DE3800591A1 - Peptide derivatives, their preparation and use - Google Patents

Abstract

Compounds of the formula <IMAGE> in which A, B, C, D, Y, R1, R2, R3, R4 and R5 have the meaning stated in Claim 1, with renin-inhibiting activity for use for hypertension and heart failure.

Description

The invention relates to that defined in claims 1 to 8 Object.

The C atoms substituted by R₂ and R₃ can be the R or S Own configuration. Compounds of the formula I are preferred wherein the C atoms substituted by R₂ and R₃ are those in the formula Iy have the specified configuration.

Preferred compounds of the formula I have the formula Iy

wherein

A ^y tert-butyloxycarbonyl, pivaloyl, bis (1-naphthylmethyl) acetyl, benzoyl or 1-adamantylcarbonyl, B ^y a bond, phenylalanine or β- cyclohexylalanine, C ^y histidine, norleucine, phenylalanine or leucine,

R₁ ^y hydrogen or methyl, R₂ ^y isobutyl, benzyl, cyclohexylmethyl or 1-adamantylmethyl, R₃ ^y hydroxy, amino or groups of the formula 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 a pyrrolidinyl, piperidinyl or morpholinyl group and
D ^y = NH, Ni-propyl, CH₂ or CH-i-propyl groups
mean.

Very particularly preferred compounds of the formula I have Formula I z

wherein
A ^z tert-butyloxycarbonyl or bis (1-naphthylmethyl) acetyl, B ^z a bond, phenylalaninyl or β- cyclohexylalaninyl, C ^z histidine, leucine or norleucine,

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 a pyrrolidinyl, piperidinyl or morpholinyl group and
D ^z = NH, or CH-isopropyl or CH₂ groups
mean.

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 additionally mean adamantyl, in particular it stands for cyclohexylethyl- or (1-adamantyl) ethyl, if it stands for ( C₆-₁₀) aryl is in particular phenyl or 1- or 2-naphthyl, preferably 1-naphthyl if it is a hereoaryl radical, it means in particular pyridyl, thienyl or furyl, if it is a heteroarylalkyl radical the heteroaryl part and the alkyl part have preferably the abovementioned meanings, if it represents a straight-chain or branched alkoxy radical, it means in particular ethoxy or tert. Butoxy and if it is (C₆-₁₀) aryl- (C _1-5 ) alkoxy it has in particular the meanings given above for aryl and alkyl and is preferably benzyloxy. A then represents the corresponding carbonyl compounds of R₆.

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

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

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 in importance of R₁₁ can, for example, an n-butyl, isobutyl, benzyl, 4-imidazolylmethyl, 2-methylthioethyl, cyclohexylmethyl or a pyridylmethyl Rest be.  

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

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

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 heteroarylalkyl radical, the heteroaryl radical means in particular pyridyl, thienyl or furyl radicals and the alkyl radical is as defined above.

If R₄ and R₅ represent a (C₆-₁₀) aryl (C₁-₅) alkyl radical, then mean this preferably a phenyl (C₁-₅) alkyl, especially one Benzyl radical, if they represent a heteroarylalkyl radical, means the heteroaryl part is in particular a pyridyl, thienyl or Furyl radical and alkyl represent the radicals indicated above. If R₄ and R₅ is (C₁-₅) alkyl, alkyl has the above Meanings.

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

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

The method for producing compounds described in claim 3 Formula I can be carried out in detail as follows:

The process according to process step a) for the preparation of compounds of the formula I a is advantageously carried out in such a way that the compounds of formula II with the compounds of formula III implemented using methods suitable for peptide couplings. For example the implementation in the presence of N, N'-dicyclohexyl carbodiimide or N-ethyl-N '- (dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide or 1-hydroxybenzotriazole take place, where as Solvent z. B. Dimethylformamide is used and the implementation at temperatures from 0 ° to preferably room temperature.

Alternatively, the reaction can also take place in the presence of 50% Propane phosphoric anhydride in methylene chloride in the presence of a Base such as B. N-methylmorpholine in a suitable solvent such as e.g. B. Dimethylformamide. The implementation is conveniently carried out at Temperatures from 0 ° C to room temperature, preferably at room temperature.

The reduction of the compounds of formula IV according to the process step b) is carried out, for example, by methods known per se by means of catalytic hydrogenation in the presence of a suitable catalyst e.g. B. palladium on activated carbon in a suitable solvent such as B. ethanol at temperatures of 0 ° to about 50 ° C preferably at room temperature and at pressures from 1 to 5 atm. preferably 1 atm.  

The reaction of compounds described in process step c) of the formula V with compounds of the formula VI is advantageously carried out in the presence of a base such as. B. triethylamine or N-methylmorpholine in an inert solvent such as e.g. B. tetrahydrofuran or dimethylformamide at temperatures from approx. 0 ° to approx. 50 ° C preferably at Room temperature. If Y stands for C = O, the implementation can also be done with the corresponding isocyanate R₄N = C = O take place, compounds of Formula I, wherein R₅ are hydrogen.

The process according to process stage d) is carried out by the action of a Oxidizing agents especially hydrogen peroxide on compounds of the Formula I e) in an acidic solvent, for example 100% Acetic acid at temperatures below room temperature is preferred approx. 10 ° C.

The process according to process stage e) is expediently carried out by exposure to sodium in liquid ammonia at room temperature from about -40 ° C to compounds of formula I g, the benzyl group is split off. The connection used here as the starting connections I g can, according to process c) above, from corresponding starting compounds getting produced.

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

The catalytic removal of a benzyl group from compounds of the Formula I j) according to process stage g) is advantageously carried out under Use of palladium (10% on activated carbon) as a catalyst in one  suitable solvents such as. B. ethanol at a hydrogen pressure from 1 to 5 atmospheres at temperatures from room temperature to approx. 60 ° C, preferably at room temperature.

The reaction of an azlactone of formula IX with compounds of Formula X according to process stage h) is carried out using from methods known in the literature, e.g. B. in a suitable solvent such as B. tetrahydrofuran or chloroform, optionally with addition an acylation catalyst such as e.g. B. 4-dimethylaminopyridine Temperatures from 0 ° to approx. 80 ° C, preferably at room temperature or 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 known For example, as described in the examples below getting produced.

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

If the compounds of the formula I contain an acidic or basic group, if necessary, they can also form salts, for example Metal salts such as sodium salts or acid addition salts such as hydrochloride.

In the following examples, all temperatures are given in ° C and are not corrected.  

Example 1 (2 R, 3 S) -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) were added at 0-5 °. After ½ h, 3.7 g of N-tert-Boc-cyclohexylalaninal are added all at once. After ½ h, the reaction mixture is poured onto ether / 2 N aqueous tartaric acid, separates the org. Phase, dries with magnesium sulfate and evaporates the solvent in vacuo. The crude product is on silica gel chromatographed with ether / hexane 30-70%. The main product is obtained as a colorless gel that solidifies on standing. M.p. 86-87 °. The (2 R, 3 S) isomer is obtained as a by-product.

