Antagonists of endothelin receptors

 

(57) Abstract:

Usage: in medicine. The inventive compound of General formula I where R1is phenyl, substituted C1- C4-alkyl, C1- C4-alkoxy or halogen; R2- C1- C4-alkyl; R3is phenyl, biphenyl, naphthyl, thienyl, furyl, tetrazolyl, imidazolyl, pyridyl, chinoline, pyridyl-phenyl, thienyl-phenyl, furyl-phenyl, imidazolyl-phenyl, isoxazolyl-phenyl; where the mentioned aryl and heteroaryl radicals are, independently of each other, are in each case unsubstituted or substituted by substituents selected from the group consisting of C1- C4-alkyl, C1- C4-alkoxy, phenyl - C1- C4-alkoxy, halogen, CF3, hydroxy, cyano, cyano - C2- C5alkanoyl and nitro; R3is hydrogen, phenyl or phenyl substituted C1- C4-alkyl, C1- C4-alkoxy, halogen, CF3, hydroxy, nitro; hydrogen; C(=X) denotes C(= O) or C(=S); Y represents NH or methylene, or C(=X) denotes SNON and Y represents methylene; means -(CH2)s- Ar, where s is the number 1 and Ar is phenyl, naphthyl, biphenyl, indole-3-yl, 1 - C1- C4-alkyl-indol-3-yl or chinoline; where named exename substituents, selected from the group consisting of C1- C4-alkyl, C1- C4-alkoxy, halogen, CF3, hydroxy, nitro; and R5- COOH, or its pharmaceutically acceptable salt. The pharmaceutical preparation contains antagonist, inhibiting the binding of endothelin, and as antagonist use an effective amount of compound I. 3 C. and 13 C.p. f-crystals, 2 tab.

1. The scope of the invention

The present invention relates to new compounds as receptor antagonists of endothelin (ET), methods for their preparation, their use and pharmaceutical compositions.

2. Description of the prior art

Endothelin are a family of vasoactive peptides of 21 amino acid residue and two intramolecular disulfide bonds. They contain ET-1, the original ET, selected from the culture media porcine endothelial cells, ET-2 and ET-3.

Endothelin, the biosynthesis of which is enhanced by many biological and pathological factors, is widely distributed in peripheral and brain tissues of mammals and exhibit a number of biological responses by binding at least two different subtypes of ET receptors, race and nervous tissues. The ET receptors are also found in the respiratory, gastrointestinal, endocrine, Central nervous, and urinary systems in the blood and blood-forming organs, sensory organs and other tissues in the body.

Endothelia are most strongly - and long-term endogenous constrictors blood vessels identified to date. Endothelin also cause reduction in avascular smooth muscles, including the respiratory tract and the heart. In addition, endothelin are ulcerogenic and anti-inflammatory. Endothelin have regulatory functions in relation to the secretion of hormones or peptides, neurotransmission, ion transport and metabolism.

Application for Europatent N A reveals endothelin-antagonistic cyclic Pentapeptide. Application for Europatent N A reveals endothelin-antagonist oligopeptides containing L-leucine and D-tryptophan. They cannot be administered orally. Application for Europatent N 460679A describes endothelin-antagonist derived peptides, and specifically disclosed tripeptides. PCT application WO 92/20706 describes antagonists endotheline, thus specifically disclosed Hexapeptide. Application for Europatent N 526 is picavet endothelin-antagonist derivatives benzosulfimide. Although derivatives benzosulfimide can be administered orally with their antagonistic activity is not high. In the application Europatent N 13891A disclosed dipeptide derivatives of phenylalanine and tryptophan, with properties on the destruction of tumor tissue. French patent N 2294694 discloses derivatives, i.e. phenylalanyl-i.e. phenylalanyl showing antiulcer effects.

THE ESSENCE OF THE PRESENT INVENTION

The present invention provides novel compounds represented by the General formula

< / BR>
R1denotes phenyl, substituted (C1-C4)-alkyl, (C1-C4) alkoxy or halogen;

R2means (C1-C4)-alkyl;

R3denotes phenyl, biphenyl, naphthyl, thienyl, furyl, tetrazolyl, imidazolyl, pyridyl, chinoline, pyridyl-phenyl, thienyl-phenyl, furyl-phenyl, imidazolyl-phenyl, isoxazolyl-phenyl; where the mentioned aryl and heteroaryl radicals, independently of one another, are in each case unsubstituted or substituted by substituents selected from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, phenyl-(C1-C4)-alkoxy, halogen, CF3, hydroxy, cyano, cyano-(C2-C5)-alkanoyl, no, halogen, CF3, hydroxy, nitro;

denotes hydrogen;

C(=X) denotes C(=O) or C(=S); and Y represents NH or methylene, or C(= X) denotes CHOH and Y represents methylene;

R4represents -(CH2)s- Ar', where s is an integer 1; and

Ar' denotes phenyl, naphthyl, biphenyl, indole-3-yl, I-(C1-C4)-alkyl-indol-3-yl, or chinoline; where mentioned aryl and heteroaryl radicals, independently Druva, are in each case unsubstituted or substituted by substituents selected from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, CF3, hydroxy and nitro; and R5denotes COOH; or its pharmaceutically acceptable salt.

Extensive pharmacological studies have shown that the compounds I and their pharmaceutically acceptable salts, for example, have strong pharmaceutical, such as endothelin receptor-antagonistic properties and favorable pharmacological profile. Compounds of the invention bind with receptors ETAand with receptors ETB. In comparison with the known antagonists of endothelin receptors, the compounds in accordance with the present invention contain samnay and favorable stability.

Antagonists of ET receptors of the present invention is suitable for various human diseases caused by endotheline, either alone or in combination with other factors. In particular, they are suitable in the treatment of various cardiovascular diseases, such as cerebral and coronary vasospasm, cerebral and coronary ischemia, subarachnoid hemorrhage, various types of hypertension, pulmonary hypertension, heart failure, disease, Raynaud's disease, diabetes, atherosclerosis or restenosis due to Dendarii after plastic surgery on the blood vessels.

Compounds of the present invention also provide new therapeutic opportunities in asthma, renal failure, dialysis, glomerular lesions, liver failure, stomach ulcer and duodenal ulcers, trophic ulcers, various dysfunctions of the brain, including migraine, benign prostatic hyperplasia and eye diseases, glaucoma in particular.

They are also suitable for eliminating the negative effects of cyclosporine and can be used against bacterial endotoxin-toxic shock or dessiminating inside the crystals I and their pharmaceutically acceptable salts can therefore be used, for example, as a pharmaceutically active components, which are used, for example, in the treatment of various cardiovascular diseases, such as cerebral and coronary vasospasm, cerebral and coronary ischemia, subarachnoid hemorrhage, various types of hypertension, pulmonary hypertension, heart failure, disease, Raynaud's disease, diabetes, atherosclerosis or restenosis due to Dendarii after plastic surgery on vessels, as well as in the treatment of asthma, renal failure, dialysis, glomerular lesions, liver failure, stomach ulcer and duodenal ulcers, trophic ulcers, various dysfunctions of the brain, including migraine, benign prostatic hyperplasia and eye diseases, glaucoma in particular. Thus, the present invention relates to the use of compounds in accordance with the invention and their pharmaceutically acceptable salts to obtain the appropriate drugs and therapeutic treatment of various cardiovascular diseases, such as cerebral and coronary vasospasm, cerebral and coronary ischemia, subarachnoid hemorrhage, R is lerosa or restenosis due to Dendarii after plastic surgery on vessels, as well as in the treatment of asthma, renal failure, dialysis, glomerular lesions, liver failure, stomach ulcer and duodenal ulcers, trophic ulcers, various dysfunctions of the brain, including migraine, benign prostatic hyperplasia and eye diseases, glaucoma in particular. Industrial production of active substances are also included in obtaining pharmaceutical drugs.

In addition, the compounds of the present invention can be used as research tools, for example to determine the leading compounds exhibiting excellent profile of binding with receptors ETAand with receptors ETB.

