NL8800100A - NEW PEPTIDE DERIVATIVES AND METHODS FOR PREPARING AND USING THESE DERIVATIVES. - Google Patents

Description

£ s i Λ

Novel peptide derivatives and methods for preparing and using these derivatives.

The present invention relates to novel renin inhibitors, to their preparation and use, and to pharmaceutical compositions containing them.

The invention provides compounds of formula I, wherein

A an acyl grower with formula VII

wherein Rg represents a straight or branched chain alkyl group of 1 to 10 carbon atoms which is optionally substituted by alkoxy with 1 to 5 carbon atoms or aryloxy with 6 to 10 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, a (C3-10) -cycloalkyl- (C1-5) alkyl group, an aryl group of 6-10 carbon atoms, a 5- or 6-membered heteroaryl group containing one or two nitrogen atoms, oxygen or sulfur atoms, and one nitrogen atom and / or contains one sulfur atom or a heteroaryl- (C 1-6) alkyl group, wherein the heteroaryl moiety consists of 5 or 6 members and contains one or two nitrogen atoms, oxygen or sulfur atoms or one nitrogen atom and / or one sulfur atom a straight or branched chain alkoxy group having 1 to 5 carbon atoms or a (cg-10) aryl-20 .6800100

* V

- 2 - (C, c) -alkyl group or a group of formula R, nO (CHoCHoO) (CH ') -1-o iu z zn zm 4 where R iq is a straight or branched alkyl group with 1 to 5 carbon atoms, n an integer from 1-20 and m are an integer from 1-5, or a group of formula VIII, wherein 5 R is a hydrogen atom or an acetyl group, or A represents a group of formula XI, wherein Ry is an alkyl group straight or branched chain and 1-5 carbon atoms or an aryl group with 6-10 carbon atoms, 10 and

Rg and Rg are respectively a hydrogen atom, a straight or branched chain alkyl group and 1-5 carbon atoms or an aryl group with 6-10 carbon atoms,

Rj represents a hydrogen atom or a straight or branched chain alkyl group with 1 to 5 carbon atoms, B and C, which are the same or different, represent a bond or a group of formula XII, wherein

Rj has a predefined meaning and Rj j is a hydrophilic or lipophilic amino acid side chain, wherein B and C cannot be a bond simultaneously, D represents a bond or -0-, -N- or -CH- tf R1 R1, wherein R 1 has a predefined meaning, 25 1 * 2 a straight or branched chain alkyl group and 1-10 'C atoms, a (C 1 -C 12 icycloalkyl (C 12) alkyl group of which the cycloalkyl portion is optionally substituted, a ( C 8-8 aryl (C 1-8) alkyl group or a heteroaryl (C 1-8) alkyl group, wherein the heteroryly portion consists of 5 or 6 members and 1 or 2 nitrogen atoms, oxygen or sulfur atoms, or one nitrogen atom and an oxygen atom, and / or contains a sulfur atom, or a group of formula XIII, wherein

Rj is - a hydrogen atom, an alkyl group with 1-4 carbon atoms or the benzyl group, s = 0 or 1 and p = 1 or 2.35, .8800100 - 3 -

Rg represents a hydrogen atom, a hydroxyl group, an amino group or a group of the formula -OCOR2, wherein R2 has a previously defined meaning, R1 and R2, which may or may not be the same, respectively, a hydrogen atom, an alkyl group with straight or branched chain and 1 to 5 carbon atoms, a (C 8 -JQ) -aryl- (C 1 -J) alkyl group or a heteroaryl (C 1 -J) alkyl group, wherein the heteroaryl portion is 5 or 6 members and one or two nitrogen atoms , oxygen or sulfur atoms or one nitrogen atom and one oxygen-10 atom and / or one sulfur atom, or a group of formula XIV, wherein R 2 is a straight or branched chain alkyl group and 1 to 5 carbon atoms or a straight or branched chain hydroxyalkyl group and 1-5 carbon atoms and Rjj is a hydroxyl group, a straight or branched chain alkoxy group and 1-5 carbon atoms, an amino group or an alkylamino group of 1-5 carbon atoms, the alkyl group having a straight or branched chain, an aminomethylpyridyl group or a benzyl or wherein the group of formula XV represents a group of formula XVI, XVII, XVIII or XIX, wherein R1 is a hydrogen-20 atom, an alkyl group of 1-5 carbon atoms, a benzyl group or a group of formula XX, wherein Rj ^ represents an alkyl group of 1-4 carbon atoms or a (Cj_ ^) alkoxy (0C2H2) q-CH2 group, wherein q is an integer of 2-5 and Y represents a group of formula XXI, XXII or XXIII 25, wherein R ^ and R ^ have the meanings given above.

The carbon atoms substituted by R 2 and R 2 may have the R or S configuration. Compounds of formula I in which the carbon atoms substituted by R 2 and R 2 have the configuration given in formula Iy are recommended.

Recommended compounds of formula I have formula Iy, wherein A represents tert-butyloxycarbonyl, pxvaloyl, bis (1-naphthyl-methyl) acetyl, benzoyl or 1-adamantylcarbonyl, y 35 B represents a bond, phenylalanine or ψ-cyclohexyl-alanine t , .880011, - 4 -

Cy represents histidine, norleucine, phenylalanine or leucine,

Yy is a group of formula XXI or XXII, y

Rj represents a hydrogen atom or the methyl group, y represents isobutyl, benzyl, cyclohexylmethyl or 1-adamantylmeth yl, y

Rg represents a hydroxyl group, ammogroup or a group of formula OCOCH2 or OCOCCCHL], y 10 R ^ represents a hydrogen atom, a methyl, propyl, i.-butyl or n-butyl group,

R ,. " a methyl, propyl, butyl or (n-butyl) group, or wherein the group of formula XXIV

a pyrrolidinyl, piperidinyl or a morpholinyl group represents 15 and

y S S N

D represents a NH, N-N-propyl, CE, or CH-1-propyl group.

Especially recommended compounds of formula I.

have formula Iz, wherein 2 20 A represents a tert-butyloxycarbonyl or bis (1-naphthyl-methyl) -acetyl group, 2 B represents a bond, phenylalaninyl or β-cyclohexylalaninyl, 2 C represents histidine, leucine or norleucine , 2 25 Y represents a group of formula XXI or XXII,

R 2 is a hydrogen atom, 2 R 1 represents cyclohexylmethyl or 1-adamantylmethyl, 2 R 1 represents a hydroxyl or amino group, 2 R 2 represents a hydrogen atom or the methyl group, 2 R 1. represents a hydrogen atom or an isopropyl or isobutyl group, or wherein the group of formula XXV is a pyrrolidinyl, piperidinyl or morpholinyl group and 35 8800100-5 Z 'N. \ D represents a ^ NH or ^ CH-isopropyl or C ^ group.

When in formula I Rg represents a straight or branched chain alkyl group having 1 to 10 carbon atoms, this group is in particular the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2, 2-dimethylethyl, pentyl or hexyl group etc., in particular the methyl, tert.-butyl and 2,2-dimethyl-ethyl group and when this group is substituted by aryl oxy, this group is in particular the enoxymethyl or 10 1-or 2-naphthyloxymethyl group, preferably the 1-naphthyloxy-methyl group and if this group represents a cycloalkyl group with 3-7 carbon atoms, it gives the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, if it represents a (C 5 -cycloalkyl-C 1-6 alkyl) group, cycloalkyl 15 may have a meaning as defined above and may additionally be the adamantyl group and in particular is a cyclohexylethyl or (1-adamentyl) ethyl group, if this group represents an aryl group with 6-10 carbon atoms, in particular it is phenyl or I- or 2-naphthyl group, preferably a 1-naphthyl group and if it represents a heteroaryl group, it is especially a pyridyl, thienyl or furyl group, if it represents a heteroaryl alkyl group, the heteroaryl portion and the alkyl portion preferably have the above said meanings, when it represents a straight or branched chain alkoxy group, it is in particular an ethoxy or tert-butoxy group and when it represents a (C 8 -JQ) aryl (C 12 -2) alkoxy group, it has in particular the meanings given above for alkyl and aryl and it is preferably the benzyloxy group.

30 A then represents the corresponding carbonyl compounds of Rg.

When R 1 represents an alkyl group of 1 to 5 carbon atoms, this substituent has the meanings given above for alkyl and if it is an aryl group, this substituent is in particular a phenyl or 1 or 2-naphthyl group, 8800100

l

- 6 - in particular the 1-naphthyl group.

If Rg and Rg represent an alkyl group with 1 to 5 carbon atoms, these substituents have the alkyl g eg ar and meanings above and if they are an aryl group, they represent enphenyl, 1 or 2-naphthyl, preferably 1 -naf tyl group, front. The latter meaning is recommended for Rg, while hydrogen is the recommended meaning for Rg.

In the R 1 () O (CH 2 CH 2 O) m group, R jq preferably represents a methyl group, n is preferably an integer from 4-12, especially 7, and it is recommended that m = 1.

For example, the hydrophilic or lipophilic amino acid side chain in the definition of R j may be an n-butyl, isobutyl, benzyl, 4-imidazolylmethyl, 2-methylthioethyl, cyclohexyl-15 methyl or a pyridylmethyl group.

If Rj represents an alkyl group with 1 to 5 carbon atoms, the alkyl groups may have the previously defined meanings and are in particular the methyl group.

R 2 represents an alkyl group having 1 to 10 carbon atoms, then this group may be straight or branched chain and the above-mentioned alkyl groups and if this substituent represents a C 8 -JQ) cycloalkyl (C 1 -J) alkyl group optionally substituted in the cycloalkyl portion , then this substituent is preferably the cyclohexylmethyl group, wherein the cycloalkyl group is optionally substituted by oxo or hydroxyl or disubstituted (spiro fused) by a group of formula XXVI, wherein o is a 2- or 3-adamantyl group, preferably 1 -adamantylmethyl, while where each substituent represents a (C 8 -g) aryl (C 1-8) alkyl group, this substituent preferably represents a benzyl or naphthylmethyl group, and when it represents a heteroarylalkyl group, the heteroaryl portion particularly a pyridyl, thienyl or furyl group and the alkyl portion has a previously defined meaning.

When R 1 and R 1 represents a (C 8 -JQ) aryl (C 1 -J) alkyl group, these substituents preferably give a 4. 8 8 0 0 1 0 0 4 -7-phenyl- (C 1-4) -alkyl group, in particular a benzyl group, while if they represent a heteroarylalkyl group, the heteroaryl portion in particular a pyridyl, thienyl or furyl group and alkyl has a previously defined meaning. If R 1 represents an alkyl group with 1 to 5 carbon atoms, alkyl has a previously defined meaning.

When R 2 represents an alkyl group with 1 to 5 carbon atoms, alkyl has one of the meanings defined above, but in particular is the isopropyl, n-butyl, isobutyl and 2-methylbutyl group. Hydroxyalkyl is preferably a hydroxymethyl or hydroxyethyl group. When R 1 represents an aminomethyl-pyridyl group, this is preferably the aminomethyl-2-pyridyl group.

In R 1, alkyl of 1 to 5 carbon atoms has the meanings indicated above.

Preparation of the compounds of formula I can be carried out as follows: a) compounds of formula Ia, wherein A, B, C, 20 D, Y, R 1, R 2> R 1 and R 1. have the previously defined meanings and R 1 'is a hydrogen atom, hydroxyl group or a group of formula -OGOR 2, wherein R 2 has a previously defined meaning, can be obtained by reacting a compound of formula II, wherein A, B and C have the above have defined meanings, with a compound of formula III, wherein R 1, R 2, R 1, R 1, R 2, Y, and D have the meanings defined above, b) compounds of formula 1, wherein A, B, C, D, Y, Rj, R2, R ^ and R ^ having the meanings defined above can be obtained by reduction of a compound of formula IV, wherein A, B, C, B, Y, Rj, R ^, R 1 and R 2 have the meanings defined above, and c) compounds of formula Ic, wherein A, B, C, Y, R 1, R 2, R 3 ', R 4 and R 3. the meanings defined above have D * and represents an -O- or -N- group, wherein Rj. 8 8 0 0 1 0 0 '

ί V.