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

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

Example 3 (2 R, 3 S) -3- (tert-butyloxycarbonylamino) -4-cyclohexyl-2- azido-butanesulfonic acid dimethylamide

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

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

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

Example 5 (2 R, 3 S) -3- (tert-butyloxycarbonylamino) -2-hydroxy-5- methyl hexanesulfonic acid dimethyl amide

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

Example 6 (3 S, 4 S) -4- (tert-butyloxycarbonylamino) -5-cyclohexyl-3- hydroxypentane sulfonic acid dimethylamide

1 g of methanesulfonic acid dimethylamide are dissolved in 10 ml of tetrahydrofuran. 5.1 ml of n-butyllithium are added dropwise at 0-5 °. After ½ h, 1 g (2 S) -2 - ((1 S) -tert-Butyloxycarbonylamino-2-cyclohexyl-ethyl) oxirane added. After 20 min. distributed between ether and 2 N aqueous Tartaric acid, separates the org. Phase, dries and evaporates. The raw product is recrystallized from methylene chloride / hexane. M.p. 110-111 ° C.

Example 7 (1 S, 3 S, 4 S) -4- (tert-butyloxycarbonylamino) -5-cyclohexyl- 3-hydroxy-1-isopropylpentanesulfonic acid dimethylamide

Analogously to Example 6, 0.4 g of dimethyl isobutanesulfonate is obtained from 1.5 ml n-butyllithium and 200 mg epoxide the title compound as a mixture of diastereomers (approx. 1: 5).  

Example 8 (2 R, 3 S) -3- (N-BOC-phenylalanyl-phenylalanyl)) amido 4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide

330 mg of the sulfonamide 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 2 N 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. The mixture is cooled to 0-5 °, 170 mg of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for about 15 hours. The precipitated dicyclohexylurea is filtered off and the crude product is chromatographed on silica gel with ether / methylene chloride 50-90%. [ α ] = -29.1 ° (c = 0.6 in CH₂CH₂).

Example 9 (2 R, 3 S) -3- (N-BOC- β -cyclohexylalanyl- β- cyclohexyl alanyl) 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 over 24 hours at 40 ° / 2 atm hydrogen over Rh-Alox (5%). The catalyst is filtered off and the product is lyophilized from benzene. [ a ] = -46.1 ° ( c = 0.6 in CH₂Cl₂).

Example 10 (2 R, 3 S) -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. [ α ] = -32.4 ° ( c = 0.2 in CH₂Cl₂).

Example 11 (2 R, 3 S) -3- (N-BOC- β- cyclohexylalanyl- β- 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. [ α ] = -38.2 ° ( c = 0.1 in CH₂Cl₂).

Example 12 (2 R, 3 S) -3- (N-BOC-phenylalanyl-histidyl) amido-4-cyclo- hexyl-2-hydroxybutanesulfonic 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: [ α ] = -32.2 ° ( c = 0.2 in CH₂Cl₂ / MeOH 9: 1; Diastereomers B: [ α ] = -26 , 0 ° ( c = 0.6 in CH₂Cl₂ / MeOH 9: 1).

Example 13 (2 R, S) -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. [ α ] = -43.9 ° ( c = 0.2 in CH₂Cl₂).

Example 14 (2 R, 3 S) -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 dicycloxycarbodiimide. The crude product is dissolved in ethanol and 4 hours at 20 ° / 1 atm. Hydrogen hydrogenated over Pd / C (10%). Chromatography on silica gel with MeOH / CH₂Cl₂ 0-5% gives the title compound [ α ] = -37.1 ° ( c = 0.2 in CH₂Cl₂) and Boc-Phe-Nle-SO₂-deoxychatineNMe₂ [ α ] = -26.4 ° ( c = 0.2 in CH₂Cl₂).

Example 15 (2 R, 3 S) -3- (N-BOC-phenylalanylyl-norleucyl) amido-4- (1,4- dioxaspiro [4,5] undec-8-yl) -2-hydroxy-butanesulfonic acid dimethyl amid

Analogously to Example 8, 335 mg of sulfonamides from Example 2 are reacted with 290 mg of Boc-Phe-NleOH, 200 mg of hydroxybenzotriazole and 158 mg of dicyclohexylcarbodiimide. [ α ] = -32.6 ° ( c = 0.2 in CH₂Cl₂).

Example 16 (2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4- (4'oxocyclohexyl) - 2-hydroxybutanesulfonic acid dimethylamide

200 mg of the product from Ex. 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. [ α ] = -45.6 ° ( c = 0.2 in CH₂Cl₂).

Example 17 (2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido 4- (4'-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 minutes and then partitioned between ethyl acetate and 2 N aqueous sodium carbonate solution. [ α ] = -31.1 ° ( c = 0.2 in CH₂Cl₂).

Example 18 (3 S, 4 S) -4- (N-BOC-phenylalanyl-norleucyl) amido-5-cyclohexyl- 3-hydroxy-pentanesulfonic acid dimethylamide

Analogously to Example 8, 135 mg of sulfonamides from Example 6 are reacted with 75 mg of Boc-Phe-Nle-OH, 70 mg of hydroxybenzotriazole and 52 mg of dicyclohexylcarbodiimide. [ α ] = -10 ° ( c = 0.2 in CH₂Cl₂).

Example 19 (1 S, 3 S, 4 S) -4- (N-BOC-phenylalanyl-norleucyl) amido 5-cyclohexyl-3-hydroxy-1-isopropylpentanesulfonic 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: [ α ] = -36.4 ° B: [ α ] = -10.0 ° ( c = 0.1 in CH₂Cl₂).

Example 20 (2 R, 3 S) -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. [ α ] = -43.7 ° ( c = 0.2 in CH₂Cl₂).

Example 21 (2 R, 3 S) -3- [N- (BIS- (1-naphthylmethyl) acetyl) norleucyl] - amido-2-hydroxy-5-methyl-hexanesulfonic acid dimethylamide

Analogously to Example 8, 100 mg of the diastereomer mixture from Example 5 with 70 mg BocPheNleOH, 70 mg hydroxybenzotriazole and 51 mg dicyclohexylcarbodiimide. The product is obtained as an inseparable mixture of diastereomers (approx. 2: 1).

Example 21 (2 S, 3 S) - and (2 R, 3 S) -3- (BOC-phenylalanyl-norleucyl) - amido-4-cyclohexyl-1-isobutyl-sulfamoylamino-2-butanol

A mixture of 273 mg (2 S, 3 S) -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 of isobutylsulfamoyl chloride in 1 ml of dioxane are 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 solid, [ α ] = - 7 ° ( c = 0.5 in dichloromethane).

Starting from (2 R, 3 S) -3- (Boc-phenylalaninyl-norleucinyl) amido-1-amino-4-cyclohexyl-2-butanol, (2 R, 3 S) -3- (Boc- Phenylalaninyl-norleucinyl) -amido-4-cyclohexyl-isobutyl-sulfamoylamino-2-butanol as an amorphous solid, [ α ] = -3.2 ° ( c = 0.5 in dichloromethane).

