound 7B is obtained as colorless crystals of mp. 168-169 DEG (dec.), [Alpha] D <2> <0> = -25.6 ° (c = 1 in methanol).


 Example 23:
 


 (2S, 3S) -3- (BOC-phenylalaninyl-norleucyl) amido-4-cyclohexyl-1-dimethylsulfamoylamino-2-butanol
 



  Analogously to Example 22, the title compound, [alpha] D. Is obtained using dimethylsulfamoyl chloride instead of isobutylsulfamoyl chloride <2> <0> = -11 ° (c = 0.1 in CH2Cl2).


 Example 24:
 


 (2RS, 3S) -3- (N-Benzoyl-dehydrophenylalaninyl-norleucyl) -amido-1-dimethylsulfamoyl-amino-5-methyl-2-hexanol
 



  Analogously to Example 21, using N-benzoyldehydrophenylalaninyl-norleucine instead of BOC-Phe-Nle-OH, the title compound is obtained as a mixture of diastereomers (approx. 2: 1), mp. 194-196 DEG (dec.).


 Example 25:
 


 N- (3-Cyclohexylpropionyl) norleucine
 (Intermediate product)
 



  A solution of 1.31 g of norleucine in 22 ml of 1N aqueous sodium hydroxide is treated with ice cooling with a solution of 1.92 g of 3-cyclohexylpropionic acid chloride in 22 ml of ether and the mixture is stirred at 0 ° C. for 1 hour. The mixture is then acidified with 0.25 N hydrochloric acid, the mixture is extracted twice with ether, the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. Crystallization of the residue from ether / hexane gives the title compound of mp. 138-139 ° C.


 Example 26:
 


 (2S, 3S) -3- (3-Cyclohexyl-propionyl-norleucyl) amido-1-Cbz-amino-4-cyclohexyl-2-butanol
 (Intermediate product)
 



  Analogously to example 22f), the title compound is obtained as an amorphous substance using 3-cyclohexyl-propionyl-norleucine (example 25) instead of BOC-Phe-Nle-OH.


 Example 27:
 


 (2S, 3S) -3- (3-Cyclohexyl-propionyl-norleucyl) amido-1-amino-4-cyclohexyl-2-butanol
 (Intermediate product)
 



  Analogously to Example 22g), the title compound is obtained as an amorphous substance by hydrogenation of the compound of Example 26.


 Example 28:
 


 (2S, 3S) -3- (3-Cyclohexyl-propionyl-norleucyl) amido-4-cyclohexyl-1-dimethylsulfamoylamino-2-butanol
 



  Analogously to Example 22, using (2S, 3S) -3- (3-cyclohexyl-propionyl-norleucyl) amido-1-amino-4-cyclohexyl-2-butanol and dimethylsulfamoyl chloride, the title compound, [alpha] D <2> <0> = -25.7 DEG (c = 1 methanol) as an amorphous substance (sinters from 78 DEG C)


 Intermediate products:
 


 N- (bis-1-naphthylmethyl) acetyl-Nle-OH
 



  660 mg of bis (1-naphthylmethyl) acetic acid and 280 mg of norleucine methyl ester are dissolved in methylene chloride and cooled to 0 °. 400 mg of dicyclohexylcarbodiimide are added and the mixture is stirred for about 15 hours at room temperature. The precipitated dicyclohexylurea is filtered off, the filtrate is evaporated, dissolved in methanol and mixed with 200 mg of sodium hydroxide (dissolved in water). After 2 hours, acidified with 2N hydrochloric acid, extracted with methylene chloride, dried and evaporated. The crude product is recrystallized from methylene chloride / hexane. Mp 157-159 DEG.


 Bis (1-naphthylmethyl) acetic acid
 



  4.6 g of sodium are dissolved in 100 ml of ethanol. 16 g of diethyl malonate and 40 g of 1-chloromethylnaphthalene are added. The mixture is then boiled under reflux for 24 hours, cooled and the precipitated salts are dissolved by adding ice water. The org. Phase is separated, the aqueous phase extracted with ether and the combined org. Phases dried with magnesium sulfate and evaporated. The crude product is introduced into a mixture of 50 ml of water, 700 ml of ethanol and 20 g of potassium hydroxide and boiled under reflux for 4 hours. Then it is cooled, acidified with hydrochloric acid conc and extracted with ether. The ether solution is dried, evaporated and the residue heated to 180-200 °. After cooling to room temperature, the glassy residue is dissolved in methylene chloride and precipitated with hexane. M.p. 171-172 DEG.


 (1-tert-Butyloxycarbonylamino-6-cyclohexyl-ethyl) -oxirane
 



   6 g of sodium hydride dispersion (80% in white oil) are suspended in a mixture of 60 ml of dimethyl sulfoxide and 30 ml of tetrahydrofuran. It is cooled to 0-5 ° and a solution of 13 g of trimethylsulfonium iodide in 50 ml of dimethyl sulfoxide is added dropwise. After 10 min, 50 ml of t-Boc cyclohexylalaninal (0.54 M in toluene) are added, and the mixture is allowed to warm to room temperature. The reaction mixture is diluted with ice water, the org. Phase separated, washed 4x with water, dried over magnesium sulfate and evaporated. Chromatography on silica gel with ether / hexane 10-30% gives the title compound in addition to a little of the diastereomer (ratio approx. 3: 1). 58-59 DEG.


 Example 29:
 


 (2R, 3S) -3- [N- (1-Adamantyl) propionyl) norleucyl)] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide
 



  Analogously to Example 8, using N- [3- (1-adamantyl) propionyl] -norleucine instead of BOCPhePheOH, the title compound, [alpha] D <2> <0> = -27.5 ° (c = 1 in methanol).



  The starting compound adamantylpropionylnorleucine, mp. 119-120 °, is prepared analogously to Example 25 from adamantylpropionyl chloride and norleucine.


 Example 30:
 


 (2R, 3S) -3- (N-BOC-beta-Cyclohexylalanyl-histidyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide
 



  Analogously to Example 8, 190 mg of BOC-SO2-Chatin-NMe2 (Example 1) are reacted with 201 mg of BOC-Cha-His-OH, in the presence of 70 mg of hydroxybenzotriazole and 102 mg of dicyclohexylcarbodiimide. The crude product is chromatographed with methanol / methylene chloride 1-10% on silica gel. ([alpha] D <2> <0> = -38.9 ° (c = 0.2 in methylene chloride).


 Example 31:
 


 (2R, 3S) -3- [N- (BIS- (1-Naphthylmethyl) acetyl) histidyl] amido-4-cyclohexyl-2-hydroxybutanesulfonic acid dimethylamide
 



  Analogously to Example 8, 80 mg of BOC-SO2Chatin-NMe2 (Example 1) are reacted with 100 mg of N- (bis (1-naphthylmethyl) acetyl) -His-OH, in the presence of 50 mg of hydroxybenzotriazole and 44 mg of dicyclohexylcarbodiimide, and the crude product is reacted with Methanol / methylene chloride 1-10% chromatographed. [alpha] D <2> <0> = -17.1 ° (c = 0.2 in methylene chloride).


 Example 32:
 


 ((2R, 3S) -3- [N-BOC-beta - (2,1,3-Benzoxadiazol-4-yl) alanylnorleucyl] amido-4-cyclohexyl-2-hydroxybutanesulfonic acid dimethylamide </u>
 



  Analogously to Example 8, 96 mg of BOC-SO2-Chatin-NMe2 (Example 1) are reacted with 98 mg of BOC-Bol-Nle-OH, in the presence of 35 mg of hydroxybenzotriazole and 50 mg of dicyclohexylcarbodiimide. The crude product is recrystallized from methylene chloride / hexane. [alpha] D <2> <0> = -52.4 ° (c = 0.2 in methylene chloride).


 Example 33:
 


 (2R, 3S) -3 - ((N- [2-methoxy-poly (2-ethoxy) acetyl] phenylalanyl-histidyl)) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide </u>
 



  35 mg H-Phe-His-SO2-Chatin-NMe2 are reacted with 60 mg of an oligomer mixture of polyethylene glycol acids (MG & tilde & 350), in the presence of 13 mg dicyclohexylcarbodiimide and 10 mg hydroxybenzotriazole in methylene chloride and by chromatography on silica gel with methanol / methylene chloride 5 -10% cleaned.


 Example 34:
 


 (2R, 3S) -3- [N- (bis- (1-Naphthylmethyl) acetyl) methionyl] amido-4-cyclohexyl-2-hydroxybutanesulfonic acid dimethylamide
 



  Analogously to Example 8, 165 mg of BOC-SO2-Chatin-NMe2 (Example 1) are reacted with 203 mg of N- (bis- (1-naphthylmethyl) acetyl) -Met-OH, in the presence of 115 mg of hydroxybenzotriazole and 90 mg of dicyclohexylcarbodiimide. [alpha] D <2> <0> = -45.3 ° (c = 0.1 in CH2Cl2).


 Example 35:
 


 (2R, 3S) -3- [N- (bis (1-naphthylmethyl) acetyl) methion- (D, L, S-oxide) yl] amido-4-cyclohexyl-2-hydroxybutanesulfonic acid dimethylamide
 



  20 mg of the title compound from Example 34 are dissolved in glacial acetic acid and 10 mg of sodium perborate are added. After 1 hour between methylene chloride and sat. aqueous sodium bicarbonate solution distributed. The org. Phase is dried and evaporated. The product is obtained as an approx. 1: 1 mixture of diastereomers.