κ - 8 - having a previously defined meaning can be obtained by reacting a compound of formula V, wherein A, B, C, D ', Rj, R2 and R ^' have the previously defined meanings, with a compound of formula VI, wherein Y, R ^ and R ^ have the meanings defined above and X represents a halogen atom, in particular a chlorine atom, d) compounds of formula Id, wherein A, B, C, D, Y, Rj, R ^ ', R ^, Ry Rj ^ and p have the meanings defined above and s' = 1, can be obtained by oxidation of a compound of formula Ie, wherein A, B, C, D, Y,

Rj, R ^ ', Ry Rjcj and p have the previously defined meanings and, e) compounds of formula If, wherein A, B, C, D, Y, Rj, Rg, R ^ j R ^ and p have the previously defined meanings can be obtained by the benzyl group of compounds of formula Ig, wherein A, B, C, D, Y, Rj,

Rg, R ^, R, - and p have the meanings defined above, to be split off, f) compounds of formula Ih, wherein A, B, C, 20 D, Y, Rj, Rg, R ^, Rj- and p the previously defined meanings can be obtained by introducing an alkyl group into compounds of formula If, as defined above, g) compounds of formula II, wherein A, B, C, D, Y, Rj, R2 and Rg have the previously defined meanings can be obtained by cleaving off the benzyl group of compounds of formula Ij, wherein A, B, C, D, Y, Rj, R2 and Rg have the previously defined meanings, h) compounds of formula Ik, wherein C, D, Y,

Rj - Rj - and R ^ - Rg have the previously defined meanings, can be obtained by reacting a compound of formula IX, wherein R ^, Rg and Rq have the previously defined meanings, with a compound of formula X, wherein C , D, Y, Rj - Rj - have the previously defined meanings and the resulting precursors of compounds of formula I are optionally converted into compounds of __________________- a .8800100> »- 9 - formula I.

The process of step a) for preparing compounds of formula Ia is suitably carried out in such a way that the compounds of formula II are reacted with a compound of formula geschikt by a method suitable for peptide coupling. The reaction can proceed, for example, in the presence of N, Nf-dicyclohexylcarbodiimide or N-ethyl-Ν '- (dimethylaminopropyl) -carbodiimide and N-hydroxy succinimide or 1-hydroxybenzotriazole, the solvent being, for example, dimethylformamide and the reaction is carried out at a temperature between 0 ° C and preferably room temperature. The reaction can also be run in the presence of 50% propane-phosphoric anhydride in methylene chloride in the presence of a base such as N-methylmorpholine in a suitable solvent, for example dimethylformamide. In that case, the reaction is also conveniently carried out at a temperature between ° C and room temperature, preferably at room temperature.

The reduction of the compounds of formula IV according to step b) takes place according to known methods, for example by catalytic hydrogenation in the presence of a suitable catalyst, for example palladium on active charcoal, in a suitable solvent, such as ethanol, at temperatures between 0 and about 50 ° C, preferably at room temperature, and a pressure in between atmosphere, preferably 1 atmosphere.

The reaction of compounds of formula V with compounds of formula VI described in step c) suitably takes place in the presence of a base, for example triethylamine or N-methylmorpholine, in an inert solvent, such as tetrahydrofuran or dimethylformamide, at a temperature of about 0 ° C to about 50 ° C, preferably at room temperature. If Y represents the C = O group, the reaction may also proceed with the corresponding isocyanate R 1 N = C = O) wherein compounds of formula I, wherein R 1. represents a hydrogen .8800100 Λ - 10 atom.

In method d), the oxidation is carried out using an oxidizing agent, for example hydrogen peroxide, which reacts with the compounds of formula Ie in an acidic solvent, for example 100% acetic acid, at a temperature below room temperature, for example 10 ° C.

The process of step e) is carried out by reacting sodium in liquid ammonia at a temperature of about -40 ° C with a compound of formula Ig, whereby the benzyl group is cleaved off. The starting compounds of formula Ig can be obtained from suitable starting materials according to method c).

The process of step f) is an alkylation process in which compounds of formula If first react at about -40 ° C with sodium in liquid ammonia and then with a (C 1-4) alkyl halide, in particular an alkyl bromide with 1-4 carbon dust atoms.

The catalytic cleavage of the benzyl group 20 of compounds of formula Ij according to step g) takes place in the presence of a palladium (10% on charcoal) catalyst in a suitable solvent, for example ethanol, at a hydrogen pressure of 1-5 atm., At temperatures of about 60 ° C, preferably at room temperature.

The reaction of a lactone of formula IX with a compound of formula X according to method h) is carried out according to methods known from the literature, for example in a suitable solvent, such as tetrahydrofuran or chloroform, optionally in the presence of an acylation 30 catalyst, such as 4-dimethylaminopyridine, at a temperature between 0 and about 80 ° C, preferably at room temperature or the reflux temperature of tetrahydrofuran or chloroform.

The methods described in the foregoing have been added

suitable starting compounds are either known (see, for example, 35 E. Wünsch in: Houben-Weyl, "Methods of Organic Chemistry", .8800100 - 11 - * *

Volume XV / 1 and XV / 2, "Synthesis von Peptiden", Georg Thieme,

Stuttgart, 1984), or αρ can be prepared in a known manner, as described, for example, in the following examples.

The compounds of formula I obtained according to the invention can be separated and purified in a known manner. Racemic and / or diastereoisomeric mixtures can be separated in a known manner.

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

The temperatures given in ° C in the following examples are uncorrected.

Example 1: (2R, 3S) -3- (tert-butyloxycarbonylamino) -4-cyclohexyl-2-hydroxybutane-sulfonic acid dimethylamide.

They dissolved 4 g of methanesulfonic acid. dim thylamide in 50 ml tetrahydrofuran and mix this solution at a temperature of 0

Temperature between 0 and 5 C with 20 ml of N.-butyl lithium (1.6 M

in hexane). After 30 minutes, 3.7 g of N-t-BOO cyclohexylalaninal were added suddenly. After 30 minutes, the reaction mixture was poured into ether in a 2N aqueous solution of tartaric acid, the organic phase separated, dried over magnesium sulfate and the solvent evaporated under reduced pressure. The crude product was chromatographed on silica gel with a mixture of ether and hexane (30-70%). The main product was obtained as a colorless oil, which solidified on standing. Melting point: 86-87 ° C. The 2R, 3R) isomer was obtained as a by-product.

Example 2: (2R, 3S) -3- (tert.-butyloxycarbonylamino) -4- (1,4-dioxaspiro / 4,5 / undec-8-yl) -2-hydroxybutane-sulfonic acid dimethylamide De in the title said compound was obtained analogously to Example 1 from 5.2 g of methanesulfonic acid dimethyl. 8 8 0 0 U * * - 12-amide, 26 ml of n-butyl lithium and 6 g of the corresponding aldehyde, mp .: 48-50 ° C.

Example 3: (2R, 3S) -3- (tert-butyloxycarbonylamino) -4-5 cyclohexyl-2-azido-butanesulfonic acid dimethyl amide

1 g of the by-product of Example 1 (2R, 3R isomer) was dissolved in 10 ml of toluene and this solution was mixed at -30 ° C with 1.5 g of triphenylphosphine, 30 ml of ammonia (an approximately 1N solution in benzene and 0 9 ml of the diethyl -10 ester of azodicarboxylic acid, then the reaction mixture was stirred overnight at room temperature and then filtered over silica gel to give an inseparable mixture of the title compound and (3S) - ( tert.-butyloxycarbonyl) -4-cyclohexyl-1-butene-sulfonic acid dimethyl-15 amide.

Example 4: (2R, 3S) -3- (tert-butyloxycarbonylamino) -2-hydroxy-4- (2-naphthyl) -butane-sulfonic acid dimethyl amide. The title compound was as a colorless oil analogous to example I obtained from 1.7 g of methanesulfonic acid dimethyl amide, 8.5 ml butyl lithium and 2 g of the corresponding aldehyde.

Example 5: 25 (2R, 3S) -3- (tert-butyloxycarbonylamino) 2-hydroxy-5-methyl-hexanesulfonic acid. d imethylamide. The title compound was obtained as a mixture of dia stereoisomer and (about 2: 1) analogous to example uit from 4-methanesulfonic acid dimethylamide, 60 ml n-butyl lithium and 4 g N-tert-BOC- leucinal.

Example 6 (3S, 4S) -4- (tert.-butyloxycarbonylamino) -5-cyclohexyl-3-hydroxy-pentane-sulfonic acid dimethylamide 1 g of methanesulfonic acid dimethyl amide 35 was dissolved in 10 ml of tetrahydrofuran and dripped thereon at a temperature. 8 8 0 & U '0 * * - 13 - between 5.1 and 5 ° C, add 5.1 ml of n-butyl lithium. After 30 min, 1 g of (2S) -2 - ((1S) -tert.-butyloxy-carbonylamino-2-cyclohexyl-ethyl) oxiran was added. After 20 min. The mixture was partitioned between ether and a 2N aqueous solution of tartaric acid, the organic phase separated, dried and concentrated by evaporation. The crude product was recrystallized from a mixture of methylene chloride and hexane. Melting point: 110-111 ° C-Example 7: (1S, 3S, 4S) -4- (tert.-butyloxycarbonylamino) -5-10 cyclohexyl -3-hydroxy-1-isopropyl pentasulfonic acid d imethylamide

The title compound was obtained as a mixture of slide stereoisomer and (about 1: 5) in an analogous manner as described in Example 6 from 0.4 g of isobutane-15 sulf acidic imethylamide, 1.5 ml of n-butyl lithium and 200 mg of epoxide.

Example 8: (2R, 3S) -3- (N-B0C-phenylalanyl-phenylalanyl) amido-4-cyclohexyl-2-hydroxy-butane-sulfoic acid-20-dimethylamide

330 mg of the sulfonic acid amide of Example 1 was dissolved in 1 ml of methylene chloride and 1 ml of trifluoroacetic acid was added. After 1 hour, the mixture was partitioned between a 2N aqueous solution of sodium carbonate and methylene chloride, the organic phase separated, dried with potassium carbonate and concentrated by evaporation. 230 mg of BocPhePheOH, 225 mg of ΒΤ0Η and about 5 ml of methylene chloride were then added.

The mixture was cooled to 0-5 ° C, 170 mg of dicyclohexyl carbodiimide were added and stirred at room temperature for about 30 more hours. The precipitated dithyclohexyl urea was filtered off and the crude product was chromatographed on silica gel with a mixture of ether and methylene chloride 50-90 Z. / ¾¾) 2 ° = -29.1 ° (c = 0.6 in CHjCHj) -).

.8800100

Example 9: - 14 - (2R, 3S) -3- (N-B0C- $ -cyclohexylalanyl-β -cyclo-hex yl -a la nyl) am ido- 4 -c yc 1 o hex yl -2-h ydroxy -bu t a n- su lphoic acid -d ime th yl amide 5 50 mg of the product of example 8 were dissolved in 5 ml of ethanol and hydrogenated over Rh-Alox for 24 hours at 40 ° C / 2 atmosphere of hydrogen. (5%). The catalyst was filtered off and the product was lyophilized from benzene. ftQ = -46.1 ° (c = 0.6 in CH 2 Cl 2).

Example 10: (2R, 3S) -3- (N-BOC-phenylala nyl-norl-eucyl) amido 4-cyclohexyl-2-hydroxy-butane-sulfoic acid dimethyl amide

160 mg of BOC-SO2-Chatin-NMe2 (Example 1) was reacted analogously to Example 8 with 100 mg of BOCPheN1 eOH, 100 mg of hydroxybenzotriazole and 80 mg of dicyclohexylcarbodiimide.

[yard D20 = -32.4 ° (c = 0.2 in CH2 Cl2).

Example 11: (2R, 3S) -3- (1H30C-β-cyclohexylalanyl-norleucyl) -20 amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide

20 mg of the product of Example 10 were hydrogenated in exactly the same manner as described in Example 9. / aTo2O = -38.2 ° (c - 0.1 inCH 2 Cl 2).

Example 12: (2R, 3S) -3- (N-B0C-phenylalanyl-histidyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethyl amide.

225 mg of BOC-SO2-Chatin-NMe2 (Example 30L) was reacted with 236 mg of BOCPheHisOH, 160 mg of hydroxybenzotriazole and 120 mg of dicyclohexylcarbodiimide analogous to Example 8. For the peptide coupling, dimethylformamide was used instead of methylene chloride. After chromatography on a mixture of methanol and CH 2 Cl 2, 0-10%, two diastereo-isomers were obtained: / ¾¾20 - -32.2 ° (c - 0.2 in CH.Cli / MeOH 9: 1; 8 8 0 0 1 0 0? E.

Diastereoisomer B: £ / t / D ^ = 26.0 ° (c = 0.6 in CI ^ C ^ / MeOH 9: 1).

Example 13: (2R, 3S) -3- / N- (bis- (1-naphthylmethyl) acetyl) nor-1-eucyl / amido-4-cyclohexyl-2-hydroxy-butane-sulfonic acid dimethylamide.

200 mg of B0C-SO2-ChatinNMe2 (Example 1) was reacted with 240 mg of N- (bis- (1-naphthyimethyl) acetyl) -NIe-0H, 140 mg of hydroxybenzotriazoo 1 and 110 mg of dicyclohexylcarbodiimide analog 2020 to Example 8./ot / ^ = -43.9 ° (c = 0.2 in CH 2 Cl 2>.

Example 14: (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-amin-4-cyclohexyl-butanesulfonic acid imethylamide. 150 mg of the sulfonic acid amide mixture of Example 3 was reacted analogously to Example 8 with 100 mg of BOCPheNJ eOH, 700 mg of hydroxybenzotriazole and 80 mg of dicyclohexyl carbodiimide. The crude product was then dissolved in ethanol and hydrogenated at 20 ° C and 1 atmosphere of hydrogen over palladium on carbon (10%) for 4 hours. Chromatographing on silica gel with a mixture of methanol and CH 2 Cl 2 (0-5%) gave the title compound / ft / D = -37.1 (c = 0.2 in CH 2 Cl 2) j as well as B0C-Fhe-Nle-SO2-deoxy-chatine-NMe2 = -26.4 ° (c = 0.2 in CH2Cl2).