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

• a) (3 S) -3-BOC-amido-4-cyclohexyl-1-nitro-2-butanone
  (Intermediate 1)
  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- β -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) (2 S, 3 R) - and (2 R, 3 S) -3-BOC-amino-4-cyclohexyl-1-nitro-2-butanol
  (Interconnections 2 A and 2 B)
  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 the isomer 2 B of mp. 116-118 ° (dec.). Chromatography of the mother solution on silica gel using hexane / ether (2: 1) as the eluent gives the isomer 2A as an oil.
  Rf values (silica gel, hexane / ether 2: 1): 2 A, 0.136; 2 B, 0.106.
• c) (2 S, 3SO) and (2 R, 3 S) -1-amino-3-BOC-amino-4-cyclohexyl-2-butanol
  (Interconnections 3 A and 3 B)
  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 were added in small portions over a period of 1 hour Ammonium formate added. After stirring for 17 hours at room temperature, the suspension is filtered through Celite and the filtrate 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 the intermediate 3 A of mp 165-166 ° (dec.) Is obtained.
• The hydrogen oxalate of intermediate 3 B, which in analog How is obtained from the intermediate compound 2 B, melts 137-138 ° (dec.)
• d) (2 S, 3 S) - and (2 R, 3 S) -3-BOC-amino-1-Cbz.-amino-4-cyclohexyl-2-butanol
  (Interconnections 4 A and 4 B)
  4.18 ml of benzyl chloroformate are added to a solution of 5.28 ml of triethylamine and 6.3 g of intermediate 3 A, which was obtained according to the above method, in 120 ml of dichloromethane at a temperature of 2 to 5 ° and the solution obtained stirred at room temperature for 30 minutes. It is then diluted with dichloromethane and washed with 0.25 N 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 the intermediate 4 A as a slightly yellowish oil.
• Using the same method, one obtains from Intermediate 3 B, the intermediate 4 B as an oil.  
• e) (2 S, 3S) and (2 R, 3 S) -3-amino-1-Cbz-amino-4-cyclohexyl-2-butanol
  (Interconnections 5 A and 5 B)
  8.06 g of the intermediate 4 A 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 the intermediate 5 A is obtained as a colorless foam.
• Using the same procedure, one obtains from the Intermediate 4 B the hydrochloride of intermediate 5 B.
• f) (2 S, 3S) and (2 R, 3 S) -3- (BOC-phenylalaninyl-norleucinyl) amino-1-Cbz-amino-4-cyclohexyl-2-butanol
  (Interconnections 6 A and 6 B)
  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 5 A in dimethylformamide, and the clear solution obtained is added Stirred at room temperature overnight, then concentrated in vacuo, taken up in dichloromethane and the dichloromethane solution washed with 0.25 N 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 from the interconnect 5 B, the intermediate compound 6 B is obtained from the mp. 150-151 ° (dec.).
• g) (2 S, 3S) and (2 R, 3 S) -1-amino-3- (BOC-phenylalaninyl-norleucinyl) - amino-4-cyclohexyl-2-butanol
  (Interconnections 7 A and 7 B)
  7.0 g of the intermediate 6 A 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 7 A is obtained as colorless crystals of mp 140-141 °, [ α ] = -38.5 ° ( c = 1 in methanol).
• Using the same process, starting from intermediate 6 B, intermediate 7 B is obtained as colorless crystals of mp. 168-169 ° (decomp.), [ Α ] = -25.6 ° ( c = 1 in methanol).

Example 23: (2 S, 3 S) -3- (BOC-phenylalaninyl-norleucyl) amido-4-cyclohexyl- 1-dimethylsulfamoylamino-2-butanol

Analogously to Example 22, using dimethylsulfamoyl chloride instead of isobutylsulfamoychloride, gives the title compound, [ α ] = -11 ° ( c = 0.1 in CH₂Cl₂).

Example 24: (2 RS, 3 S) -3- (N-benzoyl-dehydrophenylalaninyl-norleucyl) - amido-1-dimethylsulfamoyl-amino-5-methyl-2-hexanol

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

Example 25: N- (3-Cyclohexylpropionyl-norleucine

A solution of 1.31 g of norleucine in 22 ml of 1N aqueous sodium hydroxide is cooled with ice with a solution of 1.92 g of 3-cyclohexylpropionoyl chloride in 22 ml ether and the mixture at 0 ° C for 1 h touched. The mixture is then acidified with 0.25 N hydrochloric acid Mixture extracted 2 × with ether, the combined organic phases washed with saturated saline, dried over sodium sulfate and evaporated in vacuo. Crystallization of the residue Ether / hexane gives the title compound of mp. 138-139 ° C.  

Example 26: (2 S, 3 S) -3- (3-cyclohexyl-propionyl-norleucyl) amido-1- Cbz-amino-4-cyclohexyl-2-butanol

Analogously to Example 22 f), 3-cyclohexyl propionyl-norleucine (Ex. 25) instead of BOC-Phe-Nle-OH, the Title compound, as an amorphous substance.

Example 27: (2 S, 3 S) -3- (3-cyclohexyl-propionyl-norleucyl) amido-1- amino-4-cyclohexyl-2-butanol

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

Example 28: (2 S, 3 S) -3- (3-cyclohexyl-propionyl-norleucyl) amido-4- cyclohexyl-1-dimethylsulfamoylamino-2-butanol

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

Intermediates 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 was evaporated, dissolved in methanol and with 200 mg of sodium hydroxide  (dissolved in water) added. After 2 hours you acidify 2 N hydrochloric acid, extracted with methylene chloride, dried and evaporate. The crude product is recrystallized from methylene chloride / hexane. Mp 157-159 °.

Bis (1-naphthylmethyl) acetic acid

4.6 g of sodium are dissolved in 100 ml of ethanol. Add 16 g Diethyl malonate and 40 g of 1-chloromethylnaphthalene. Then turns 24 Heated at reflux, cooled and the precipitated salts solved 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 raw product is in a mixture of 50 ml of water, 700 ml of ethanol and 20 g of potassium hydroxide entered and boiled for 4 hours at reflux. Then it cools down acidified with hydrochloric acid conc and extracted with ether. The Ether solution is dried, evaporated and the residue on Heated 180-200 °. After cooling to room temperature, the glassy Residue dissolved in methylene chloride and precipitated with hexane. M.p. 171-172 °.

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

6 g of sodium hydride dispersion (80% in white oil) are mixed suspended from 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 added dropwise in 50 ml of dimethyl sulfoxide. After 10 minutes, add 50 ml t-Boc cyclohexylalaninal (0.54 M in toluene), and leave at room temperature heat. The reaction mixture is diluted with ice water, the org. Phase separated, washed 4 × with water, over magnesium sulfate  dried 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). M.p. 58-59 °.

Example 29: (2 R, 3 S) -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 BOC-Phe-Nle-OH, the title compound, [ α ] -25.7 ° ( c = 1 in methanol).

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

Example 30: (2 S, 3 S) -3- (N-BOC- β- Cyclohexylalanyl-histidyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide

Analogously to Example 8, 190 mg of BOC-SO₂-Chatin-NMe₂ (Example 1) 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. [ α ] = -38.9 ° ( c = 0.2 in methylene chloride).

Example 31: (2 S, 3 S) -3- [N- (BIS- (1-naphthylmethyl) acetyl) histidyl] - amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide

Analogously to Example 8, 80 mg of BOC-SO₂-Chatin-NMe₂ (Example 1) with 100 mg of N- (bis- (7-naphthylmethyl) acetyl)) - Nle-OH, in the presence of 50 mg of hydroxybenzotriazole and 44 mg of dicyclohexylcarbodiimide implemented and the crude product chromatographed with methanol / methylene chloride 1-10%. [ α ] = -17.1 ° ( c = 0.2 in methylene chloride).

Example 32: ((2 R3 S) -3- [N- (BOC- β - (2,1,3-Benzoxadiazol-4-yl) alanyl-norleucyl] amido-4-cyclohexyl-2-hydroxyl-2-butanesulfonic acid dimethylam id

Analogously to Example 8, 96 mg of BOC-CO₂-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. [ α ] = -52.4 ° ( c = 0.2 in methylene chloride).

Example 33: (2 R, 3 S) -3 - ((N- [2-methoxy-poly (2-ethoxy) acetyl] phenyl- alanyl-norleucyl)) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimet-hylamide

35 mg H-Phe-His-SO₂-Chatin-NMe₂ with 60 mg of an oligomer mixture of polyethylene glycolic acids (MG∼350), in the presence of 13 mg dicylohexylcarbodiimide and 10 mg hydroxybenzotriazole in methylene chloride implemented and by chromatography on silica gel with methanol / Methylene chloride 5-10% cleaned.  