 Example 36:
 


 (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4- (1-adamantyl) -2-hydroxy-butanesulfonic acid dimethylamide
 



  Analogously to Example 8, 69 mg of BOC-SO2-Adatin-NMe2 are reacted with 61 mg of BOC-Phe-Nle-OH, in the presence of 64 mg of hydroxybenzotriazole and 62 mg of N-ethyl-N- (3-dimethylaminopropyl) carbodiimide (EDCI) . The crude product is chromatographed on silica gel using hexane / ethyl acetate (1: 1). According to the min H-NMR, the title compound is present as a mixture of diastereomers (2R, 3S: 3S, 3S = 60:40).



  The starting compound BOC-SO2-Adatin-NMe2 (69:40 diastereomer mixture) is prepared analogously to Example 1 from N-tert-BOC-adamantylalaninal and methanesulfonic acid dimethylamide.


 Example 37:
 


 (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-5,5-dimethyl-2-hydroxy-hexanesulfonic acid dimethylamide
 



  As in Example 8, 235 mg of BOC-SO2-Neotin-NMe2 are reacted with 180.3 mg of BOC-Phe-Nle-OH, in the presence of 198 mg of hydroxybenzotriazole and 187 mg of EDCl. The crude product is chromatographed on silica gel using hexane / ethyl acetate (1: 2). Subsequent recrystallization in ethyl acetate / hexane gives the title compound as a mixture of diastereomers (2R, 3S: 2S, 3S = 65:35) with a melting point of FP: 159-163 ° C.



  The starting compound BOC-SO2-Neotin-NMe2 (65:35 diastereomer mixture) is prepared analogously to Example 1 from N-tert-BOC-neopentylglycinal and methanesulfonic acid dimethylamide.


 Example 38:
 


 (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid pyrrolidinamide
 



  Analogously to Example 8, the title compound is obtained from BOC-SO2-chatin-pyrrolidine, which is prepared analogously to Example 1 from BOC-cyclohexylalaninal and methylsulfonylpyrrolidine, and BOC-Phe-Nle-OH. [alpha] D <2> <0> = -30.0 ° (c = 0.28 in ethanol).


 Example 39:
 


 (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid piperidinamide
 



  Analogously to Example 8, the title compound is obtained from BOC-SO2-chatin-piperidine, which is prepared analogously to Example 1 from BOC-cyclohexylalaninal and methylsulfonylpiperidine, and BOC-Phe-Nle-OH. [alpha] D <2> <0> = -32.6 ° (c = 0.27 in ethanol).


 Example 40:
 


 (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid- (4-benzyl) piperazinamide
 



   Analogously to Example 8, BOC-SO2-chatin- (4-benzyl) piperazine, which is prepared analogously to Example 1 from BOC-cyclohexylalaninal and 4-benzyl-1-methylsulfonylpiperazine, and BOC-Phe-Nle-OH give the Title compound [alpha] D <2> <0> = -25.6 ° (c = 0.32 in ethanol).



  The starting compound 4-benzyl-1-methylsulfonylpiperazine is prepared analogously to literature examples, by reacting N-benzylpiperazine with methanesulfonyl chloride in the presence of pyridine in acetonitrile at -10 ° to 30 °.


 Example 41:
 


 (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid piperazinamide
 



  A solution of 110 mg BOC-Phe-Nle-SO2-Chatin- (4-benzyl) piperazine (Example 40) in 120 ml 100% acetic acid is mixed with 20 mg 10% palladium on activated carbon and hydrogenated for 6 hours at room temperature and normal pressure . The reaction mixture is filtered through Hyflo and evaporated to dryness. The residue is dissolved in an ice-water mixture, made slightly alkaline with 10% sodium carbonate solution, extracted with methylene chloride, dried over sodium sulfate, filtered and evaporated to dryness.



  The residue is chromatographed on silica gel with methylene chloride containing 10% ethanol. [alpha] D <2> <0> = -22.5 ° (c = 0.20 in ethanol).


 Example 42:
 


 (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid- (4-acetyl) piperazinamide
 



  Analogously to Example 8, the title compound is obtained from BOC-SO2-Chatin- (4-acetyl) -piperazine and BOC-Phe-.Nle-OH. [alpha] D <2> <0> = -19.5 ° (c = 0.21 in ethanol).



  The starting compound BOC-SO2-Chatin (4-acetyl) piperazine is obtained, starting from BOC-SO2-Chatin (4-benzyl) piperazine (Example 40), by hydrogenation analogously to Example 41 and reaction of the BOC-SO2-Chatin obtained -piperazine, analogous to literature examples, with acetyl chloride in the presence of triethylamine in methylene chloride at 0 °.


 Example 43:
 


 (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid- [4- (2,5,8,11-tetraoxadodecanyl) carbonyl] pip erazinamide
 



  Analogously to Example 8, the title compound is obtained from BOC-SO2-Chatin- (4- [2,5,8,11-tetraoxadodecanyl] carbonyl) piperazine and BOC-Phe-Nle-OH. [alpha] D <2> <0> = -16.7 ° (c = 0.12 in ethanol). The starting compound BOC-SO2-Chatin- (4- [2,5,8,11-tetraoxadodecanyl] -carbonyl) piperazine is obtained, according to a known method, by reacting 500 mg of BOC-SO2-Chatin-piperazine (Example 42) with 260 mg 2,5,8,11-tetraoxadodecanylcarboxylic acid, in the presence of 240 mg dicyclohexylcarbodiimide and 320 mg hydroxybenzotriazole in 10 ml N, N-dimethylformamide.


 Example 44:
 


 (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid- (4-methyl) piperazinamide
 



  Analogously to Example 8, BOC-SO2-chatin- (4-methyl) -piperazine, which is prepared analogously to Example 1 from BOC-cyclohexylalaninal and 4-methyl-1- (methylsulfonyl) piperazine, and BOC-Phe-Nle -OH the title compound. [alpha] D <2> <0> = -25.0 ° (c = 0.44 in ETOH).


 Example 45:
 


 (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid morpholinamide
 



  Analogously to Example 8, the title compound is obtained from BOC-SO2-chatin-morpholide, which is prepared analogously to Example 1 from BOC-cyclohexylalaninal and morpholine, and BOC-Phe-Nle-OH. [alpha] D <2> <0> = -31.9 ° (c = 0.87 in ethanol).


 Example 46:
 


 (2R, 3S) -3- (N-BOC-phenylalanyl-histidyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid piperidinamide
 



  Analogously to Example 12, the title compound is obtained from BOC-SO2-chatin-piperidine (Example 39) and BOC-Phe-His-OH. [alpha] D <2> <0> = -14.1 ° (c = 0.17 in pyridine).


 Example 47:
 


 (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-5-methylmercapto-pentanesulfonic acid dimethylamide
 



  Analogously to Example 8, the title compound is obtained from BOC-SO2-Mettin-NMe2 and BOC-Phe-Nle-OH. [alpha] D <2> <0> = -31.0 ° (c = 0.67 in ethanol). The starting compound BOC-SO2-Mettin-NMe2 is prepared analogously to Example 1 from BOC-methioninal and methanesulfonic acid dimethylamide.


 Example 48:
 


 (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-5-methylsulfinyl-pentanesulfonic acid dimethylamide
 



  A solution of 50 mg of BOC-Phe-Nle-SO2-Mettin-NMe2 (Example 47) in 0.25 ml of 100% acetic acid is mixed with 0.01 ml of 30% H2O2 solution at 10 ° and stirred for a further 40 minutes at 10 °. The reaction mixture is evaporated to dryness and the residue is chromatographed on silica gel with methylene chloride containing 7% ethanol. The title compound results as an approx. 1: 1 mixture of diastereomers. Mp .: sintering from 82 DEG.


 Example 49:
 


 (2R, 3R) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-4-benzylmercapto-butanesulfonic acid dimethylamide
 



  Analogously to Example 8, BOC-Cys (BZL) (OH) CH2SO2NMe2, which is prepared analogously to Example 1 from BOC-S-benzyl-L-cysteinal and methanesulfonic acid dimethylamide, and BOC-Phe-Nle-OH give the title compound. [alpha] D <2> <0> = -32.0 ° (c = 0.40 in ethanol).



  BOC-S-benzyl-L-cysteinal is, analogous to literature examples, by reacting BOC-5-benzyl-L-cysteine with 3,5-dimethylpyrazole in the presence of dicyclohexylcarbodiimide in chloroform and reducing the resulting BOC-5-benzyl-L -cysteine-3,5-dimethylpyrazolids with diisobutylaluminium hydride in toluene.


 Example 50:
 


 (2R, 3R) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-4-mercapto-butanesulfonic acid dimethylamide
 



  A solution of 300 mg of BOC-Phe-Nle-Cys (BZL) (OH) CH2SO2NMe2 (Example 49) in 8 ml of tetrahydrofuran and 20 ml of liquid ammonia is mixed with 60 mg of sodium in portions at -40 °. The blue-colored reaction mixture is stirred for a further 15 minutes at -40 ° C. and then ammonium chloride is added in portions until the blue color disappears. The reaction mixture is evaporated to dryness, the residue is taken up in water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. The residue is chromatographed on silica gel with methylene chloride containing 2% ethanol.