Example 15: (2R, 3S) -3- (K-BOC-phenylalanyl-norl-eucyl) amido-25- (1,4-dioxaspiro / 4,5 / undec-8-yl) -2-hydroxy-butane- sulfic acid. d imeth ylamide.

335 mg of the sulfonamide of Example 2 was reacted with 290 mg of BOC-Phe-NleOH, 200 mg of hydroxybenzotriazole and 158 mg of dicyclohexylcarbodiimide analogous to Example 8.

30 / ¾) 2 ° = -32.6 ° (c = 0.2 in CI ^ C ^)

Example 16: (2R, 3S) -3- (K-BOC-phenylalanyl-norleucyl) amido-4- (4-oxocyclohexyl) -2-hydroxy-butane-sulfonic acid dimethyl amide.

200 mg of the product of Example 15.8800100-16 were dissolved in 10 ml of a mixture of tetrahydrofuran and water and mixed with a few drops of concentrated hydrochloric acid. After 10 hours, the mixture was partitioned between ethyl acetate and an aqueous sodium bicarbonate solution, the organic phase separated, dried and concentrated by evaporation. / tt = -45.6 ° (c = 0.2 in CH 2 Cl 2).

Example 17: (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4- (4, -oxycyclohexyl) -2-hydroxy-butane-sulfonic acid-10-dimethylamide.

70 mg of the product of Example 16 were dissolved in 5 ml of methanol. Then 10 mg of sodium borohydride was added, stirred at room temperature for 15 minutes and then partitioned between ethyl acetate and a 2N aqueous sodium 15 carbonate solution. / tt / D ^ = -31.1 ° (c = 0.2 in C 1 -C 6).

Example 18: (3S, 4S) -4- (N-B0C-phenylalanyl-norleucyl) amido-5-cyclohexyl-3-hydroxy-pentane-sulfonic acid dimethylamide.

135 mg of the sulfonamide of Example 6 was reacted with 75 mg of BOC-Phe-Nle-OH, 70 mg of hydroxybenzotriazole and 52 mg of dicyclohexylcarbodiimide analogous to Example 8. / a? D = -10 ° (c = 0.2 in CH2C12)

Example 19: 25 (1S, 3S, 4S) -4- (N-BOC-phenylalanyl-norleucyl) amido 5-cyclohexyl-3-hydroxy-1-isopropyl-pentane-sulfonic acid dimethyl amide.

Analogous to Example 8, 47 mg of the mixture of diastereoisomers of Example 7 were reacted with 40 mg of BOCPhe-Nle-OH, 28 mg of hydroxybenzotriazole and 22 mg of dicyclohexylcarbodiimide. By chromatography on silica gel with a mixture of ether and hexane 50-100%, two diastereoisomer and: A: / cl7d ^ = -36.4 °, B: foT / D ^ = -10.0 ° (c = 0, 1 in CH 2 Cl 2).

.8800100

Example 20; 17 - (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-4- (2-naphthyl) -butane-sulfoic acid dimethyl amide.

130 mg of the sulfonamide of Example 4 was reacted analogously to Example 8 with 115 mg of BOC-PheNeOHH, 85 mg of hydroxybenzotriazole and 65 mg of dicyclohexylcarbodiimide. / A? D 2 O = -43.7 ° (c = 0.2 in CH 2 Cl 2).

Example 21: 10 (2R, 3S) -3- / N- (bis- (1-naphthylmethyl) acetyl) -norleucyl / amido-2-hydroxy-5-methyl-hexane-sulfonic acid dim thylamide.

100 mg of the mixture of diastereoisomers of Example 5 were reacted with 70 mg of BOCPheNleOH, 70 mg of hydroxybenzotriazole and 51 mg of dicyclohexylcarbodiimide according to Example 8. The product was obtained as an inseparable mixture of diastereoisomers (about 2: 1) .

Example 22: (2S, 3S) - and (2R, 3S) -3- (B0C-phenylalanyl-norleucyl) -20 amido-4-cyclohexyl-1-isobutyl-sulfamoylamino-2-butanol.

A solution of 94 mg of isobutyl-sulfamoyl chloride in 1 ml of dioxane was added to a mixture of 273 mg (2S, 3S) -3-BQC-phenyl-alanyl-norleucynyl) amido-1-amino-4-cyclohexyl-25 2- butanol and 0.1 ml of triethylamine in 11 ml of dioxane. and stirred the resulting mixture at room temperature for 20 hours and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate and the solution was washed with dilute hydrochloric acid, a solution of sodium bicarbonate in water and a solution of sodium chloride in water. Drying over anhydrous sodium sulfate, evaporation under reduced pressure and chromatography (silica gel with a mixture of dichloromethane and methanol 40: 1 as eluent) gave the title compound as an amorphous solid product, / ct / D ^ = - 7 ° (c = 0.5 in dichloromethane).

Using (2R, 3S) -3- (BOC-phenyl-.8800100-18-alaninyl-norleucinyl) amido-1-amino-4-cyclohexyl-2-butanol, (2R, 3S) -3- (BOC-phenylalaninyl-norleucinyl) -amido-4-cyclohexyl-isobutyl-sulfamoylamino-2-butanol as 20 o an amorphous solid product, / tt / D = -3.2 (c = 0.5 in 5 dichloromethane).

The starting materials used in this process were obtained in the manner described below; a) (3S) -3-B0C-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 acid triamide was added with cooling with ice and vigorous stirring to a suspension of 18.0 g of sodium hydride (80% in mineral oil) in 180 ml of tetrahydrofuran. The resulting solution was stirred at room temperature for 15 hours, then cooled to 0 ° C and a solution of 69.9 q, N-B0C-L-β-cyclohexyl-alanine-3,5-dimethylpyrazolide in 700 ml was added. tetrahydrofurantoaFa stirring for 20 hours, the mixture was mixed with 600 ml of zout-hydrochloric acid, extracted 2x with ether, washed the combined organic extracts with a solution of sodium chloride in water, dried over anhydrous sodium sulfate and evaporated under reduced pressure.

After chromatography of the crude product on silica gel using a mixture of toluene and ethyl acetate (6: 1) as the eluent, the aforementioned intermediate 1 was obtained as colorless crystals, m.p. 97-98 ° C.

b) (2S, 3R) - and (2R, 3S) -3-BOC-amino-4-cyclohexyl-1-nitro-2-butanol. (Intermediates 2A and 2B) 2.27 g of sodium borohydride were added in small amounts. portions to an ice-cooled solution of 18.9 g of intermediate 1, as obtained above, in 190 ml of ethanol. It was then stirred for one hour without cooling, after which the pH of the solution was adjusted to 3 by adding a 10% aqueous solution of tartaric acid in water while cooling. Evaporated under reduced pressure, extracted 2x with ether, washed the combined organic phases with an aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. By treating the residual oily mixture of two diastereoisomers with a mixture of ether and hexane, isomer 2B was obtained, which was m.p. of 116-118 ° C (dec.).

Chromatography of the mother liquor over silica gel using a mixture of hexane and ether (2: 1) as an eluant gave isomer 2B as an oil.

The Rf values (silica gel, a mixture of hexane and ether 2: 1) were 0.136 for 2A and 0.106 for isomer 2B.

c) (2S, 3S) - and (2R, 3S) -1-amino-3-BOC-amino-4-cyclohexyl-2-butanol. 15 (the intermediates A and 3B)

5.96 g of ammonium formate was added in small portions over an hour, in an inert atmosphere, to a mixture of 7.5 g of the intermediate 2A obtained as described above and 0.75 g of palladium (10 % on 20 animal cabbage) in 50 ml of methanol. After stirring at room temperature for 17 hours, the suspension was filtered through celite and the filtrate was evaporated under reduced pressure. The residue was taken up in 2N hydrochloric acid, washed 2x with ether and the aqueous phase was made alkaline by addition of sodium bicarbonate.

The water phase was extracted 2x with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The foamy residue was converted into the hydrogen oxalate and crystallized from ether. The hydrogen oxalate of the intermediate 3A 30 was obtained with a melting point. 165-166 ° C (dec.).

The hydrogen oxalate of the intermediate 3B, which was obtained analogously from intermediate 2B, melted at 137-138 ° C (dec.).

8800100 - 20 - d) (2S, 3S) - and (2R, 3S) -3-BOC-amino-1-Cbz-amino-4-cyclohexyl-2-butanol (intermediates 4A and 4B).

At a temperature between 2 and 5 ° C 5 4.18 ml of benzyl chloroformate were added to a solution of 5.28 ml of triethylamine and 6.3 g of the intermediate 3A, which was obtained according to the method described above, in 120 ml of dichloromethane the resulting solution was stirred at room temperature for 30 minutes. It was then diluted with dichloro-10 methane and washed with 0.25 N hydrochloric acid, a saturated solution of sodium bicarbonate in water and water. The organic phase was dried over sodium sulfate and evaporated under reduced pressure. Chromatographing the residue on silica gel using a mixture of toluene and ethyl acetate (3: 1) as the eluent gave the intermediate 4A as a slightly yellowish oil.

Intermediate 4B was obtained as an oil from intermediate 3B by the same method.

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

8.06 g of the intermediate 4A was added to 80 ml of the mixture of acetic acid and concentrated hydrochloric acid (9: 1) with cooling, the resulting solution was stirred at room temperature for 1 hour and then evaporated to dryness. The hydrochloride of the intermediate 5A was obtained as a colorless foam.

The hydrochloride of intermediate 5B was obtained from intermediate 4B by the same method.

F) (2S, 3S) - and (2R, 3S) -3- (BOC-phenylalaninyl-norleucinyl) -amino-1-Cbz-amino-4-cyclohexyl-2-butanol_

4.06 ml of diphenylphosphorylazide and 4.94 ml of triethylamine were gradually added to an ice-cooled solution of 6.68 g of BOC-Phe-Nle-OH and 6.3 g of the crude .8800100-21 hydrochloride of the intermediate 5A in dimethylformamide and the resulting clear solution was stirred overnight at room temperature, after which this solution was concentrated under reduced pressure, the residue was taken up in dichloromethane and the solution was washed in dichloromethane with 0.25N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and water and dried over anhydrous sodium sulfate. After evaporation under reduced pressure, the residue was chromatographed on silica gel (a mixture of dichloromethane and ethanol (49: 1 as eluent) and the resulting product crystallized from a mixture of dichloromethane and hexane. The intermediate 6A thus obtained was melted at 167-168 ° C C (dec.).

The intermediate 6B, which has a melting point of 150-151 ° C (dec.), Was obtained by the same method from the intermediate 5B.

g) (2S, 3S) - and (2R, 3S) -1-amino-3- (B0C-phenylalaninyl-norleucinyl) -amino-4-cyclohexyl-2-butanol (intermediates 7A and 7B)

7.0 g of the intermediate 6A and 0.7 g of palladium on active charcoal (10%) were hydrogenated in 140 ml of methanol for 1.5 hours at room temperature in a hydrogen atmosphere at atmospheric pressure, then the mixture was diluted with dichloromethane and filtered by celite. After evaporation of the filtrate under reduced pressure and crystallization of the residue from a mixture of methanol and ether, the intermediate product 7A was obtained as colorless crystals with a melting point of 140-141 ° C / ct / D2 = -38.5 ° (c = 1 in methanol).

Intermediate 7B was obtained from intermediate 6B as colorless crystals with a melting point of 168 DEG-169 DEG C. (dec.) Using the same procedure.

/ CL / D 2 O = -25.6 ° (c = 1 in methanol).

. 8 8 0 C 1 0 0

Example 23-22 - (2S, 3S) -3- (BOC-phenylalaninyl-norleucyl) amido-4-cyclohexyl-1-dimethylsulfamoylamino-2-butanol.

The title compound was obtained analogously to Example 22 using dimethylsulfamoyl chloride instead of isobutylsulfamoyl chloride.

/ Ct 7ü 2 ° = -11 ° (c = 0.1 in CH 2 Cl 2).

Example 24: (2R, 3S) -3- (N-benzoyl-dehydrophenylalaninyl-nor-10-leucyl) -amido-1-dimethyl sulfamoyl-amino-5-methyl-2-hexanol.

The title compound was obtained / as a mixture of diastereoisomers (about 2: 1) with a melting point. of 194-196 ° C (dec.) analogous to example 21, using N-benzoyldehydrophenylalaninyl-norleucine instead of BOC-Phe-Nle-OH.

Example 25: N- (3-cyclohexylpropionyl) -norleucine.