Example 34: (2 R, 3 S) -3- [N- (BIS- (1-naphthylmethyl) acetyl) methionyl] - amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide

Analogously to Example 8, 165 mg of BOC-SO₂-Chatin-NMe₂ (Example 1) are reacted with 203 mg of N- (bis- (7-naphthylmethyl) acetyl) -met-OH, in the presence of 115 mg of hydroxybenzotriazole and 90 mg of dicyclohexylcarbodiimide . [ α ] = -45.3 ° ( c = 0.1 in CH₂Cl₂).

Example 35: (2 R, 3 S) -3- [N- (BIS- (1-naphthylmethyl) acetyl) methion- (D, L-S-oxide) yl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethyl amide

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

Example 36: (2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido 4- (1-adamantyl) -2-hydroxy-butanesulfonic acid dimethylamide

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

The starting compound BOC-SO₂-Adatin-NMe₂ (60:40 mixture of diastereomers) is analogous to Example 1 from N-tert. -BOC-Adamantylalaninal and Methanesulfonic acid dimethylamide produced.

Example 37: (2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido 5,5-dimethyl-2-hydroxy-hexanesulfonic acid dimethylamide

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

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

Example 38: (2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido 4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide

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. [ α ] = -30.0 ° ( c = 0.28 in ethanol).

Example 39: (2 R, 3 S) -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. [ α ] = -32.6 ° ( c = 0.27 in ethanol).

Example 40: (2 R, 3 S) -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 is obtained, which is prepared analogously to Example 1 from BOC-cyclohexylalaninal and 4-benzyl-1-methylsulfonylpiperazine, and BOC-Phe-Nle-OH Title compound [ α ] = -25.6 ° ( c = 0.32 in ethanol).

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

Example 41: (2 R, 3 S) -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 (Ex. 40) in 120 ml of 100% acetic acid with 20 mg of 10% palladium Activated carbon added and for 6 hours at room temperature and Normal pressure hydrogenated. The reaction mixture is filtered through Hyflo  and evaporated to dryness. The residue is in an ice-water mixture dissolved, made slightly alkaline with 10% soda solution, with methylene chloride extracted, dried over sodium sulfate, filtered and evaporated to dryness.

The residue is chromatographed on silica gel with methylene chloride containing 10% ethanol. [ α ] = -22.5 ° ( c = 0.20 in ethanol).

Example 42: (2 R, 3 S) -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-chartin- (4-acetyl) -piperazine and BOC-Phe-Nle-OH. [ α ] = -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 (Ex. 40), by Hydrogenation analogous to Example 41 and implementation of the BOC-SO₂- obtained Chatin-piperazine, analogous to literature examples, with acetyl chloride in Presence of triethylamine in methylene chloride at 0 °.

Example 43: (2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido 4-cyclohexyl-2-hydroxybutanesulfonic acid- [4- (2,5,8,11- tetraoxadodecanyl) carbonyl] piperazinamide

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. [ α ] = -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 (Ex. 42) with 260 mg 2,5,8,11-tetraoxadodecanylcarboxylic acid, in the presence of 240 mg dicylohexylcarbodiimide and 320 mg hydroxybenzotriazole in 10 ml N, N-dimethylformamide.

Example 44: (2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido 4-cyclohexyl-2-hydroxybutanesulfonic 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. [ α ] = -25.0 ° ( c = 0.44 in ETOH).

Example 45: (2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido 4-cyclohexyl-2-hydroxy-butanesulfonic acid morpholinamide

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

Example 46: (2 R, 3 S) -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. [ α ] = -14.1 ° ( c = 0.17 in pyridine).

Example 47: (2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy- 5-methylmercapto-pentanesulfonyl acid dimethylamide

Analogously to Example 8, the title compound is obtained from BOC-SO₂-mettin-NMe₂ and BOC-Phe-Nle-OH. [ α ] = -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: (2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-2- hydroxy-5-methylsulfinyl-pentanesulfonic acid dimethylamide

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

Example 49: (2 R, 3 R) -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. [ α ] = -32.0 ° ( c = 0.40 in ethanol).

BOC-S-Benzyl-L-cysteinal is, analogous to literature examples, by Reaction of BOC-5-benzyl-L-benzyl-L-cysteine with 3,5-dimethylpyrazole in the presence of dicyclohexylcarbodiimide in chloroform and reduction of resulting BOC-5-benzyl-L-cysteine-3,5-dimethylpyrazolids with Diisobutylaluminum hydride made in toluene.

Example 50: (2 R, 3 R) -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 (Ex. 49) in 8 ml of tetrahydrofuran and 20 ml of liquid ammonia is mixed with 60 mg of sodium in portions at -40 ° C. The blue-colored reaction mixture is stirred for a further 15 minutes at -40 ° 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. [ a ] = -33.6 ° ( c = 0.30 in ethanol).

Example 51: (2 R, 3 R) -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 (Ex. 49) in 8 ml of tetrahydrofuran and 20 ml of liquid ammonia is, as described in Example 50, 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 °, the mixture is stirred at -40 ° for a further 10 minutes and then worked up and purified as described in Example 50. The title connection results. [ α ] = -37.2 ° ( c = 0.36 in ethanol).

Example 52: (2 R, 3 S) -3- [N- (2,3,4,6-Tetra-0-acetyl- β- D-glucosyl-1-0) -isobuturyl-phenylalanyl-norleucyl] amido-4-cyclohexyl -2-hydroxybutanesulfonic acid dimethylamide

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

The starting compound (2,3,4,6-tetra-0-acetyl- β- glucosyl-1-0) isobutyric acid is, analogous to literature examples, by condensation of α- D-acetobromoglucose and 2-hydroxy-2-methylpropionic acid benzyl ester and subsequent Hydrogenation with 10% palladium on carbon as a catalyst.

Example 53: (2 R, 3 S) -3- [N- ( β -D-Glucosyl-1-00) -isobuturyl-phenylalanyl-norleucyl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide

A solution of 150 mg (2,3,4,6-tetra-0-acetyl- β- D-glucosyl-1-0) 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. [ α ] = -41.6 ° ( c = 0.30 in ethanol).

Example 54: (2 S, 3 S) -3- (N-BOC-phenylalaninyl-histidyl) amido-1- (n-butylcarbamoylamino) -4-cyclohexyl-2-butanol

402 mg BOC-Phe-His-OH, 322 mg (2 S, 3 S) -3-amino-1- (n-butylcarbamoylamino) -4-cyclohexyl-2-butanol hydrochloride (intermediate 8 A) and 0 , 28 ml of triethylamine in 6.7 ml of dimethylformamide are mixed with ice cooling with 0.23 ml of diphenylphosphoryl azide, the mixture is stirred for 19 hours at room temperature 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. 141-2 ° C, [ α ] = -11.8 ° ( c = 1 in methanol).