   The title connection results. [alpha] D <2> <0> = -33.6 ° (c = 0.30 in ethanol).


 Example 51:
 


 (2R, 3R) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-4-ethylmercapto-butanesulfonic acid dimethylamide
 



  A solution of 300 mg of BOC-Phe-Nle-Cys (BZL) (OH) CH2SO2NMe2 (Example 49) in 8 ml of tetrahydrofuran and 20 ml of liquid ammonia, as described in Example 50, is mixed with sodium and then ammonium chloride. After the addition of ammonium chloride, a solution of 0.05 ml of ethyl bromide in 2 ml of tetrahydrofuran is poured into the reaction mixture at -40 ° C., the mixture is stirred for a further 10 minutes at -40 ° C. and then worked up and purified as described in Example 50. The title connection results. [alpha] D <2> <0> = -37.2 ° (c = 0.36 in ethanol).


 Example 52:
 


 (2R, 3S) -3- [N- (2,3,4,6-Tetra-O-acetyl-beta -D-glucosyl-1-O) -isobuturyl-phenylalanyl-norleucyl] amido-4-cyclohexyl-2 -hydroxy-buta nsulfonic acid dimethylamide
 



  Analogously to Example 8, the title compound is obtained from BOC-Phe-Nle-SO2-Chatin-NMe2 (Example 10) and (2,3,4,6-tetra-O-acetyl-beta-D-glucosyl-1-O) isobutyric acid . [alpha] D <2> <0> = -39.2 ° (c = 0.68 in ethanol).



  The starting compound (2,3,4,6-tetra-O-acetyl-beta-D-glucosyl-1-O) isobutyric acid is, analogous to literature examples, by condensation of alpha-D-acetobromoglucose and 2-hydroxy-2-methylpropionic acid benzyl ester and subsequent hydrogenation with 10% palladium on carbon as a catalyst.


 Example 53:
 


 (2R, 3S) -3- [N- (beta -D-gluconesyl-1-O) -isobuturyl-phenylalanyl-norleucyl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethyla mid
 



  A solution of 150 mg (2,3,4,6-tetra-O-acetyl-beta-D-glucosyl-1-O) isobutyryl-Phe-Nle-SO2-Chatin-NMe2 (Example 52) in 5 ml of methanol at room temperature with a solution of 34 mg sodium in 1.5 ml methanol, stirred for 30 minutes at room temperature, neutralized with 100 mg of the acidic cation exchanger Amberlyst 15, filtered and evaporated to dryness. The residue is chromatographed on silica gel with methylene chloride containing 10% ethanol. The title connection results. [alpha] D <2> <0> = -41.6 ° (c = 0.30 in ethanol).


 Example 54:
 


 (2S, 3S) -3- (N-BOC-phenylalaninyl-histidyl) amido-1- (n-butylcarbamoylamino) -4-cyclohexyl-2-butanol
 



  402 mg BOC-Phe-His-OH, 322 mg (2S, 3S) -3-amino-1- (n-butylcarbamoylamino) -4-cyclohexyl-2-butanol hydrochloride (intermediate 8A) and 0.28 ml triethylamine in 6.7 ml of dimethylformamide are mixed with 0.23 ml of diphenylphosphoryl azide while cooling with ice, the mixture is stirred at room temperature for 19 hours and evaporated under a high vacuum. The residue is taken up in ethyl acetate and washed successively with aqueous tartaric acid, saturated sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate and evaporated. Chromatography of the residue (silica gel, 4 bar, methylene chloride-ethanol 19: 1) gives the title compound, mp. 141-142 ° C, [alpha] D <2> <0> = -11.8 ° (c = 1 in methanol).


 Example 55:
 


 (2R, 3S) -3- (N-BOC-phenylalaninyl-histidyl) amido-1- (n-butylcarbamoylamino) -4-cyclohexyl-2-butanol
 



  Using (2R, 3S) -3-amino-1- (n-butylcarbamoylamino) -4-cyclohexyl-2-butanol hydrochloride (8B), the title compound is obtained analogously to Example 54, mp. 148-9 °, [ alpha] D <2> <0> = -14.5 ° (c = 1 in methanol.



  Intermediates 8A and 8B used in Examples 54 and 55 can be prepared as follows:


 a) (3S) -3-BOC-amido-4-cyclohexyl-1-nitro-2-butanone
 (Intermediate 1D)
 



  A solution of 32.6 ml of nitromethane in 160 ml of tetrahydrofuran and 160 ml of hexamethylphosphoric triamide are added to a suspension of 18.0 g of sodium hydride (80% in mineral oil) in 180 ml of tetrahydrofuran with ice cooling and vigorous stirring. The solution obtained is stirred at room temperature for 1 hour, then cooled to 0 ° and a solution of 69.9 g of N-BOC-L-beta -cyclohexylalanine-3,5-dimethylpyrazolide in 700 ml of tetrahydrofuran is added. After stirring for 20 hours, the mixture is mixed with 600 ml of 1N hydrochloric acid, extracted twice with ether, the combined organic extracts are washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo.

  Chromatography of the crude product on silica gel using toluene / ethyl acetate (6: 1) as the eluent gives the above intermediate 1D) as colorless crystals of mp 97-98 °.


 b) (2S, 3R) - and (2R, 3S) -3-BOC-amino-4-cyclohexyl-1-nitro-2-butanol
 (Intermediates 9A and 9B)
 



  2.27 g of sodium borohydride are added in small portions to an ice-cooled solution of 18.9 g of the intermediate 1D) obtained above in 190 ml of ethanol. The mixture is then stirred for one hour without cooling, then the pH of the solution is adjusted to 3 by adding 10% aqueous tartaric acid with cooling, the solution is evaporated in vacuo, extracted twice with ether, the combined organic phases are washed with aqueous sodium chloride solution, Dried over anhydrous sodium sulfate and evaporated in vacuo. Treatment of the remaining oily mixture of two diastereoisomers with ether / hexane gives the isomer 9B of mp. 116-118 DEG (dec.). Chromatography of the mother solution on silica gel using hexane / ether (2: 1) as eluent gives the isomer 9A as \ l.



  Rf values (silica gel, hexane / ether 2: 1): 9A, 0.136; 2B, 0.106.


 c) (2S, 3S) - and (2R, 3S) -1-amino-3-BOC-amino-4-cyclohexyl-2-butanol
 (Intermediates 10A and 10B)
 



  To a mixture of 7.5 g of intermediate 9A, which was obtained as described above, and 0.75 g of palladium (10% on animal charcoal) in 50 ml of methanol in an inert atmosphere, 5.96 g of ammonium formate are added in small portions over a period of 1 hour added. After stirring for 17 hours at room temperature, the suspension is filtered through Celite and the filtrate is evaporated in vacuo. The residue is taken up in 2N hydrochloric acid, washed twice with ether and the aqueous phase is made alkaline by adding sodium bicarbonate. The aqueous phase is extracted twice with ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate and evaporated in vacuo. The foamy residue is converted into the hydrogen oxalate and crystallized from ether. The hydrogen oxalate of intermediate 10A of mp 165-166 ° (dec.) Is obtained.



   The hydrogen oxalate of intermediate 10B, which is obtained in an analogous manner from intermediate 9B, melts at 137-138 ° (dec.).


 d) (2S, 3S) -3-BOC-amino-1- (n-butylcarbamoyl) amino-4-cyclohexyl-2-butanol
 (Intermediate 11A)
 



  A solution of 1.15 g of intermediate 10A (free base) in 5 ml of anhydrous tetrahydrofuran is mixed with ice cooling with 0.45 ml of n-butyl isocyanate, stirred for 1 hour at room temperature and evaporated in vacuo. The residue is taken up in ethyl acetate, washed successively with 0.25 N hydrochloric acid, saturated sodium hydrogen carbonate and brine, dried over sodium sulfate and evaporated. The title compound is obtained as a raw foam.



  Analogously, intermediate 10B (free base) (2R, 3S) -3-BOC-amino-1- (n-butylcarbamoyl) amino-4-cyclohexyl-2-butanol (intermediate 11B) is obtained as a raw foam.


 e) (2S, 3S) -3-amino-1- (n-butylcarbamoyl) amino-4-cyclohexyl-2-butanol hydrochloride
 (Intermediate 8A)
 



  1.39 g of the crude intermediate 11A are dissolved in 14 ml glacial acetic acid / conc. Hydrochloric acid (9: 1) stirred for 1 hour at room temperature and evaporated in a high vacuum. The residue is taken up twice in toluene and evaporated to dryness again. The title compound is obtained as an amorphous foam.



  Analogously, the intermediate 11B (2R, 3S) -3-amino-1- (n-butylcarbamoyl) amino-4-cyclohexyl-2-butanol hydrochloride (intermediate 8B) is obtained as an amorphous residue.


 Example 56:
 


 (2S, 3S) -3- (N-BOC-phenylalaninyl-norleucyl) amido-1- (isopropylcarbamoyl) amino-4-cyclohexyl-
 2-butanol
 



  A solution of 273 mg (2S, 3S) -1-amino-3- (N-BOC-phenylalaninyl-norleucyl) -amido-4-cyclohexyl-2-butanol (intermediate 12A) in 10 ml of anhydrous tetrahydrofuran is added at 0 ° with 0.055 ml of isopropyl isocyanate are added, the mixture is stirred at room temperature for 1 hour and evaporated in a high vacuum. Crystallization of the residue from methylene chloride / methanol / hexane gives the title compound, mp. 167-8 DEG (dec.), [Alpha] D <2> <0> = -16.2 ° (c = 1 in methanol).