A solution of 1.92 g of 3-cyclohexylpropionic acid chloride in 22 ml of ether was added to a solution of 1.31 g of norleucine in 22 ml of an 1N solution of sodium hydroxide in water under ice-cooling and the mixture was stirred at 0 for 1 hour ° C. The mixture was then acidified with 0.25N hydrochloric acid, extracted 2x with ether, washed the combined organic phases with a saturated sodium chloride solution, dried by evaporation over sodium sulfate and concentrated under reduced pressure. Crystallization of the residue from a mixture of ether and hexane gave the title compound, which had a melting point of 138-139 ° C.

Example 26: (2S, 3S) -3- (3-cyclohexyl-prop ionyl-norl-eucyl) amido-1-Cbz-amino-4-cyclohexyl-2-butanol.

The title compound was obtained analogously to Example 22 f) as an amorphous product using 3-cyclohexyl-propionyl-norleucine (Example 25), 8 8 0 0 1 0 0 - 23 - instead of BOC-Phe -Nle-OH.

Example 27: (25.35) -3- (3-cyclohexyl-propionyl-norleucyl) amido-1-am ino-4-cyclohexyl-2-butano [5] The title compound was analogous to Example XXII g) as an amorphous product obtained by hydrogenating the compound of Example 26.

Example 28: (25.35) -3- (3-cyclohexyl-propionyl-norleucyl) 10 amido-4-cyclohexyl-1-dimethyl sulf amoylamino-2-butanol.

The title compound was obtained analogously to Example 22 as an amorphous product using (2S, 3S) -3-cyclobexyl-pr (<pionyl-norleucyl) amido-15-amino-4-cyclohexyl-2-butanol and dimethylsulfamoyl chloride, ΓαΐΏ20 = -25.7 ° (c = 1 in methanol) (sintering from 78 ° C).

Intermediates: N ~ (bis-1-naphthylmethyl) -acetyl-Nl-OH.

660 mg of bis- (1-naphthylmethyl) -acetic acid 20 and 280 mg of the methyl ester of norleucine were dissolved in methylene chloride and cooled to 0 ° C. 400 mg of dicyclohexylcarbodiimide were then added and stirred at room temperature for about 15 hours. Then, the precipitated dicyclohexyl-urea was filtered off, the filtrate concentrated by evaporation, the resulting residue dissolved in methanol and mixed with 200 mg of sodium hydroxide (dissolved in water). After 2 hours, the mixture was acidified with 2N-hydrochloric acid, extracted with methylene chloride, dried and evaporated under reduced pressure. The crude product was recrystallized from a mixture of methylene chloride and hexane, mp: 157-159 ° C.

B is- (I-naphthylmethyl) -acetic acid.

4.6 g of sodium were dissolved in 100 ml of ethanol.

Then 16 g of the diethyl ester of malonic acid and 40 g of 1-chloromethylnaphthalene were added. Then, the mixture was refluxed for 24 hours, cooled. 8 8 0 0 1 0 0 - 24 - and the precipitated salts were dissolved by adding ice water. The organic phase was separated, the water phase was extracted with ether and the combined organic phases were dried over magnesium sulfate and concentrated by evaporation. The crude product was added to a mixture of 50ml water, 700ml ethanol and 20ml potassium hydroxide and refluxed for 4 hours. The reaction mixture was then cooled, acidified with concentrated hydrochloric acid and extracted with ether. The ether solution was dried, concentrated by evaporation and the resulting residue was heated to 180-200 ° C. After cooling to room temperature, the glassy residue was dissolved in methylene chloride and precipitated with hexane. M.p .: 171-172 ° C.

(1-tert-butyloxycarbonylamino-6-cyclohexyl-ethyl) - 15 oxiran__

6 g of a sodium hydride dispersion (80% in white oil) were suspended in a mixture of 60 ml of dimethyl sulfoxide and 30 ml of tetrahydrofuran. The suspension was cooled to 0-5 ° C and a solution of 13 g of trimethylsulfonium-20 iodide in 50 ml of dimethylsulfoxide was added dropwise. After 10 min, 50 ml of t-BOC cyclohexylalaninal (0.54 M in toluene) was added and the temperature was allowed to rise to room temperature. The reaction mixture was diluted with ice water, the organic phase was separated, washed 4x with water, dried over magnesium sulfate and concentrated by evaporation. Chromatography on silica gel with a mixture of ether and hexane 10-30% gave the title compound, together with a little of the diastereoisomer (ratio about 3: 1). mp .: 58-59 ° C.

Example 29: 30 (2R, 3S) -3- / N-1-adamentyl) propionyl) norleucyl / -amido-4-cyclohexyl-2-hydroxy-butane-sulfonic acid dimethylamide.

The title compound was obtained analogous to Example 8 using N- / 3- (1-adamantyl) propionyl / norleucine instead of BOCPhePheOH.

/ & _ / D = -25.7 ° (c = 1 in methanol).

.8600100 - 25 -

The starting material adamantyl-propionyl norleucine, m.p .: 119-120 ° C, was obtained analogous to example 25 starting from adamantylpropionyl chloride and norleucine. Example 30: 5 (2R, 3S) -3- (N-B0C-β-cyclohexylalanylhistidyl) -amido-4-cyclohexyl-2-hydroxy-butane-sulfonic acid dimethylamide.

The title compound was obtained analogously to Example 8 by reacting 190 mg of BOC-SO2-10 Chatin-NfMe - Example I - with 201 mg of BOC-Cha-His-OH

in the presence of 70 mg of hydroxybenzotriazole and 102 g of dicyclohexylcarbodiimide. The crude product was chromatographed on silica gel (a mixture of methanol and methylene chloride 1-10% as eluent).

15 / ct / D2 ^ -38.9 ° (c = 0.2 in methylene chloride).

Example 31: (2R, 3S) -3- / N / - (bis- (1-naphthylmethyl) acetyl) histidyl / amido-4-cyclohexyl-2-hydroxy-butane-sulfonic acid dimethyl amide.

80 mg of B0C-SO2-Chatin-N Me2 (Example 1) was reacted analogously to Example 8 with 100 mg of N- (bis- (7-naphthyl-methyl) -acetyl) -NIe-QH in the presence of 50 mg of hydroxybenzotriazole and 44 mg of dicyclohexylcarbodiimide. The crude product obtained was then chromatographed on silica gel using a mixture of methanol and methylene chloride 1-10% as eluent.

/ C & 7d2 ^ = -17.1 ° (c = 0.2 in methylene chloride).

Example 32; (2R, 3S) -3- / N-B0C- β- (2,1,3-benzoxadiazol-4-yl) -30 alanyl-norleucyl / amido-4-cyclohexyl-2-hydroxy-buta n-sulf o nzuu rd imethylam id e.

Analogous to Example 8, 96 mg of B0C-SO2-Chatin-iMe2 (Example I) was reacted with 98 mg of BOC-BOL-HLE-0H in the presence of 35 mg of hydroxybenzotriazole and 50 mg of dicyclohexylcarbodiimide. Then it was recrystallized. 8 8 0 010 0 - 26 - crude product from a mixture of methylene chloride and hexane.

ΛΛ / aTD = -52.4 ° (c = 0.2 in methylene chloride).

Example 33: (2R, 3S) -3- (N- / 2-methoxy-poly (2-ethoxy) acetyl-5-phenylalanyl-norl-eucyl) -amido-4-cyclohexyl-2-hydroxy-butane-sulfonic acid-dimethyl amide.

35 mg of H-Phe-HIS-SO2-Chatin-NMe2 was reacted with 60 mg of a mixture of oligomers of polyethylene glycol acids (molecular weight about 350) in the presence of 13 mg of dicyclohexylcarbodiimide and 10 mg of hydroxybenzotriazolin methylene chloride and purified the reaction product obtained by chromatography on silica gel (using a mixture of methanol and methylene chloride 5-10% as eluent).

Example 34; (2R, 3S) -3- / N- (bis- (1-naphthylmethyl) acetyl) -methionyl / amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethyl amide.

Analogous to Example 8, 165 mg of 20 C-SO2-Chatin-NMe2 (Example 1) was reacted with 203 mg of N- (bis- (7-naphthylmethyl) acetyl) -Met-0H in the presence of 115 mg of hydroxybenzotriazole and 90 mg dicyclohexylcarbodiimide.

/ a7D = -45.3 ° (c = 0.1 in methylene chloride).

Example 35; (2R, 35) -3-7 N- (bis- (1-naphthylmethyl) acetyl) methion (D, L-S-oxyd) yl / amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethyl amide.

20 mg of the title compound of Example 34 were dissolved in glacial acetic acid and 10 mg of sodium perborate were added to this solution. After 1 hour, the mixture was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic phase was dried and evaporated. The title product was obtained as a mixture of dia stereoisomer and (1: 1).

35 «8 fa y ύ 1 ü ö - 27 -

Example 36: (2R, 3S) -3- (N-BOC-phenylalanyl-nor-1-eucyl) amido-4- (1-adamantyl) -2-hydroxy-butane-sulfonic acid dimethylamide.

Analogous to Example 8, 69 mg of B0C-SO2 “adatin-HMe2 was reacted with 61 mg of BOC-Phe-Nl e-OH in the presence of 64 mg of hyiroxybenzotriazole and 62 mg of N-ethyl-N- (3-dimethylaminopropyl) -carbodiimide (EDCI). The crude product was then chromatographed on silica gel using a mixture of hexane and ethyl acetate (1: 1) as the eluent.

The title compound is, according to H-NMR, a mixture of diastereoisomers (2R, 3S: 2S, 3S = 60:40.)

The starting material B0C-SO2 "Adatin-NMe2 (60 to 40 mixture of diastereoisomers) was prepared analogously to Example 1 by reaction of N-t-BOC-adamantylalaninal and methanesulfonic acid dimethylamide.

Example 37: (2R, 3S) -3- (N-B0C-phenylalanyl-norleucyl) amido-5,5-dimethyl-2-hydroxy-hexane-sulfonic acid-20-dimethylamide.

Analogous to Example 8, 235 mg of BOC-SO2 "Neotin-NMe2 was reacted with 180.3 mg of BOC-Phe-K1 e-OH in the presence of 198 mg of hydroxybenzotriazole and 187 mg of EDCI (see Example 36). The crude product Chromatographed on silica gel using a mixture of hexane and ethyl acetate (1: 2) as eluent. Recrystallization from a mixture of hexane and ethyl acetate afforded the title compound as a mixture of slide stereoisomer and (2R, 3S: 2S, 3S = 65:35) with a melting point of 159-163 ° C.

The starting compound B0C-S0 2-Neotin-Me2 (a 65:35 mixture of dia stereoisomer and) was prepared analogously to Example 1 from N-t-BOC-neopental glycinal and methanesulfonic acid with thylamide.

35 .8800100 - 28 -

Example 38: (2R, 3S) -3- (N-BOC-phenylalethyl-norylucyl) -amido-4-cyclohexyl-2-hydroxy-butanone-sulfonic acid-pyrrole-1-amide.

The title product was obtained analogous to Example 8 by reacting BOC-SO--Chatin-py -pyrrolidine with BOC-Phe-Nl-OH. / a / D = -30.0 ° (c = 0.28 in ethanol).

The starting material B0C-SO2_chatin-pyrrolidine 1Θ was obtained analogously to Example 1 from BOC-cyclohexylalaninal and methyl sulfonyl-pyrrolidine.

Example 39; (2R, 3S) -3- (NHBOC-phenylalanyl-nor-1-eucyl) amido-4-cyclohexyl-2-hydroxy-buta n-sulfonic acid-15 piperid ineamide.

The title product was obtained analogously to Example 8 from BOC-SO4 -Chatine-piperidine and BOC-Phe-Nl-OH. / CtU = -32.6 ° (c = 0.27 in ethanol).

The starting material B0C-SO2 ~ Chatin-piperidine 20 was obtained analogously to Example 1 from BOC-cyclohexylalaninal and methylsulfonyl piperidine.

Example 40: (2R, 3S) -3- (N-BOC-phenylalanyl-norl-eucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid (4-25 benzyl) piperazine amide.

The title product was obtained analogously to Example 8 from BOC-SO2-Chatin- (4-benzyl) -piperazine and BOC-Phe-Nl-OH. ?tt ^ 2 = -25.6 ° (c = 0.32 in ethanol). The starting compound B0C-SO2_Chatine- (4-30 benzyl) piperazine was obtained analogously to Example 1 from BOC-cyclohexylalaninal and 4-benzyl-2-methylsulfonylpiperazine.

The starting material 4-b enzyl-1-methyl sulf onylpiperazine was obtained analogous to the methods described in the literature by reaction of N-benzylpiperazine with methanesulfonyl chloride in the presence of pyridine in acetonitrile at a * 8 8 0 C 1 µm - 29 - temperature between -10 and 30 ° C.

Example 41; (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid-5 piperazine amide

To a solution of 110 mg of BOC-Phe-K1 e-SO2-Chatin (4-benzyl) -piperazine (the compound of Example 40) in 120 ml of glacial acetic acid, 20 mg of a 10% palladium on charcoal catalyst was added. The mixture was then hydrogenated at room temperature and atmospheric pressure for 6 hours.