Example 55: (2 R, 3 S) -3- (N-BOC-phenylalaninyl-histidyl) amido-1- (n-butylcarbamoylamino) -4-cyclohexyl-2-butanol

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

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

• a) (3 S) -3-BOC-amido-4-cyclohexyl-1-nitro-2-butanone
  (Intermediate 1 D)
  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- β -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 D) as colorless crystals of mp 97-98 °.
• b) (2S, 3 R) - and (2 R, 3 S) -3-BOC-amino-4-cyclohexyl-1-nitro-2-butanol
  (Intermediate products 9 A and 9 B)
  2.27 g of sodium borohydride are added in small portions to an ice-cooled solution of 18.9 g of the intermediate 1 D) 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 9 B of mp. 116-118 ° (dec.). Chromatography of the mother solution on silica gel using hexane / ether (2: 1) as eluent gives the isomer 9 A as an oil. Rf values (silica gel, hexane / ether 2: 1): 9 A, 0.136; 2 B, 0.106.
• c) (2 S, 3S) and (2 R, 3 S) -1-amino-3-BOC-amino-4-cyclohexyl-2-butanol
  (Intermediate products 10 A and 10 B)
  To a mixture of 7.5 g of intermediate 9 A, 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 in small portions over 1 hour Ammonium formate added. After stirring for 17 hours at room temperature, the suspension is filtered through Celite and the filtrate 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 the intermediate compound 10 A of mp 165-166 ° (dec.) Is obtained.
• The hydrogen oxalate of intermediate 10 B, which in analog Is obtained from the intermediate compound 9 B, melts 137-138 ° (dec.)
• d) (2 S, 3 S) -3-BOC-amino-1- (n-butylcarbamoyl) amino-4-cyclohexyl-2-butanol
  (Intermediate 11 A)
  A solution of 1.15 g of the intermediate 10 A (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, 10 B (free base) (2 R, 3 S) -3-BOC-amino-1- (n-butylcarbamoyl) amino-4-cyclohexyl-2-butanol (Intermediate 11 B) as a raw foam.  
• e) (2 S, 3 S) -3-amino-1- (n-butylcarbamoyl) amino-4-cyclohexyl-2-butanol hydrochloride
  (Intermediate 8 A)
  1.39 g of the crude intermediate 11 A 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, 11 B (2 R, 3 S) -3-amino-1- is obtained from the intermediate product. (n-butylcarbamoyl) amino-4-cyclohexyl-2-butanol hydrochloride (Intermediate 8 B) as an amorphous residue.

Example 56: (2 S, 3 S) -3- (N-BOC-phenylalaninyl-norleucyl) amido-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol

A solution of 273 mg (2 S, 3 S) -1-amino-3- (N-BOC-phenylalaninyl-norleucyl) amido-4-cyclohexyl-2-butanol hydrochloride (intermediate 12 A) in 10 ml of anhydrous tetrahydrofuran 0.055 ml of isopropyl isocyanate is added at 0 °, 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 ° C (dec.), [ Α ] = -16.2 ° ( c = 1 in methanol).

The intermediate 12 A used in this example can be as follows getting produced:  

• a) (2 S, 3 S) - and (2 R, 3 S) -3-BOC-amino-1-Cbz.-amino-4-cyclohexyl-2-butanol
  (Intermediate products 13 A and 13 B)
  4.18 ml of benzyl chloroformate are added to a solution of 5.28 ml of triethylamine and 6.3 g of intermediate 10 A, which was obtained according to the procedure in Example 55, in 120 ml of dichloromethane at a temperature of 2 to 5 ° and the solution obtained stirred at room temperature for 30 minutes. It is then diluted with dichloromethane and washed with 0.25 N 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 the intermediate 13 A as a slightly yellowish oil.
• Using the same procedure, one obtains from Intermediate 10 B, the intermediate 13 B as an oil.
• b) (2 S, 3S) and (2 R, 3 S) -3-amino-1-Cbz-amino-4-cyclohexyl-2-butanol
  (Intermediate products 14 A and 14 B)
  8.06 g of the intermediate 13 A 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 14 A is obtained as a colorless foam.
• Using the same procedure, one obtains from the Intermediate 13 B is the hydrochloride of intermediate 14 B.
• c) (2 S, 3 S) - and (2 R, 3 S) -3- (BOC-phenylalaninyl-norleucinyl) amino-1-Cbz-amino-4-cyclohexyl-2-butanol
  (Intermediate products 15 A and 15 B)
  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 14 A in dimethylformamide, and the clear solution obtained is added Stirred at room temperature overnight, then concentrated in vacuo, taken up in dichloromethane and the dichloromethane solution washed with 0.25 N 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 product 15 A thus obtained melts at 167-168 ° C. (dec.).
• Using the same procedure from the intermediate 14 B gives the intermediate 15 B of mp. 150-151 ° (Dec.).
• d) (2 S, 3 S) and (2 R, 3 S) -1-amino-3- (BOC-phenylalaninyl-norleucinyl) - amino-4-cyclohexyl-2-butanol
  (Intermediate products 16 A and 16 B)
  7.0 g of the intermediate 15 A 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 16 A is obtained as colorless crystals of mp 140-141 °, [ α ] = -38.5 ° ( c = 1 in methanol).
• Using the same process, starting from intermediate 15 B, intermediate 16 B is obtained as colorless crystals of mp. 168-169 ° (dec.), [ Α ] = -25.6 ° ( c = 1 in methanol).

Example 57: (2 S, 3 S) -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 (2 S, 3 S) -3-amino-1- (isopropylcarbamoyl) amino-2-butanol-hydrochloride and 150 ml of 1-hydroxybenzotriazole in 2.6 ml of dimethylformamide is mixed at 0 ° C with 104 mg of N, N'-dicyclohexylcarbodiimide and 0.07 ml of triethylamine, stirred for 1 hour at 0 °, then for 15 hours at RT, cooled again to 0 ° C and the dicyclohexylurea formed is filtered off . The filtrate is evaporated under high vacuum, the residue is taken up in methylene chloride and washed successively with 0.25 N 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, [ α ] = -18.0 ° ( c = 1 in methanol).

The intermediates used in Example 57 can be as follows getting produced:

• 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 °, stirred at 0 ° for 1 hour and then acidified with 0.25 N hydrochloric acid and extracted 2 × with ether. 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 ° C (dec.).
• b) (2 S, 3 S) -3-amino-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol-HCl
  Analogously to Example 55 d), using intermediate 10 A and isopropyl isocyanate, (2 S, 3 S) -3-BOC-amino-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol is obtained. Analogously to Example 55 e), the BOC protective group is split off from the product obtained, and the amorphous title compound is thus obtained.

Example 58: (2 S, 3 S) -3- (N-BOC-phenylalaninyl-norleucyl) amido-1- [bis- (dimethylamino)] phosphorylamido-4-cyclohexyl-2-butanol

A solution of 273 mg (2 S, 3 S) -3- (N-BOC-phenylalaninyl-norleucyl) - amido-1-amino-4-cyclohexyl-2-butanol (intermediate 16 A, see Example 56 d)) 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 0.25 N 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 ° C, (dec.), [ Α ] = -27.7 ° ( c = 1 in chloroform).

Example 59 (2 S, 3 S) -3- (N-BOC-phenylalaninyl-norleucyl) -1- (N-benzyl- 4-piperidinocarbamoyl) amino-4-cyclohexyl-2-butanol

Analogously to Example 56, using N-benzyl-4-piperidino-isocycanate instead of isopropyl isocyanate, the title compound, mp. 166-8 ° C., [ α ] = -13.5 ° ( c = 1 in methanol) .

Example 60 (2 S, 3 S) -3- (N-BOC-phenylalaninyl-norleucyl) amido-1- (4- piperidinocarbamoyl) amino-4-cyclohexyl-2-butanol

200 mg of the title compound from Example 59 in 20 ml of methanol are hydrogenated in the presence of palladium (10% on activated carbon) for 20 hours at room temperature in a hydrogen atmosphere, the suspension is then filtered through Celite and the filtrate is evaporated. Crystallization of the residue with methanol-ether gives the title compound, mp. 173-5 °, [ α ] = -15.5 ° ( c = 1 in methanol).