  Intermediate 12A used in this example can be prepared as follows:


 a) (2S, 3S) - and (2R, 3S) -3-BOC-amino-1-Cbz.-amino-4-cyclohexyl-2-butanol
 (Intermediates 13A and 13B)
 



  4.18 ml of benzyl chloroformate are added to a solution of 5.28 ml of triethylamine and 6.3 g of intermediate compound 10A, which was obtained according to the procedure in Example 55, in 120 ml of dichloromethane at a temperature of 2 to 5 ° and the resulting Solution stirred at room temperature for 30 minutes. The mixture is then diluted with dichloromethane and washed with 0.25N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water. The organic phase is dried over sodium sulfate and evaporated in vacuo. Chromatography of the residue on silica gel using toluene / ethyl acetate (3: 1) as the eluent gives intermediate 13A as a pale yellowish oil.



  Using the same procedure, starting from intermediate 10B, intermediate 13B is obtained as \ I.


 b) (2S, 3S) - and (2R, 3S) -3-amino-1-Cbz-amino-4-cyclohexyl-2-butanol
 (Intermediates 14A and 14B)
 



  8.06 g of the intermediate 13A are cooled in 80 ml of the mixture of acetic acid / conc. Hydrochloric acid (9: 1) entered and the solution obtained stirred at room temperature for 1 hour and then evaporated to dryness. The hydrochloride of intermediate 14A is obtained as a colorless foam.



  Using the same process, the hydrochloride of intermediate 14B is obtained from intermediate 13B.


 c) (2S, 3S) - and (2R, 3S) -3- (BOC-phenylalaninyl-norleucinyl) amino-1-Cbz-amino-4-cyclohexyl-2-butanol
 (Intermediates 15A and 15B)
 



  4.06 ml of diphenylphosphoryl azide and 4.94 ml of triethylamine are gradually added to an ice-cooled solution of 6.68 g of BOC-Phe-Nle-OH and 6.3 g of crude hydrochloride of intermediate 14A in dimethylformamide and the clear solution obtained at room temperature Stirred overnight, then concentrated in vacuo, taken up in dichloromethane and the dichloromethane solution washed with 0.25N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water and dried over anhydrous sodium sulfate. After evaporation in vacuo, the residue is chromatographed on silica gel (dichloromethane / ethanol 49: 1 as eluent) and the product obtained is crystallized from dichloromethane / hexane. The intermediate 15A thus obtained melts at 167-168 ° (dec.).



  Using the same procedure, starting from intermediate 14B, intermediate 15B of mp 150-151 ° C (dec.) Is obtained.


 d) (2S, 3S) - and (2R, 3S) -1-amino-3- (BOC-phenylalaninyl-norleucinyl) -amino-4-cyclohexyl-2-butanol
 (Intermediates 16A and 16B)
 



  7.0 g of the intermediate 15A and 0.7 g of palladium on activated carbon (10%) in 140 ml of methanol are hydrogenated at room temperature in a hydrogen atmosphere at atmospheric pressure for 1.5 hours and then the mixture is diluted with dichloromethane and filtered through Celite. After evaporating the filtrate in vacuo and crystallizing the residue from methanol / ether, the intermediate 16A is obtained as colorless crystals of mp. 140-141 DEG, [alpha] D <2> <0> = -38.5 ° (c = 1 in methanol).



  Using the same process, starting from intermediate 15B, intermediate 16B is obtained as colorless crystals of mp. 168-169 ° (decomp.), [Alpha] D <2> <0> = -25.6 ° (c = 1 in methanol).


 Example 57:
 


 (2S, 3S) -3- [N- (3-Cyclohexylpropionyl) norleucyl] amido-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol
 



  A solution of 135 mg of N- (3-cyclohexylpropionyl) norleucine, 154 mg (2S, 3S) -3-amino-1- (isopropylcarbamoyl) amino-2-butanol hydrochloride and 150 ml of 1-hydroxybenzotriazole in 2.6 ml of dimethylformamide is added 0 ° C. with 104 mg of N, N min -dicyclohexylcarbodiimide and 0.07 ml of triethylamine, stirred for 1 hour at 0 ° C., then for 15 hours at RT, cooled again to 0 ° C. and the dicyclohexylurea formed was filtered off. The filtrate is evaporated under high vacuum, the residue is taken up in methylene chloride and washed successively with 0.25N hydrochloric acid, saturated sodium bicarbonate solution and water. The organic phase is dried over sodium sulfate and evaporated. Chromatography of the residue (silica gel, 6 bar, methylene chloride-ethanol 19: 1) gives the amorphous title compound, [alpha] D <2> <0> = -18.0 ° (c = 1 in methanol).



   The intermediate products used in Example 57 can be produced as follows:


 a) N-3-Cyclohexylpropionyl-norleucine
 



  A solution of 1.31 g of L-norleucine in 22 ml of ether and 22 ml of 1N sodium hydroxide solution is mixed with 1.92 g of 3-cyclohexylpropionic acid chloride at 0 ° C., stirred for 1 hour at 0 ° C., then prepared with 0.25N hydrochloric acid and twice with Ether extracted. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. Crystallization of the residue from ether / hexane gives the title compound, mp. 138-9 ° (dec.).


 b) (2S, 3S) -3-amino-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol-HCl
 



  Analogously to Example 55d), using intermediate 10A and isopropyl isocyanate, (2S, 3S) -3-BOC-amino-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol is obtained. Analogously to Example 55e), the BOC protective group is split off from the product obtained, and the amorphous title compound is thus obtained.


 Example 58:
 


 (2S, 3S) -3- (N-BOC-phenylalaninyl-norleucyl) amido-1- [bis- (dimethylamino)] phosphorylamido-4-cyclohexyl-2-butanol
 



  A solution of 273 mg (2S, 3S) -3- (N-BOC-phenylalaninyl-norleucyl) -amido-1-amino-4-cyclohexyl-2-butanol (intermediate 16A, see Example 56d) and 0.07 ml of triethylamine in 3.4 ml of anhydrous tetrahydrofuran is mixed at 0 ° C. with a solution of 0.076 ml of phosphoric acid bis (dimethylamide) chloride in 3.4 ml of anhydrous tetrahydrofuran. A further 6.8 ml of tetrahydrofuran and 3.4 ml of hexamethylphosphoric acid triamide and a spatula tip of 4-dimethylaminopyridine are added to the resulting suspension at room temperature and the clear solution is stirred for 5 days at room temperature. It is then concentrated in a high vacuum, the residue is taken up in ethyl acetate, washed successively with ice-cold 0.25N hydrochloric acid, saturated sodium bicarbonate and sodium chloride solution, dried over sodium sulfate and evaporated.

  Crystallization of the residue from methylene chloride / hexane gives the title compound, mp. 171-2 DEG (dec.), [Alpha] D <2> <0> = -27.7 ° (c = 1 in chloroform).


 Example 59:
 


 (2S, 3S) -3- (N-BOC-phenylalaninyl-norleucyl) amido-1- (dimethyl-carbamoyl) amino-4-cyclohexyl-
 2-butanol
 



  Analogously to Example 56, using dimethylcarbamoyl chloride and triethylamine instead of isopropyl isocyanate, the title compound, mp. 157-8 ° C., [alpha] D <2> <0> = -10.0 ° C (c = 2 in methanol)


 Example 60:
 


 (2S, 3S) -3- (N-BOC-phenylalaninyl-norleucyl) amido-1- (isopropyl-carbamoyl) -isopropylamino-4-cyclohexyl-2-butanol
 



  A solution of 189 mg N-BOC-phenylalaninyl-norleucine, 172 mg (2S, 3S) -3-amino-1- (isopropylcarbamoyl) isopropylamino-4-cyclohexyl-2-butanol (intermediate 17) and 150 mg 1-hydroxybenzotriazole in 3.4 ml of dimethylformamide, 99 mg of N-ethyl-N min - (3-dimethylamino-propyl) carbodiimide hydrochloride and 0.07 ml of triethylamine are added at 0 ° C. for 1 hour at 0 ° C. and 20 hours at room temperature stirred and then evaporated on a Rotavapor at 303 ° C. The residue is taken up in methylene chloride, washed successively with cold 0.25N hydrochloric acid, saturated sodium bicarbonate solution and water, dried over sodium sulfate and evaporated. Chromatography of the residue (silica gel, 5 bar, methylene chloride-ethanol) gives the title compound, [alpha] D <2> <0> -5.0 ° (c = 1 in methanol).