Obtaining compounds of formula I and their salts carried out by the method known per se and in which, for example,

a) compound of the formula

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or its salt or reactive derivative is subjected to interaction with the compound of the formula

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this otscheplaut free functional groups, with the exception of those that participate in the reaction, being optionally in protected form, and any present protective group, or

b) with the compound of the formula

< / BR>
this otscheplaut free functional groups, with the exception of those that participate in the reaction, being optionally in protected form, and any present protective group and, if desired, make the connection I received in accordance with the method or otherwise, in free form or in salt form, the compound of formula I, divide the mixture of isomers obtained in accordance with the method and produce the desired isomer and/or energy of the free compound of formula I obtained in accordance with the method, a Sol, or turn salt of compound I, received in accordance with the method, in a free compound I or into another salt.

The reactions described above and below in different ways, exercise is known per se manner, for example, in the absence of

or, as a rule, in the presence of a suitable solvent or diluent or a mixture thereof, and the reaction, depending on the requirements, carried out with cooling, at room temperature or with heating, for example at a temperature in the range from approximately -80oC to the boiling temperature of the reaction medium, preferably at a temperature of from about -10oC to +200oC, and if the/P> Variants of the method (a) and (b)

The compounds of formula IIa and IIIa, respectively, contain a free carboxyl group or a reactive acid derivative, for example, obtained activated esters or reactive anhydrides, and also reactive cyclic amides. Reactive acid derivatives can also be formed in situ.

Activated esters of compounds of formulae IIa and IIIa, respectively, having a carboxyl group are, in particular, esters, which are not saturated at the linking carbon atom esterificados radical, such as vinyl ester, such as a complex vinyl ether (obtained, for example, transesterification corresponding complex ester with vinyl acetate; method of activated vinyl esters), complex carbamoylation esters (obtained, for example, by treating the appropriate acid with the reagent isoxazole; method 1,2-oxazole or method Woodward) or 1-lower alkoxyphenyl ester (obtained, for example, by treating the appropriate acid lowest alkoxyethanol; ethoxyacetylene method), or esters of the type amidino, such as N,N'-DV is emenim a carbodiimide, for example N,N'-DICYCLOHEXYL-carbodiimide; carbodiimide method), or N,N-disubstituted amicinemici (obtained, for example, by treating the corresponding acid with a suitable N,N-disubstituted by cyanamide; cyanamide method), suitable complex akrilovye esters, particularly phenyl esters which are substituted by substituents that attracts electrons (obtained, for example, by treatment with appropriate acids suitable substituted phenol, for example 4-NITROPHENOL, 4-methylsulfinylphenyl, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyl-disophenol, in the presence of the capacitor, such as N,N'-dicyclohexylcarbodiimide; method of activated aryl esters), cyanomethylene esters (obtained, for example, by treating the corresponding acid with chloroacetonitrile in the presence of a base; method cyanomethylene esters, thioesters, in particular phenylthiophene, which is not substituted or substituted, for example nitro (obtained, for example, by treating the corresponding acid with thiophenolate, which is not substituted or substituted, for example, using nitro, inter alia, using anhydrous method or carbodiimide method; method of activated thiol esters), or, in particular, complex Eminem or N-gidrosiimidazolyatnye, for example N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide, imide, N-hydroxy-5 - norbornene-2,3-dicarboxylic acid, 1-hydroxybenzotriazole or 3-hydroxy-3,4-dihydro-1,2,3-benzotriazin-4-one, for example in accordance with anhydrite method or carbodiimide method; method of activated complex N-hydroxy-esters). Can also be used in the internal esters such as lactones.

Anhydrides of acids may be symmetric or preferably mixed anhydrides of these acids, for example anhydrides with inorganic acids, such as galodamadruga, in particular floramerica (obtained, for example, by treating the appropriate acid, such as cryptorchidism), anhydrides (obtained, for example, by treating the corresponding acid with thionyl chloride, pentachloride phosphorus, phosgene or oxalylamino; method anhydrides), azides (obtained, for example, from a corresponding acid ester via the corresponding hydrazide and treatment nitrous acid; azide method), anhydrides with polufinale carbonic acid, for example lower alkyl-polufinale carbonic acid (obtained, for example, by treating the corresponding 2-dihydroquinoline; the method of mixed anhydrides O-alkylphenol acid); or anhydrides with dihalogenoalkane, especially deklarirovannoe, phosphoric acid (obtained, for example, by treating the appropriate acid with the acid chloride phosphoric acid; a method of anhydrides of phosphoric acid), anhydrides with other derivatives of phosphoric acid (for example those that can be obtained with phenyl N-phenyltetramagnesium or by reaction of amides alkylphosphoric acid in the presence of anhydrides of sulfonic acids and/or additives that reduce racemization, such as N-hydroxybenzotriazole, or in the presence of a complex of diethyl ether cyanophosphonate acid) or a derivative of phosphoric acid, or anhydrides with organic acids, such as mixed anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (obtained, for example, by treating the corresponding acid with a lower alkane - or phenyl-lower alkane-carbonylchloride, which is not substituted or substituted, as for example, phenylacetylene, pivaloyloxy or cryptomaterial; method of mixed anhydrides of carboxylic acid) or with organic sulfonic acids (obtained, for example, the definition of sulphonylchloride, such as lower alkane - or aryl-, for example methane - or p-toluene-sulfonyl chloride; method of mixed anhydrides of sulfonic acids), as well as asymmetric anhydrides (obtained, for example, by condensing the corresponding acid in the presence of a carbodiimide or 1-diethylaminopropyl; the method of symmetrical anhydrides).

Suitable cyclic inorganic salts are, in particular, amides with five-membered deathcycle of aromatic character, such as amides with imidazoles, for example imidazole (obtained, for example, by treating the corresponding acid with N,N'-carbonyl diimidazol; method of imidazoles) or pyrazole, for example 3,5-dimethylpyrazole (obtained, for example, by the acid hydrazide by treatment with acetylacetone; method of pyrazolidone).

The condensation of a free carboxylic acid (IIb or IIIb, respectively), using the corresponding amine can preferably be carried out in the presence of a conventional condensing agent, or with the use of anhydrides of carboxylic acids or halides of carboxylic acids, such as chlorides or activated esters of carboxylic acids, such as complex p-nitrophenolate esters. Examples of conventional condensing AG is particularly, dichlorochlordene, and, in addition, suitable carbonyl compounds, for example carbonyldiimidazole, the compounds 1,2-oxazole, for example 2-ethyl-5-phenyl-1,2-oxazole-3'-sulfonate and 2-tert-butyl-5-methylisoxazole perchlorate, or a suitable acylaminoacyl, for example 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline, the compounds N,N, N',N'-tetramethylurea, such as O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea hexafluorophosphate, and, in addition, activated derivatives of phosphoric acid, for example diphenylphosphoryl azide, diethylphosphinic cyanide, phenyl-N-phenylphosphonothioic, bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride or 1-benzotriazolyl-Tris(dimethylamino)phosphonium hexaflurophosphate.

If you want, then add an organic base, preferably a tertiary amine, such as tri-lower alkylamine dimensional radicals, for example ethyl of Diisopropylamine or triethylamine, and/or heterocyclic base, for example 4-dimethylaminopyridine or preferably N-methyl-morpholine or pyridine.

Condensation of activated esters, reactive anhydrides or reactive cyclic amides to the corresponding amines is usually carried out in prelamin, or one from among the above-mentioned organic bases. If desired, you can optionally use a condensing agent, such as described in relation to the free carboxylic acids.

The condensation of acid anhydrides with amines can be accomplished, for example, in the presence of inorganic carbonates, such as carbonates, ammonium or alkali metal or hydrogen carbonates such as sodium carbonate or potassium, or hydrogen-carbonate (optionally together with a sulfate).

The carboxylic acid anhydrides, such as derivatives harpalinae acid derived from the acid of formula IIa or IIIa respectively condense with the corresponding amines, preferably in the presence of an organic amine, such as the aforementioned tri-lower alkylamines followed or heterocyclic bases, and if appropriate, in the presence of hydrogen sulfate.