Example 61: (2 S, 3 S) -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 isobutyl isocyanate, the title compound, mp. 157-8 ° C, [ α ] = -10.0 ° ( c = 2 in methanol).

Example 62: (2 S, 3 S) -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 (2 S, 3 S) -3-amino-1- (isopropylcarbamoyl) -isopropylamino-4-cyclohexyl-2-butanol (intermediate 17) and 150 mg 1 Hydroxybenzotriazole in 3.4 ml of dimethylformamide is mixed at 0 ° C with 99 mg of N-ethyl-N '- (3-dimethylamino-propyl) carbodiimide hydrochloride and 0.07 ml of triethylamine, one hour at 0 ° C and 20 hours stirred at room temperature and then evaporated on a Rotavapor at 30 ° C. The residue is taken up in methylene chloride, washed successively with cold 0.25 N hydrochloric acid, saturated sodium hydrogen carbonate solution and water, dried over sodium sulfate and evaporated. Chromatography of the residue (silica gel, 5 bar, methylene chloride-ethanol) gives the title compound, [ α ] = -5.0 ° ( c = 1 in methanol).

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

• a) (2 S, 3 S) -3-N-BOC-amino-1-isopropylamino-4-cyclohexyl-2-butanol
  A mixture of 3.26 g of the intermediate 10 A (see example 55 c), 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) (2 S, 3 S) -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 with 0 ml of isopropyl isocyanate at 0 °, 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.

Example 63: (2 S, 3 S) -3- [N- (1-Adamantyl-propionyl) -norleucyl] -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., [ α ] = -24.5 ° ( c = 1 in dimethylformamide).

Example 64: (2 S, 3 S) -3- (N-BOC-norleucyl) amido-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol

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

Example 65: (2 S, 3 S) -3- (norleucyl) amido-1- (isopropylcarbamoyl) amino- 4-cyclohexyl-2-butanol hydrochloride

339 mg of the product from Example 64 are made analogously to Example 55 e) with 3.4 ml glacial acetic acid / conc. Hydrochloric acid treated and worked up. Man receives the title compound as a colorless foam.

Example 66: (2 S, 3 S) -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 65, 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 Chloroform is mixed with a 4-dimethylamino-pyridine spatula, refluxed for 4 hours and then evaporated. Chromatography of the residue (silica gel, 6 bar, ethyl acetate) gives the amorphous title compound, [ α ] = -58.2 ° ( c = 1 in methanol).

Example 67: (2 S, 3 S) -3- [N- (bis (1-naphthylmethyl) acetyl) norleucyl] - amino-4-cyclohexyl-1- (isopropylcarbamoyl) amino-2-butanol

Analogously to Example 57, using N- (bis (1-naphthylmethyl) acetyl) norleucine instead of N- (3-cyclohexylpropionyl) norleucine, the title compound, mp. 173-4 °, [ α ] = -52.0 ° ( c = 1 in methanol).

Example 68: (2 S, 3 S) -3- (N-cyclopentyl-carbonyl-phenylalaninyl- norleucyl) amino-4-cyclohexyl-1- (isopropyl-carbamoyl) amido-2-butanol

Coupling of N-cyclopentylcarbonyl-phenylalanine and (2 S, 3 S) -3- (norleucyl) amido-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol-hydrochloride (Example 65) analogously to Example 57 the title compound, m.p. 213-5 ° (dec.), [ α ] = -18.2 ° ( c = 0.5 in methanol).

Example 69: (2 S, 3 S) -3- (N-BOC-phenylalaninyl-histidyl) amino-1- (isopropylcarbamoyl) 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, [ α ] = -10.8 ° ( c = 1 in methanol) .

The following abbreviations are used in the previous examples used:

SO₂Adatin (2 R, 3 S) -4- (1-adamantyl) -3-amino-2-hydroxy-butanesulfonic acid
SO₂Chatin (2 R, 3 S) -3-amino-4-cyclohexyl-2-hydroxy-butanesulfonic acid
SO₂Sta (2 R, 3 S) -4-amino-2-hydroxy-5-methyl-hexanesulfonic acid
SO₂Aminochatin (2 R, 3 S) -2,3-diamino-4-cyclohexyl-butanesulfonic acid
SO₂Desoxychatin (3 S) -3-amino-4-cyclohexyl-butanesulfonic acid
SO₂-dioxolane (2 R, 3 S) -3-amino-4- (1,4-dioxaspiro [4,5] undec-8-yl) -2-hydroxybutanesulfonic acid
SO₂-onChatin (2 R, 3 S) -3-amino-4- (4'-oxocyclohexyl) -2-hydroxy-butanesulfonic acid
SO₂-olChatin (2 R, 3 S) -3-amino-4- (4'hydroxycyclohexyl) -2-hydroxybutanesulfonic acid
SO₂ (2-naphthin) (2 R, 3 S) -3-amino-2-hydroxy-4- (2-naphthyl) butanesulfonic acid
SO₂-neotin (2 R, 3 S) -3-amino-5,5-dimethyl-2-hydroxy-hexanesulfonic acid
Achps (3 S, 4 S) -4-amino-5-cyclohexyl-3-hydroxy-pentanesulfonic acid
Achipx (1 S, 3 S, 4 S) -4-amino-5-cyclohexyl-3-hydroxy-3-hydroxy-1-isopropylpentanesulfonic acid
SO₂-mettin (2 R, 3 S) -3-amino-5-methylmercapto-2-hydroxy-pentanesulfonic acid
SO₂-mettin (O) (2 R, 3 S) -3-amino-5-methylsulfinyl-2-hydroxypentanesulfonic acid
Cys (BZL) (OH) CH₂SO₂ (2 R, 3 R) -3-amino-4-benzylmercapto-2-hydroxybutanesulfonic acid
Cys (Et) (OH) CH₂SO₂ (2 R, 3 R) -3-amino-4-äthylmercapto-2-hydroxy-butanesulfonic acid
Cys (OH) CH₂SO₂ (2 R, 3 R) -3-amino-4-mercapto-2-hydroxybutanesulfonic acid

The compounds according to the invention have pharmacological activity on. They can be used as a medicine.

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 depends of course on the overall petid structure. The above compounds, which are particularly suitable as inhibitors of renin activity, bring about a 50% inhibition of the enzyme activity of pure human renin according to the method of F. Cumin et al. On the human synthetic tetradecapeptide substrate at a concentration of 10 ^-5 M to 10 ^-11 M. (Bioch. Biophys. Acta 913, 10-19 (1987).

In the "antibody trapping" method by K. Poulsen and J. Jørgensen (J. Clin. Endocrin. Metab. 39 [1974] 816-825), they inhibit human plasma arena activity at a concentration of 10 ^-5 M to 10 ^-11 M.

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

As renin inhibitors, they are e.g. B. for use in prophylaxis and Treatment of hypertension and heart failure ("congestive heart failure ").

For the above applications, the dose to be administered depends on the compound used, the route of administration and the desired Treatment. Generally will be satisfactory Get results if the compounds are in a daily dose from 0.02 mg / kg to approx. 10 mg / kg animal body weight. For larger mammals, the recommended daily dose is about 1 mg to about 500 mg, conveniently administered e.g. B. orally in Doses from 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 is the title compound of Examples 11, 12, 23, 30, 54 and 67, in particular Examples 11, 12, 23 and 30 and all especially Examples 12 and 23.