  The intermediate 17 used in this example can be prepared as follows:


 a) (2S, 3S) -3-N-BOC-amino-1-isopropylamino-4-cyclohexyl-2-butanol
 



  A mixture of 3.26 g of intermediate 10A (see Example 55c), 1.59 g of sodium carbonate and 1.02 ml of isopropyl iodide in 30 ml of tetrahydrofuran is refluxed for 16 hours, then the cooled suspension is filtered and the filtrate is evaporated. Chromatography of the residue (silica gel, 4 bar, methylene chloride-methanol conc. Ammonia 90: 9: 1) gives the title compound (amorphous).


 b) (2S, 3S) -3-N-BOC-amino-1- (isopropylcarbamoyl) isopropylamino-4-cyclohexyl-2-butanol
 



  A solution of 591 mg of the above product in 6 ml of tetrahydrofuran is mixed at 0 ° C. with 0.2 ml of isopropyl isocyanate, stirred for 20 hours at room temperature and then evaporated. Chromatography (silica gel, 5 bar, methylene chloride-ethanol 19: 1) gives the amorphous title compound.


 c) (2S, 3S) -3-amino-1- (isopropylcarbamoyl) isopropylamino-4-cyclohexyl-2-butanol
 (Interconnection 17)
 



  From the process product of stage b) the BOC protective group is analogous to Example 55e using glacial acetic acid conc. Cleaved hydrochloric acid and thereby obtained the intermediate compound 17.


 Example 61:
 


 (2S, 3S) -3- [N- (1-Adamantyl-propionyl) -norleucyl] amido-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol
 



  Analogously to Example 57, using N- (1-adamantylpropionyl) norleucine instead of N- (3-cyclohexylpropionyl) norleucine, the title compound, mp. 230-1 ° C., [alpha] D <2> <0> = -24.5 ° (c = 1 in dimethylformamide).


 Example 62:
 


 (2S, 3S) -3- (N-BOC-norleucyl) amido-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol
 



  Analogously to Example 57, using N-BOC-norleucine instead of N- (3-cyclohexylpropionyl) norleucine, the title compound, mp. 225-6 ° C. (dec.) Is obtained.


 Example 63:
 


 (2S, 3S) -3- (norleucyl) amido-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol hydrochloride
 (Intermediate product)
 



  339 mg of the product from Example 62 are analogous to Example 55e) with 3.4 ml of glacial acetic acid / conc. Hydrochloric acid treated and worked up. The title compound is obtained as a colorless foam.


 Example 64:
 


 (2S, 3S) -3-N- [1-benzoyl-amino-2- (1-naphthyl) propenoyl-norleucyl] amino-4-cyclohexyl-1- (isopropylaminocarbamoyl) amino-2-butanol
 



  A solution of 168 mg of the product from Example 63, 120 mg of 5- (1-naphthylmethylidene) -2-phenyl-4-oxazolone (azlactone from 1-naphthaldehyde and N-benzoylglycine) and 0.056 ml of triethylamine in 2.7 ml of chloroform mixed with a 4-dimethylamino-pyridine spatula, boiled under reflux for 4 hours and then evaporated. Chromatography of the residue (silica gel, 6 bar, ethyl acetate) gives the amorphous title compound, [alpha] D <2> <0> -58.2 ° (c = 1 in methanol).


 Example 65:
 


 (2S, 3S) -3- [N- (bis (1-naphthylmethyl) acetyl) norleucyl] amino-4-cyclohexyl-1- (isopropylcarbamoyl) amino-2-butanol
 



   Analogously to Example 57, using N- (bis (1-naphthyl-methyl) acetyl) norleucine instead of N- (3-cyclohexylpropionyl) norleucine, the title compound, mp. 173-4 DEG, [alpha] D <2> <0> = -52.0 ° (c = 1 in methanol).


 Example 66:
 


 (2S, 3S) -3- (N-Cyclopentyl-carbonyl-phenylalaninyl-norleucyl) amino-4-cyclohexyl-1- (isopropyl-carbamoyl) amino-2-butanol
 



  Coupling of N-cyclopentylcarbonyl-phenylalanine and (2S, 3S) -3- (norleucyl) amido-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol hydrochloride (Example 63) analogously to Example 57 gives the title compound, mp 213-5 DEG (dec.), [Alpha] D <2> <0> = -18.2 ° (c = 0.5 in methanol).


 Example 67:
 


 (2S, 3S) -3- (N-BOC-phenylalaninyl-histidyl) amido-1- (isopropyl-carbamoyl) amino-4-cyclohexyl-2-butanol
 



  Analogously to Example 57, using N-BOC-phenylalaninyl-histidine instead of N- (3-cyclohexylpropionyl) norleucine, the title compound is obtained as an amorphous powder, [alpha] D <2> <0> = -10.8 ° (c = 1 in methanol).



  The following abbreviations are used in the previous examples:
 SO2Adatin (2R, 3S) -4- (1-adamantyl) -3-amino-2-hydroxy-butanesulfonic acid
 SO2Chatin (2R, 3S) -3-amino-4-cyclohexyl-2-hydroxy-butanesulfonic acid
 SO2Sta (2R, 3S) -3-amino-2-hydroxy-5-methyl-hexanesulfonic acid
 SO2-aminochatin (2R, 3S) -2,3-diamino-4-cyclohexyl-butanesulfonic acid
 SO2-deoxychatine (3S) -3-amino-4-cyclohexyl-butanesulfonic acid
 SO2-dioxolane (2R, 3S) -3-amino-4- (1,4-dioxaspiro [4,5] dec-8-yl) -2-hydroxybutanesulfonic acid
 SO2-onChatin (2R, 3S) -3-amino-4- (4 min -oxocyclohexyl) -2-hydroxy-butanesulfonic acid
 SO2-olChatin (2R, 3S) -3-amino-4- (4 min hydroxycyclohexyl) -2-hydroxy-butanesulfonic acid
 SO2 (2-naphthin) (2R, 3S) -3-amino-2-hydroxy-4- (2-naphthyl) butanesulfonic acid
 SO2 neotin (2R, 3S) -3-amino-5,5-dimethyl-2-hydroxy-hexanesulfonic acid
 Achps (3S, 4S) -4-amino-5-cyclohexyl-3-hydroxy-pentanesulfonic acid
 Achips

   (1S, 3S, 4S) -4-amino-5-cyclohexyl-3-hydroxy-1-isopropylpentanesulfonic acid
 SO2-Mettin (2R, 3S) -3-amino-5-methylmercapto-2-hydroxypentanesulfonic acid
 SO2-Mettin (O) (2R, 3S) -3-amino-5-methylsulfinyl-2-hydroxypentanesulfonic acid
 Cys (BZL) (OH) CH2SO2 (2R, 3R) -3-amino-4-benzylmercapto-2-hydroxybutanesulfonic acid
 Cys (Et) (OH) CH2SO2 (2R, 3R) -3-amino-4-ethylmercapto-2-hydroxybutanesulfonic acid
 Cys (OH) CH2SO2 (2R, 3R) -3-amino-4-mercapto-2-hydroxybutanesulfonic acid



  The compounds according to the invention have pharmacological activity. They can be used to make a drug.



  As can be seen from the results of standard tests, they have typical effects, in particular for enzyme inhibitors. The inhibitory effect with regard to a specific enzyme naturally depends on the peptide structure as a whole. The above compounds, which are particularly suitable as inhibitors of renin activity, act on the human synthetic tetradecapeptide substrate at a concentration of 10 <-> <5> M to 10 <-> <1> <1> M a 50% inhibition of the enzyme activity of pure human renin according to the method of F. Cumin et al. (Bioch. Biophys. Acta 913, 10-19 (1987)).



  In the "antibody trapping" method by K. Poulsen and J. J rgensen (J. Clin. Endocrin. Metab. 39 [1974] 816-825), they inhibit human plasma arena activity at a concentration of 10 <-> <5> M to 10 <-> <1> <1> M.



  The compounds according to the invention are therefore suitable for use for the prophylaxis and treatment of conditions which are characterized by an enzymatic dysfunction and for which an inhibition of the enzymatic activity is indicated.



  As renin inhibitors they are e.g. suitable for use in the prophylaxis and treatment of hypertension and heart failure ("congestive heart failure").



  For the above applications, the dose to be administered depends on the particular compound used, the type of administration and the desired treatment. In general, satisfactory results are obtained if the compounds are administered in a daily dose of 0.02 mg / kg to approximately 10 mg / kg of animal body weight. For larger mammals, the recommended daily dose is from about 1 mg to about 500 mg, conveniently administered e.g. orally in doses of 0.25 mg to approx. 500 mg 1-4 times a day or in sustained release form



  Preferred for the prophylaxis and treatment of hypertension and heart failure are the title compounds of Examples 11, 12, 23, 30, 54 and 65, in particular Examples 11, 12, 23 and 30 and very particularly Examples 12 and 23.



   The compounds according to the invention can be administered in free form or, if acidic or basic groups are present, in pharmacologically acceptable salt form. Such salt forms have an effect on the same order of magnitude as the free forms and can be produced in a known manner. The present invention also relates to pharmaceutical preparations containing a compound according to the invention in free form or in pharmaceutically acceptable salt form, optionally together with pharmaceutically acceptable auxiliaries and / or carriers. Such pharmaceutical preparations can be formulated for use in enteral, preferably oral, administration, e.g. as tablets, or for use in parenteral administration, e.g. as injectable solutions or suspensions.


