DE3839401A1 - N-HETEROCYCLIC ALCOHOL DERIVATIVES - Google Patents

Abstract

Compounds of the formula <IMAGE> are disclosed. These compounds are inhibitors of renin and therefore useful as cardiovascular agents. The symbols have the following definitions: <IMAGE> R1 is a fully saturated, partially saturated, or unsaturated monocyclic N-heterocyclic ring of 5 or 6 atoms containing at least one N atom or a bicyclic ring in which said N-heterocyclic ring is fused to a benzene ring, R3, R4 and R5 are independently selected from hydrogen or optically substituted alkyl, m, m' and m'' are zero or an integer from 1 to 5; n is an integer from 1 to 5; p and p' are zero or 1; g is an integer from 2 to 5; R10 is -(CH2)m'-R6'; A and A' are a single bond or -(CH)-(CH2)m''-R6''; and R6, R6' and R6'' are independently selected from hydrogen, alkyl, aryl, and cycloalkyl, or R6 and R6' taken together with the atom to which they are bonded may form a ring of 3 to 5 carbons.

Description

The invention relates to N-heterocyclic alcohol derivatives and especially those compounds that are known as renin Inhibitors are suitable.

The invention relates to new compounds, the Inhibi gates of the enzyme renin and are therefore a medicine suitable substances with an effect on the cardiovascular system. The compounds of the invention including their phy Siologically compatible salts have the general formula I.

in the X one of the remains

means
R₁ is a fully saturated, partially saturated, or unsaturated monocyclic N-heterocyclic ring with 5 or 6 atoms which contains at least one N atom or a bicyclic ring in which such an N-heterocyclic ring is fused to a benzene ring . The N-heterocyclic ring can also contain an oxygen or sulfur atom or up to three additional N atoms. The N-heterocyclic ring is through an available carbon atom to the group

bound.

An available N atom in the N-heterocyclic ring can be linked with an N-protecting group such as one of the residues

be substituted. Similarly, an available carbon atom in the monocyclic ring or an available carbon atom in the benzene Part of the bicyclic ring with a lower alkyl radical or one of the remains

be substituted.

Preferred N-heterocyclic rings are the residues

R₂ means one of the residues

or 2,4-dinitrophenyl, a hydrogen atom, a Niederal kylrest or one of the residues

in which Y represents the group -CH₂-, an oxygen or sulfur atom, or N-R₉, a is an integer from 1 to 4, and b is an integer from 1 to 4, with the proviso that the sum from a and b is an integer from 2 to 5, or such a heterocyclic ring in which a carbon atom is substituted with a lower alkyl radical.
R₃ and R₅ independently represent a hydrogen atom, a lower alkyl radical, a halogen atom-substituted lower alkyl radical or one of the radicals

R₄ represents a hydrogen atom, a lower alkyl radical, a halogen atom-substituted lower alkyl radical or one the leftovers

R₆, R′₆ and R′′₆ independently represent a hydrogen atom, an alkyl, aryl, pyridyl or cycloalkyl radical, or R₆ and R′₆ together with the atom to which they are attached form a ring with 3 to 5 carbon atoms.
m, m ′ and m ′ ′ have the value 0 or are an integer from 1 to 5.
n is an integer from 1 to 5.
p and p ′ have the value 0 or 1.
g is an integer from 2 to 5.
R₇ means one of the residues

R₈ represents the radical 2,4-dinitrophenyl or one of the radicals

R₉ represents a hydrogen atom, a lower alkyl radical or one of the remains

R₁₀ represents a radical CH₂) _{m ′} R′₆.
A and A 'represent a single bond or the rest

The invention relates to the compounds of the above Formula I given, agents and the method of use such compounds as antihypertensive agents.  

The expression used to define various symbols Lower alkyl means unbranched or branched residues with up to 7 carbon atoms. Similarly, the terms never mean deralkoxy and lower alkylthio radical such lower alkyl radicals, which are bound to an oxygen or sulfur atom. The preferred lower alkyl radicals are unbranched or ver branched C₁-C₅ chains.

The term cycloalkyl radical means saturated C₄-C₇ rings, with the residues cyclopentyl and cyclohexyl most preferred are moving.

The term halogen atom means chlorine, bromine or Fluorine atom.

The term halogen-substituted lower alkyl means those lower alkyl radicals in which one or more water atoms are replaced by chlorine, bromine or fluorine atoms, such as the trifluoromethyl group, which is preferred, or the Groups pentafluoroethyl, 2,2,2-trichloroethyl, chloromethyl and bromomethyl.

The term aryl radical means a phenyl, 1-naphthyl or 2-naphthyl group, a monosubstituted phenyl, 1- Naphthyl or 2-naphthyl group, the substituent being a C₁-C₄ lower alkyl, C₁-C₄ lower alkylthio or C₁-C₄-never deralkoxy radical, a halogen atom, a hydroxy or amino group, the radical -NH-alkyl, the alkyl radical 1 to 4 C- Has atoms, or the radical is -N (alkyl) ₂, the Al kylreste have 1 to 4 carbon atoms or a di- or tri substituted phenyl, 1-naphthyl or 2-naphthyl group, where the substituents are methyl, methoxy or methylthio groups, halogen atoms, or hydroxyl groups.

The term heterocyclic radical means completely saturated or unsaturated rings with 5 or 6 atoms, the one or two oxygen and sulfur atoms and / or one to four N-  Atoms contain, with the proviso that the total number of Heteroatoms in the ring is not larger than 4. The heteroring is bound via an available carbon atom. Before Preferred hetero radicals include the groups 2-thiazolyl, 2- and 4-imidazolyl, 2- and 3-thienyl, 2- and 3-furyl and 2-, 3- and 4-pyridyl. The term hetero residue also includes bicycli rings in which the oxygen, sulfur and N atoms containing 5- or 6-membered ring on a benzene ring is condensed. The preferred bicyclic ring is Benzimidazolyl group.

Compounds of formula I are obtained by coupling an amine of formula II

with a compound of formula III

in a solvent, for example dimethylformamide and in the presence of a coupling agent, for example dicyclo hexylcarbodiimide.

To prepare the amine of formula II, the starting ma material H-R₁ mixed with n-butyllithium, whereby a Ver binding of formula IV

is obtained. The compound IV is then with a Aldehyde of the formula V  

(in the Prot an amino protective group, for example tert.- Butoxycarbonyl means) to the protected amine of the formula VI

implemented. Compound VI can be in a solvent, such as ethyl acetate, by known methods, for example by treatment with hydrogen chloride from the protecting group are freed, whereby an amine of formula VII

is obtained. The amine of formula II can then be prepared be protected by the amine of formula VII with an N-protected Amino acid of formula VIII

in the presence of a coupling agent, for example dicyclo hexylcarbodiimide is implemented and then protection group by known methods, for example by Be act with hydrogen chloride in the case of a tert-butoxy carbonyl protecting group, is split off.

For the preparation of compounds of formula I in which X den rest

means, a compound of formula IX

(The production of this connection is, for example, in Tetrahedron Letters, 26 (1970), 5611-5616) a coupling reaction with a diethyl malonate derivative of Formula X

in a solvent, for example tetrahydrofuran and in the presence of a base, for example sodium hydride a compound of formula XI

implemented.

Those present in a solvent such as aqueous ethanol Compound XI is mixed with a strong base, such as sodium hydroxide, and then treated with hydrochloric acid with heating, whereby the compounds of formula III, in which X the rest

means to be provided. By implementing with Compound II, as indicated above, corresponds to that corresponding compounds of formula I obtained.  

For the preparation of compounds of the formula I in which X means one of the residues

means R₅ the rest

means and n has the value 1, a compound of formula XII

(the preparation of this compound is described in J. Amer. Chem. Soc. 90 (1968), 3495) in the presence of Palla dium-on-activated carbon as a catalyst, which results in a Compound of formula XIII

is obtained.

The compound XIII is with a compound of formula XIV

or of formula XV

in the presence of a catalyst such as hydroxybenzotriazole and from dicyclhexylocarbodiimide to the ethyl ester of the formula XVI  

or the formula XVII

implemented.

The compound XVI or XVII is in a solvent, such as aqueous ethanol, with a strong base, for example Sodium hydroxide, which creates compounds of the formula III, in which X is one of the residues

means R₅ the rest

means and n has the value 1, can be obtained. By reaction with compound II, the corresponding compounds of formula I are obtained as indicated above.

In another embodiment, the manufacture of Compounds of formula I in which X is one of the radicals

means R₅ the rest

means and n has a value of 1 to 5, a dialkyl malonate of the formula XVIII

in a solvent, for example tetrahydrofuran, with Sodium hydride added and then with a compound of the formula XIX

R₅-Cl or R₅-Br (XIX)

implemented, whereby a compound of formula XX

is obtained.