The reaction mixture was filtered over hyflo and the filtrate was evaporated to dryness. The resulting residue was dissolved in an ice-water mixture and made alkaline with a 10% aqueous sodium carbonate solution, extracted with methylene chloride, dried over sodium sulfate, filtered and evaporated to dryness.

Chromatographing on silica gel using methylene chloride containing 10% ethanol as an eluent gave the title product 20 = -22.5 ° (c = 0.2 in ethanol).

Example 42: (2R, 3S) -3- (K-BOC-phenylala nyl-norleucyl) -amido-4-eye lo hexyl -2-hydroxy-bu ta n-sulfoic acid (4-acetyl) piperaz ineamide .

The title product was obtained analogous to Example 8 by reacting BOC-SQ2-Chatin (4-acetyl) -piperazine with BOC-Phe-Nl-OH. _ / t / D = -19.5 ° (c = 0.21 in ethanol).

The starting material B0C-SO2_Chatine- (4-acetyl) -30 piperazine was obtained by hydrogenating B0C-SO2 ~ Chatine- (4-benzyl) piperazine analogously to Example 41 (see Example 40) and the obtained B0C-SO2_Chatinepiperazine analogous to the literature describe methods of reacting with acetyl chloride in the presence of triethylamine in methylene chloride at 0 ° C.

.8600100 '- 30 -

Example 43: (2R, 3S) -3- (R-BOC-phenylala-noryl-nor-cy1) amido-4-cyclohexyl-2-hydroxy-butane-sulfoic acid- / 4- (2,5,8,1 l-tetraoxadodecanyl) carbonyl / -5 piperazineamid e

The title product was obtained by reacting analogous to Example 8 BOC-SO2-Chatine- (4- / 2,5,8,11-tetraoxadodecanyl / carbonyl) -piperazine with BOC-Phe-R1 e-OH. / 07 ^ ° = “16.7 ° (c = 0.12 in ethanol).

The starting material B0C-SO2_Chatine- (4- / 2,5,8,11-tetraoxadodecanyl / -carbonyl) piperazine was obtained in a manner known per se by leaving 500 mg of BOC-SO2-Chatine piperazine (see example 42) react with 260 mg of 2,5,8,11-tetraoxadodecanylcarboxylic acid in the presence of 240 mg of dicyclohexylcarbodiimide and 320 mg of hydroxybenzotriazole in 10 ml of N, N-dimethylformamide.

Example 44: (2R, 3S) -3- (R-BOC-phenylala nyl-norleucyl) -amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid 20 (4-methyl) piperazine amide

The title product was obtained analogous to Example 8 by reacting BOC-SO--Chatin- (4-methyl) -piperazine with BOC-Phe-Nl-OH. ~ 25.0 ° (c = 0.44 in ethanol).

B0C-SO2_Chatine- (4-methyl) -piperazine was obtained analogously to Example 1 from BOC-cyclohexylalaninal and 4-methyl-1 - (methyl-suflonyl) -piper azine.

Example 45: (2R, 3S) -3- (R-BOC-phenylalanyl-norleucyl) amido-4-30 cyclohexyl-2-hydroxy-butane-sulfoic acid-morpholamine amide.

The title product was obtained analogous to Example 8 by reacting BOC-S0 -Chatine morpholide with BOC-Phe-Nl-OH. ~ / ^ = -31.9 ° (c = 0.87 in ethanol).

"8 6 0 0 1 h -31- B0C-SO2" Chatin morpholide was obtained analogously to Example 1 from BOC cyclohexylalaninal enmorpholine. Example 46: (2R, 3S) -3- (N-BOC-phenylalanyl-histidyl) amido-5-4-cyclohexyl-2-hydroxy-butane-sulfonic acid piperidine amide.

The title product was obtained analogous to Example 12 by reacting BOC-SO-Chatine-piperidine (see Example 39) with BOC-Phe-His-OH. / Gt / ^ = -14.1 ° 10 (c = 0.17 in pyridine).

Example 47: (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-5-methyl-mercapto-pentane-sulfonic acid dimethylamide.

The title product was obtained analogous to Example 8 by reacting BOC-SO-mettin-NMe with BOC-Phe-K1-OH. / CtTp = -31.0 ° (e = 0.67 in ethanol).

BOC-SO2-mettine-NMe2 was 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-methyl-sulfinyl-pentane-sulfonic dimethylamide.

Under stirring at 10 ° C, they added 0.01 ml of a 30% hydrogen peroxide solution to a solution of 50 mg of BOC-Phe-Nle-SO2-mettine-NMe2 (the title product of Example 47) in 0.25 ml glacial acetic acid and stir the resulting mixture for an additional 40 min at 10 ° C. The mixture was then evaporated to dryness and the residue was chromatographed on silica gel 30 using methylene chloride containing 7% ethanol as the eluent. The title product obtained is an approximately 1: 1 mixture of diastereoisomers, melt sintering from 82 ° C.

.8800100 - 32 -

Example 49: (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-4-benzyl mercapto-butane sulfoic acid dimethylamide.

The title product was obtained analogous to Example 8 by reacting BOC-CYS (BZL) (0H) CH 2 SO 2 Me 2 with BOC-Phe-Nle-OH. 32.0 ° (c = 0.40 in ethanol).

BOC-CYC (BZL) (0H) CH 2 SO 2 Me 2 was prepared analogously to Example 1 by reacting BOC-S-benzyl-L-cysteinal with methanesulfonic acid dimethyl amide.

BOC-S-benzyl-L-cysteinal was prepared in analogy to methods described in the literature by reacting BOC-5-benzyl-L-cysteine with 3,5-dimethylpyrazole in chloroform 15 in the presence of dicyclohexylcarbodiimide and reduction of the obtained BOC- 5-Benzyl-L-cysteine-3,5-dimethylpyrazolide with diisobutylaluminum hydride in toluene.

Example 50: (2R, 3R) -3- (N-BOC-phenylalanyl-norleucyl) amido-2-hydroxy-4-mercapto-butane-sulfonic acid dimethyl amide.

A solution of 300 mg of BOC-Phe-Nle-CYS (BZL) (0H) CH2SO2NMe2 (the title product of Example 49) in 8 ml of tetrahydrofuran and 20 ml of liquid ammonia at -40 ° C in portions of 60 was added. mg of sodium.

The blue-colored reaction mixture was then stirred for an additional 15 min at -40 ° C, after which ammonium chloride was added in portions until the blue color disappeared. The reaction mixture was evaporated to dryness, the residue was taken up in water and extracted with ethyl acetate. The organic phase was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness.

The residue was chromatographed on silica gel using methylene chloride containing 2% ethanol as the eluent. The product obtained in the title had an 8 8 0 0% - 33 - / Qt = -33.6 ° (c = 0.3 in ethanol).

Example 51: (2R, 3R) -3- (N-BOC-phenylalanyl-norl-eucyl) arnido 2-hydroxy-4-ethyl mercapto-butanesulfonic acid - dimethyl amide.

A solution of 300 mg of BOC-Phe-Nle-Cys (BZL) (OH) CH 2 SO 2 NMe 2 (the title product of Example 49) in 8 ml of tetrahydrofuran and 20 ml of liquid ammonia was added as described in example 50, sodium and then ammonium chloride. After adding ammonium chloride at -40 ° C, a solution of 0.05 ml ethyl bromide in 2 ml tetrahydrofuran was added. The reaction mixture was stirred at -40 ° C for an additional 10 min and then worked up and purified as described in Example 50. This gave the title product.

-20 o / Ot / p = -37.2 (c = 0.36 in ethanol).

Example 52: (2R, 3S) -3- / ~ N- (2,3,4,6-tetra-0-acetyl-β-D-glucosyl-1-O / -isobutyrylf enylalanyl-norleucyl / -amido-4 -cyclohexyl-2-hydroxy-butane-sulfonic acid dimethylamide.

The title product was obtained analogous to Example 8 by reaction of BOC-Phe-Nle-SO4.

Chatin-NMe2 (the title product of Example 10) with (2,3,4,6-tetra-0-acety1-O-D-glycosyl-1-0-) isobutyric acid.

25 onon l l ^ /)) = 39.2 ° (c = 0.68 in ethanol).

(2,3,4,6-Tetra-0-acetyl-β-D-glucosyl-1-0) isobutyric acid was obtained analogously to methods described in the literature by condensation of & -D-acetobromo glucose with 2 2-hydroxy- 2-methyl-propionic acid benzyl ester and then hydrogenation using a 10% palladium on charcoal catalyst.

35 .8600100

Example 53: - 34 - (2R, 3S) -3- / N- (0-D-glucosyl-1-O) -isobutyryl-phenylalanyl-norleucyl / amido-4-cyclohexyl-2-hydroxybutane-sulfonic acid dimethylamide 5 was added to a solution of 150 mg (2,3,4,6-tetra-0-acetyl-0-D-glucosyl-1-0) isobutyryl-Phe-Nle-S02-Chatine-NMe2 (the title product of Example 52) in 5 ml of methanol at room temperature add a solution of 34 mg of sodium in 1.5 ml of methanol. The reaction mixture was then stirred at room temperature for 30 min, neutralized with 100 ml of the acidic ion exchanger Amberlyst 15, filtered and evaporated to dryness. The residue was chromatographed on silica gel using methylene chloride containing 10% ethanol as the eluent. The resulting title product 15 had an IPO-~-41.6 ° (c = 0.30 in ethanol).

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

402 mg of B0C-Phe-His-0H, 332 mg (2S, 3S) -3-amino-1- (n-butyl-carbamoylamino) -4-cyclohexyl-2-butanol hydrochloride (het. intermediate 8A) and 0.28 ml of triethylamine in 6.7 ml of dimethylformamide with 0.23 ml of diphenylphosphoryl azide. The mixture was then stirred at room temperature for 19 hours and concentrated by evaporation under high vacuum. The residue was taken up in ethyl acetate and washed successively with aqueous tartaric acid, a saturated sodium hydrogen carbonate solution and a sodium chloride solution, then dried over anhydrous sodium sulfate and concentrated by evaporation. By chromatography of the residue (silica gel, 4 bar, a mixture of methylene chloride and ethanol, 19: 1), the title compound, m.p. 141-142 ° C, /GC = -11.8 ° (c = 1 in methanol).

35. 8 8 0 ü i. ,

Example 55: - 35 - (2R, 3S) -3- (N-B0C-phenylalaninyl-histidyl) amidö-1- (n-butylcarbamoylamino) -4-cyclohexyl-2-butanol.

The title compound was obtained analogously to Example 54 using (2R, 3S) -3-amino-1- (n-butylcarbamoylamino) -4-cyclohexyl-2-butanol hydrochloride (8B), m.p .: 148-9 ° C, -14.5 ° (c = 1 in methanol).

Intermediates 8A and 8B used in Examples 54 and 55 can be prepared as follows: 10 a) (3S) -3-B0C-amido-4-cyclohexyl-1-nitro-2-butanone____ (intermediate 1D)

See example 22a.

b) (2S, 3R) ~ and (2R, 3S) -3-BOC-amino-4-cyclohexyl-15-nitro-2-butanol (intermediates 9A and 9B)

See example 22b.

c) (2S, 3S) - and (2R, 3S) -1-amino-3-B0C-amino-4-cyclohexyl-2-butanol-20 (intermediates 10A and 10B)

See example 22c.

d) (2S, 3S) -3-B0C-amino-1- (n-butylcarbamoyl) amino-4-cyclohexyl-2-butanol (intermediate IA) 25 A solution of 1.15 g of intermediate IOA was mixed ( free base) in 5 ml anhydrous tetrahydrofuran under ice-cooling with 0.45 ml n-butyl isocyanate, stirred the mixture at room temperature for one hour and evaporated under reduced pressure. The residue was taken up in ethyl acetate, washed successively with 0.25 N hydrochloric acid, a saturated sodium bicarbonate solution and a sodium chloride solution, dried over sodium sulfate and concentrated by evaporation.

The title compound was obtained as a raw foam.

35 (2R, 3S) -3-BOC-amino-1- (n-butylcarbamo yl) amino-4-cyclohexyl-2-butanol (intermediate 1IB) on an analog δf f ''. The result is obtained as a raw foam from intermediate 10B.

e) (2S, 3S) -3-amino-1- (n-butylcarbamoyl) amino-4-cyclohexyl-2-butanol hydrochloride (intermediate 8A) 5 1.39 g of the crude intermediate 11A was stirred for 1 hour at room temperature in 14 ml of a mixture of glacial acetic acid and concentrated hydrochloric acid (9: 1) and concentrated by evaporation under high vacuum. The residue was reacted 2x resp. taken up in toluene and evaporated to dryness again. The title compound 10 was obtained as an amorphous foam.

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

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

A solution of 273 mg (2S, 3S) -1-amino-20 3- (N-BOC-phenylalaninyl-norleucyl) -amido-4-cyclohexyl-2-butanol (intermediate 12A) in 10 ml anhydrous tetrahydrofuran was mixed at 0 ° C with 0.055 ml of isopropyl isocyanate, stirred at room temperature for 1 hour and concentrated by evaporation under high vacuum.