    

Claims (15)

      1. A compound of formula I EMI52.1      wherein A den  Bis (1-naphthylmethyl) acetyl or an acyl group of the formula EMI52.2      where R6 is a straight-chain or branched (C6-10) alkyl radical which is optionally substituted by (C1-5) alkoxy or (C6-C10) aryloxy, a (C3-7) cycloalkyl radical, a (3-10) cycloalkyl- ( 1-5) alkyl radical, a (C6-10) aryl radical, a 5- or 6-membered, one or two nitrogen atoms, oxygen or sulfur atoms or a nitrogen atom and an oxygen atom and / or a sulfur atom or heteroaryl radical or for a heteroaryl radical (C1-5) alkyl radical, in which the heteroaryl part is 5 or 6-membered and contains one or two nitrogen atoms, oxygen or sulfur atoms or a nitrogen atom and an oxygen atom and / or a sulfur atom,  a straight-chain or branched (C1-5) alkoxy radical or a (C6-10) aryl (C1-5) alkoxy radical, a group of the formula R10O (CH2CH2O) n (CH2) m-, in which R10 is a straight-chain or branched (C1-5) alkyl radical, n is an integer from 1 to 20 and m is an integer from 1 to 5, or a group of the formula EMI53.1      where R is hydrogen or acetyl,  or  A is a group of the formula EMI53.2      wherein  R7 is a straight-chain or branched (C1-5) alkyl radical or a (C6-10) aryl radical and  R8 and R9 each represent hydrogen, a straight-chain or branched (C1-5) alkyl radical or a (C6-10) aryl radical,  R1 is hydrogen or a straight-chain or branched (C1-5) alkyl radical,    B and C are the same or different and are a bond or a group of the formula EMI54.1      mean,  in which R1 has the above meaning and R11 represents a hydrophilic or lipophilic amino acid side chain,  where B and C cannot simultaneously be a bond,  D for -O- or EMI54.2  where R1 has the above meaning, where  D also a bond or EMI54.3  means in which R1 has the above meaning if  Y for EMI54.4  where R4 and R5 have the following meanings.  R2 for a straight-chain or branched (C1-10) alkyl radical, a (C3-10) cycloalkyl- (C1-5) alkyl radical optionally substituted in the cycloalkyl part, a (C6-10) aryl- (C1-5) alkyl radical or a heteroaryl- (C1-5) alkyl radical, in which the heteroaryl part is 5- or 6-membered and one or two nitrogen atoms,  Contains oxygen or sulfur atoms or a nitrogen atom and an oxygen atom and / or a sulfur atom, or for a group of the formula EMI54.5      stands in what  R15 is hydrogen, (C1-4) alkyl or benzyl, s is 0 or 1 and p is 1 or 2,  R3 is hydrogen, a hydroxyl group, an amino group or a group of the formula -OCOR2, in which R2 has the above meaning.  R4 and R5 are identical or different and are each hydrogen, a straight-chain or branched (C1-5) alkyl radical, a (C6-10) aryl- (C1-5) alkyl radical or a heteroaryl- (C1-5) alkyl radical, wherein the heteroaryl part is 5- or 6-membered and contains one or two nitrogen atoms, oxygen or sulfur atoms or a nitrogen atom and an oxygen atom and / or a sulfur atom, mean or for a group of the formula EMI55.1      stand,  wherein R12 represents a straight-chain or branched (C1-5) alkyl radical or a straight-chain or branched (C1-5) hydroxyalkyl radical, R13 represents a hydroxyl radical, a straight-chain or branched (C1-5) alkoxy group, an amino or a (C1-5 ) Alkylamino group, the alkyl radical being straight-chain or branched, an aminomethylpyridyl group or a benzyl group, or the rest EMI55.2      for groups of formulas EMI55.3      in which R14 is hydrogen, (C1-5) alkyl, benzyl or a group of the formula EMI56.1      means what  R16 is (C1-4) alkyl or (C1-4) alkoxy (C2H4O) q-CH2-, where q is an integer from 2-5 and Y is EMI56.2      stands in which R4 and R5 have the above meaning. 2nd The compounds of claim 1    (2S, 3S) -3- (N-BOC-phenylalaninyl-histidyl) amino-1- (n-butylcarbamoylamino) -4-cyclohexyl-2-butanol    (2R, 3S) -3- (N-BOC-phenylalaninyl-histidyl) amido-1- (n-butylcarbamoylamino) -4-cyclohexyl-2-butanol    (2S, 3S) -3- (N-BOC-phenylalaninyl-norleucyl) amido-1- (iso-propylcarbamoyl) amino-4-cyclohexyl-2-butanol    (2S, 3S) -3- [N- (3-Cyclohexylpropionyl) norleucyl] amido-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol    (2S, 3S) -3- (N-BOC-phenylalaninyl-norleucyl) amido-1- [bis- (dimethylamino)] phosphorylamido-4-cyclohexyl-2-butanol    (2S, 3S) -3- (N-BOC-phenylalaninyl-norleucyl) amido-1- (dimethyl-carbamoyl) amino-4-cyclohexyl-2-butanol    (2S, 3S) -3- (N-BOC-Phenylalaninyl-norleucyl) amido-1- (iso-propyl-carbamoyl) -isopropylamino-4-cyclohexyl-2-butanol    (2S, 3S) -3- [N- (1-Adamantyl-propionyl) -norleucyl] amido-1- (iso-propylcarbamoyl) amino-4-cyclohexyl-2-butanol      (2S, 3S) -3- (N-BOC-norleucyl) amido-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol    (2S, 3S) -3-N- [1-benzoyl-amino-2- (1-naphthyl) propenoyl-norleucyl] amino-4-cyclohexyl-1- (isopropylcarbamoyl) amino-2-butanol    (2S, 3S) -3- [N- (bis (1-naphthylmethyl) acetyl) norleucyl] amino-4-cyclohexyl-1- (isopropylcarbamoyl) amino-2-butanol    (2S, 3S) -3- (N-Cyclopentyl-carbonyl-phenylalaninyl-norleucyl) amino-4-cyclohexyl-1- (isopropyl-carbamoyl) amino-2-butanol    (2S, 3S) -3- (N-BOC-Phenylalaninyl-histidyl) amido-1- (isopropyl-carbamoyl) -amino-4-cyclohexyl-2-butanol    (2R, 3S) -3- (N-BOC-phenylalanyl-phenylalanyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC beta -cyclohexylalanyl-beta -cyclohexylalanyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide      (2R, 3S) -3- (N-BOC-beta-Cyclohexylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-phenylalanyl-histidyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- [N- (BIS (1-naphthylmethyl) acetyl) norleucyl] amido-4-cyclohexyl-2-hydroxybutanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-amino-4-cyclohexyl-butanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4- (1,4-dioxaspiro [4.5] dec-8-yl) -2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4- (4 min -oxocyclohexyl) -2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4- (4 min -hydroxycyclohexyl) -2-hydroxy-butanesulfonic acid dimethylamide    (3S, 4S) -4- (N-BOC-Phenylalanyl-norleucyl) amido-5-cyclohexyl) -3-hydroxy-pentanesulfonic acid dimethylamide      (1R, 3S, 4S) -4- (N-BOC-Phenylalanyl-norleucyl) amido-5-cyclohexyl-3-hydroxy-1-isopropyl-pentanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-2-hydroxy-4- (2-naphthyl) butanesulfonic acid dimethylamide    (2R, 3S) -3- [N- (bis- (1-Naphthylmethyl) acetyl) -norleucyl] amido-2-hydroxy-5- (methyl-hexanesulfonic acid dimethylamide)    (2S, 3S) - and (2R, 3S) -3- (BOC-phenylalanyl-norleucyl) -amido-4-cyclohexyl-1-isobutyl-  sulfamoylamino-2-butanol    (2S, 3S) -3- (BOC-phenylalaninyl-norleucyl) amido-4-cyclohexyl-1-dimethylsulfamoylamino-2-butanol    (2RS, 3S) -3- (N-Benzoyl-dehydrophenylalaninyl-norleucyl) -amido-1-dimethylsulfamoyl-amino-5-methyl-2-hexanol    (2S, 3S) -3- (3-cyclohexyl-propionyl-norleucyl) amido-4-cyclohexyl-1-dimethylsulfamoylamino-  2-butanol    (2R, 3S) -3- [N (1-adamantyl) propionyl) norleucyl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-beta  -Cyclohexylalanylhistidyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- [N- (BIS- (1-Naphthylmethyl) acetyl) histidyl] amido-4-cyclohexyl-2-hydroxybutanesulfonic acid dimethylamide    (2R, 3S) -3- [N-BOC-beta - (2,1,3-Benzoxadiazol-4-yl) alanyl-norleucyl] amido-4-cyclohexyl-2-hydroxy-  butanesulfonic acid dimethylamide    (2R, 3S) -3 - ((N- [2-methoxy-poly (2-ethoxy) acetyl] phenylalanyl-norleucyl)) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- [N- (BIS- (1-Naphthylmethyl) acetyl) methionyl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- [N- (BIS- (1-Naphthylmethyl) acetyl) methion (D, L-S-oxide) yl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4- (1-adamantyl) -2-hydroxy-butanesulfonic acid dimethylamide      (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-5,5-dimethyl-2-hydroxy-hexanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid pyrrolidinamide    (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid piperidinamide    (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid- (4-benzyl) piperazinamide    (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid piperazinamide    (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid- (4-acetyl) piperazinamide    (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid- [4- (2,5,8,11-tetraoxadodecanyl) carbonyl] pi perazinamide    (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid- (4-methyl) piperazinamide      (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid morpholinamide    (2R, 3S) -3- (N-BOC-phenylalanyl-histidyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid piperidinamide    (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-2-hydroxy-5-methyl-mercapto-pentanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-5-methylsulfinyl-pentanesulfonic acid dimethylamide    (2R, 3R) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-4-benzylmercapto-butanesulfonic acid dimethylamide    (2R, 3R) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-4-mercapto-butanesulfonic acid dimethylamide    (2R, 3R) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-4-ethylmercapto-butanesulfonic acid dimethylamide    (2R, 3S) -3- [N- (2,3,4,6-Tetra-O-acetyl-beta -D-glucosyl-1-O) -isobutyrylphenylalanyl-norleucyl] amido-4-cyclohexyl-2-hydroxy -butanesulfonic acid dimethylamide      (2R, 3S) -3- [N- (beta -D-glucosyl-1-O) -isobutyryl-phenylalanyl-norleucyl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide 3. A compound according to claim 1 as a medicament. 