Compound XX is in a solvent such as aqueous Ethanol, with a strong base, for example sodium hy droxid, and then mixed with hydrochloric acid, whereby a compound of formula XXI

is obtained.

The compound XXI is with benzyl alcohol and 4-dimethyl aminopyridine in a solvent, for example methyl len chloride, in the presence of bicyclohexylcarbodiimide delt, whereby the ester of formula XXIII

is obtained with diisopropylamine and n-butyllithium in a solvent such as tetrahydrofuran and then with tert-butyl bromoacetate to a compound of the formula XXIII  

is implemented.

Compound XXIII is in a solvent such as methyl Lenchlorid with a strong acid, for example trifluor added acetic acid, whereby a compound of formula XXIV

is obtained.

Compound XXIV is in a solvent such as Tetrahydrofuran, in a coupling reaction with one of the Re ste

in the presence of a catalyst such as hydroxybenzotriazole or dimethylaminopyridine, and dicyclohexylcarbodiimide to compounds of the formula III in which X is one of the radicals

means R₅

means and n has a value from 1 to 5, implemented. By reaction with compound (II), the corresponding compounds of formula I are provided as indicated above.

For the preparation of compounds of formula I in which X den rest

means a connection of For mel XXV

with dimethylamine in the presence of formaldehyde to a ver Binding of formula XXVI

implemented.

Compound XXVI is used to provide acrylic acid with the formula XXVII

heated.

Compound XXVII is in a solvent such as Piperidine, with a compound of formula XXVIII

to a compound of formula XXIX,

namely compounds of formula III, in which X represents the rest

means implemented. By implementing with the  Compound II, as indicated above, correspond provided compounds of formula I.

In another embodiment, a connection of the Formula XXVII by reaction with ethanol in the presence of Dicyclohexylcarbodiimide and a catalyst such as dimethyl aminopyridine, are esterified, thereby connecting the Formula XXVIIa

is obtained.

The compound XXVIIa is then in a solvent such as Ethanol, with a compound of formula XXVIII in the presence a base, such as sodium ethylate, to a compound of For mel XXIXa

implemented.

The compound XXIXa is mixed with sodium hydroxide, where is obtained through connection XXIX.

If X does the rest

means the verb dung XXIX in a solvent, for example methanol, mixed with hydrogen peroxide. If X does the rest

means the compound XXIX in a solution medium, such as methanol, mixed with potassium monopersulfate. The Compounds of formula III obtained can with Ver bond II, as indicated above, to compounds of Formula I, in which X is one of the radicals

means to be implemented.

For the preparation of compounds of formula I in which X den rest  

means and p and p 'have the value 1, a compound of formula XXX

with the acrylic acid of formula XXVII in dichloromethane and in Presence of bis (trimethylsilyl) acetamide to the compound of the formula III, in which X represents the rest

means implemented.

By reaction with compound II, as above indicated, the corresponding compounds of formula I he hold.

For the preparation of compounds of formula I in which X den rest

means and p and / or p 'have the value 0, a compound of the formula XXX, in which p and p' have the value 1, with a compound of the formula XXXI

implemented. The compound obtained is then acrylic acid of the formula XXVII to the compound of the formula III in which X the rest

means and either p or p ′ or both have the value 0, implemented. As indicated above, the corresponding compounds of the formula I are provided by reaction with the compound (II).

For the preparation of compounds of formula I in which X den rest

means a compound of formula XXXII

with an acrylic acid of formula XXVII to a compound of the formula XXXIII

implemented.  

By reacting compound XXXIII with compound II as stated above, the corresponding verb receive formulations of formula I.

For the preparation of compounds of the formula I in which X HS means a compound of formula I in which X is the rest

means treated with an ammonium hydroxide solution.

For the preparation of compounds of formula I in which X den rest

means a compound of formula XXXIII with a Ammonium hydroxide solution added, whereby a connection of the Formula XXXIV

is obtained.

The compound of formula XXXIV is esterified, for example wise by treatment with ethanol and dicyclohexylcarbodi imide in the presence of a catalyst such as dimethylaminopyri din, whereby a compound of formula XXV

is obtained.

The compound XXXV is mixed with chlorine gas in a solvent, such as aqueous acetic acid, whereby the compound of the formula XXXVI  

is obtained with an amine of the formula XXXVII

to a compound of formula XXXVIII

is implemented.

The compound XXXVIII is made with a strong base, such as Sodium hydroxide, saponified, whereby a compound of For mel XXXIX

is obtained.

By reacting compound XXXIX with compound II as stated above, the corresponding verb of formula I provided.

In the above reactions, if one of the radicals R₃, R₄ and R₅ a radical

wherein the aryl radical is one with one or more hydroxy or ami phenyl, 1-naphthyl or 2-naphth substituted by n groups thyl group, a residue

being the hete rocyclo radical is an imidazolyl group or one of the radicals  

means the hydroxy, amino, imidazole, mercaptan, Carbonyl or guanidyl group protected during the reaction will. Suitable protecting groups include the groups benzyl oxycarbonyl, tert-butoxycarbonyl, benzyl, benzyhydryl, tri tyl, tosyl and a nitro to protect a guanidyl group group. The protecting group becomes after the completion of the reaction by hydrogenation, acid treatment or by other known ones Process split off.

The different, in the above procedures Peptide intermediates used are in the literature known or can quickly be obtained by known methods be put; see. for example: The Peptides, Vol. 1 Major Methods of Peptide Bond Formation, Academic Press (1979).

Preferred compounds of the invention are those of the formula I, in the X one of the residues

means R₁ one of the radicals

means R₃ is an unbranched or branched C _3-5 lower alkyl radical or one of the radicals

or

where n is an integer from 1 to 3;
R₄ is a hydrogen atom, an unbranched or branched lower alkyl radical having up to 5 carbon atoms or one of the radicals below

or

means and R₅ a unbranched or branched never deralkylrest with up to 5 carbon atoms or one of the radicals

means.

The most preferred compounds are those compounds of the formula I in which R₆ is a cycloalkyl radical, a Mor means pholinyl, ethyl or ethoxy group, R₁ one of the residues

means R₃ one of the radicals

means R₄ one of the residues

means, and R₅ one of the residues

means.

The compounds of formula I form with a variety of inorganic and organic acid salts. The non-toxic physiologically acceptable salts are preferred, although other salts are also used to isolate or purify the Product are useful. Such physiologically acceptable Salts include those with hydrochloric acid, methanesulfonic acid, Schwe Rock acid, acetic acid and maleic acid formed salts. The  Salts are created by reacting the product with an equiva lenten amount of acid in a medium in which the Salt fails.

The compounds of formula I contain asymmetric Centers when one or all of the radicals R₃, R₄ and R₅ none Mean hydrogen atom, as well as on the carbon atom, to the the -OH group is attached. Thus the connections of formula I in diastereomeric forms or in mixtures from present. In the procedures described above can racemates, enantiomers or diastereomers as Aus gear materials are used. When making diastereo meren products can this by usual chromatographi separation or fractional crystallization will.

The compounds of formula I and their pharmaceutically ver Inactive salts are active substances that lower blood pressure. You hem the conversion of angiotensinogen to angiotensin I and are therefore suitable for lowering or alleviating Hypertension associated with angiotensin. Due to the effect of Enzyme renin on angiotensinogen, a pseudoglobulin in the Blood plasma, angiotensin I is produced. Angiotensin I is by the angiotensin converting enzyme (ACE) in Angio tensin II converted. The latter is a blood pressure stone annoying substance that causes various hypertension Forms in various mammals, for example the men is viewed. The compounds of the invention reach into the reaction sequence angiotensinogen → (renin) → Angiotensin I → (ACE) → Angiotensin II by using Renin inhibit and the formation of the hypotensive sub Reduce or switch off angiotensin II. Thus by the application of an agent that is an inventive moderate connection or a combination of the invention Contains compounds in angiotensin-dependent hypertension a mammal, for example humans. A Single dose or preferably 2 to 4 divided daily Thu  sen based on about 100 to 1000 mg, preferably about 250 to 500 mg per body weight are suitable to the Lower blood pressure. The substance is preferably taken orally applied, but it can also be applied parenterally, for example subcutaneously, intramuscularly, intravenously or intraperitoneally.

The compounds of the invention can be used to treat Hypertension also in combination with a diuretic formu be lated.