The condensation is preferably carried out in inert aprotic, preferably anhydrous, solvent or mixtures of solvents, for example in carboxamide, for example formamide or dimethylformamide, alojamiento hydrocarbon, such as methylene chloride, carbon tetrachloride or chlorobenzene, ketone, for example acetone, lonitrile, or mixtures thereof; if desired, at reduced or elevated temperature, for example at a temperature of from about -40 to +100oC, preferably at a temperature of from about -10 to +50oC, as in the case of complex arylsulfonate esters at temperatures from about +100 to +200oC, and if appropriate, in the atmosphere of inert gas, for example nitrogen or argon.

You can also use water, such as alcohol, solvents such as benzene or toluene. Acetone is also possible if desired to add to the presence of hydroxides of alkali metals as grounds.

Condensation can also be carried out in accordance with the method known as solid-phase synthesis, which is open in the works of R. Merrifield and described, for example, in Angew. Chem. 97, 801 - 812 (1985), Sciences) 71, 252 - 258 (1984) or in the work of R. A. Houghten, Proc. Natl. Acad. Sci. USA 82, 5131 - 5135 (1985).

Starting material, intermediate compounds can be obtained in accordance with conventional methods known in the art, the methods described in General terms in this application, and methods illustrated in the examples.

The educt of the formula IIa, in which Y denotes oxygen or seriesvideo with a complex ester of the formula

< / BR>
using, for example, binding conditions described in relation to the options method a) and b), the optional conversion of ester obtained in the corresponding thioether, for example by treatment of ester Lawesson's reagent, followed by hydrolysis of ester obtained, for example using suitable bases, such as lithium hydroxide.

The compounds of formula (IIc), derived from natural / -amino acids, are essentially known or can be obtained using conventional methods known in the art. The compounds of formula (IIc) in which R3denotes aryl or heteroaryl, either known or can be obtained using conventional methods known in the art, for example, as disclosed in schemes II-IV and in the working examples.

Compounds of formula (IIb) and (IIIa) are either known or can be obtained using conventional methods known to the specialists.

The educt of the formula (IIIb) are either known or may be obtained using conventional methods known in the art, for example by reacting N-protected compounds of formula (IIc) with the compound of the formula (IIb), for example from the unity of the present invention, represented by the General formula (I) in which X represents oxygen, Y represents-NH-, lower alkyl-N or oxygen and R5denotes COOH (formula I') are, for example, in accordance with the SCHEME I from the intermediate compounds represented by formula (IIa).

The intermediate compound (IIa) are obtained, for example, according to SCHEMES II and III.

As an example, the compounds in accordance with the present invention, represented by General formula (I) in which C(=X) represents C=O, CH-OH or C= N-OH, Y denotes CH2and R5denotes a carboxy, receive, for example, in accordance with SCHEME IV;

compounds in accordance with the present invention, represented by General formula (I), where C=(X) denotes C=S or C=H-lower alkyl and Y represents NH, receive, for example, according to SCHEME V;

compounds in accordance with the present invention, represented by General formula (I) in which R5denotes CH2OH, CONH2CN, tetrazolyl or CO-NO-OH, receive, for example, according to SCHEME VI.

Functional groups in the original substances (e.g., R5) that do not participate in the reaction, especially carboxy, can be protected using suitable is.

These protective groups may already be present in the precursors and they are designed to protect the relevant functional groups from unwanted secondary reactions, such as acylation, esterification or solvolysis, and so on. In certain cases, the protective group can cause selective reactions, for example stereoselective. A characteristic feature of the protective groups is that they can be easily derived, i.e. without undesired secondary reactions, for example by means of solvolysis, recovery, photolysis, as well as enzymatic, for example also in physiological conditions. Radicals, similar protective groups can, however, be present in the final products. Above and below in this description reference is given on the protective group in the narrow sense, if the end products are not relevant radicals.

Protection of functional groups such protective groups are themselves protective group and the reaction of their removal are described, for example, in standard works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; Th. W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981; "The Peptides", Volume 3 (E. Gross and J. Meienhofer, editors), Academic Press, London and New York 1981; Method("Amino acids, peptides, proteins"), Verlag Chemie, Weinheim, Deerfield Beach and Basel, 1982; Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" ("The Chemistry of Carbohydrates: monosaccharides and derivatives"), Georg Thieme Verlag, Stuttgart 1974.

The carboxyl group is protected, for example, as the group of ester, which can be selectively split in mild conditions. Carboxyl group which is protected in esterified form, esterification mainly by the group of lower alkyl, which is preferably branched in position 1 of the group of lower alkyl or protected by suitable substituents in position 1 or 2 groups lower alkyl.

Protected carboxyl group, which esterification group of lower alkyl represents, for example, methoxycarbonyl or etoxycarbonyl.

Protected carboxyl group, which esterification group of lower alkyl, branched in position 1 of the group of lower alkyl represents, for example, tert-lower alkoxycarbonyl, for example, tert-butoxycarbonyl.

Protected carboxyl group, which esterification group of lower alkyl, substituted in position 1 or 2 group of the lower alkyl suitable substituents, represents, for example, arylethoxysilanes having one or two arilin the example, lower alkyl, for example tert-lower alkyl, such as tert-butyl, lower alkoxy, for example methoxy, hydroxyl, halogen, for example chlorine, and/or nitro, for example benzyloxycarbonyl, benzyloxycarbonyl, substituted mentioned substituents, for example 4-nitrobenzenesulfonyl or 4-methoxybenzeneboronic, diphenylmethylene or diphenylmethylene, substituted mentioned substituents, for example di-(4-methoxyphenyl)-methoxycarbonyl, and, in addition, carboxy, esterification group of lower alkyl, where the lower alkyl group substituted in position 1 or 2 is suitable substituents, for example 1-lower alkoxy-lower alkoxycarbonyl, such as methoxyethoxymethyl, 1-methoxyethoxymethyl or 1-ethoxyacetylene, 1-lower alkylthio lowest alkoxycarbonyl, for example, 1-methylthio-methoxycarbonyl or 1-ethyldiethanolamine, roulettecasino, where a group of Arola represents benzoyl, not substituted or substituted, e.g. by halogen, such as bromine, for example ventilatsioonil, 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichlorocyanuric, 2-pomatoceros or 2-iodocholesterol, and 2-(tizamidine silyl) lowest alkoxycarbonyl, where the substituents, ical or aromatic hydrocarbon radical, not substituted or substituted, for example, lower alkyl, lower alkoxy, aryl, halogen and/or nitro, for example lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl, each of which is not substituted or substituted, as described above, for example 2-tri-lower alkylsilane lowest alkoxycarbonyl, such as 2-tri-lower alkyltrimethylammonium, for example 2-trimethylsilylethynyl or 2-(di-n-butyl-methyl-silyl)- etoxycarbonyl or 2-trainsimulator, such as trivinylcyclohexane.

The carboxyl group can also be protected in the form of organic groups siliconserver. Organic group siliconserver represents, for example, a group of three or lower alkylalkoxysilane, such as trimethylsilylacetamide. Silicon atom group siliconserver can also be substituted by two groups of lower alkyl, for example methyl groups, and amino - or carboxyl group of the second molecule of formula I. Compounds with such protective groups can be obtained, for example, using dimethyl-CHLOROSILANES as cilleruelo agent.

Protected carboxyl group is preferably a lower alkoxycarbonyl, naproxenambien or diphenylcarbinol.

Cleavage of the protective groups that are not components of the desired final product of formula I, for example carboxy-protective group, carry out a known per se manner, for example using solvolysis, in particular hydrolysis, alcoholysis or acidolysis, either by restoring, especially hydrogenolysis or chemical reduction, as well as photolysis, optionally in stages or simultaneously, you can also use fermentation methods. Cleavage of the protective groups are described, for example in the standard works mentioned above in the section relating to "Protective groups".