4. A compound according to claim 1 as a renin inhibitor. 5. A compound according to claim 1 as an agent for combating hypertension and heart failure. 6. Pharmaceutical preparation containing a compound according to claim 1, together with pharmacologically acceptable auxiliaries and / or diluents. 7. A process for the preparation of compounds of formula Ia according to claim 1 EMI63.1      wherein A, B, C, D, Y, R1, R2, R4 and R5 have the meaning given in claim 1 and R3 min represents hydrogen, hydroxyl or a radical of the formula -OCOR2, wherein R2 has the meaning given in claim 1 , characterized in that compounds of the formula II,    A-B-C-OH II    wherein A, B and C have the meaning given in claim 1, with compounds of the formula III, EMI63.2      wherein R1, R2, R4, R5, Y and D implements the indicated in claim 1 and R3 min have the meaning given above. 8th. Process for the preparation of compounds of formula Ib according to claim 1 EMI64.1      wherein A, B, C, D, Y, R1, R2, R4 and R5 have the meaning given in claim 1, characterized in that compounds of the formula IV EMI64.2      wherein A, B, C, D, Y, R1, R2, R4 and R5 have the meaning given in claim 1, reduced. 9. A process for the preparation of compounds of formula Ic according to claim 1 EMI64.3      wherein A, B, C, Y, R1, R2, R4 and R5 have the meaning given in claim 1 and R3 min as defined in claim 7 and D min for -O- or EMI64.4  stands, characterized in that compounds of formula V EMI65.1      wherein A, B, C, R1 and R2 which in claim 1 and R3 min in Claim 7 and D min have the meaning given above with a compound of formula VI EMI65.2      wherein Y, R4 and R5 have the meaning given in claim 1 and X is halogen. 10th A process for the preparation of compounds of formula Id according to claim 1 EMI65.3      wherein A, B, C, Y, R15, R1, D, R4, R5 and p have the meaning given in claim 1 and R3 min in claim 7 and s min stands for 1, characterized in that compounds of the formula Ie according to claim 1 EMI66.1      wherein A, B, C, Y, R15, R1, D, R4, R5 and p have the meanings given in claim 1 and R3 min have the meaning given in claim 7. 11. A process for the preparation of compounds of the formula If according to claim 1 EMI66.2      wherein A, B, C, Y, R1, R3, D, R4, R5 and p have the meaning given in claim 1, characterized in that compounds of the formula Ig EMI66.3      wherein A, B, C, Y, R1, R3, D, R4, R5 and p have the meaning given in claim 1, which cleaves the benzyl group. 12. A process for the preparation of compounds of the formula Ih according to claim 1 EMI67.1      wherein A, B, C, Y, R1, R3, D, R4, R5 and p have the meaning given in claim 1, characterized in that in compounds of the formula if according to claim 11, the (C1-4) alkyl radical introduces. 13. A process for the preparation of compounds of formula Ii according to claim 1 EMI67.2      wherein A, B, C, R1, R2, R3, D and Y have the meaning given in claim 1, characterized in that compounds of the formula Ij EMI67.3      wherein A, B, C, R1, R2, R3, D and Y has the meaning given in claim 1, cleaves the benzyl group catalytically. 14.   A process for the preparation of compounds of the formula Ik according to claim 1 EMI68.1      wherein C, D, Y, R1 to R5 and R7 to R9 have the meaning given in claim 1, characterized in that a compound of formula IX EMI68.2      wherein R7, R8 and R9 have the meaning given in claim 1, with compounds of the formula X. EMI68.3      wherein C, D, R1, R2, R3, R4, R5 and Y have the meaning given in claim 1. 15. Use of compounds of formula I for the manufacture of medicaments with renin-inhibiting activity for the treatment of hypertension and heart failure.       1. A compound of formula I EMI52.1      wherein A den  Bis (1-naphthylmethyl) acetyl or an acyl group of the formula EMI52.2      where R6 is a straight-chain or branched (C6-10) alkyl radical which is optionally substituted by (C1-5) alkoxy or (C6-C10) aryloxy, a (C3-7) cycloalkyl radical, a (3-10) cycloalkyl- ( 1-5) alkyl radical, a (C6-10) aryl radical, a 5- or 6-membered, one or two nitrogen atoms, oxygen or sulfur atoms or a nitrogen atom and an oxygen atom and / or a sulfur atom or heteroaryl radical or for a heteroaryl radical (C1-5) alkyl radical, in which the heteroaryl part is 5 or 6-membered and contains one or two nitrogen atoms, oxygen or sulfur atoms or a nitrogen atom and an oxygen atom and / or a sulfur atom,  a straight-chain or branched (C1-5) alkoxy radical or a (C6-10) aryl (C1-5) alkoxy radical, a group of the formula R10O (CH2CH2O) n (CH2) m-, in which R10 is a straight-chain or branched (C1-5) alkyl radical, n is an integer from 1 to 20 and m is an integer from 1 to 5, or a group of the formula EMI53.1      where R is hydrogen or acetyl,  or  A is a group of the formula EMI53.2      wherein  R7 is a straight-chain or branched (C1-5) alkyl radical or a (C6-10) aryl radical and  R8 and R9 each represent hydrogen, a straight-chain or branched (C1-5) alkyl radical or a (C6-10) aryl radical,  R1 is hydrogen or a straight-chain or branched (C1-5) alkyl radical,    B and C are the same or different and are a bond or a group of the formula EMI54.1      mean,  in which R1 has the above meaning and R11 represents a hydrophilic or lipophilic amino acid side chain,  where B and C cannot simultaneously be a bond,  D for -O- or EMI54.2  where R1 has the above meaning, where  D also a bond or EMI54.3  means in which R1 has the above meaning if  Y for EMI54.4  where R4 and R5 have the following meanings.  R2 for a straight-chain or branched (C1-10) alkyl radical, a (C3-10) cycloalkyl- (C1-5) alkyl radical optionally substituted in the cycloalkyl part, a (C6-10) aryl- (C1-5) alkyl radical or a heteroaryl- (C1-5) alkyl radical, in which the heteroaryl part is 5- or 6-membered and one or two nitrogen atoms,  Contains oxygen or sulfur atoms or a nitrogen atom and an oxygen atom and / or a sulfur atom, or for a group of the formula EMI54.5      stands in what  R15 is hydrogen, (C1-4) alkyl or benzyl, s is 0 or 1 and p is 1 or 2,  R3 is hydrogen, a hydroxyl group, an amino group or a group of the formula -OCOR2, in which R2 has the above meaning.  R4 and R5 are identical or different and are each hydrogen, a straight-chain or branched (C1-5) alkyl radical, a (C6-10) aryl- (C1-5) alkyl radical or a heteroaryl- (C1-5) alkyl radical, wherein the heteroaryl part is 5- or 6-membered and contains one or two nitrogen atoms, oxygen or sulfur atoms or a nitrogen atom and an oxygen atom and / or a sulfur atom, mean or for a group of the formula EMI55.1      stand,  wherein R12 represents a straight-chain or branched (C1-5) alkyl radical or a straight-chain or branched (C1-5) hydroxyalkyl radical, R13 represents a hydroxyl radical, a straight-chain or branched (C1-5) alkoxy group, an amino or a (C1-5 ) Alkylamino group, the alkyl radical being straight-chain or branched, an aminomethylpyridyl group or a benzyl group, or the rest EMI55.2      for groups of formulas EMI55.3      in which R14 is hydrogen, (C1-5) alkyl, benzyl or a group of the formula EMI56.1      means what  R16 is (C1-4) alkyl or (C1-4) alkoxy (C2H4O) q-CH2-, where q is an integer from 2-5 and Y is EMI56.2      stands in which R4 and R5 have the above meaning. 