A compound according to the invention and a diuretic holding combination product can be a mammal be applied in an effective amount that a total daily dosage of about 1000 to 6000 mg, before preferably about 3000 to 4000 mg of a Ver bond and about 15 to 300 mg, preferably about 15 to 200 mg of the diuretic. Examples of diuretics, their Use together with a compound according to the invention is considered are thiazide diuretics, for example wise chlorothiazide, hydrochlorothiazide, flumethiazide, Hy droflumethiazide, bendroflumethiazide, methylclothiazide, tri chloromethiazide, polythiazide or benzthiazide, but also Ethacrynic acid, Tricrynafen, Chlorthalidon, Furosemid, Muso limin, bumetanide, triamterene, amiloride and sprionolactone and Salts of these compounds.

The compounds of formula I can be used in the Lowering blood pressure for oral administration in agents such as Ta tablets, capsules, or elixirs, to be formulated while for parenteral administration in sterile solutions or Suspensions can be formulated. About 100 to 500 mg a compound of formula I are according to the phar pharmaceutical practice together with a physiologically ver inert carrier, carrier, excipient, binder, con preservative, stabilizer and flavoring in one Unit dosage form mixed. The active ingredient in these  There is such an amount of agents or preparations that a suitable dosage in the above Area is reached.

The invention is illustrated by the following examples wrote. However, the examples are not limitative of The invention.

Example 1 N - [(S) -2-cyclohexyl-1 - [(R) -hydroxy- (1H-imidazol-2-yl) -me thyl] ethyl] -N2- [4- (4-morpholinyl) -1,4-dioxo-2- (phenylmethyl) butyl] -L-histidinamide, isomer B, dihydrochloride A. (phenylmethyl) succinic acid, 1-ethyl ester

A mixture of 16.3 g (70 mmol) of α- ethyl- α- benzalsuccinate (prepared as described by Cohen and Milovanovic, J. Amer. Chem. Soc., 90 (1968), 3495) and 1.2 g of 10% Palladium on activated carbon in 250 ml of absolute ethanol was hydrogenated for 24 hours at 2,109 atmospheres in a Parr apparatus, then filtered and concentrated. The residue was dissolved in ether, 70 mmol of dicyclohexylamine was added and the mixture was filtered. Hexane was added to the filtrate and the crystals formed upon cooling to -30 ° C were collected. The solid was recrystallized from ethyl acetate to 10.7 g of the title compound A, dicyclohexylammonium salt. The salt was dissolved in ethyl acetate and washed with 1N aqueous hydrochloric acid. The ethyl acetate layer was dried and concentrated. The residue was dissolved in ether and extracted with a sodium bicarbonate solution. The combined aqueous layers were acidified by the addition of concentrated hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated to 6.2 g (38% yield) of the title compound as a pale yellow oil which solidified overnight.

B. α - (Phenylmethyl) - q -oxo-4-morpholine butanoic acid ethyl ester

A mixture of 3.05 g (15 mmol) of the title compound A and 1.3 ml (15 mmol) of morpholine in 50 ml of tetrahydrofuran and 5 ml of dimethylformamide became 2.1 g (15 mmol) of 1-hydroxybenzotriazole hydrate and 3.1 g Add (15 mmol) dicyclohexylcarbodiimide. The mixture was stirred at 25 ° C for 16 hours, then filtered and concentrated. The residue was dissolved in ethyl acetate, washed successively with 1N hydrochloric acid and a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. 3.6 g of the residue was subjected to flash chromatography on 10 g of Merck silica gel, eluting with 1: 1 hexane: ethyl acetate. 3.4 g (75%) of the title compound B were obtained as a clear colorless oil with an R _f value of 0.25.

C. α - (Phenylmethyl) - γ- oxo-4-morpholine butanoic acid

A mixture of 3.3 g (10.8 mmol) of title compound B and 11 ml (11 mmol) of 1 N aqueous sodium hydroxide solution in 11 ml absolute ethanol was stirred at 25 ° C for 22 hours finally concentrated under reduced pressure. The back was dissolved in water, washed with ether and washed through Add 50 ml of 1N hydrochloric acid acidified and then three times extracted with ethyl acetate. The combined extracts were Dried over anhydrous magnesium sulfate and concentrated trier, and the residue was umcri from ethyl acetate / hexane installed. There were 2 g (67%) of the title compound C as white solid of mp 133-134 ° C obtained.  

D. (S) -2 - [[(1,1-dimethylethoxy) carbonyl] amino] -2-phenylme ethyl 1-ethanol

To a solution of 10 g (37.7 mmol) of N - [(1,1-dimethyl ether oxy) -carbonyl] -L-phenylalanine in 40 ml of dimethylformamide the 4.75 g (56.6 mmol) solid sodium bicarbonate and 16 g (113 mmol) methyl iodide added. The mixture will last 12 hours heated under argon at 40 ° C, then cooled and to 150 ml Divided water and 250 ml ether. The organic Layer is washed twice with 100 ml of 2% aqueous sodium bicarbo nat, 100 ml 2% aqueous sodium bisulfate, 2 × with 100 ml Rinsed water and saline, then over magnesium sulfate dried and under reduced pressure to 10.5 g of N - [(1.1- Dimethylethoxy) carbonyl] -L-phenylalanine methyl ester as an oil concentrated.

A solution in which 10 g (35.8 mmol) of N - [(1,1-dimethyl ether oxy) -carbonyl] -L-phenylalanine methyl ester in a mixture of 190 ml of tetrahydrofuran and 190 ml of absolute ethanol are dissolved, 6.09 g (143.2 mmol) of lithium chloride are added ben. The homogeneous solution obtained is 5.42 g (143.2 mmol) Sodium borohydride added, and the reaction mixture is stirred for 24 hours under argon at room temperature. The Reaction mixture is used in the next step of about 700 ml ether for rinsing the filter cake fil trated. The filtrate obtained is 3 × with 200 ml of water and rinsed with 200 ml of saline, over magnesium sulfate dries and under reduced pressure to 9 g of crude product centered. By recrystallization from ether / hexane Obtained 7.59 g of the title compound D of mp 94-96 ° C.

Analysis for C₁₄H₂₁NO₃
calc .:
C 66.90, H 8.42, N 5.57
found:
C 66.80, H 8.57, N 5.38

E. [(S) -2-cyclohexyl-1- (hydroxymethyl) ethyl] carbamic acid - 1,1-dimethyl ethyl ester

A solution of 7 g (27.8 mmol) of the title compound D in 70 ml Methanol is made up to 500 mg using 5% rhodium Aluminum as a catalyst at 3.867 atmospheres on one Pair of shakers hydrogenated. After 17 hours, the reak tion mixture filtered and under reduced pressure to 7.36 g the title compound E concentrated as an oil.

Analysis for C₁₄H₂₇NO₃
calc .:
C 65.33, H 10.57, N 5.44
found:
C 64.94, H 10.55, N 5.23

F. (S) - (2-Cyclohexyl-1-formylethyl) carbamic acid, 1,1-dime ethyl ethyl ester

A solution of 4.6 g (17.9 mmol) of the title compound E in 40 ml of methylene chloride is added to a mixture of 8 g (19 mmol) of the Dess-Martin periodic reagent (manufactured according to Dess et al., J. Org. Chem., Vol. 48 (1983), 4155) and 1.5 g (19 mmol) tert-butanol in 70 ml methylene chloride, which before addition Was stirred overnight at room temperature, added. A weak exothermic reaction (up to 32 ° C) occurs. After 30 Minutes, the reaction mixture is poured into 800 ml of ether frightens, whereby a white solid is separated. A Mixture of 31.1 g (126 mmol) sodium thiosulfate pentahydrate in 200 ml of saturated sodium bicarbonate solution Stirring added. The two-phase mixture obtained is ge separates and the organic phase with water, 2 × with 100 ml saturated sodium bicarbonate, water and saline solution washed, dried over magnesium sulfate and under reduced pressure to 3.8 g of the title compound F as colorless oil concentrated.  

G. [(1S) -1- (cyclohexylmethyl) -2-hydroxy-2- [1- [(phenylmethoxy) methyl] -1H-imidazol-2-yl] ethyl] carba midic acid, 1,1-dimethylethyl ester

A 2.5 M n-butyllithium solution in 12 ml (31 mmol) hexane a solution of 5.3 g (28 mmol) of 1 - [(phenylmethoxy) -me thyl] -1H-imidazole in 90 ml of tetrahydrofuran at -70 ° C under Argon added. After stirring for 15 minutes, 3.6 g (14 mmol) the title compound F in 36 ml of tetrahydrofuran trop in a period of 5 minutes at one Reaction temperature from -65 to -70 ° C added. After 2 Hours at -70 ° C, the bath is heated to 0 ° C, and 25 ml saturated ammonium chloride are added first, then 300 ml ether and 2 × 50 ml water and finally Saline is added and it is then over magnesium dried sulfate and concentrated under reduced pressure. 8.4 g of the crude product obtained are subjected to a flash Chromatographed by using acetone: petroleum ether (1: 4) is eluted. 580 mg of the title compound G (fast moving isomer), 370 mg of a mixed frak tion and 2 g of a slowly moving isomer.