For example, protected carboxy, for example lower alkoxycarbonyl, tert-lower alkoxycarbonyl, lower alkoxycarbonyl, which is substituted in position 2 three-substituted group silila or in position 1 lower alkoxy or lower alkyl-thio, or diphenylmethylene, which is not substituted or substituted, can be converted into free carboxy by treatment with a suitable acid, such as formic acid, hydrogen chloride or triperoxonane acid, optionally with the simultaneous addition of nucleophilic compounds, such as phenol or anisole. Carboxy can also be asvab is yellow, such as lithium hydroxide, sodium hydroxide or potassium hydroxide. Benzyl oxycarbonyl, which is not substituted or substituted, may be released, for example, by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a metal hydrogenation catalyst such as palladium-based catalyst. In addition, suitable substituted benzyloxycarbonyl, such as 4-nitrobenzyl-oxy-carbonyl, can be converted into free carboxy recovery, for example by treatment with detonator alkali metal, such as ditional sodium, or reducing metal, for example zinc, or a salt recovery of metal, such as chromium salt (II), for example chloride, chromium (II), usually in the presence of the agent, releasing hydrogen, which together with the metal to produce hydrogen at the time of allocation, such as acid, is mainly suitable carboxylic acid, such as lower alcantarea acid, which is not substituted or substituted with, for example, hydroxy, such as, for example, acetic acid, formic acid, glycolic acid, diphenylpyraline acid, lactic acid, mandelic acid, 4-charmingalina acid or tartaric acid, or in the presence of alcohol or the metal that as described above, 2-halo-lower alkoxycarbonyl (optionally after conversion of 2-bromo-lower alkoxycarbonyl to the appropriate group, 2-iodo-lower alkoxycarbonyl) or roulettecasino can also be converted into free carboxy. Roulettecasino can be split by treatment with a nucleophilic, preferably salt-forming reagent, such as thio-sodium phenolate or sodium iodide. 2-(Tri-substituted silyl) lowest alkoxycarbonyl, such as 2-tri-lower alkylsilane lowest alkoxycarbonyl can also be converted into free carboxy by treatment with a salt of hydrofluoric acid, which produces the fluoride anion, such as fluoride of an alkali metal such as sodium fluoride or potassium, if appropriate, in the presence of a macrocyclic polyether ("crown ether"), or a fluoride of an organic Quaternary base, such as fluoride, Tetra-lower alkylamine or fluoride three lowest alkylaryl-lower alkylamine, such as a fluoride of tetraethylammonium or tetrabutylammonium fluoride, in the presence of an aprotic polar solvent such as dimethylsulfoxide or N,N-dimethylacetamide. Carboxy, protected in the form of organic cellarstone, such as the Eski traditional way, for example by treatment with water, alcohol or acid or fluoride, as described above. Esterified carboxy can be released from the enzymatic protection, for example with the use of esterases or suitable peptidases, for example esterified arginine or lysine, such as lysine-methyl ester, using trypsin.

Connection in accordance with the present invention, which is obtained in this way can be converted into another compound in accordance with the present invention are known per se manner.

Connection in accordance with the present invention containing a hydroxyl group may be esterified using methods known per se. Esterification can be done, for example, with the use of alcohol, such as substituted or unsubstituted lower alkanol, or its reactive complex ester. Suitable reactive esters of the desired alcohols are, for example, those with strong inorganic or organic acids, such as the corresponding halides, sulfates, lower alkanesulfonyl or substituted or unsubstituted benzosulfimide, for example chlorides, bromides, iodides, metoda, hydroxide or carbonate of an alkali metal or an amine. On the contrary, the corresponding ethers, such as connections lower alkoxy, can be derived, for example using strong acids such as mineral acids, for example kaleidotrope acid, such as Hydrobromic or itestosterone acid, which may preferably be present in the form of pyridinium halides, or with Lewis acids, for example halides of elements of main group III or relevant subgroups. These reactions can be carried out, if necessary, with cooling or heating, for example at a temperature of from about -20 to +100oC, in the presence or in the absence of a solvent or diluent, in an atmosphere of inert gas and/or under pressure and, where appropriate, in a closed reactor.

The compounds of formula I in which R2denotes hydrogen, can be N-alkylated known per se manner. The alkylation is carried out, for example, using reactive complex ester of the lower haloalkyl, for example bromide or iodide, lower alkanesulfonyl, such as methanesulfonate or p-toluensulfonate, or di-lower alkylsulfate, for example dimethyl of sulfadoxine potassium, and favorably in the presence of a phase transfer catalyst such as tetrabutylammonium bromide or designed chloride, if there may be a need for a more powerful basic condensing agents, such as amides, hydrides or alkoxides of the alkali metal, for example sodium amide, sodium hydride or sodium ethylate. In addition, the compounds of formula I in which R2means is other than hydrogen, for example, which is lower alkyl, can be obtained in reducing conditions, for example using a suitable aldehyde. The corresponding compounds of formula I in which R2denotes hydrogen, can also be etilirovany known per se manner, for example in accordance with the acylation described for option a).

In the compounds of formula I, which contain as Deputy esterification or amidinophenoxy group carboxyl, a group of this type can be converted into a free carboxyl group, for example by hydrolysis, for example in the presence of a basic agent or an acid agent, such as a mineral acid. Tert-butyloxycarbonyl, for example, can also be converted into carboxyl, for example, the known per se method, such as processing trihaloacetic to methods, described in the examples.

Salts of compounds of formula I can be obtained in known per se manner. For example, the acid additive salts of compounds of formula I are obtained by treatment with an acid or a suitable ion exchange reagent. Salts can be converted into the free compounds in a traditional way, and acid additive salts can be converted, for example, by treatment with a suitable basic agent.

Depending on the procedure and reaction conditions, the compounds in accordance with the invention, having soleobrazutaya, especially basic properties can be obtained in free form or, preferably, in the form of salts.

In light of the close interaction between the new compound in the free form and in the form of its salts, in the preceding and following description of a free compound or its salts can be understood as meaning the corresponding salts or the free compound. New compounds, including their salts of salt-forming compounds can also be obtained in the form of their hydrates, or they can include other solvents used for crystallization.

Depending on the choice of the starting substances and procedures new connections can prisutstvie is such as antipodes, or as mixtures of isomers, such as racemates, diastereoisomeric mixtures or mixtures of racemates, depending on the number of asymmetric carbon atoms.

Acid additive salts can be obtained by neutralizing the compounds of formula (I) having a basic group, with an acid or an acid ion exchanger.

Salt with a base can be obtained by neutralization of the compounds of formula (I) having an acid group, using the primary connection.

The racemates and mixtures of diastereoisomers received in accordance with the present invention, can be separated into the pure isomers or racemates known per se manner on the basis of physico-chemical differences in these compounds, for example, by fractional crystallization. The racemates obtained in accordance with the present invention, can also be converted into the optical antipodes by known methods, for example by recrystallisation from an optically active solvent, by chromatography on chiral-absorbents, using suitable microorganisms, by cleavage of a specific immobilized enzymes, via the formation of compounds including, for example using chiral crown ethers, whereas the emer by the interaction of the racemate primary outcome of substance with an optically active acid, such as carboxylic acid, for example tartaric acid or malic acid, or acid, for example camphorsulfonic, and separating the mixture of diastereoisomers obtained in this way, for example on the basis of differences in the solubility of the components constituting the mixture, to separate the stereoisomers, from which the desired enantiomer can be freed under the action of suitable agents. The more active enantiomer preferentially excrete.

The present invention also relates to variants of the method, in accordance with which the connection is obtained as an intermediate at any stage of the method, used as the initial substance and spend the missing stage, or use or, in particular, is formed in the reaction conditions of the original substance in the form of a derivative or salt and/or its racemates or antipodes.

In the method of the present invention is used preferably those of the original substances, which result in the compounds described at the beginning as particularly suitable. The invention likewise relates to a new source substances, which are specially designed for connections with the new starting compounds of formula IIa, IIb, IIIa and IIIb, in which the variables have the values specified above, their preparation and use, for example, as the starting material.