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

Claims (8)

1. A compound of formula I whereinA is an acyl group of the formula means in which R₆ for a straight-chain or branched (C₁-C₁₀) alkyl radical which may optionally be substituted by (C₁-C₅) alkoxy or (C₆-C₁₀) aryloxy, a (C₃-C₇) cycloalkyl radical, a (C₃-₁₀) cycloalkyl - (C₁-₅) - 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-containing heteroaryl radical or for a heteroaryl (C _1-5 ) - 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 -, wherein R₁₀ is a straight-chain or branched (C₁-₅) alkyl radical, n is a whole Number from 1 to 20 and m are an integer from 1 to 5, or a group of For mel where R is hydrogen or acetyl; orA is a group of the formula means in which R₇ represents 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, R₁hydrogen or represents a straight-chain or branched (C₁-₅) alkyl radical, B and C are the same or different and a bond or a group of the formula mean in which R₁ has the above meaning and R₁₁ is a hydrophilic or lipophilic amino acid side chain, where B and C cannot simultaneously mean a bond, your bond means or for -O-, where R₁ has the meaning given above, is where R₄ and R₅ have the following meanings. R₂ for a straight-chain or branched (C₁-₁₀) alkyl radical, an optionally substituted (C₃-₁₀) cycloalkyl- (C₁-₅) alkyl radical in the cycloalkyl part, 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, or for a group of the formula is in which R₁₅ hydrogen, (C₁-₄) alkyl or benzyl, s is 0 or 1 and p is 1 or 2, R₃ is hydrogen, a hydroxyl, an amino group or a group of the formula -OCOR₂ where R₂ is as defined above. R₄und R₅ are the same or different and each is hydrogen, a straight-chain or branched (C₁-₅) alkyl radical, a (C₆-₁₀) aryl- (C₁-₅) alkyl or a heteroaryl- (C₁-₅) alkyl radical in which the Heteroaryl 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 stand in which 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 one (C₁-₅) alkylamino group where the alkyl radical is straight-chain or branched, an aminomethylpyridyl group or a benzyl group or the rest for groups of formulas is in which R₁₄ is hydrogen, (C₁-₅) alkyl, benzyl or a group of the formula means what
R₁₆ represents (C₁-₄) alkyl or (C₁-₄) alkoxy (OC₂H₂) q -CH₂-, where q is an integer from 2-5. 2. The compounds of claim 1 are
(2 S, 3 S) -3- (N-BOC-Phenylalaninyl-histidyl) amido-1- (n-butylcarbomoyl-amino) -4-cyclohexyl-2-butanol
(2 R, 3 S) -3- (N-BOC-phenylalaninyl-histidyl) amido-1- (n-butylcarbamoyl-amino) -4-cyclohexyl-2-butanol
(2 S, 3 S) -3- (N-BOC-Phenylalaninyl-norleucyl) amido-1- (iso-propylcarobamoyl) amino) -4-cyclohexyl-2-butanol
(2 S, 3 S) -3- [N-3-Cyclohexylpropionyl) norleucyl] amido-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol
(2 S, 3 S) -3- (N-BOC-Phenylalaninyl-norleucyl) amido-1- [bis- (dimethyl amino)] phosphorylamido-4-cyclohexyl-2-butanol
(2 S, 3 S) -3- (N-BOC-Phenylalaninyl-norleucyl) -1- (N-benzyl-4-piperidino carbamoyl) amino-4-cyclohexyl-2-butanol
(2 S, 3 S) -3- (N-BOC-Phenylalaninyl-norleucyl) amido-1- (4-piperidino carbamoyl) amino-4-cyclohexyl-2-butanol
(2 S, 3 S) -3- (N-BOC-Phenylalaninyl-norleucyl) amido-1- (dimethyl-carbamoyl) amino-4-cyclohexyl-2-butanol
(2 S, 3 S) -3- (N-BOC-Phenylalaninyl-norleucyl) amido-1- (iso-propyl-carbamoyl) -isopropylamino-4-cyclohexyl-2-butanol
(2 S, 3 S) -3- [N- (1-Adamantyl-propionyl) -norleucyl] -1- (iso-propylcarbamoyl) amino-4-cyclohexyl-2-butanol
(2 S, 3 S) -3- (N-BOC-norleucyl) amido-1- (isopropylcarbamoyl) amino-4-cyclohexy-l-2-butanol
(2 S, 3 S) -3- (norleucyl) amido-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol hydrochloride
(2 S, 3 S) -3-N- [1-Benzoyl-amino-2- (1-naphthyl) propenoyl-norleucyl] amino 4-cyclohexyl-1- (isopropylaminocarbamoyl) amino-2-butanol
(2S, 3S) -3- [N- (bis (1-naphthylmethyl) acetyl) norleucyl] amino-4-cyclohexyl-- 1- (isopropylcarbamoyl) amino-2-butanol
(2 S, 3 S) -3- (N-Cyclopentyl-carbonyl-phenylalaninyl-norleucyl) amino-4-cyclohexyl-1- (isopropyl-carbamoyl) amino-2-butanol
(2 S, 3 S) -3- (N-BOC-Phenylalaninyl-histidyl) amido-1- (isopropyl-carbamoyl) - amino-4-cyclohexyl-2-butanol
(2 R, 3 S) -3- (tert-Butyloxycarbonylamino) -4-cyclohexyl-2-hydroxybutanesulfonic acid dimethylamide
(2 R, 3 S) -3- (tert-Butyloxycarbonylamino) -4- (1,4-dioxaspiro [4,5] undec-8-yl) -2-hydroxybutanesulfonic acid dimethylamide
(2 R, 3 S) -3- (tert-Butyloxycarbonylamino) -4-cyclohexyl-2-azidobutanesulfonic acid re-dimethylamide
(2 R, 3 S) -3- (tert-Butyloxycarbonylamino) -2-hydroxy-4- (2-naphthyl) butanesulfonic acid dimethylamide
(2 R, 3 S) -3- (tert-Butyloxycarbonylamino) -2-hydroxy-5-methyl-hexanesulfonic acid dimethylamide
(3 S, 4 S) -4- (tert-Butyloxycarbonylamino) -5-cyclohexyl-3-hydroxy-pentanesulfonic acid dimethylamide
(1 S, 3 S, 4 S) -4- (tert-Butyloxycarbonylamino) -5-cyclohexyl-3-hydroxy-1-isopropyl-pentanesulfonic acid dimethylamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-phenylalanyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide
(2 R, 3 S) -3- (N-BOC- β- cyclohexylalanyl-2 β -cyclohexylalanyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide
(2 R, 3 S) -3- (N-BOC- β- cyclohexylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-histidyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide
(2 R, 3 S) -3- [N- (bis- (1-Naphthylmethyl) acetyl) norleucyl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-amino-4-cyclohexyl-butanesulfonic acid dimethylamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4- (1,4-dioxaspiro [4,5] undec-8-yl] -2-hydroxy-butanesulfonic acid dimethylamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4- (4'-oxocyclohexyl) -2-hydroxybutanesulfonic acid dimethylamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4- (4'-hydroxy-cyclohexyl) -2-hydroxy-butanesulfonic acid dimethylamide
(3S, 4S) -3- (N-BOC-phenylalanyl-norleucyl) amido-5-cyclohexyl) -3-hydroxy-pentanesulfonic acid dimethylamide
(1 R, 3 S, 4 S) -4- (N-BOC-phenylalanyl-norleucyl) amido-5-cyclohexyl-3-hydroxy-1-isopropyl-pentanesulfonic acid dimethylamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-4- (2-naphthyl) -butane sulfonic acid dimethylamide
(2 R, 3 S) -3- [N- (BIS- (1-Naphthylmethyl) acetyl) norleucyl] amido-2-hydroxy-5- (methyl-hexanesulfonic acid dimethylamide
(2 S, 3 S) - and (2 R, 3 S) -3-BOC-phenylalanyl-norleucyl) - amido-4-cyclohexyl-1-isobutyl-sulfamoylamino-2-butanol
(2S, 3S) -3- (BOC-phenylalanine-norleucyl) amido-4-cyclohexyl-1-dimethylsulfamoylamino-2-butanol
(2 RS, 3 S) -3- (N-benzoyl-dehydrophenylalaninyl-norleucyl) amido-1-dimethylsulfamoyl-amino-5-methyl-2-hexanol
N- (3-Cyclohexylpropionyl) norleucine
(2 S, 3 S) -3- (3-Cyclohexyl-propionyl-norleucyl) amido-1-Cbz-amino-4-cyclohexyl-2-butanol
(2 S, 3 S) -3- (3-Cyclohexyl-propionyl-norleucyl) amido-1-amino-4-cyclohexyl-2-butanol
(2 S, 3 S) -3- (3-Cyclohexyl-propionyl-norleucyl) amido-4-cyclohexyl-1-dimethylsulfamoylamino-2-butanol
(2 R, 3 S) -3- [N (1-adamantyl) propionyl) norleucyl] amido-4-cyclohexyl-2-hydroxybutanesulfonic acid dimethylamide
(2 R, 3 S) -3- (N-BOC- β- Cyclohexylalanylhistidyl) amido-4-cyclo-hexyl-2-hydroxy-butanesulfonic acid dimethylamide
(2 R, 3 S) -3- [N- (BIS- (1-Naphthylmethyl) acetyl) histidyl] amido-4-cyclohexyl-2-hydroxybutanesulfonic acid dimethylamide
(2 R, 3 S) -3- (N-BOC- β - (2,1,3-Benzoxadiazol-4-yl) alanyl-norleucyl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide
(2 R, 3 S) -3 - ((N- [2-methoxy-poly (2-ethoxy) acetyl] phenylalanyl-norleucyl)) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamido-d
(2 R, 3 S) -3- [N- (BIS- (1-Naphthylmethyl) acetyl) methionyl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide
(2 R, 3 S) -3- [N- (BIS- (1-Naphthylmethyl) acetyl) methion (D, LS-oxide) yl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4- (1-adamantyl) -2-hydroxy-butanesulfonic acid dimethylamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-5,5-dimethyl-2-hydroxy-hexanesulfonic acid dimethylamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid pyrrolidinamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid piperidinamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid piperidinamide
(2 R, 3 S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid- (4-benzyl) piperazinamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid piperazinamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid- (4-acetyl) piperazinamide
(2 R, 3 S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid- [4- (2,5,8,11-tetraoxadodecanyl) carbonyl] piperazinam-id
(2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid- (4-methyl) piperazinamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid morpholinamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-histidyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid piperidinamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-5-methyl-mercapto-pentanesulfonic acid dimethylamide
(2 R, 3 S) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-5-methylsulfinyl-pentanesulfonic acid dimethylamide
(2 R, 3 R) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-4-benzyl-mercapto-butanesulfonic acid dimethylamide
(2 R, 3 R) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-4-mercapto-butanesulfonic acid dimethylamide
(2 R, 3 R) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-4-ethyl-mercapto-butanesulfonic acid dimethylamide
(2 R, 3 S) -3- [N- (2,3,4,6-tetra-O-acetyl] - β -D-glucosyl-1-0) -isobutyryl-phenylalanyl-norleucyl] amido-4- cyclohexyl-2-hydroxybutanesulfonic acid dimethylamide
(2 R, 3 S) -3- [N- ( β- D-glucosyl-1-0) -isobutyryl-phenylalanyl-norleucyl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid-dimethylamide- 3. A process for the preparation of compounds of formula I according to claim 1, characterized in that