H. [R- (R *, S *)] - α - (1-amino-2-cyclohexylethyl) -1- [(phenylmethoxy) methyl] -1H-imidazole-2-methanol

A solution of 3.92 g (8.83 mmol) of the title compound G in 200 ml of ethyl acetate is cooled to 0 ° C, and chlorine water Material gas is blown through the solution for 30 minutes. The Ge Mix is then stirred for 3.5 hours while it is at room temperature is heated and then under reduced pressure 3.56 g (97%) of the title compound H as a white powder con centered.

I. L-histidine methyl ester dihydrochloride

A 38.75 g (240 mmol) solution in the ice bath L-histidine in 500 ml of methanol becomes 27.2 ml (375 mmol)  Thionyl chloride added in drops. After 15 minutes the ice bath removed and the reaction mixture at 1 hour Room temperature stirred. After heating for 48 hours The reaction mixture is refluxed under reduced pressure concentrated. 48.93 g of the separated crystals are filtered using methanol as the wash solution. After dilution of the methanolic solution with ether receive a further 10 g of the title compound I of mp 208-209 ° C. ten.

J. N, 1-bis [(1,1-dimethylethoxy) carbonyl] -L-histidine methyl ester

A suspension of 24.2 g (100 mmol) of the title compound I 28 ml (200 mmol) of triethylamine and 48 g (220 mmol) of di-tert-butyl dicarbonate were added. After 3.5 Filtration is carried out for hours and the methanoli concentrated solution under reduced pressure. The back Stand is taken up in chloroform and with 10% lemons acid washed. The crude product results from crystallization from isopropyl ether 23.1 g of the title compound J of F. 88- 95 ° C. After evaporating and redissolving 15.75 g of courage 10 g (45.9 mmol) of di-tert. butyl dicarbonate added. After the reaction mixture was stirred overnight, it is taken up in chloroform and washed with 10% citric acid. The backlog results after chromatography on silica gel 6.4 g of the homogeneous Title connection J.

K. N - [(1,1-dimethylethoxy) carbonyl] -3 - [(phenylmethoxy) - methyl] -L-histidine methyl ester monohydrochloride

A solution of 24.7 g (66.9 mmol) of the title compound J in 156 ml of dry methylene chloride become 11.6 ml (88.6 mmol) Benzylchloromethyl ether added, and the reaction mixture is stirred for 5 hours at room temperature. According to the Konzen tration under reduced pressure and dissolving in 100 ml  Ethyl acetate crystallize 17.85 g (65%) of the title compound dung K from F. 152-153 ° C.

L. N - [(1,1-dimethylethoxy) carbonyl] -3 - [(phenylmethoxy) - methyl] -L-histidine

18.66 g (43.8 mmol) of the title compound K are dissolved in 50 ml Dissolved methanol. 92 ml of 1 N aqueous sodium hydroxide followed by 83 ml of water. After the reaction gene has been kept at room temperature for 90 minutes, it will further diluted by adding 650 ml of water and by acidified aqueous hydrochloric acid to a pH of 4.5. The aq The solution is extracted with chloroform. The chloroform solution is evaporated and 15.13 g (92%) residue of F. 155-157 ° C are obtained as crystals from ethyl acetate.

M. [(1,1-dimethylethoxy) carbonyl] -N - [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- [1- (phenylmethoxy) me thyl] -1H-imidazol-2-yl] ethyl] -3 - [(phenylmethoxy) -me thyl] -L-histidinamide

A solution of 3.06 g (7.35 mmol) of the title compound H, 1.13 g (7.35 mmol) of 1-hydroxybenzotriazole hydrate and 2.76 g (7.35 mmol) of the title compound L in 20 ml of tetrahydrofuran 2.06 ml (14.7 mmol) of triethylamine and 1.52 g (7.35 mmol) Dicyclohexylcarbodiimide added. The mixture turns 18 Stirred at 25 ° C for hours and then filtered. The Filtrate is diluted with ethyl acetate, with a saturated Sodium bicarbonate solution washed over anhydrous magne dried and concentrated sodium sulfate. 4.92 g of the residue are chromatographed on Merck silica gel by using Ethyl acetate: pyridine: acetic acid: water (80: 20: 6: 11) eluted becomes. 3.98 g (77%) of the title compound M are used as Main product received.  

N. N - [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- [1- [(phenylmethoxy) methyl] -1H-imidazol-2-yl] ethyl] -3- [(phenylmethoxy) methyl] -L-histidinamide

A solution of 3.88 g (5.53 mmol) of the title compound M in 200 ml of ethyl acetate is cooled to 0 ° C. in an ice bath and Hydrogen chloride gas is blown through the solution for 30 minutes sen. The resulting mixture is then kept for 2.5 hours heated to 25 ° C stirred. Then it becomes one small volume concentrated. The preserved white low Impact is made on a PTFE filter with 3.33 g (85%) of the Ti telverbindung N as a white powder of F. 143-157 ° C total melt.

O. [4- (4-Morpholinyl) -1,4-dioxo-2- (phenylmethyl) butyl] -N- [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- [1- [(phenylmethoxy) methyl] -1H-imidazol-2-yl] ethyl] -3- [(phenylmethoxy) methyl] -L-histidinamide, isomer B

A mixture of 610 mg (2.2 mmol) of the title compound C, 337 mg (2.2 mmol) 1-hydroxybenzotriazole hydrate and 1.47 g (2 mmol) the title compound N in 8 ml of tetrahydrofuran at 0 ° C 0.84 ml (6 mmol) of triethylamine and then 453 mg (2.2 mmol) dicyclohexylcarbodiimide added. The received Mixture is warmed to 25 ° C for 18 hours, stirred, then it is filtered. The filtrate is diluted with ethyl acetate, with a saturated Sodium bicarbonate solution washed over anhydrous magne dried and concentrated sodium sulfate. 1.64 g of the mixture are chromatographed on 165 g of Merck silica gel by using Ethyl acetate: pyridine: acetic acid: water (80: 20: 6: 11) eluted becomes. 5.5 g (32%) of isomer A of the title compound O and isomer B of the title compound O obtained. The isomer B the title compound O is further obtained by preparative HPLC 580 mg of the title compound O purified.  

P. N - [(S) -2-cyclohexyl-1 - [(R) -hydroxy- (1H-imidazol-2-yl) -me thyl] ethyl] -N2- [4- (4-morpholinyl) -1,4-dioxo-2- (phenylmethyl) butyl] -L-histidinamide, isomer B, dihydro chloride

A mixture of 580 mg (0.53 mmol) of the title compound O (Isomer B), 120 mg 20% palladium hydroxide on activated carbon and 1.17 ml (1.17 mmol) of 1 N aqueous hydrochloric acid in 15 ml of methanol is hy under a slow stream of hydrogen for 19 hours third. The mixture is then filtered and dried concentrated. 350 mg of the residue are dissolved in 10 ml of 1N aqueous hydrochloric acid and dissolved under reduced pressure Dry concentrated. The residue is again in 1 N Hydrochloric acid dissolved and concentrated to dryness again, then dissolved in water, millipore filtered and 330 mg (90%) the title compound as a fluffy white solid lyophili siert.

Example 2 [4- (4-morpholinyl) -1,4-dioxo-2- (1-naphthalenylmethyl) -bu tyl] -N - [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imida zol-2-yl) ethyl] -L-histidinamide, isomer B, dihydrochloride A. (1-Naphthalinylmethyl-malonsäurediäthylester)

A suspension of sodium hydride (8 g (200 mmol) of a 60 % dispersion in mineral oil) in 200 ml tetrahydrofuran 30.5 ml (200 mmol) of diethyl malonate are added dropwise inside added half of 15 minutes; gas evolution will be takes care. After the addition is complete, the mixture is 10 Mi grooves stirred at 25 ° C. A solution of 35.5 g (200 mmol) 1- Chloromethylnaphthalene in 20 ml of tetrahydrofuran is internal added dropwise over 15 minutes, then the mixture is refluxed under argon for 18 hours is heating. An excess of 1N hydrochloric acid is then added, and the mixture is extracted with ether. The extract comes with  a saturated aqueous sodium bicarbonate solution , dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The backlog is in a Kol provided with a vacuum distillation head ben convicted. Unreacted diethyl malonate (boiling point 45-55 ° C / 26.664 Pa) and 1-chloromethylnaphthalene (boiling point 120-130 ° C) are distilled off, and the residue cooled again to 25 ° C. 43.5 g of the distillation back are crystallized from petroleum ether at -30 ° C. There are 27.3 g (46%) of the title compound A as a solid obtained with a low melting point (F. about 30 ° C).