The present invention also relates to pharmaceutical preparations which contain compounds according to the invention or their pharmaceutically acceptable salts as active ingredients, and to methods for their preparation.

The pharmaceutical preparations according to the invention, which contain the connection in accordance with the invention or its pharmacologically acceptable salts are those which are intended for enteral, such as oral, rectal and parenteral (a) warm-blooded animals, while the active component is present as such or together with a pharmaceutically acceptable carrier. The daily dose of active ingredient depends on the age and individual condition of the patient and mode of administration of the medicinal product. New pharmaceutical preparations contain, for example, from about 10% to 80%, preferably 20% to 60%, of the active component.

The pharmacologically active compounds of the present invention can be ispolzovanie or in combination or mixture with fillers or carriers, suitable for enteral or parenteral administration. Preferred tablets and gelatin capsules, which comprise the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, (b) galantai, for example silica, talc, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also C) binders, e.g. magnesium aluminum silicate, starch paste, gelatinous, Trianta, methylcellulose, carboxymethylcellulose sodium and/or polyvinylpyrrolidone, if desired, d) a dispersant or disintegrators, for example starches, agar, alginic acid or its sodium salt, or foaming mixtures and/or (e) adsorbents, colorants, flavouring and sweetening agents. Injectables are preferably aqueous isotonic solutions or suspensions, and suppositories are predominantly derived from fatty emulsions or suspensions. These compounds can be sterilized and/or to enter additional substances, such as preservatives, stabilizers, wetting agents or emulsifiers, soljubilizatory, salt regulirovanie valuable substances. These drugs receive in accordance with conventional methods of mixing, granulating or coating, and with a content of approximately from 0.1 to 100%, preferably from 1 to 50%, of the active component. A uniform dose for a mammal weighing approximately 50 to 70 kg may contain from about 0.2 to 2000 mg, preferably from 1 to 200 mg, of the active component.

The following examples illustrate the invention described above; however, they should not be construed as limiting the scope of the claims. Temperatures are indicated in degrees Celsius.

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Are not commercially available 3-substituted derivatives of alanine were synthesized in accordance with Scheme II, or in accordance with the work of M. J. O'donnell, Tetrahedron Lett. 30, 2641 (1978).

Example 1:

N-(3,5-Dimethylbenzoyl)-N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan

To a stirred solution of N-BOC-N-methyl-(D)-phenylalanine (2.1 g, 7.5 mmol) [BOC = tert-butyloxycarbonyl] in dry DMF (N,N - dimethylformamide] (15 ml) was added the hydrochloride difficult methyl ester (L)-tryptophan (2 g, 7.8 mmol) and hydroxybenzotriazole (1.2 g, 8,8 mmol). The mixture is cooled to a temperature of 0oC and added dropwise 1-(3-dimethylaminopropyl)-W continued for 2 hours. Homogeneous mixture is diluted with ethyl acetate (500 ml) and washed with three portions of water (200 ml). The organic layer is dried in the presence of magnesium sulfate, filtered and concentrated in vacuo to obtain a complex of methyl ester of N-BOC-N-methyl-(D)- i.e. phenylalanyl-(L)-tryptophan in the form of a white foam. []D= +42o(c = 1.0, ethanol).

The above crude substance dissolved in a mixture triperoxonane acid (6 ml) and ethicial (1.5 ml) and stirred under nitrogen atmosphere at room temperature for 1 hour. Added a 4 M solution of hydrogen chloride in dioxane (2 ml). Hydrochloric salt precipitated by adding simple ether (400 ml) and hexane (200 ml), filtered and washed with simple ether to obtain the hydrochloride complex of methyl ester of N-BOC-N-methyl- (D)-i.e. phenylalanyl-(L)-tryptophan in the form of a white powder. []D= -29o(c = 1.0, ethanol).

A solution of the above-mentioned hydrochloric salt (200 mg, 0.48 mmol) and 3,5-dimethylbenzoic acid (87 mg, or 0.57 mmol) in DMF (1 ml) is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (of 0.11 ml, 0.6 mmol). The reaction mixture is slowly warmed to room temperature and stirring is continued for 2 hours. Homogeneous mixture is diluted with ethyl acetate (100 ml) and the industry is comfort in a vacuum. Chromatography on silica using ethyl acetate/hexane, 1:1, results in a complex methyl ester N-(3,5-dimethylbenzoyl)-N-methyl-(D)-i.e. phenylalanyl(L)-tryptophan in the form of a white foam.

This substance hydrolyzing at a temperature of 0oC using lithium hydroxide (20 mg, 0.47 mmol) in a mixture of 2:1 MeOH/water (9 ml). After 3 hours the reaction mixture was diluted with simple ether (200 ml) and washed with three portions of water (100 ml). The combined aqueous layers are acidified to pH = 2 with 1 M hydrochloric acid and extracted with two portions of ethyl acetate (200 ml). An ethyl acetate extracts are dried in the presence of magnesium sulfate, filtered and concentrated in vacuo to obtain specified in the title compound as a white foam; melting point 91 - 94oC. FAB-MS (mass spectroscopy with the bombardment of accelerated atoms) m/e 498 (M+H)+[]D= -46o(c = 1,095; ethanol). GHUR (Chiralcel OD, hexane/isopropanol/TFA (triperoxonane acid) 900 : 100: 3)) ee > 95%. NMR (CDCl3, 400 MHz): d [ppm] 8,29 (C), 8,15 (C), 7,56 (d, J = 7.8 Hz), 7,47 (d, J = 7.8 Hz), 7,3 - 6,7 (m), 6.48 in (C) of 5.92 (C) 5,41 (DD, J = 6,8, 9.7 Hz), 4,84 (DD, J = 5,8, 13,2 Hz) to 4.33 (DD, J = 2, 7,2 Hz), 3,4 - 2,75 (m), 2,70 (C) to 2.18 (C) 1,91 ().

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Example 2:

Recovery complex methyl ester N-(3,5-is drid lithium] in dry THF [tetrahydrofuran] at a temperature of 0oC leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophanol in the form of a colourless oil; FAB-MS m/e 484 (M+H)+.

Example 3:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D)- phenylalanine (derived from the corresponding complex methyl ester, described in Example 78 by hydrolise using lithium hydroxide in methanol/water: []D= + 88o(C = 1.0, ethanol)) with the hydrochloride (L)-tryptophanate in accordance with Example 12 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-i.e. phenylalanyl-(L)- tryptophanate; FAB-MS m/e 494 (M+H)+.

Example 4:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D)- (4-phenyl)phenylalanine (see Example 55) hydrochloride (L)-cryptofaunal (see Example 8) in accordance with Example 12 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenyl-phenyl)alanyl-(L)-cryptofaunal.

The solution of the above nitrile (100 mg, 0.18 mmol) in toluene (10 ml) is treated with azide tetrabutyrate (71 mg, 0.21 mmol) and heated under reflux for 4 hours in nitrogen atmosphere. The cooled solution is treated with a mixture of dichloromethane (10 ml), methanol (6 ml) and ammonia (0.2 ml), stirred at room temperature for 30 min is 1 : 1 : 0,01, to ethyl acetate/acetic acid, 1 : 0,01, leads to the production of 5-[N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)alanyl-(L)- tryptophanyl]-1H-tetrazole in the form of a colorless solid; FAB-MS m/e 598 (M+H)+; melting point 141 - 143oC.