Crystallization of the residue from a mixture of methylene chloride, methanol and hexane gave the title compound, m.p .: 167-168 ° C (dec.),% -16.2 ° (c = 1 in methanol).

The 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 at a temperature of 2 - 5 ° C were added to a solution of 5.28 ml of triethylamine and 6.3 g of intermediate 10A, obtained according to the procedure 8800100 - 37 of Example 55, in 120 ml of dichloromethane and stirring the resulting solution at room temperature for 30 min. It was then diluted with dichloromethane and washed with 0.25N hydrochloric acid, a saturated solution of sodium bicarbonate in water and water. The organic phase was dried over sodium sulfate and evaporated under reduced pressure. Chromatographing the residue on silica gel using a mixture of toluene and ethyl acetate (3: 1) as an eluent to obtain the intermediate 13A as a slightly yellowish oil,

Intermediate I3B was obtained as an oil from intermediate 10B using the same procedure, b) (28.38) - and (2R, 3S) -3-amino-1-CBZ-amino-4-cyelohexyl-2-butanol_ 15 (intermediates 14A and 14B)

See example 22e.

c) (2S, 3S) - and (2R, 3S) -3- (B0C-phenylalaninyl-norleucinyl) amino-1-CBZ-amino-4-cyclohexyl-2-butanol-20 (intermediates I5A and 15B)

See example 22f.

d) (2S, 3S) - and (2R, 3S) -1-amino-3- (B0C-phenylalinyl-norleucyl) -amino-4-cyclohexyl-2-hutanol (intermediates I6A and I6B) 25 See example 22g .

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-hydroxy- was mixed benzotriazole in 2.6 ml dimethylformamide at 0 ° C with 104 mg NjN'-dicyclohexylcarbodiimide and 0.07 ml triethylamine, first stirring at 0 ° C for 1 hour and then at room temperature for 15 hours. 8 C 0 f ·. t-38- cooled again to-° C and filtered off the resulting dicyclohexyl-urea. The filtrate was evaporated under high vacuum and the residue was taken up in methylene chloride and washed successively with 0.25N hydrochloric acid, a saturated sodium hydrogen 5 carbonate solution and water. The organic phase was dried over sodium sulfate and concentrated by evaporation. Chromatography of the residue (silica gel, 6 bar, a mixture of methylene chloride and ethanol 19: 1) gave the amorphous, title compound, 2O q, 18.0 (c = 1 in 10 methanol) ).

The intermediates used in Example 57 can be obtained as follows: a) N-3-cyclohexylpropionyl-norleucine

A solution of 1.31 g of L-norleucine 15 in 22 ml of ether and 22 ml of a 1N sodium hydroxide solution at 0 ° C was mixed with 1.92 g of 3-cyclohexylpropionic acid chloride, stirred at 0 ° C for 1 hour, then acidified with 0.25N hydrochloric acid and extracted 2x with ether. The combined organic phases were washed with a saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. Crystallization of the residue from a mixture of ether and hexane gave the title compound, m.p. 138 DEG-139 DEG (dec.).

b) (2S, 3S) -3-am ino-3- (iso pro py1carbamo yl) am ino-4-cyclohexyl-2-butanol-HCl_

(2S, 3S) -3-BOC-amino-1- (isopropyl-carbamoyl) amino-4-cyclohexyl-2-butanol analogous to example 55d) was obtained, using the intermediate 10A and isopropyl isocyanate. The BOC protecting group was cleaved from the product obtained analogous to Example 55e) and thus the amorphous title compound was obtained.

.8800100 - 39 -

Example 58; (2S, 3S) -3- (N-BOC-phenylalaninyl-norleucyl) amido-1 - / bis- (dimethylamino) / phosphorylamido-4-cyclohexyl-2-butanol 5 A solution of 273 mg ( 2S, 3S) -3- (N-BOC-phenylalaninyl-norleucyl) -amido-1-amino-4-cyclohexyl-2-butanol (intermediate I6A, see example 56 d)) and 0.07 ml

triethylamine in 3.4 ml anhydrous tetrahydrofuran at 0 ° C

with a solution of 0.076 ml of phosphoric acid bis (dimethylamide) chloride in 3.4 ml of anhydrous tetrahydrofuran. The resulting suspension was mixed at room temperature with an additional 6.8 ml of tetrahydrofuran and 3.4 ml of hexamethylphosphoric acid triamide and a. Spatula 4-dimethylaminopyridine and stir the clear solution at room temperature for 5 days. Then, the solution was concentrated under high vacuum: the residue was washed in ethyl acetate, washed successively with ice cold 0.25N hydrochloric acid, a saturated sodium hydrogen carbonate solution and sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. Crystallization of the residue from a mixture of methylene chloride and hexane afforded the title compound, m.p. 171-172 ° C (dec.), & / Β = 27.7 ° (c = 1 in chloroform).

Example 59: (2S, 3S) -3- (N-B0C-phenylalaninyl-norleucyl) -! - (N-benzy1-4-piperidinocarbamoyl) amino-4-cyclohexyl-2-butanol.

The title compound was obtained analogous to Example 56, using N-benzyl-4-30 piperidino isocyanate instead of isopropyl isocyanate, mp .: 166-8 ° C, = 13.5 ° (c = 1 in methanol).

. 8 8 0 C 1 e o * »- 40 -

Example 60: (25.35) -3- (N-BOC-phenylalaninyl-norleucyl) amido-1- (4-piper id inocarbamoyl) amino-4-cyclohexyl-2-butanol.

200 mg of the title compound of Example 59 were hydrogenated in 20 ml of methanol for 20 hours at room temperature in a hydrogen atmosphere in the presence of palladium (10% on active charcoal), then the suspension was filtered through Celite. and concentrated the filtrate by evaporation. Crystallization of the residue with a mixture of methanol and ether gave the title compound, mp: 173-175 ° C = 15.5 ° (c = 1 in methanol).

Example 61; 15 (2S, 3S) -3- (N-BOC-phenylalaninyl-norleucyl) amido- 1- (dimethyl-carbamoyl) amino-4-cyclohexy1-2-butanol

The title compound was obtained analogous to Example 56, using dimethyl-20-carbamoyl chloride and triethylamine in place of isobutyl isocyanate, mp: 157-158 ° C / Ct7p = -10.0 ° (c = 2 in methanol).

Example 62: (25.35) -3- (N-BOC-phenylalaninyl-norleucyl) amido-1- (isopropyl-carbamoyl) -isopropylamino-4-cyclohexyl-2-butanol.

A solution of 189 mg of N-BOC-phenylalaninyl-norleucine, 172 mg (2S, 3S) -3-amino-1- (isopropyl-carbamoyl) -isopropylamino-4-cyclohexyl-2-butanol (intermediate 17) was mixed and 150 mg of 1-hydroxybenzotriazole in 3.4 ml of dimethylformamide at 0 ° C with 99 mg of N-ethyl-N'-iS-dimethylamino-propylicarbodiimide hydrochloride and 0.07 ml of triethylamine, stirred at 0 ° C for 1 hour and for 20 hours at room temperature and then concentrated in a rotary evaporator at 30 ° C. The residue was taken up in methylene chloride, washed successively with 0.25N cold hydrochloric acid, a saturated sodium hydrogen carbonate, 8 8 0 0 1 0 0 - 41 solution and water, dried over sodium sulfate and concentrated by evaporation. Chromatographing the residue (silica gel, 5 bar, a mixture of methylene chloride and ethanol) gave the title compound »= 5“ 5.0 ° (c = 1 in methanol).

The intermediate 17 used in this example can be obtained 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 were refluxed for 36 hours, then the cooled suspension was filtered and the filtrate was concentrated by evaporation. The title compound (amorphous) was obtained by chromatography of the residue (silica gel, 4 bar, a mixture of methylene chloride, methanol and concentrated ammonia 90: 9: 1).

b) (2S, 3S) -3-N-BOC-amino-1- (isopropylcarbamoyl) -isopropyl-amino-4-cyclohexyl-2-butanol. A solution of 591 mg of the product described above was mixed in 6 ml of tetrahydrofuran at 0 ° C with 0.2 ml of isopropyl isocyanate, stirred at room temperature for 20 hours and then concentrated by evaporation. The amorphous title compound was obtained by chromatography (silica gel, 5 bar, a mixture of methylene chloride and ethanol 39: 1).

Example 63: (2S, 3S) -3- / N- (1-adamantyl-propionyl) -norueyl] -1-isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol_ The title compound was obtained analogously to Example 57 using N- (1-adamantyl-propionyl) norleucine instead of N- (3-cyclohexyl-propionyl) norleucine m.p .: 230-231 ° C, / ¾_ / ^ = -24.5 ° (c = 1 in dimethylformamide).

35, 88 0 Dl 0 0

Example 64; * * - 42 - (2S, 3S) -3- (N-BOC-norleucyl) -amido-1- (isopropyl-carbamoyl) amino-4-cyclohexyl-2-butanol The title compound was analogous to example 57 obtained, using N-BOC-norleucine instead of N- (3-cyclohexylpropionyl) norleucine, mp .: 225-226 ° C (dec.)

Example 65: (25.35) -3-norleucyl) amido-1- (isopropylcarbamoyl) -10 amino-4-cyclohexyl-2-butanol hydrochloride.

339 mg of the product of Example 64 was treated with 3.4 ml of a mixture of glacial acetic acid and concentrated hydrochloric acid and the reaction mixture was then worked in an analogous manner to Example 55e. The title compound 15 was obtained as a colorless foam.

Example 66: (25.35) -3-N- / 1-benzoyl-amino-2- (1-naphthyl) propenoyl-norleucyl / amino-4-cyclohexyl-1- (isopropylamino-carbamoyl) amino-2-butanol 20 Mixed a solution of 168 mg of the product of Example 65, 120 mg of 5- (1-naphthylmethylidene) -2-phenyl-4-oxazolone (azalactone of 1-naphthyldehyde and N-benzoyl-glycine) and 0.056 ml of triethylamine in 2.7 ml of chloroform with a spatula point of 4-dimethylaminopyridine, the mixture was refluxed for 4 hours and then concentrated by evaporation. Chromatography of the residue (silica gel, 6 bar, ethyl acetate) gave the amorphous compound, titled "20 o, =" 58.2 (c = 1 in methanol).

Example 67: 30 (2S, 3S) -3- / N- (bis (1-naphthyl-methyl) acetyl) norleucyl / amino-4-cyclohexyl-1- (isopropylcarbamoyl) -amino-2-butanol.

The title compound was obtained analogously to Example 57, using N- (bis (1-naphthyl-35 methyl) acetyl) norleucine instead of N- (3-cyclohexylpropionyl) -8 8 0 010 0 -43- norleucine, mp .: 173-174 ° C = -52.0 ° (c = 1 in methanol).

Example 68; (2S, 3S) -3- (N-cyclopentyl-carbonyl-phenylalaninyl) -norleucyl) amino-4-cyclohexyl-1- (isopropyl-5-carbamoyl) -amino-2-butanoI.

By coupling K-cyclopentylcarbonyl-phenyl-alanine and (2S, 3S) -3- (norleucyl) amido-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol hydrochloride (example 65), analogous to example 57, the title compound, m.p .: 213-215 ° C (dec.), = -18.2 ° (c = 0.5 in methanol),

Example 69: (2S, 3S) -3- (K-BOC-phenylalininyl-idyl) amido-1 - (isopropyl-carbamoyl) am ino-4-cyclohexyl-2-butanol The title compound was 15 obtained as an amorphous powder, analogous to example 57 using K-BOC-phenylalaninyl-histidine instead of K- (3-cyclohexylpropionyl) norleucine = -10.8 ° (c = 1 in methanol).