B. 1-naphthalene propionic acid

A solution of 10 g (33.3 mmol) of the title compound A in 70 ml Ethanol and 70 ml (70 mmol) of 1 N aqueous sodium hydroxide solution is stirred at 25 ° C for 2 hours and then for 2 hours heated under reflux. The ethanol is min dert pressure removed, and the remaining aqueous mixture diluted with water and washed with ether. The watery Layer is acidified by adding 100 ml of 1N hydrochloric acid Ert. 100 ml of dioxane are then added because of the solubility ben and the mixture is refluxed for 18 hours, then concentrated under reduced pressure. water and ethyl acetate are added to the residue and the Ge Mix is extracted three times with ethyl acetate. The extract is washed with 1N hydrochloric acid, over anhydrous Magnesium sulfate dried and concentrated. The residue is with ether to 4.6 g (60%) of the title compound B as ground white solid of mp 151-153 ° C.

C. Phenylmethyl 2-naphthalene propionate

A solution of 7 g (35 mmol) of title compound B, 3.8 ml (37 mmol) benzyl alcohol and 420 mg (3.5 mmol) 4-dimethylami nopyridine in 175 ml of methylene chloride, 7.6 g (37 mmol) at 0 ° C. Dicyclohexylcarbodiimide added. The Ge obtained  the mixture is first mixed at 0 ° C. for 2 hours and then for 18 hours Stirred at 25 ° C, then it is filtered. The fil is washed with water and a saline solution, Dried over anhydrous magnesium sulfate and concentrated trated. 10.9 g of the residue are dissolved in benzene and filtered through 180 g of a coarse silica gel pad. The Filtrate is 9.66 g (95%) of the title compound C as kla res, colorless oil concentrated.

D. (2-Naphthalenemethyl) succinic acid 4- (1,1-dimethyl ethyl) -1- (phenylmethyl) ester

A solution of 4.4 ml of diisopropylamine in 58 ml of tetrahy 11.3 ml of n-butyllithium are drofuran under argon at -10 ° C. a 2.6 M solution in hexane. The mixture is at this temperature stirred for 15 minutes, then abge to -78 ° C. cools. A solution of 8.5 g (29 mmol) of the title compound C In 10 ml of tetrahydrofuran, the cold solution is added dropwise added, then the solution is 15 minutes at -78 ° C. touched. 5.2 ml (32 mmol) of tert-butyl bromoacetate are then added, and the mixture is first at 15 minutes -78 ° C and then stirred at 25 ° C for 2 hours while it was slowly warmed up. The mixture is then 1N in excess Poured hydrochloric acid and extracted with ethyl acetate. The ex is treated with a saturated sodium bicarbonate solution and a saline solution, over anhydrous magnesium dried and concentrated sulfate. 8.06 g of the residue are flash chromatographed on 500 g of silica gel pulled by first to discharge a yellow colored Band is eluted with benzene: hexane (2: 1), then with benzene and finally eluting with benzene: ethyl acetate (4: 1). The title compound D is obtained as a colorless oil, that after standing to 6.62 g (56%) crystals of F. 64-66 ° C converts.  

E. (2-naphthalinylmethyl) succinic acid, 1- (phenylmethyl) - ester

A solution of 9.5 g (23.5 mmol) of the title compound D in 50 ml of methylene chloride are 50 ml of trifluoroacetic acid at 0 ° C acid added. The mixture is stirred at 0 ° C. for 2 hours, then it is concentrated to dryness. The back was made from acetonitrile to 6.89 g (84%) of the title compound E crystallized from mp 124-126 ° C.

F. (2-naphthalinylmethyl) succinic acid, 1- (phenylmethyl) - ester, (+) - isomer

5.8 g (16.6 mmol) of the title compound E are dissolved in 100 ml of ether and 2.75 g (16.6 mmol) of (-) - ephedrine are added. The mixture is stored for 3 days at -30 ° C, whereby a collectable wax-like solid is obtained. The solid is first crystallized twice from 35 ml of ethyl acetate and 165 ml of ether and then twice from 50 ml of ethyl acetate and 150 ml of ether, whereby 3.0 g of a solid with a constant melting point (mp 114.5-115.5 ° C) and speci fi c rotation [ α ] _D = + 31.7 ° is obtained. The crystalline solid is then divided up into ethyl acetate and 1N hydrochloric acid and extracted with ethyl acetate. The extract is dried and concentrated to 1.89 g of the title compound F [ α ] _D = + 54.8 ° (methanol).

G. α - (2-Naphthalinylmethyl) - γ- oxo-4-morpholine-butanoic acid, phenylmethyl ester, (+) - isomer

A mixture of 1.89 g (5.4 mmol, [ α ] _D = + 54.8 °) of the title compound F, 0.525 ml (6 mmol) of morpholine and 730 mg (5.4 mmol) of 1-hydroxybenzotriazole in 15 ml of tetrahydrofuran are added to 1.1 g (5.4 mmol) of dicyclohexylcarbodiimide. The mixture he is stirred for 20 hours at 25 ° C, then it is filtered. The filtrate is diluted with ethyl acetate, washed with 1N hydrochloric acid and a saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and to 2.1 g (93%) of the title compound G [ α ] _D = + 32.1 ° (c 4 , Methanol) concentrated.

H. α - (2-Naphthalinylmethyl) - γ- oxo-4-morpholine-butanoic acid, (-) - isomer

A mixture of 2.1 g (5 mmol) of the title compound G and 5 ml a 1 N sodium hydroxide solution in 10 ml dioxane becomes 16 Stirred at 25 ° C for hours, then it is mixed with water diluted and washed with ether. The aqueous layer becomes acidified with HCl and extracted three times with ethyl acetate. The extract is dried over anhydrous magnesium sulfate net and to 1.58 g (97%) of the title compound H as colorless glassy substance concentrated.

I. [R- (R *, S *)] - N- [1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imi dazol-2-yl) ethyl] -L-histidinamide

A mixture of 1.46 g (2 mmol) of the title compound M of Example 1, 350 mg (Aldrich) 20% palladium hydroxide on activated carbon and 4 ml (4 mmol) of 1N hydrochloric acid in 15 ml of methanol is 20 hours at 25 ° C under a slow hydrogen Stream hydrogenated, then the mixture is filtered (PTFE filter) and concentrated to dryness. 1.1 g of the back are dissolved in 30 ml of acetic acid and dry Hydrogen chloride gas is 30 minutes at 25 ° C by the Lö blown solution. The mixture is then ge at 25 ° C for 2 hours stirred, then it is concentrated under reduced pressure trated. The residue is treated with 833 mg of acetonitrile white solid ground. The solid is in one Dissolve excess 1N hydrochloric acid and concentrate to dryness trated; the procedure is repeated three times in total to obtain the title compound I as a white solid.  

J. [4- (4-Morpholinyl) -1,4-dioxo-2- (1-naphthalinylmethyl) -bu tyl] -N - [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imi dazol-2-yl) ethyl] -L-histidinamide, isomer B, dihydrochloride

A solution of 164 mg (0.5 mmol) of the title compound H, 84 mg (0.55 mmol) of 1-hydroxybenzotriazole hydrate and 276 mg (0.55 mmol) of the title compound I in 2.5 ml of dimethylformamide are at 0 ° C 0.24 ml (1.65 mmol) of triethylamine and 113 mg (0.55 mmol) of dicyclohexylcarbodiimide were added. The resulting mixture is stirred for 18 hours while warming to 25 ° C, then the mixture is concentrated to dryness under reduced pressure. The residue is dissolved in a mixture of 3 ml of methanol and 2 ml of 1N hydrochloric acid, filtered and concentrated. 814 mg of the residue are chromatographed on Merck silica gel by eluting with ethyl acetate: pyridine: acetic acid: water (50: 20: 6: 11). Fractions containing the main product (R _f 0.25) are pooled and concentrated. The residue is dissolved in an excess of 1N hydrochloric acid and concentrated three times with dryness. 295 mg (74%) of the reddish residue are chromatographed on HP-20 by eluting with a gradient from 0.01 N hydrochloric acid to 0.01 N methanolic hydrochloric acid. Fractions containing the main product are combined and partially concentrated, then lyophilized to dryness. The residue is lyophilized again from water to 120 mg (29%) of the title compound as a fluffy white solid.