Example 5:

N-(3,5-Dimethylbenzoyl)-TRANS-3-phenyl-(D)-Proline-(L)- tryptophan and

N-(3,5-dimethylbenzoyl)-TRANS-3-phenyl-(L)-prolinol-(L)- tryptophan

A solution of the hydrochloride difficult methyl ester of TRANS-3-phenyl-(D,L)-Proline (2.0 g, 8.3 mmol) (J. Y. L. Chung et al., J. Org. Chem. 55, 270 (1990)) and 3,5-dimethylbenzonitrile (1.6 g, 9.5 mmol) in dichloromethane (20 ml) was treated with DMAP [dimethylaminopyridine] (2.4 g, a 19.6 mmol). The reaction mixture is stirred for 2 hours, diluted with dichloromethane (300 ml) and washed with three portions of water (200 ml). The organic layer is dried in the presence of magnesium sulfate, filtered and concentrated in vacuo. The crude material chromatographic on silica using ethyl acetate/hexane, 1 : 1, to obtain the complex methyl ester N-(3,5-dimethylbenzoyl)-3-phenyl-(D,L)-Proline in the form of a mixture of TRANS - and CIS-isomers.

This substance is hydrolized at room temperature using a 1 M solution of lithium hydroxide (6 ml) in THF to obtain N-(3,5-dimethylbenzoyl)-TRANS-3-phenyl- (D,L)-is 225 mg, 0.69 mmol) in dry DMF (2 ml) was added the hydrochloride difficult methyl ester (L)-tryptophan (180 mg, 0.7 mmol) and hydroxybenzotriazole (115 mg, 0.85 mmol). The mixture is cooled to a temperature of 0oC and added dropwise 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.15 ml, 0.85 mmol). The reaction mixture is slowly warmed to room temperature and stirring is continued over night. Homogeneous mixture is diluted with ethyl acetate (100 ml) and washed with sodium bicarbonate (70 ml) and two portions of water (70 ml). The organic layer is dried in the presence of magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica using ethyl acetate/hexane, 1:1, results in 2 diastereoisomeric esters: complex methyl ester N-(3,5-dimethyl-benzoyl)-TRANS-3-phenyl-(D)-Proline-(L)-tryptophan and complex methyl ester N-(3,5-dimethylbenzoyl)-TRANS-3-phenyl-(L)-prolinol-(L)-tryptophan, each of which is presented in the form of a white foam.

Each of the above esters separately hydrolyzing at a temperature of 0oC using 1 M solution of lithium hydroxide in methanol. The reaction mixture was diluted with simple ether and washed with three portions of water. The combined aqueous layers are acidified to pH 2 stricty dried in the presence of magnesium sulfate, filtered and concentrated in vacuo to obtain specified in the title compounds, each in the form of a white foam; FAB-MS m/e 510 (M+H)+each.

Example 6:

Hydroxamic acid N-(3,5-dimethylbenzoyl)-N-methyl- (D)-(4-phenylphenyl)alanyl-(L)-tryptophan

To a stirred solution of sodium methylate (1.2 mmol) in dry methanol (5 ml) was added at room temperature in a nitrogen atmosphere of hydroxylamine hydrochloride. After 20 minutes of mixing, add methyl ester N-(3,5-dimethylbenzoyl)-N-methyl- (D)-(4-phenylphenyl) alanyl-(L)-tryptophan (260 mg, 0.44 mmol; see Example 55). The reaction mixture is stirred for 3 hours, diluted with simple ether (100 ml) and washed with three portions of water (70 ml). The organic layer is dried in the presence of magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica using a gradient from ethyl acetate/hexane, 1 : 2 to ethyl acetate results specified in the title compound as a white foam; FAB-MS m/e 589 (M+H)+.

Example 7:

Interaction (3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)alanine (Example 55) with the hydrochloride difficult methyl ester (D,L)-(3-benzo[b]thienyl)alanine (P. N. Rao, Int. J. Peptide Protein Res. 29, 118 (1987)) with subsequent storage in accordance with Example 1 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)alanyl- (D)-(3-benzo[b] thienyl)alanine; FAB-MS m/e 591 (M+H)+and N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)-alanyl-(L)-(3 - benzo[b] thienyl)alanine; FAB-MS m/e 591 (M+H)+.

Example 8:

N-(3,5-Dimethylbenzoyl)-N-methyl-(D)-i.e. phenylalanyl-(L)- tryptophanate

To a stirred solution of hydrochloride (L)-tryptophanate (1 g, 4.2 mmol) and di-tert-butyl dicarbonate (1.1 g, 5 mmol) in dichloromethane (10 ml) was added drop wise addition of triethylamine (0.7 ml, 5 mmol). After 1 hour the reaction mixture was diluted with dichloromethane (200 ml) and washed with 1 M hydrochloric acid (100 ml), saturated sodium bicarbonate solution (100 ml) and water (100 ml). The organic layer is dried in the presence of magnesium sulfate, filtered and concentrated in vacuo to obtain N-BOC-(L)-tryptophanate.

The above crude substance was dissolved in dichloromethane (40 ml) and treated with imidazole (0.4 g) and the acid chloride phosphoric acid (0.4 ml). After stirring at room temperature over night added pyridine (4 ml) and again the acid chloride phosphoric acid (0.4 ml). After stirring for one hour at room temperature, the reaction mixture was diluted with dichloromethane (200 ml) and washed with three portions of 1 M hydrochloric acid (100 ml). Organic SL is using ethyl acetate/hexane, 1:2, leads to the production of N-BOC-(L)-cryptofaunal (0.5 g) as a white solid. The above substance dissolved in a mixture triperoxonane acid (4 ml) and ethicial (1 ml) and stirred under nitrogen atmosphere at room temperature for one hour. Added a 4 M solution of hydrogen chloride in dioxane (2 ml). The hydrochloride is precipitated by adding a simple ether (400 ml) and hexane (200 ml), filtered and washed with simple ether to obtain the hydrochloride (L)-cryptofaunal in the form of a white solid.

To a stirred solution of N-(3,5-dimethylbenzoyl)-N-methyl-(D)- phenylalanine (200 mg, 0.64 mmol), obtained from the corresponding complex methyl ester, described in Example 78 by hydrolysis with lithium hydroxide in methanol/water: []D= + 88o(c = 1.0, ethanol) in dry DMF (5 ml) was added the above hydrochloride (L)- cryptofaunal (120 mg, of 0.65 mmol) and hydroxybenzotriazole (90 mg, 0.66 mmol). The mixture is cooled to a temperature of 0oC and added dropwise 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0,13 ml of 0.68 mmol). The reaction mixture is slowly warmed to room temperature and stirring is continued for 2 hours. Homogeneous mixture is diluted with ethyl acetate (200 ml) and prirot in vacuum. Chromatography on silica using ethyl acetate/hexane, 2 : 3, results indicated in the title compound as a slightly yellow foam; FAB-MS m/e 479 (M+H)+.

Example 9:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine (derived from the corresponding complex methyl ester, described in Example 78 by hydrolysis with lithium hydroxide in methanol/water: []D= + 88o(c = 1.0, ethanol)) with the hydrochloride (L)-tryptamine in accordance with Example 12 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenyl-alanyl-(L)-tryptamine; FAB-MS m/e 454 (M+H)+.

Example 10:

In accordance with the procedure described in Example 1, but starting with N-BOC-(D)-phenylalanine hydrochloride and complicated methyl ester (L)-tryptophan, receive N-(3,5-dimethylbenzoyl)-(D)-i.e. phenylalanyl-(L)-tryptophan; melting point 95-98oC; []D= + 19o(c = 0,465; ethanol); FAB-MS m/e 484 (M+H)+.

Example 11:

In accordance with the procedure described in Example 12, but starting with N-(3,5-dimethylbenzoyl)-(D)-phenylalanine hydrochloride and complicated methyl ester of N-methyl-(L)-tryptophan, receive N-(3,5-dimethylbenzoyl)-(D)-i.e. phenylalanyl-N-methyl-(L)-tryptophan; FAB-MS m/e 498 (M+H)+.