2nd The compounds of claim 1    (2S, 3S) -3- (N-BOC-phenylalaninyl-histidyl) amino-1- (n-butylcarbamoylamino) -4-cyclohexyl-2-butanol    (2R, 3S) -3- (N-BOC-phenylalaninyl-histidyl) amido-1- (n-butylcarbamoylamino) -4-cyclohexyl-2-butanol    (2S, 3S) -3- (N-BOC-phenylalaninyl-norleucyl) amido-1- (iso-propylcarbamoyl) amino-4-cyclohexyl-2-butanol    (2S, 3S) -3- [N- (3-Cyclohexylpropionyl) norleucyl] amido-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol    (2S, 3S) -3- (N-BOC-phenylalaninyl-norleucyl) amido-1- [bis- (dimethylamino)] phosphorylamido-4-cyclohexyl-2-butanol    (2S, 3S) -3- (N-BOC-phenylalaninyl-norleucyl) amido-1- (dimethyl-carbamoyl) amino-4-cyclohexyl-2-butanol    (2S, 3S) -3- (N-BOC-Phenylalaninyl-norleucyl) amido-1- (iso-propyl-carbamoyl) -isopropylamino-4-cyclohexyl-2-butanol    (2S, 3S) -3- [N- (1-Adamantyl-propionyl) -norleucyl] amido-1- (iso-propylcarbamoyl) amino-4-cyclohexyl-2-butanol      (2S, 3S) -3- (N-BOC-norleucyl) amido-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol    (2S, 3S) -3-N- [1-benzoyl-amino-2- (1-naphthyl) propenoyl-norleucyl] amino-4-cyclohexyl-1- (isopropylcarbamoyl) amino-2-butanol    (2S, 3S) -3- [N- (bis (1-naphthylmethyl) acetyl) norleucyl] amino-4-cyclohexyl-1- (isopropylcarbamoyl) amino-2-butanol    (2S, 3S) -3- (N-Cyclopentyl-carbonyl-phenylalaninyl-norleucyl) amino-4-cyclohexyl-1- (isopropyl-carbamoyl) amino-2-butanol    (2S, 3S) -3- (N-BOC-Phenylalaninyl-histidyl) amido-1- (isopropyl-carbamoyl) -amino-4-cyclohexyl-2-butanol    (2R, 3S) -3- (N-BOC-phenylalanyl-phenylalanyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC beta -cyclohexylalanyl-beta -cyclohexylalanyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide      (2R, 3S) -3- (N-BOC-beta-Cyclohexylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-phenylalanyl-histidyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- [N- (BIS (1-naphthylmethyl) acetyl) norleucyl] amido-4-cyclohexyl-2-hydroxybutanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-amino-4-cyclohexyl-butanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4- (1,4-dioxaspiro [4.5] dec-8-yl) -2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4- (4 min -oxocyclohexyl) -2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4- (4 min -hydroxycyclohexyl) -2-hydroxy-butanesulfonic acid dimethylamide    (3S, 4S) -4- (N-BOC-Phenylalanyl-norleucyl) amido-5-cyclohexyl) -3-hydroxy-pentanesulfonic acid dimethylamide      (1R, 3S, 4S) -4- (N-BOC-Phenylalanyl-norleucyl) amido-5-cyclohexyl-3-hydroxy-1-isopropyl-pentanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-2-hydroxy-4- (2-naphthyl) butanesulfonic acid dimethylamide    (2R, 3S) -3- [N- (bis- (1-Naphthylmethyl) acetyl) -norleucyl] amido-2-hydroxy-5- (methyl-hexanesulfonic acid dimethylamide)    (2S, 3S) - and (2R, 3S) -3- (BOC-phenylalanyl-norleucyl) -amido-4-cyclohexyl-1-isobutyl-  sulfamoylamino-2-butanol    (2S, 3S) -3- (BOC-phenylalaninyl-norleucyl) amido-4-cyclohexyl-1-dimethylsulfamoylamino-2-butanol    (2RS, 3S) -3- (N-Benzoyl-dehydrophenylalaninyl-norleucyl) -amido-1-dimethylsulfamoyl-amino-5-methyl-2-hexanol    (2S, 3S) -3- (3-cyclohexyl-propionyl-norleucyl) amido-4-cyclohexyl-1-dimethylsulfamoylamino-  2-butanol    (2R, 3S) -3- [N (1-adamantyl) propionyl) norleucyl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-beta  -Cyclohexylalanylhistidyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- [N- (BIS- (1-Naphthylmethyl) acetyl) histidyl] amido-4-cyclohexyl-2-hydroxybutanesulfonic acid dimethylamide    (2R, 3S) -3- [N-BOC-beta - (2,1,3-Benzoxadiazol-4-yl) alanyl-norleucyl] amido-4-cyclohexyl-2-hydroxy-  butanesulfonic acid dimethylamide    (2R, 3S) -3 - ((N- [2-methoxy-poly (2-ethoxy) acetyl] phenylalanyl-norleucyl)) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- [N- (BIS- (1-Naphthylmethyl) acetyl) methionyl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- [N- (BIS- (1-Naphthylmethyl) acetyl) methion (D, L-S-oxide) yl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4- (1-adamantyl) -2-hydroxy-butanesulfonic acid dimethylamide      (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-5,5-dimethyl-2-hydroxy-hexanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid pyrrolidinamide    (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid piperidinamide    (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid- (4-benzyl) piperazinamide    (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid piperazinamide    (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid- (4-acetyl) piperazinamide    (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid- [4- (2,5,8,11-tetraoxadodecanyl) carbonyl] pi perazinamide    (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid- (4-methyl) piperazinamide      (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid morpholinamide    (2R, 3S) -3- (N-BOC-phenylalanyl-histidyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid piperidinamide    (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-2-hydroxy-5-methyl-mercapto-pentanesulfonic acid dimethylamide    (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-5-methylsulfinyl-pentanesulfonic acid dimethylamide    (2R, 3R) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-4-benzylmercapto-butanesulfonic acid dimethylamide    (2R, 3R) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-4-mercapto-butanesulfonic acid dimethylamide    (2R, 3R) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-4-ethylmercapto-butanesulfonic acid dimethylamide    (2R, 3S) -3- [N- (2,3,4,6-Tetra-O-acetyl-beta -D-glucosyl-1-O) -isobutyrylphenylalanyl-norleucyl] amido-4-cyclohexyl-2-hydroxy -butanesulfonic acid dimethylamide      (2R, 3S) -3- [N- (beta -D-glucosyl-1-O) -isobutyryl-phenylalanyl-norleucyl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide 3. A compound according to claim 1 as a medicament. 4. A compound according to claim 1 as a renin inhibitor. 5. A compound according to claim 1 as an agent for combating hypertension and heart failure. 6. Pharmaceutical preparation containing a compound according to claim 1, together with pharmacologically acceptable auxiliaries and / or diluents. 7. A process for the preparation of compounds of formula Ia according to claim 1 EMI63.1      wherein A, B, C, D, Y, R1, R2, R4 and R5 have the meaning given in claim 1 and R3 min represents hydrogen, hydroxyl or a radical of the formula -OCOR2, wherein R2 has the meaning given in claim 1 , characterized in that compounds of the formula II,    A-B-C-OH II    wherein A, B and C have the meaning given in claim 1, with compounds of the formula III, EMI63.2      wherein R1, R2, R4, R5, Y and D implements the indicated in claim 1 and R3 min have the meaning given above. 8th. Process for the preparation of compounds of formula Ib according to claim 1 EMI64.1      wherein A, B, C, D, Y, R1, R2, R4 and R5 have the meaning given in claim 1, characterized in that compounds of the formula IV EMI64.2      wherein A, B, C, D, Y, R1, R2, R4 and R5 have the meaning given in claim 1, reduced. 9. A process for the preparation of compounds of formula Ic according to claim 1 EMI64.3      wherein A, B, C, Y, R1, R2, R4 and R5 have the meaning given in claim 1 and R3 min as defined in claim 7 and D min for -O- or EMI64.4  stands, characterized in that compounds of formula V EMI65.1      wherein A, B, C, R1 and R2 which in claim 1 and R3 min in Claim 7 and D min have the meaning given above with a compound of formula VI EMI65.2      wherein Y, R4 and R5 have the meaning given in claim 1 and X is halogen. 10th A process for the preparation of compounds of formula Id according to claim 1 EMI65.3      wherein A, B, C, Y, R15, R1, D, R4, R5 and p have the meaning given in claim 1 and R3 min in claim 7 and s min stands for 1, characterized in that compounds of the formula Ie according to claim 1 EMI66.1      wherein A, B, C, Y, R15, R1, D, R4, R5 and p have the meanings given in claim 1 and R3 min have the meaning given in claim 7. 11. A process for the preparation of compounds of the formula If according to claim 1 EMI66.2      wherein A, B, C, Y, R1, R3, D, R4, R5 and p have the meaning given in claim 1, characterized in that compounds of the formula Ig EMI66.3      wherein A, B, C, Y, R1, R3, D, R4, R5 and p have the meaning given in claim 1, which cleaves the benzyl group. 12. A process for the preparation of compounds of the formula Ih according to claim 1 EMI67.1      wherein A, B, C, Y, R1, R3, D, R4, R5 and p have the meaning given in claim 1, characterized in that in compounds of the formula if according to claim 11, the (C1-4) alkyl radical introduces. 13. A process for the preparation of compounds of formula Ii according to claim 1 EMI67.2      wherein A, B, C, R1, R2, R3, D and Y have the meaning given in claim 1, characterized in that compounds of the formula Ij EMI67.3      wherein A, B, C, R1, R2, R3, D and Y has the meaning given in claim 1, cleaves the benzyl group catalytically. 14.   A process for the preparation of compounds of the formula Ik according to claim 1 EMI68.1      wherein C, D, Y, R1 to R5 and R7 to R9 have the meaning given in claim 1, characterized in that a compound of formula IX EMI68.2      wherein R7, R8 and R9 have the meaning given in claim 1, with compounds of the formula X. EMI68.3      wherein C, D, R1, R2, R3, R4, R5 and Y have the meaning given in claim 1. 15. Use of compounds of formula I for the manufacture of medicaments with renin-inhibiting activity for the treatment of hypertension and heart failure.