Abbreviations: In the previous examples the following abbreviations were used: SO ^ Adatin (2R, 3S) -4- (I-adamantyl) -3-amino-2-hydroxy-butanesulfonic acid, SO2 Chatin (2R, 3S) -3- amino-4-cyclohexyl-2-hyiroxy-butanesulfonic acid, SÜ2Sta (2R, 3S) -3-amino-2-hydroxy-5-methyl-hexanesulfonic acid, SO2-Aminochatine (2R, 3S) -2,3-diamino- 4-cyclohexyl-butane-sulfonic acid, 30 SO2-deoxychatin (3S) -3-amino-4-cyclohexyl-butanesulfonic acid, SO2-Dioxolan (2R, 3S) -3-amino-4- (1,4-dioxaspiro / 4 1,5-undec-8-yl) -2-hydroxybutanesulfonic acid, S02 -NChatine (2R, 3S) -3-amino-4- (21-oxocyclohexyl) -2-22-hydroxybutanesulfonic acid, SO2 -olChatin (2R, 3S) -3-amino-4- (4'-hydroxycyclohexyl) -2-hydroxy-butanesulfonic acid,. 8 £ 0 C 1 ö Ü f * - 44 - SC> 2 (2-Na pht ine) (2R, 3S) -3-am ino-2-hydroxy-4- (2-naphthyl) - butanesulfonic acid, S02Neot ine (2R, 4S) -3-amino-5,5-dimethyl-2-hydroxy-hexanesulfonic acid, 5 Achps (3S, 4S) -4-amino-5-cyclohexyl-3-hydroxy-pentanesulfonic acid,

Ach ips (1S, 3S, 4S) -4-amino-5-cyclohexyl-3-hydroxy-1-iso propyl-pentane sulfonic acid, SC ^ -Mettine (2R, 3S) -3-amino-5-methyl mercapto -2-hydroxy 10 pentanesulfonic acid, SO2_Mettine (0) (2R, 3S) -3-amino-5-methyl sulfinyl-2-hydroxypentane su lphonic acid,

Cys (BZL) (0H) CH2S02 (2R, 3R) -3-amino-4-benzyl-mercapto-2-hydroxy-butanesulfonic acid, 15 Cys (Et) (0H) CH2S02 (2R, 3R) -3-amino-4- ethyl mercapto-2-hydroxybutanesulfonic acid and

Cys (0H) CH2SO2 (2R, 3R) -3-amino-4-mercapto-2-hydroxybutanesulfonic acid

The compounds of the invention have a pharmacological action. They can be used as a medicine.

As can be seen from standard pro, they have typical actions, especially for enzyme inhibitors.

The inhibitory activity with respect to a specific enzyme, of course, depends on the entire peptide structure. The compounds described above, which are particularly suitable as inhibitors of the renin activity, when applied to a human synthetic tetradecapeptide substrate in a concentration of 10 - 10 µM, inhibit 50% of the enzyme activity of pure human renin by the method from F. Cumin and med. (Bioch. Biophys.

Acta 913, 10-19 (1987)).

According to the antibody-trapping method of K. Poulsen and J. Jorgensen (J. Cl in. Endocrin. Metab. 39/1974 / 816-825), they inhibit human plasma renin activity at a concentration of 10 - 10 µM. .

The title compounds of Examples 12, diastereoisomer A (lowest inhibitory concentration I b 0 D 1 0 i * s - 45 - 0.17 µm / l, highest inhibitory concentration 17 µM / l = 1, 7 nM / l), 23 (lowest inhibiting concentration 0.75 rIM / 1, highest inhibiting concentration 75 nM / l, IC, .q = 7.5 nM / l), II (lowest inhibiting concentration 0.75 rIM / I , highest inhibiting concentration 75 nM / l 5 IC ^ q = 31 (lowest inhibiting concentration 0.8 hM / 1, highest inhibiting concentration 80 nM / l; IC ^ q = 8.0 nM / l), 67 (lowest rattling concentration 1.1 hM / l, highest inhibitory concentration 110 riM / l; IC ^ q = H hM / 1) and 54 (lowest inhibitory concentration 1.6 nM / l, highest inhibitory concentration 160 nM / l; 10 IC50 = 16 nM / l) are recommended for the prevention and treatment of hypertension and heart failure.

The compounds according to the invention are therefore suitable for the prevention and treatment of conditions characterized by poor enzyme function and for which an inhibition of the enzymatic activity is indicated.

For example, as renin inhibitors, they are suitable for use in the prevention and treatment of hypertension and heart failure ("decompensatio cordis").

For the aforementioned applications, the dose to be administered depends on the compound used, the mode of administration and the desired treatment. In general, satisfactory results are obtained when the compounds are administered in a daily dose of from 0.02 mg / kg to about 10 mg / kg body weight of the animal. For larger mammals, the recommended daily dose is between about 1 mg and about 500 mg, suitably, for example, administered orally in a dose from 0.25 mg to about 500 mg 1-4 times daily or in a slow-release form.

The compounds of the invention can be administered either in free form or, if acidic or basic groups are present, in a pharmacologically acceptable salt form. Such salt forms have the same degree of action as the free forms and can be obtained in a known manner. The present invention also relates to pharmaceutical preparations containing one or a number of compounds of the invention in free form and / or in a pharmaceutically acceptable salt form, if desired, together with pharmaceutically acceptable adjuvants and / or carriers. . Such pharmaceutical preparations can be formulated for use in enteral, for example, oral, for example, as tablets, or for in, for parenteral, administration, for example, as injectable solutions or suspensions.

i, 8800100

Claims (11)