Example 12:
oC and added dropwise 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (of 0.12 ml, 0.66 mmol). The reaction mixture is slowly warmed to room temperature and stirring is continued over night. Homogeneous mixture is diluted with ethyl acetate (200 ml) and washed with three portions of water (100 ml). The organic layer is dried in the presence of magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica using ethyl acetate/hexane, 1 : 3, results in a complex methyl ester N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)-alanyl-(L)-tryptophan in the form of a white foam. Substance hydrolyzing at a temperature of 0oC using lithium hydroxide (5 mg, 0.12 mmol) in MeOH (0.6 ml) and water (60 ml). After 3 hours the reaction mixture was diluted with simple ether (100 ml) and washed with three portions of water (60 ml). The combined aqueous layers are acidified to pH 2 using 1 M hydrochloric acid and extracted with two portions of ethyl acetate (100 ml). An ethyl acetate extracts are dried in the presence of magnesium sulfate, filter the; []D= - 17oC (=0,96; methanol).

Example 13:

In accordance with the procedure described in Example 12 and starting from N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine hydrochloride and complicated methyl ester of N-methyl-(L)-tryptophan, receive N-(3,5-dimethylbenzoyl)-N-methyl-(D)-i.e. phenylalanyl-N-methyl-(L)-tryptophan; FAB-MS m/e 510 (M-H)-.

Example 14:

In accordance with the procedure described in Example 12 and starting from N-(3,5-dimethylbenzoyl)-(1-methylpropyl)-(D)-phenylalanine (derived by reductive alkylation difficult methyl ester (D)-phenylalanine using ethylmethylketone in the presence of cyanoborohydride sodium with subsequent N-acylation using 3,5-dimethylbenzoyl chloride in the presence of DMAP and hydrolysis of complex methyl ester in accordance with Example 1) and hydrochloride difficult methyl ester (L)-tryptophan, receive N-(3,5-dimethylbenzoyl)-N-(1-methylpropyl)- (D)-i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 540 (M+H)+.

Example 15:

In accordance with the procedure described in Example 12 and starting from N-(3,5-dimethylbenzoyl)-N-ethyl-(D)-phenylalanine (derived by alkylation difficult methyl ester N-(3,5-dimethylbenzoyl)- (D)-phenylalanine using ethyliodide in the presence of hydride soda is th methyl ester (L)-tryptophan, get N-(3,5-dimethylbenzoyl)-ethyl-(D)-i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 510 (M-H)-.

Example 16:

In accordance with the procedure described in Example 12 and starting from N-(3,5-dimethylbenzoyl)-N-(cyclohexylmethyl)- (D)-phenylalanine (derived by reductive alkylation difficult methyl ester (D)-phenylalanine using cyclohexanecarboxaldehyde in the presence of cyanoborohydride sodium with subsequent N-acylation using 3,5-dimethylbenzoyl chloride in the presence of DMAP and hydrolysis of complex methyl ester in accordance with Example 1) and hydrochloride difficult methyl ester (L)-tryptophan, receive N-(3,5-dimethylbenzoyl)-N-(cyclohexylmethyl)-(D)-i.e. phenylalanyl- (L)-tryptophan; FAB-MS m/e 580 (M+H)+.

Example 17:

In accordance with the procedure described in Example 12, starting from N-(3,5-dimethylbenzoyl)-N-cyclohexyl-(D)-phenylalanine (derived by reductive alkylation difficult methyl ester (D)-phenylalanine with cyclohexanone in the presence of cyanoborohydride sodium with subsequent N-acylation using 3,5-dimethylbenzoyl chloride in the presence of DMAP and hydrolysis of complex methyl ester in accordance with Example 1) and the hydrochloride of methyl complex ASS="ptx2">

Example 18:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with acetic acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-acetyl-N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 408 (M+H)+.

Example 19:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with benzoic acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-benzoyl-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 470 (M+H)+.

Example 20:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with TRANS-2-phenyl-1-cyclopropanecarbonyl acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(TRANS-2-phenyl-1 - cyclopropanecarbonyl)-N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 510 (M+H)+.

Example 21:

Interaction hydrochloride difficult methyl ester N-mate the m hydrolysis part of a complex methyl ester in accordance with Example 1 leads to the production of N-(2-naphtol)-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 520 (M+H)+.

Example 22:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with p-Truelove acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(4-methylbenzoyl)-N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan: FAB-MS m/e 484 (M+H)+.

Example 23:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with m-Truelove acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(3-methylbenzoyl)-N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 484 (M+H)+.

Example 24:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with 3,5-dichlorobenzoyl acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of (3,5-dichlorobenzoyl)-N-methyl-(D)-i.e. phenylalanyl- (L)-tryptophan; FAB-MS m/e 538 (M+H)+.

Example 25:

Interaction hydrochloride difficult methyl who am 12, with the subsequent hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of (3,5-differentail)-N-methyl-(D)-i.e. phenylalanyl- (L)-tryptophan; FAB-MS m/e 506 (M+H)+.

Example 26:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with 3,5-bis(trifluoromethyl)benzoic acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-[(3,5-bis(trifluoromethyl)benzoyl] -N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 606 (M+H)+.

Example 27:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with 3,5-bis(trifluoromethyl)phenylacetic acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-[(3,5-bis(trifluoromethyl)phenylacetyl]-N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 620 (M+H)+.

Example 28:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with 3-methyl-1-cyclohexanecarbonyl acid in accordance with Example 12, with posleduyushchikh)- N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 490 (M+H)+.

Example 29:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with 3-methylvaleramide acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(3-methylvalerate)-N-methyl-(D)-i.e. phenylalanyl- (L)-tryptophan; FAB-MS m/e 464 (M+H)+.

Example 30:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with 2-methylmalonic acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(2-methylbutanoyl)-N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 450 (M+H)+.

Example 31:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with 3,5-dihydroxybenzoic acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(3,5-dihydroxybenzyl)-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 502 (M+H)+.

Example 32:

Interaction hydrochloride is Auteuil in accordance with Example 12, with the subsequent hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(2,5-dihydroxybenzyl)-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 502 (M+H)+.

Example 33:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with 2-thiophencarboxylic acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(2-thiophencarboxylic)-N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 474 (M+H)+.

Example 34:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with 5-methyl-2-thiophencarboxylic acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(5-methyl-2-thiophencarboxylic)-N-methyl-(D)- i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 488 (M+H)+.

Example 35:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with 3-methyl-2-thiophencarboxylic acid according to Example 12 followed by hydrolysis of part of a complex of methyl OPANA; FAB-MS m/e 488 (M+H)+.

Example 36:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with 4-vinylbenzoic acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(4-vinylbenzyl)-N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 546 (M+H)+.

Example 37:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with 3,5-dimethoxybenzoic acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(3,5-dimethoxybenzoyl)-N - methyl-(D)-i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 530 (M+H)+.

Example 38:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with 4-methoxybenzoic acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(4-dimethoxybenzoyl)-N-methyl-(D)- i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 500 (M+H)+.

Example 39:

Interaction larger the Oh in accordance with Example 12, with the subsequent hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(2-dimethoxybenzoyl)-N-methyl-(D)-i.e. phenylalanyl- (L)-tryptophan; FAB-MS m/e 498 (M+H)+.

Example 40:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with 3,5-dinitrobenzoic acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(3,5-dinitrobenzoyl)-N-methyl-(D)-i.e. phenylalanyl- (L)-tryptophan; FAB-MS m/e 558 (M+H)+.

Example 41:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with 3,5-dibromobenzoic acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(3,5-dibromobenzyl)-N-methyl-(D)-i.e. phenylalanyl- (L)-tryptophan; FAB-MS m/e 626 (M+H)+.

Example 42:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with 3-methoxybenzoic acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in the CE is +.

Example 43:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with isonicotinic acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(4-pyridylcarbonyl)-N-methyl-(D)- i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 471 (M+H)+.

Example 44:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) from 6-chloro-2-pyridineboronic acid according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(6-chloro-2-pyridylcarbonyl)-N-methyl-(D)- i.e. phenylalanyl-(L)-tryptophan; FAB-MS m/e 503 (M+H)+.

Example 45:

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan (see Example 1) with isopropyl-chloroformate in the presence of triethylamine, followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 results in N-isopropoxycarbonyl-N-methyl-(D)-i.e. phenylalanyl-(L)- tryptophan; FAB-MS m/e 452 (M+H)+.