Example 3 [4-Cyclohexyl-1,4-dioxo-2- (phenylmethyl) butyl] -N - [(2S, 3R) - 1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imidazol-2-yl) ethyl] - L-histidinamide, isomer B, dihydrochloride A. (2-Cyclohexyl-2-oxoethyl) - (phenylmethyl) malonic acid diethyl ester

A suspension of 8 g (0.2 mol) sodium hydride in 200 ml Tetrahydrofuran are 50 g (0.2 mol) of diethyl under argon benzyl malonate added. The mixture will be finished the addition was stirred at 25 ° C for 30 minutes, giving a homo gene solution is obtained. 20.5 g (0.1 mol) bromomethylcyclo hexyl ketone (its manufacture is in Tetrahedron Letters, 26 (1970), 5611-5615) are then described within 10 Minutes added, then the mixture is brought to 50 ° C warmed and stirred at this temperature for 16 hours. The The mixture is then poured into an excess of 1N hydrochloric acid and the mixture obtained is extracted with ether. The extract is once in 1 N hydrochloric acid and twice sodium hydrogen washed carbonate, over anhydrous magnesium sulfate dries and concentrated to a yellow oil. The oil will distilled and the residue through a short silica gel Column given by gradually elu with a gradient is. Elution with 1: 1 hexane: ethyl acetate gives 28 g (75%) of the title compound B as a yellowish oil.

B. α - (Phenylmethyl) - γ -oxocyclohexanebutanoic acid

A mixture of 28 g (0.075 mmol) of title compound A and 150 ml (0.15 mol) of a 1 N sodium hydroxide solution in 150 ml Ethanol is stirred for 15 hours at 75 ° C, then the mixture diluted with 500 ml of water and washed with ether . The aqueous solution is then in concentrated salt acidified and extracted twice with ethyl acetate. The The extract is dried and concentrated to 18 g of a yellow oil trated. The residue is dissolved in 180 ml of dioxane, 1 ml  Concentrated hydrochloric acid is added and the mixture is Stirred at 100 ° C for 22 hours. The mixture then becomes one concentrated orange oil. The oil is in 125 ml of a 1 N Dissolved sodium hydroxide solution and the mixture obtained 18th Stirred at 75 ° C for hours, then it is mixed with water diluted and washed with ether. The aqueous solution becomes acidified with hydrochloric acid and extracted twice with ether. The extract is dried over anhydrous magnesium sulfate net and concentrated to 12 g of a yellow oil. After 1 week the compound crystallizes upon standing at 25 ° C. The crystals are mixed with 8.4 g (41%) of the Ti using petroleum ether Tear compound B as a white powder with a melting point of 71-73 ° C ben.

C. [4-Cyclohexyl-1,4-dioxo-2- (phenylmethyl) butyl] -N- [(2S, 3R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imidazole-2- yl) ethyl] -L-histidinamide, isomer B, dihydrochloride

A solution of 754 mg (1.5 mmol) of the title compound I from Example 2, 230 mg (1.5 mmol) of 1-hydroxybenzotriazole hydrate and 230 mg (1.5 mmol) of the title compound B in 7 ml of dimethylformamide are at 0 ° C 0.68 ml (4.9 mmol) of triethylamine and 309 mg (1.50 mmol) of dicyclohexylcarbodiimide were added. The resulting mixture is stirred at 25 ° C for 18 hours, then it is concentrated to dryness. 9 ml of methanol and 6 ml of 1N hydrochloric acid are added to the residue. The solution obtained is filtered and the filtrate is concentrated to dryness. 2.56 g of the residue are chromatographed on Merck silica gel; Fractions containing the main product (R _f 0.2) are collected and concentrated. 640 mg of the residue are further purified by preparative HPLC. Two main fractions (isomer A and isomer B) are collected separately and concentrated. The Trifluorace tatsalze obtained are not water-soluble, so the residues are separately dissolved in an excess of 1N hydrochloric acid and concentrated three times again for conversion into soluble hydrochloride salts. The residues are then dissolved in water, filtered through charcoal and lyophilized to 162 mg (16%) isomer A and 134 mg (13%) isomer B of the title compound.

Example 4 [3 - [(Cyclohexylthio) methyl] -1-oxo-3-phenylpropyl] -N- [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imidazole-2- yl) -ethyl] -L-histidinamide, dihydrochloride A. α- methylene benzene propionic acid

13 g (0.067 mol) of benzylmalonic acid is mixed with 7.6 g (0.068 mol, 40%) aqueous dimethylamine and 5.4 g (0.068 mol, 37%) For malin mixed in 150 ml of water. Which is out in 15 minutes voluminous solid which forms is filtered off after 2 hours , washed with water and partly in air 20.8 g dried. The solid is in a 170 ° oil bath melted and heated for 10 minutes until the amine evolution has stopped and the blistering has practically ended. The cooled product, a mobile liquid, becomes acidified with 10% potassium hydrogen sulfate, with extra hexane hiert, dried over sodium sulfate and 6.3 g of one Solids evaporated. The aqueous filtrates from the Mannich reactions are left overnight and then at 100 ° C over a steam cone until the bla Sen formation heated. By the above-mentioned cooling Treatment, acidification and extraction become a further 1.2 g of solid Substance for a total of 7.5 g benzyl acrylic acid receive.

B. α - [(Cyclohexylthio) methyl] benzene propionic acid

A solution of 8.1 g (50 mmol) of the title compound A in 16 ml Piperidine are 6 ml (50 mmol) of cyclohexyl under argon mercaptan added. The mixture is made under argon for 24 hours stirred at 100 ° C, then it is cooled to 25 ° C and acidified by adding concentrated hydrochloric acid. The mixture is then saturated with sodium chloride and two  times extracted with ether. The ether extracts are combined and extracted with a 1 N sodium hydroxide solution. The ba sische aqueous extract is concentrated by adding Acidified hydrochloric acid and extracted with ethyl acetate. The ex is dried over anhydrous magnesium sulfate and concentrated. 4 g of the residue are one on silica gel Flash chromatographed by using 1: 1 ethyl acetate did: hexane is eluted. It will be the title compound A as get colorless oil.

C. [3 - [(Cyclohexylthio) methyl] -1-oxo-3-phenylpropyl] -n- [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imidazole-2- yl) -ethyl] -L-histidinamide, dihydrochloride

A solution of 557 mg (2 mmol) of the title compound B, 337 mg (2.2 mmol) of 1-hydroxybenzotriazole hydrate and 1.1 g (2.2 mmol) of the title compound I from Example 2 in 8 ml of dimethylformamide are added 0 ° C 0.92 ml (2.2 mmol) of triethylamine and 453 mg (2.2 mmol) of dicyclohexylcarbodiimide were added. The mixture he was stirred for 18 hours at 25 ° C, then it is concentrated to dryness. The residue is dissolved in a mixture of 9 ml of methanol and 6 ml of 1N hydrochloric acid, filtered and the filtrate is concentrated to dryness. 3.68 g of the residue are subjected to flash chromatography on silica gel by eluting with ethyl acetate: pyridine: acetic acid: water (80: 20: 6: 11). 940 mg of a main fraction with R _f = 0.31 are obtained. This reddish substance is further purified on 400 ml of HP-20 by chromatography, eluting with a gradient from 0.01 N hydrochloric acid to 0.01 N hydrochloric acid in methanol. Fractions are monitored by HPLC analysis; those fractions containing the desired products (7.1 minutes and 8.3 minutes of YMC S. ODS column, 4.6 × 150 mm, 1.0 ml / minutes of 66% aqueous methanol containing 0.01% of phosphoric acid, λ = 220 nm) are combined and partially concentrated under reduced pressure to remove methanol, then frozen and lyophilized. The residue is lyophilized again from water. 386 mg (28%) of the title compound are obtained as a fluffy, eggshell-colored (pink) solid.

Example 5 [2 - [(Cyclohexylsulfinyl) methyl-1-oxo-3-phenylpropyl] -N- [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imidazole-2- yl) -ethyl] -L-histidinamide, isomer 2B, trifluoroacetate- (1: 2) - salt A. a - [(Cyclohexylsulfinyl) methyl] benzene propionic acid, isomer 1 and 2

A solution of 1.95 g (7 mmol) of the title compound B of Example 4 and 4.76 ml (42 mmol) hydrogen peroxide in 35 ml Methanol is stirred at 25 ° C for 2 hours, then who the further 0.45 ml of hydrogen peroxide added. The Ge mixing is continued for a further 1.5 hours (3.5 hours in total) stirred and then acidified by adding 35 ml of sulfuric acid The mixture is extracted using a starch-iodine Test paper (positive test) for the presence of peroxides examined. A saturated aqueous sodium thiosulfate solution is added until no positive peroxide test is obtained becomes. The mixture is then mixed with an equal volume of Diluted ethyl acetate and stirred for 10 minutes, then the mixture is filtered and extracted with ethyl acetate. The extracts are combined over anhydrous magnesium dried and concentrated sulfate. 2.3 g of the residue are made from 95% ethanol to 670 mg (32%) isomer 1, mp 153- 154 ° C of the title compound A crystallized. The mother lye is diluted with ether and after cooling is a white solid of mp 118-120 ° C obtained. This feast Substance is made from ethanol to 365 mg (18%) isomer 2 of F. 123- 124 ° C of the title compound A recrystallized.  