• a) to compounds of the formula I a, wherein A, B, C, D, Y, R₁, R₂, R₄ and R₅ have the meaning given in claim 1 and R₃ 'represents hydrogen, hydroxyl or a radical of the formula -OCOR₂, wherein R₂ has the meaning given in claim 1 , by compounds of the formula II, ABC-OH (II) in which A, B and C have the meaning given in claim 1 with compounds of the formula III, wherein R₁, R₂, R₄, R₅, Y and D implements the indicated in claim 1 and R₃ 'have the above meaning,
• b) to compounds of the formula I b wherein A, B, C, D, Y, R₁, R₂, R₄ and R₅ have the meaning given in claim 1, is obtained by using compounds of the formula IV, wherein A, B, C, D, Y, R₁, R₂, R₄ and R₅ have the meaning given in claim 1, reduced.
• c) to compounds of the formula I c, wherein A, B, C, Y, R₁, R₂, R₄ and R₅ which in claim 1 and R₃ 'have the meaning given above and D' for -O- or is obtained by using compounds of formula V wherein A, B, C, R₁ and R₂ have the meaning given above in claim 1 and R₃ 'and D' with a compound of formula VI wherein Y, R₄ and R₅ have the meaning given in claim 1 and X is halogen, in particular chlorine.
• d) the compounds of the formula I d, wherein A, B, C, Y, R₁₅, R₁, D, R₄, R₅ and p which in claim 1 and R₃ 'have the meaning given above and s' is 1, is obtained by compounds of the formula I e wherein A, B, C, Y, R₁₅, R₁, D, R₄, R₅ and p which in claim 1 and R₃ 'have the meaning given above, oxidized,
• e) Compounds of formula I f wherein A, B, C, Y, R₁, R₃, D, R₄, R₅ and p have the meaning given in claim 1, by g from compounds of formula I. wherein A, B, C, Y, R₁, R₃, D, R₄, R₅ and p have the meaning given in claim 1, which splits off the benzyl group,
• f) Compounds of formula I h wherein A, B, C, Y, R₁, R₃, D, R₄, R₅ and p have the meaning given in claim 1, is obtained by introducing the (C₁-₄) alkyl radical into compounds of the formula I f.
• g) Compounds of formula I i wherein A, B, C, R₁, R₂ R₃, D and Y have the meaning given in claim 1, by using compounds of the formula I j wherein A, B, C, R₁, R₂ R₃, D and Y has the meaning given in claim 1, cleaves off the benzyl group or
• h) Compounds of formula I k wherein C, D, Y, R₁ to R₅ and R₇ to R₉ have the meaning given in claim 1 by using a compound of formula IX wherein R₇, R₈ and R₉ have the meaning given in claim 1, with compounds of the formula X, wherein C, D, R₁, R₂, R₃, R₄, R₅ and Y have the meaning given in claim 1, implement and, if desired, convert the reaction products thus obtained, optionally containing precursors, in the compound of the formula I.

4. A compound according to claim 1 for use as a medicine. 5. A compound according to claim 1 for use as a renin inhibitor. 6. A compound according to claim 1 for use against hypertension and heart failure. 7. Pharmaceutical preparation containing a compound according to Claim 1 and optionally pharmacologically acceptable auxiliary and / or diluents. 8. Use of compounds of formula 1 for the preparation of Medicines with renal inhibitory effects for the treatment of hypertension and heart failure.