1. Compounds of Formile I, wherein A represents an acyl group of formula VII, wherein Rg is a straight or branched chain alkyl group having 1-10 carbon atoms, which may be optionally substituted by alkoxy with 1-5 carbon atoms or aryloxy with 6-10 carbon atoms, a cycloalkyl group with 3-7 carbon atoms, a (C 2-10) cycloalkyl] yl ”(C 1-6) alkyl group, an aryl group with 6-10 10 carbon atoms, a 5 or 6 member-containing heteroaryl group having 1 or 2 nitrogen atoms, oxygen or sulfur atoms or one nitrogen atom and an oxygen atom and / or a sulfur atom, or a heteroaryl (C 1-4) alkyl group, in which the heteroaryl portion consists of 5 or 6 members and 1 or 2 nitrogen atoms, oxygen or 15 sulfur atoms or one nitrogen atom and an oxygen atom and / or one sulfur atom bsrat, a straight or branched chain alkoxy group and 1 to 5 carbon atoms or a (Cg_jQ) aryl (Cj_2) alkoxy group or a group with formula Rir.0 (CH „CH„ 0) (CH „) -, luzz nzm where Rjq is an alkyl group with straight or branched chain and 1-5 is 20 carbon atoms, n is an integer from 1-20 and m is an integer from 1-5, or a group of formula VIII, wherein R represents a hydrogen atom or an acetyl group, or wherein A represents a group of formula XI wherein 25 is a straight or branched chain alkyl group with 1 to 5 carbon atoms or an aryl group with 6 to 10 carbon atoms and Rg and Rg are a hydrogen atom, a straight or branched chain alkyl group chain and 1-5 carbon-30 atoms or an aryl group with 6-10 carbon atoms, Rj represents a hydrogen atom or a straight or branched chain alkyl group and 1-5 carbon atoms, B and C, which may or may not equivalent, represent a bond or a group of formula XII, wherein Rj has a predefined meaning. 8800100, - - 48 - and Rj j is a hydrophilic or lipophilic amino acid side chain, wherein B and C are not simultaneously a bond D may be a bond or -0-, -N- or -CH- II. R 1 represents R 1 5, wherein R 1 has a predefined meaning, R 2 represents a straight or branched chain alkyl group and 1 to 10 carbon atoms, a (C 1 -H 2-ycloall yl (C 1 -N) alkyl group, the cycloalkyl portion of which is optionally substituted is a (C 8 -JQ) aryl (C 1 -J) alkyl group or a heteroaryl (C 1 -J) alkyl group, in which the heteroaryl portion has 5 or 6 members barat and one or two nitrogen atoms, oxygen or sulfur atoms, and one nitrogen atom and one oxygen atom and / or one sulfur atom bsrat, or a group of formula XIII, wherein R15 represents a hydrogen atom, an alkyl group with 1-4 carbon atoms or the benzyl group, s = 0 or 1 and p = 1 or 2, R ^ is a hydrogen atom, a hydroxyl group, an amino group or a group of formula -OCOR ^, in which R2 has a previously defined meaning, R1 and R1 are, which may or may not be the same, or a hydrogen atom, a straight or branched chain alkyl group of 1 to 5 carbon atoms, a (C 8 -JQ> -aryl- (C 1 -J) - alkyl- or a heteroaryl- (C 1-4) -alkyl group, wherein the heteroaryl portion 25 consists of 5 or 6 members and contains one or two nitrogen atoms, oxygen or sulfur atoms or one nitrogen atom and one oxygen atom and / or one sulfur atom or a group of formula XIV, wherein R ^ a straight or branched chain alkyl group with 1 to 5 carbon atoms or a straight or branched chain hydroxyalkyl group with 1 to 5 carbon atoms, R 1 ^ a hydroxyl group, a straight or branched chain alkoxy group with 1 to 5 carbon atoms an amino group or an alkylamino group with 1 to 5 carbon atoms, wherein the alkyl group may be straight or branched, represents an aminomethylpyridyl group or a benzyl group, or wherein the group of formula XV represents a group of formula. 6 8 0 010 0 - 49 - XVI, XVII, XVIII or XIX, wherein R 1 is a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, a benzyl group or a group of formula XX, wherein R 1g is an alkyl group of 1 -4 carbon atoms or a (C 1-4) alkoxy (OC 2 H 2) -CH 2 - group, where 5 q is an integer of 2-5, Y represents a group of formula XXI, XXII or XXIII, wherein R ^ and R ^ have the meanings given above. Compounds according to claim 1 of the formula Compounds according to claim I of formula Iz, wherein: 2 A a tert-butyloxycarbonyl or bis (1-naphthyl-methyl) -acetyl group, 35. a bond or a phenylalaninyl or β-cyclo-8800100 * '. - 50 - hexylalaninyl group, 2C histidine, leucine or norleucine, YZ a group of formula XXI or XXII, 2 R a hydrogen atom, 2 A compound according to claim 1 selected from: (25.35) -3- (N-BOC-F enylalaninyl-histyl) amido-1- (n-butyl-carbomoylamino) -4-cyclohexyl-2-butanol, ( 2R, 3S) -3- (N-BOC-F enylalaninyl-hi stidyl) amido-1- (n-butyl-carbamoylamino) -4-cyclohexyl-2-butanol, 20 (2S, 3S) -3- (N- BOC-Phenylalaninyl-norleucyl) amido-1- (isopropyl-carbamoyl) amino-4-cyclohexy1-2-butanol, (25.35) -3- / N- (3-cyclohexylpropionyl) -norleucyl / amido-1- (isopropyl-carbamoyl ) amino-4-cyclohexyl-2-butanol, (25.35) -3- (N-BOC-phenylalaninyl-norleucyl) amido-1- / b is-25 (dimethylamino) / phosphorus-4-cyclohexyl-2-butanol , (25.35) -3- (N-B0C-Phenylalaninyl-norleucyl) -1- (N-benzyl-4-piperidino-carbamoyl) amino-4-cyclohexyl-2-butanol, (25.35) -3- (N-BOC -Phenylalaninyl-norleucyl) amido-1- (4-piper i-dinocarbamoyl) amino-4-cyclohexyl-2-butanol, 30 (2S, 3S) -3- (N-BOC-Phenylalaninyl-norleucyl) amido-1- ( dimethyl carbamoyl) amino-4-cyclohexyl-2-butanol, (25.35) -3- (N-BOC-Phenylalaninyl-norleucyl) amido-1- (isopropyl-carbamoyl) -isopropyl amino-4-cyclohexyl-2-butanol, (25.35) -3- / N- (1-Adamantyl) -propionyl) -norleucyl / -1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol,. 8 8 0 0 1 0 0 - 51 - (2S, 3S) -3- (N-BOC-Norleucyl) -amido-1 - (iso propyl carbamoyl) amino-4-cyclohexyl-2-butanol, (25.35) -3 - (Norleucyl) amido-1- (isopropylcarbamoyl) amino-4-cyclohexyl-2-butanol hydrochloride, 5 (2S, 3S) -3-N- / l-benzoyl-amino-2- (l-naphthyl) propenoyl - norleucyl / amino 4-cyclohexyl-1- (isopropylaminocarbamoyl) amino-2-butanol, (25.35) -3- / N- (Bis (1-naphthylmethyl) acetyl) -norleucyl7-amino-4-cyclohexyl-1- ( i so propylcarbamoyl) amino-2-butano 1, 10 (2S, 3S) -3- (N-cyclopentyl-carbonyl-phenylalaninyl-norleucyl) amino-4-cyclohexyl-1 - (isopropyl-carbamo yl) amino-2- butanol, (25.35) -3- (N-BOC-phenylalaninyl-histidyl) amido-1- (isopropyl-carbamo yl) -am ino-4-cyc 1 obexyl - 2-but ano 1, (25.35) -3- ( tert-butyloxycarbonylamino) -4-cyclohexyl-2- 15 hydroxybutanesulfonic acid dimethylamide, (2R, 3S) -3- (tert-Butyloxycarbonylamino) -4- (1,4-dioxaspiro-l 4,5 / undec-8-yl) -2 -hydroxybutane sulfonic acid dimethylamide, (2R, 3S) -3- (tert.-Butyloxycarbonylamino) -4-cyclohexyl-2-azido-butane sulfone acid dimethylamide, 20 (2R, 3S) -3- (tert-butyloxycarbonylamino) -2-hydroxy-4- (2-naphthyl) -butanesulfonic acid imethylamide, (2R, 3S) -3- (tert-butyloxycarbonylamino) -2-hydroxy-5-methyl-hexane-sulfoic acid imethylamide, ((3S, 4S) -4- (tert-butyloxycarbonylamino) -5-cyclohexyX-3-25 hydroxy-pentane-sulfonic acid dimethylamide, (1S, 3S, 4S ) -4- (tert.-Butyloxycarbonylamino) -5-cyclohexyl-3-ydroxy-1-iso propyl-pentane-sulf acidic imethylamide, (2R, 3S) -3- (N-BOC-F enylalanyl-phenylalanyl) ) amido-4-cyclohexyl-2-hydroxy-butanesulfuric acid imethylamide, 30 (2R, 3S) -3- (N-BOC-cyclohexylalanyl) amido-4-cyclohexyl-2-hydroxy-butane sulfonic imethylamide, (2R, 3S) -3- (N-B0C-Phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxybutanesulfonic acid imethylamide, (2R, 3S) -3- (N-B0C-β-Cyclohexylalanyl-norleucyl) amido- 4-35 cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide, δ ga ciop 1 * - 52 - (2R, 3S) -3- (K-B0C-phenylalanyl-histidyl) amido-4-cyclohexyl-2-hydroxy'but t su If im acid the yla m ide, (2R, 3S) -3- / K- (BIS- (1-Kaphtylmethyl) acetyl) norleucyl-7-amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide, 5 (2R, 3S) -3- (K-BOC -F enylalanyl-norleucyl) amido-2-amino-4-cyclohexyl-butanesulfic acid dimethylamide, (2R, 3S) -3- (N-BOC-F enylalanyl-norl-eucyl) amido-4 - (], 4-dioxa-spiro / 4,5 / undec-8-yl) -2-hydroxy-butanesulfomuric dimethylamide, (2R, 3S) -3- (N-BOC-Phenylalanyl-norleucyl) amido-4- (4-oxacyclo-10 hexyl) -2 -hydroxy-butanesulfonic acid imethylamide, (2R, 3S) -3- (K-BOC-Phenylalanyl-norl-eucyl) amido-4- (4'-hydroxy-cyclohexyl) -2-hydroxy-butanesulfonic acid dimethylamide, • (3S, 4S) -3 - (K-BOC-Phenylalanyl-norleucyl) amido-5-cyclohexyl) -3-hydroxy-pentanesulfonic acid dimethylamide, 15 (1R, 3S, 4S) -4- (K-BOC-Phenylalanyl-norl-eucyl) amido-5 -cyclohexyl-3-hydroxy-isopropyl-pentanesulfonic acid dimethylamide, (2R, 3S) -3- (K-BOC-Phenylalanyl-norl-eucyl) amido-2-hydroxy-4- (2-naphthyl) -butanesulfonic acid dimethylamide, (2R 3S) -3- / N- (BIS- (1-naphthylmethyl) acetyl) -norleucyl7 20 amido-2-hydroxy-5-methyl-hexane ulphonic acid dimethylamide, (25.35) - and (2R, 3S) -3- (B0C-Phenylalanyl-norleucyl) -amido-4-cyclohexyl-1-isobutyl-sulf amoylamino-2-butanol, (25.35) -3- (BOC-Phenylalaninyl) -norleucyl) amido-4-cyclo-hexyl-1-dimethyl sulfamoylamino-2-butanol, 25 (2R, 3S) -3- (K-Benzoyl-dehydrophenylalaninyl-norleucyl) -amido-1-dimethyl sulf amoyl-amino-5 -methyl-2-hexanol K- (3-cyclohexylpropionyl) -norleucine (25.35) -3- (3-cyclohexyl-propionyl-norleucyl) amido-1-Cbz-amino-4-cyclohexyl-2-butanol, 30 (2S, 3S) -3- (3-cyclohexyl-propionyl-norleucyl) amido-1-amino-4-cyclohexyl-2-butanol, (25.35) -3- (3-cyclohexyl-propionyl-norleucyl) amido-4-cyclohexyl-1d imethyl sulf amoylamino-2-butanol, (2R, 3S) -3- / K (1-adamantyl) propionyl) norleucyl7amido-4-cyclo-35 hexyl-2-hydroxy-butanesulfonic acid dimethylamide, (2R, 3S) -3- ( K-B0C- (cyclohexylalanylhistidyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide, .8800100 -53- (2R, 3S) -3- / K- (BIS- (I-naphthylmethyl) acetyl) h istidyl / amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimet hylamide, (2R, 3S) -3- / N-BOC- β- (2,1,3-benzoxadiazol-4-yl) alanyl-norleucy1 / amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid-5-dimethylamide, ( 2R, 38) -3 - ((N- / 2-methoxy-poly (2-ethoxy) acetyl / phenylalanyl-norleucyl)) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethyl amide, (2R, 3S) - 3- / N- (BIS- (1-Naphthylmethyl) acetyl) methionyl / 10-amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylaniide, (2R, 3S) -3- / K- (BIS- (1-Naphthylmethyl) acetyl) ) methion (D, LS oxide) yl / amido-4-cyclohexy1-2-hydroxy-butanesulfonic acid imethyl-amide, (2R, 3S) -3- (K-BOC-F enylalanyl-norl-euc yl) amido-4- (1-adamant yl) - 15 2-hydroxy-butanesulfonic acid dimethylamide, (2R, 3S) -3- (K-BOC-F enylalanyl-norl-euc yl) amido-5,5-dimethyl-2-ydroxy-hexanesu If unsoured imethylamide, (2R, 3S) -3- (N-B0C-Phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid pyrolide inamide, 20 (2R, 3S) -3- (N-BOC- Phenylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxybutanesulfonic acid piperidine amide, (2R, 38) -3- (K-BOC-Phenylalanyl-norleucyl) ami do-4-cyclohexyl-2-hydroxybutanesulfonic acid piper idinamide, (2R, 3S) -3- (K-BOC-F enylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxybutanesulfonic acid (4-b enzyl) piperaz inamide, (2R, 3S) -3- (K-BOC-F enylalanyl-norl-eucyl) amido-4-cyclohexyl-2-hydroxybutane sulfoic acid p iper az inamide, (2R, 3S) -3- ( N-BOC-F enylalanyl-norleucyl) amido-4-cyclohexyl-2-hydroxylbutanesulfonic acid (4-acetyl) piperazinamide, 30 (2R, 3S) -3- (N-BOC-phenylalanyl-norleucyl) amido- 4-cyclohexyl-2-hydroxybutanesulfonic acid / 4- (2,5,8,11-tetraoxadodecanyl) carbonyl / piper az inam id e7 (2R, 35) -3- (N-BOC-Phenylalanyl-norucyl) amido- 4-cyclohexyl-2-hydroxybutanesulfonic acid-4-methyl) piperazinamide, (2R, 38) -3- (K-BOC-Phenylalanyl-norleucyl) amido-4-cyclohexyl-35 2-hydroxybutanesulfonic acid morpholine amide, .880 ::. - - 54 - (2R, 3S) -3- (N-BOC-Phenylalanyl-histidyl) amido-4-cyclohexyl-2-hydroxybutanesulfonic acid piper id ineam id e, (2R, 3S) -3- (N- BOC-Phenylalanyl-norleucyl) amido-2-hydroxy-5-methyl-mercapto-pentanesulfonic acid imethylamide, 5 (2R, 3S) -3- (N-B0C-Phenylalanyl-norleucyl) amido-2-hydroxy-5-methyl- sulf inyl pentane sulf acidic imethylamide, (2R, 3R) -3- (N-BOC-Phenylalanyl-norleucyl) amido-2-hydroxy-4-benzyl-mercapto-butanesulfonic acid imethylamide, (2R, 3R) -3- (N- BOC-Phenylalanyl-norl-eucyl) amido-2-hydroxy-4-10 mercaptobutanesulfic acid dimethylamide, (2R, 3R) -3- (N-B0C-Phenylalanyl-norleucyl) amido-2-hydroxy-4-ethyl mercapto-butane if acid dimethyl amide, ( 2R, 3S) -3- / N- (2,3,4,6-Tetra-O-acetyl - & - D-glucosyl-1-0) -iso-butyryl-phenylalanyl-norleucyl / amido-4-cyclohexyl- 2-hydroxy-15-butanesulfonic acid dimethylamide and (2R, 3S) -3- / N- (pD-Glucosyl-1-O) -isobutyryl-phenylalanyl-norleucyl / amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid-dimethyl- amide. 5 R ^ 'have the previously defined meanings to be reacted with a compound of formula VI, wherein Y, R ^ and R ^ have the previously defined meanings and X is a halogen atom, in particular a chlorine atom, d) a compound of formula Id, wherein 5. Process for preparing a nitrogen-20 compound, characterized in that a compound of formula Ia, wherein A, B, C, D, Y, Rj, R2, R ^ and R ^ have the meanings defined above and R1 represents a hydrogen atom, a hydroxyl group or a group of formula -OCX ^, wherein R2 has a previously defined meaning, prepared by reacting a compound of formula II, wherein A, B and C have the previously defined meanings with a compound of formula III, wherein R 1, R 2, R 1 ', R 1, R 1, Y and D have the meanings defined above, b) a compound of formula Ib, wherein A, B, C, D, Y, Rj, R2, Rl and Rl. have the previously defined meanings, prepared by reducing a compound of formula IV, wherein A, B, C, D, Y, Rj, R2, R ^ and R ^ have the previously defined meanings, c) compounds of formula Ic, wherein 35 A, B, C, Y, Rj, R2, R ^ ', R ^ and R ^ have the previously defined, 8600 100 - 55 - meanings and Dr represents an -O- or -N- group, f R1 in which Rj has a previously defined meaning prepared by a compound of formula V, wherein A, B, C, D ', Rj, Rp and 5 R2 a cyclohexylmethyl or 1-adamantylmethyl group, 2 R ^ a hydroxyl or amino group, 2 R ^ a hydrogen atom or the methyl group, 2 R ^ a hydrogen atom or the isopropyl or isobutyl group, or the group of formula XXV a pyrrol idyl, piperidinyl or a morpholinyl group and D2 represent a / NH or ^) CH isopropyl or ^ CE ^ group. Pharmaceutical preparations containing one or more compounds according to any one of claims 1-4 in a pharmaceutically acceptable form, optionally together with a pharmaceutical carrier or diluent. 5 A method of preparing or manufacturing a medicament for treating hypertension or decompensation cordis, characterized in that a pharmaceutical preparation according to claim 6 is used for this. 8 ,. A method of preventing or treating hypertension or decompensation cordis, characterized in that it is indicated that such treatment requires administering a therapeutically effective amount of one or a number of compounds according to claim 1. 9. Compounds according to any one of claims 15 1-4 for use as a pharmaceutical. 10. Methods as described in the description and / or examples. A, B, C, D, Y, Rj, RgT, R ^, R ^, Rj ^ and p have the previously defined meanings and s' = 1, prepared by oxidation of a compound of formula Ie, wherein A, B, C, D, Y, Rj, R ^ f. R,., Rj ^ and P have the meanings defined above, e) an equation with formula If, wherein A, B, C, D, Y, Rj, Rg, R ^, R ^ and p have the meanings defined above, prepared by compounds of formula Ig, wherein A, B, C, D, Y, Rj, R ^, R ^, R ^ and p have the meanings defined above to cleave off the benzyl group, f) a compound of formula Ih, wherein A, B, C, D, Y, Rj, R ^, R ^, R ^ and p have the meanings defined above, prepared by entering an alkyl group into compounds of formula If, as defined above, g) compounds of formula II, wherein A, B, C, D, Y, R 1, R 2 and R 2 have the previously defined meanings, prepared by catalytically cleaving the benzyl group from compounds of formula I 1, wherein A, B , C, D, Y, Rj, R2 and Rg have the meanings defined above, h) a connection with formile Ik, wherein C, D, Y, Rj - R ,. and R ^ - RQ have the previously defined meanings prepared by reacting a compound of formula IX, wherein R ^, Rg and R ^ have the previously defined meanings, with a compound of formula X, wherein C, D, Y Rj - R ^ have the meanings defined above and, if desired, convert precursors of compounds of formula I to compounds of formula I. Ö $!} 0 1 0 0 • r '- 56 - 10 Iy, where Ay is a tert-butyloxycarbonyl, pivaloyl, bis (I-naphthyl-methyl) acetyl, benzoyl or 1-adamantylcarbonyl group, "By a bond or a phenylalanine or β-cyclo -15 hexylalanine group, Cy histidine, norleucine, phenylalanine or leucine, y Y a group of formula XXI or XXII, y Rj hydrogen or the methyl group, y R 2 isobutyl, benzyl, cyclohexylmethyl or 1-adamanyl-methyl, R 3 y hydroxyl, amino or groups of formula ococh3 or ococ (ch3) 3, y R, hydrogen, methyl, i-propyl or 25-butyl ,. - n-butyl, Rj.y methyl, i-propyl, i-butyl or n-butyl or the group of formula XXIV a pyrrolidinyl, piperidinyl or a morpholinyl group and Dy ^ NH, i-propyl, ^ CEL · or ^ CH-i-propyl-30 '' Si / groups. 11. Shaped therapeutic preparations obtained by using a method according to any one of the preceding claims. δ s o o i & r-