B. [2 - [(Cyclohexylsulfinyl) methyl] -1-oxo-3-phenylpropyl] -N- [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imidazole-2- yl) ethyl] -L-histidinamide, isomer 2B, trifluoroacetate (1: 2) salt

A solution of 539 g (1.83 mmol) of isomer 2 of the title compound A, 306 mg (2 mmol) of 1-hydroxybenzotriazole hydrate and 998 mg (2 mmol) of the title compound I from Example 2 in 7 ml of dimethylformamide are at 0 ° C 0.85 ml (6 mmol) of triethylamine and 412 mg (2 mmol) of dicyclohexylcarbodiimide were added. The resulting mixture is stirred for 19 hours at 25 ° C, then it is concentrated to dryness. The residue is dissolved in a mixture of 10 ml of methanol and 7 ml of 1N hydrochloric acid, filtered and concentrated. 3.6 g of the residue are subjected to flash chromatography on silica gel by eluting with ethyl acetate: (pyridine: acetic acid: water) 2: 1 (20: 6: 11). The fraction containing the major "product" (R _f 0.30) is combined and concentrated to 720 mg of a mixture of isomers. The isomers are separated by preparative HPCL to give 280 mg (31%) of isomer 2A of the title compound B and 150 mg (17%) of isomer 2B of the title compound B.

Example 6 [2 - [(cyclohexylsulfonyl) methyl] -1-oxo-3-phenylpropyl] -N- [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imidazole-2- yl) -ethyl] -L-histidinamide, isomer B, trifluoroacetate- (1: 2) - salt A. α - [(Cyclohexylsulfonyl) methyl] benzene propionic acid

A solution of 2.78 g (10 mmol) of the title compound B of Example 4 in 40 ml of methanol at 0 ° C is a solution of 9.21 g (30 mmol) of potassium monopersulfate in 40 ml of water ben. The mixture obtained is 2 hours while it is heated to 25 ° C, stirred and then with chloroform  extracted. The extract is over anhydrous magnesium sulfate fat dried and concentrated. 3.02 g of the residue who the crystallized from ethyl acetate / hexane. There will be 2.90 g (94%) of the title compound A of mp 109-111 ° C.

B. [2 - [(Cyclohexylsulfonyl) methyl] -1-oxo-3-phenylpropyl] -N- [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imidazole-2- yl) -ethyl] -L-histidinamide, isomer B, trifluoroacetate- (1: 2) - salt

A solution of 1.24 g (4 mmol) of the title compound A, 612 mg (4 mmol) of 1-hydroxybenzotriazole hydrate and 2 g (4 mmol) of the title compound I from Example 2 in 15 ml of dimethylformamide are at 0 ° C. 1 , 76 ml (12.6 mmol) of triethylamine and 824 mg (4 mmol) of dicyclohexylcarbodiimide were added. After stirring for 18 hours at 25 ° C., the mixture is concentrated to dryness. 20 ml of methanol and 14 ml of 1N hydrochloric acid are added to the residue. The mixture is filtered and the filtrate is concentrated to dryness. The residue is chromatographed on silica gel, giving 1.54 g of an isomer mixture (R _f 0.28). The isomers are separated by preparative HPLC. The individual isomer-containing fractions are partially concentrated and lyophilized. The residues are lyophilized again from water, whereby 730 mg (21%) isomer A of the title compound B and 520 mg (15%) isomer B of the title compound B are obtained.

Example 7 [2 - [(diethoxyphosphinyl) methyl] -1-oxo-3-phenylpropyl] -N- [(2S, 3R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imidazole-2- yl) -ethyl] -L-histidinamide, isomer B, trifluoroacetate- (1: 2) - salt A. α - [(Diethoxyphosphinyl) methyl] benzene propionic acid

5 g (0.024 mol, 6 ml) of bis (trimethylsilyl) acetamide at room temperature a solution of 2 g (0.012 mol) of Ben zylacrylic acid and 3.3 g (0.024 mol) of diethyl phosphite in 30 ml Dichloromethane added. The mixture is at 30 minutes Stirred at room temperature, under reduced pressure in the room temperature concentrated and the residue is at a Bath temperature of 100-110 ° C heated for 16 hours. The colorless oil reaction mixture is dissolved in ethyl acetate and extracted with 5% sodium bicarbonate (pH 9-10). The watery alkaline solution is washed with ether and with kon acidified centered hydrochloric acid to a pH of 1-2. The separated colorless oil is extracted into ethyl acetate with Washed saline over anhydrous magnesium sulfate dried and under reduced pressure to 3.6 g of one colorless oil concentrated.

B. [2 - [(Diethoxyphosphinyl) methyl] -1-oxo-3-phenylpropyl] -N- [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- [1- [(phenylmethoxy) methyl] -1H-imidazol-2-yl] ethyl] -3- [(phenylmethoxy) methyl] -L-histidinamide, isomers A and B

A solution of 1.46 g (2.0 mmol) of the title compound J of Example 1, 337 mg (220 mmol) of 1-hydroxybenzotriazole hydrate and 600 mg (2.20 mmol) of the title compound A in 8 ml of tetra Hydrofuran are 0.92 ml (6.6 mmol) of triethylamine at 0 ° C and 453 mg (2.20 mmol) of dicyclohexylcarbodiimide were added. The mixture obtained is stirred at 25 ° C. for 18 hours and then filtered. Ethyl acetate is added to the filtrate  ben and the solution obtained is saturated Sodium bicarbonate solution washed over anhydrous magne dried and concentrated sodium sulfate. 1.75 g of the residue Flash chromatography on Merck silica gel subjected by using ethyl acetate: pyridine: acetic acid: water (100: 20: 6: 11) is eluted. 680 mg (38%) of isomer A title compound B and 620 mg (35%) isomer B of the title get connection B.

C. [2 - [(Diethoxyphosphinyl) methyl] -1-oxo-3-phenylpropyl] -N- [(2S, 3R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imidazole-2- yl) -ethyl] -L-histidinamide, isomer B, trifluoroacetate- (1: 2) - salt

A mixture of 600 g (0.68 mmol) of isomer B of the title compound dung B, 150 mg of 20% palladium hydroxide on activated carbon and 1.5 ml (1.5 mmol) 1 N hydrochloric acid in 15 ml of methanol is added a slow stream of hydrogen for 18 hours at 25 ° C hy driert, then the mixture is filtered and to Dry concentrated. 470 mg of the residue are added Flash chromatography on Merck silica gel, in with chloroform: methanol: ammonium hydroxide (100: 25: 1.25) is eluted. Fractions containing the main ingredient are united and concentrated. 300 mg of the residue in an excess of 1% aqueous trifluoroacetic acid Solution solved and concentrated again. The backlog will then dissolved in 50 ml of water, with activated charcoal sets, millipore filtered and 320 mg (66%) of the title compound lyophilized as a fluffy white solid.  

Example 8 [(S) -2 - [(Benzoylthio) methyl] -1-oxo-3-phenylpropyl] -N- [(1S, 2R) -1- (cyclohexylmethyl-2-hydroxy-2- (1H-imidazol-2-yl) - ethyl] -L-histidinamide, trihydrochloride A. α - [(Benzoylthio) methyl] benzene propionic acid

A mixture of 13.7 g (85 mmol) of title compound A of Example 4 and 15 mg (127 mmol) of thiobenzoic acid in 170 ml Methylene chloride is refluxed for 3 days under argon stirred, then the mixture is reduced Concentrated pressure. The residue is made from ether / hexane to 13.7 g of the title compound A as a colorless solid of F. 99-100 ° C crystallized.

B. (S) - α - [(Benzoylthio) methyl] benzene propionic acid

A solution of 14.5 g (48.0 mmol) of the title compound A and 6.25 ml (48 mmol) of (R) - (+) - α- methylbenzylamine in 250 ml of ether is stored for 2 days at -4 ° C. whereby a rubbery solid is obtained. The solvent is decanted off and the solid is recrystallized three times from hexane / methylene chloride (1: 1) and then twice from isopropanol. A 1: 1 salt [ α ] _D = -25.0 ° (c = 1, CHCl₃) of mp 131-132 ° C is obtained. The salt is dissolved in ethyl acetate and washed with 1.0 N hydrochloric acid. The organic layer is dried over water-free magnesium sulfate and concentrated to 1.57 g of Ti telverbindung B as a white solid [ α ] _D = -53.3 ° (c = 1, CHCl₃) of mp 65-66 ° C.

C. [(S) -2- [benzoylthio) methyl] -1-oxo-3-phenylpropyl] -N- [(1S, 2R) -1- (cyclohexylmethyl-2-hydroxy-2- (1H-imidazole-2- yl) -ethyl] -L-histidinamide, trihydrochloride

A solution of 1.42 g (4.73 mmol) of the title compound B, 724 mg (4.73 mmol) of 1-hydroxybenzotriazole hydrate and 2.22 g the title compound I from Example 2 in 20 ml of dimethylforma  mid at 0 ° C 2.2 ml (16 mmol) of triethylamine and 975 mg (4.73 mmol) dicyclohexylcarbodiimide added. The received Mixture is stirred at 25 ° C for 18 hours, then it is filtered and concentrated. The residue is on silica gel chromatographed by mixing with ethyl acetate: (Pyri din: acetic acid: water) 2: 1 (20: 6: 11) is eluted. The Main product-containing fractions are pooled and concentrated. The residue is in an excess of 1 N Hydrochloric acid dissolved and concentrated under reduced pressure. The residue is then converted from water to the title compound flaky white solid lyophilized.

Example 9 [(S) -2- (Mercaptomethyl) -1-oxo-3-phenylpropyl] -N - [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imidazol-2-yl) ethyl] -L- histidinamide, trifluoroacetate (1: 2) salt

A mixture of 270 mg (0.35 mmol) [(S) -2 - [(Benzoylthio) -me thyl] -1-oxo-3-phenylpropyl] -N - [(1S, 2R) -1-cyclohexylmethyl-2- hydroxy-2- (1H-imidazol-2-yl) ethyl] -L-histidinamide, trihy hydrochloride and 1 ml concentrated ammonium hydroxide solution in 5 ml of methanol is stirred for 7 days at 50 ° C, after 2 and A further 2 ml of ammonium hydroxide are added for 6 days. To The mixture is concentrated under reduced pressure for 7 days trated and the residue purified by preparative HPLC. Fractions containing the main product are reduced Concentrated pressure. The residue is ge in water dissolves and 45 mg of the title compound as a fluffy white Powder lyophilized.  

Example 10-30

According to the procedures of Examples 1 to 9, others can Compounds falling within the scope of the invention with the formula below

in which the substituents have the meaning given above, are prepared.

Claims (24)

1. Compounds of the general formula I including their physiologically acceptable salts, in which X is one of the residues means
R₁ is a fully saturated, partially saturated, or unsaturated monocyclic N-heterocyclic ring with 5 or 6 atoms, which contains at least one N atom or a bicyclic ring in which the N-heterocyclic ring is fused to a benzene ring, wherein the N-heterocyclic ring can also contain an oxygen or sulfur atom or up to three additional N atoms, and an available N atom in the N-heterocyclic ring having one of the radicals may be substituted, an available carbon atom in the monocyclic N-heterocyclic ring or in the benzene part of the bicyclic N-he terocyclic ring with a lower alkyl radical or with one of the radicals can be substituted and the N-heterocyclic ring with an available carbon atom to the group is bound in which Y represents the group -CH₂-, an oxygen or sulfur atom or N-R₉, a is an integer from 1 to 4, and b is an integer from 1 to 4, with the proviso that the sum of a and b is an integer from 2 to 5, or denotes a heterocyclic ring of this type in which one carbon atom is substituted by a lower alkyl radical,
R₃ and R₅ independently of one another are a hydrogen atom, a lower alkyl radical, a halogen atom-substituted lower alkyl radical or one of the radicals mean,
R₄ is a hydrogen atom, a lower alkyl radical, a halogen atom-substituted lower alkyl radical or one of the radicals means
R₆, R′₆ and R′′₆ independently of one another represent a hydrogen atom, an alkyl, aryl or cycloalkyl radical, or R₆ and R′₆ together with the atom to which they are bound are a ring with 3 to 5 Carbon atoms form,
m, m ′ and m ′ ′ have the value 0 or are an integer from 1 to 5,
n is an integer from 1 to 5, p and p ′ have the value 0 or 1,
g is an integer from 2 to 5,
R₇ one of the remains means
R₈ one of the residues 2,4-dinitrophenyl, means
R₉ is a hydrogen atom, a lower alkyl radical or one of the radicals means
R₁₀ represents a radical - (CH₂) _{m '} -R'₆ and
A and A 'a single bond or the rest mean. 2. A compound according to claim 1, in which R₁ is one of the radicals means. 3. A compound according to claim 1, in which X is one of the radicals means
R₁ one of the residues means
R₃ is a C₃-C₅ unbranched or branched Niederal kylrest or one of the radicals means
where n is an integer from 1 to 3,
R₄ is a hydrogen atom, an unbranched or branched lower alkyl radical containing up to 5 carbon atoms or one of the radicals - (CH₂) ₄-NH₂, means, and
R₅ an unbranched or branched lower alkyl radical containing up to 5 carbon atoms or one of the radicals means. 4. A compound according to claim 1 in the
R₆ represents a cycloalkyl radical, a morpholinyl, ethyl or ethoxy group,
R₁ one of the residues means
R₃ one of the residues means
R₄ one of the remains means, and
R₅ one of the remains means. 5. A compound according to claim 1, in which
R₁ the rest means
R₃ the rest means
R₄ the rest means
R₅ the rest means
X the rest means and
p has the value 1. 6. A compound according to claim 1, in which
R₁ the rest means
R₃ the rest means
R₄ the rest means
R₅ the rest means
X the rest means and
p has the value 1. 7. A compound according to claim 1, in which
R₁ the rest means
R₃ the rest means
R₄ the rest means
R₅ the rest means
X the rest means and
p has the value 1. 8. A compound according to claim 1, in which
R₁ the rest means
R₃ the rest means
R₄ the rest means
R₅ the rest means
X the rest means and
p has the value 1. 9. A compound according to claim 1, in which
R₁ the rest means
R₃ the rest means
R₄ the rest means
R₅ the rest means
X the rest means and
p has the value 1. 10. A compound according to claim 1, in which
R₁ the rest means
R₃ the rest means
R₄ the rest means
R₅ the rest means
X the rest means and
p has the value 1. 11. The compound of claim 1, in which
R₁ the rest means
R₃ the rest means
R₄ the rest means
R₅ the rest means
X the rest means and
p has the value 1. 12. [4- (4-morpholinyl) -1,4-dioxo-2- (1-naphthalinylmethyl) - butyl] -N - [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H- imidazol-2-yl) ethyl] -L-histidinamide, isomer B, dihydro chloride. 13. N - [(S) -cyclohexyl-1 - [(R) -hydroxy- (1H-imidazol-2-yl) - methyl] ethyl] -N2- [4- (4-morpholinyl) -1,4-dioxo-2- (phenylmethyl) butyl] -L-histidinamide, isomer B, dihydro chloride.   14. [4-Cyclohexyl-1,4-dioxo-2- (phenylmethyl) butyl] -N- [(2S, 3R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imidazole- 2-yl) ethyl] -L-histidinamide, isomer B, dihydrochloride. 15. [3 - [(Cyclohexylthio) methyl] -1-oxo-3-phenylpropyl] -N- [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imidazole- 2-yl) ethyl] -L-histidinamide, dihydrochloride. 16. [2 - [(Cyclohexylsulfinyl) methyl] -1-oxo-3-phenylpropyl] - N - [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imida zol-2-yl) ethyl] -L-histidinamide, isomer 2B, trifluorace tat (1: 2) salt. 17. [2 - [(Cyclohexylsulfonyl) methyl] -1-oxo-3-phenylpropyl] - N - [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imida zol-2-yl) ethyl] -L-histidinamide, isomer B, trifluorace tat (1: 2) salt. 18. [2 - [(diethoxyphosphinyl) methyl] -1-oxo-3-phenylpropyl] - N - [(2S, 3R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imida zol-2-yl) ethyl-L-histidinamide, isomer B, trifluorace tat (1: 2) salt. 19. [(S) -2 - [(Benzoylthio) methyl] -1-oxo-3-phenylpropyl] -N- [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imidazole-2- yl) -ethyl] -L-histidinamide, trihydrochloride. 20. [(S) -2- (mercaptomethyl) -1-oxo-3-phenylpropyl] -N- [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-2- (1H-imidazole- 2-yl) ethyl] -L-histidinamide, trifluoroacetate (1: 2) salt. 21. Compounds according to claim 1 to 20 for use as Drugs. 22. Compounds according to claim 1 to 20 for use in the treatment of hypertension in mammals.   23. Medicinal product characterized by a content of one A compound according to claims 1 to 20 and a pharmazeu table compatible carrier. 24. Use of the compounds according to claim 1 to 20 for Treatment of hypertension in mammals.