Example 46:

The interaction of N-(3,5-dimethylbenz is amylovora ether (L)-tryptophan according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(3-dimethylbenzoyl)-N-methyl-(L)-tryptophan; FAB-MS m/e 464 (M+H)+.

Example 47:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)- (3, 5dimethylphenyl)alanine (obtained from 3,5-dimethylbenzylamine in accordance with the General method A according to scheme II) hydrochloride difficult methyl ester (L)-tryptophan according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl- (D,L)-(3, 5dimethylphenyl)alanyl-(L)-tryptophan as a mixture of 2 diastereoisomers; FAB-MS m/e 524 (M-H)-.

Example 48:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-cyclohexylamine (obtained from bromoethylamine in accordance with the General method And scheme II) hydrochloride difficult methyl ester (L)-tryptophan according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl- (D,L)-cyclohexylethyl-(L)-tryptophan as a mixture of 2 diastereoisomers; FAB-MS m/e 504 (M+H)+.

Example 49:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-cyclohexylglycine (obtained from bromocyclohexane in accordance with the General method A according to scheme II) hydrochloride methyl ester is accordance with Example 1 leads to the production of N-(3,5-dimethylbenzoyl)- N-methyl-(D, L)-cyclohexylglycine-(L)- tryptophan as a mixture of 2 diastereoisomers; FAB-MS m/e 488 (M-H)-.

Example 50:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(2-naphthyl)alanine (obtained from (D)-(2-naphthyl)alanine in accordance with Example 55) with the hydrochloride difficult methyl ester (L)-tryptophan according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(3-dimethylbenzoyl)-N-methyl-(D)-(2-naphthyl)alanyl-(L)-tryptophan; FAB-MS m/e 546 (M-H)-.

Example 51:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-phenylglycine (from benzylbromide in accordance with the General method A according to scheme II) hydrochloride difficult methyl ester (L)-tryptophan according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-phenylglycine-(L)-tryptophan as a mixture of 2 diastereoisomers; FAB-MS m/e 484 (M+H)+.

Example 52:

To a solution of 2-(hydroxymethyl)thiophene (5.7 g, a 49.9 mmol) and tetrabromomethane (24.8 g, 74.9 mmol) in THF (85 ml) was added triphenylphosphine (19.6 g, 74.9 mmol) at a temperature of 0oC. the Mixture is stirred at room temperature Tasbulat again simple diethyl ether and filtered. The filtrate is condensed under vacuum to obtain 2-(bromomethyl)thiophene.

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-(2-thienyl)alanine (obtained from 2-(bromomethyl)of thiophene in accordance with the General method A according to scheme II) hydrochloride difficult methyl ester (L)-tryptophan according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-(2-thienyl)alanyl-(L)-tryptophan as a mixture of 2 diastereoisomers; FAB-MS m/e 504 (M+H)+.

Example 53:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-(3-furyl)alanine (obtained from 3-(bromomethyl)of furan in accordance with the procedure described in Example 52, in accordance with the General method B according to scheme III) hydrochloride difficult methyl ester (L)-tryptophan according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D,L)-(3-furyl)alanyl-(L)-tryptophan as a mixture of 2 diastereoisomers; FAB-MS m/e 488 (M+H)+.

Example 54:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-(2-pyridyl)alanine (obtained from commercially available 2-(chloromethyl)pyridine in a suitable the leader 12 with subsequent hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D,L)-(2-pyridyl)alanyl-(L)-tryptophan as a mixture of 2 diastereoisomers; FAB-MS m/e 499 (M+H)+.

Example 55:

N-(3,5-Dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)alanyl-(L)-tryptophan

A solution of thionyl chloride (6.5 ml) in dry methanol (280 ml) at -20oC handle (D)-(4-phenylphenyl)alanine (3.7 g, 13.3 mmol) (Y. Yabe et al., Chem. Phaem. Bull. 24(12), 3149 (1976)). The reaction mixture was refluxed overnight and concentrated in vacuo. Recrystallization from methanol/simple ether gives the hydrochloride difficult methyl ester (D)-(4-phenylphenyl)alanine; []D= + 13o(c = 1,025; methanol). The solution of the above substances (315 mg, of 0.94 mmol) in dry THF (0.4 ml) is treated at room temperature with water (0.4 ml), formalin (0.15 ml, 1.88 mmol) and freshly distilled by cyclopentadiene (0.3 ml, 3.63 mmol). The slightly yellow solution was stirred at room temperature for 2 hours, washed with hexane (100 ml), diluted with 4% sodium bicarbonate solution (100 ml) and extracted with chloroform (200 ml). The organic layer is dried in the presence of magnesium sulfate, filtered and concentrated in vacuo to obtain the bicyclic intermediate substance (0.39 g). This substance is dissolved at room temperature in a nitrogen atmosphere in chloroform (4,7 ml) and treated triperoxonane acid (4.7 oduct dissolved in ethyl acetate (200 ml) and washed with 1 M hydrochloric acid (100 ml) and saturated sodium bicarbonate solution (100 ml). The organic layer is dried in the presence of magnesium sulfate, filtered and concentrated in vacuo to obtain N-methyl-(D)-phenyleneamine in the form of a white foam. The solution of the above substances in chloroform (5 ml) is treated with 2 M sodium carbonate solution (0.6 ml) and 3,5-dimethylbenzonitrile (0.3 ml, 1.4 mmol). The reaction mixture was stirred at room temperature for 2.5 hours, diluted with ethyl acetate (200 ml) and washed with 4 % sodium bicarbonate solution (100 ml), water (100 ml), 1 M hydrochloric acid (100 ml) and again water (100 ml). The organic layer is dried in the presence of magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica using ethyl acetate/hexane, 4:1, results in a complex methyl ester N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenyleneamine; []D= + 48o(c = 0,685; methanol); ee > 98% (IHVR: Chiralcel OF).

This substance (110 mg, 0.27 mmol) hydrolyzing at a temperature of 0oC using lithium hydroxide (13 mg, 0.31 mmol) in MeOH (0.8 ml), water (0.4 ml) and THF (0.4 ml). After 2 hours the reaction mixture was diluted with simple ether (200 ml) and washed with three portions of water (100 ml). The combined aqueous layers are acidified to pH 2 using 1 M hydrochloric acid and extragood and concentrated in vacuo to obtain N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)alanine as a white foam; []D= + 7,5o(c = 1.0; methanol).

The solution of the above substances (103 mg, 0.27 mmol), hydrochloride difficult methyl ester (L)-tryptophan (100 mg, 0,39 mmol) and hydroxybenzotriazole (70 mg, 0.52 mmol) in dry DMF (3 ml) is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (of 0.07 ml, 0.38 mmol). The reaction mixture is slowly warmed to room temperature and stirring is continued over night. Homogeneous mixture is diluted with ethyl acetate (100 ml) and washed with three portions of water (70 ml). The organic layer is dried in the presence of magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica using ethyl acetate/hexane, 1: 1, results in a complex methyl ester N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)alanyl-(L)-tryptophan in the form of a white foam; de > 98% (IHVR: Chiralcel OD).

This substance hydrolyzing at a temperature of 0oC using lithium hydroxide (10 mg, 0.23 mmol) in MeOH (methanol) (2 ml), THF (1 ml) and water (1 ml). After 3 hours the reaction mixture was diluted with simple ether (100 ml) and washed with three portions of water (60 ml). The combined aqueous layers are acidified to pH 2 using 1 M hydrochloric acid and extracted with two portions of ethyl acetate (100 ml). Ethylacetate is in the title compound as a white foam; FAB-MS m/e 574 (M+H)+; []D/= + 2,5 (c = 1.0, ethanol); NMR (CDCl3, 400 MHz): d [ppm] 8,32 (c), by 8.22 (s) of 7.6 to 6.8 (m), 6,93 (C) to 6.8 (m), 6,51 (C) 5,97 (C), 5,46 (t, J = 8 Hz), 4,85 (K, J = 6 Hz), 4,36 (m), 3,4 - 2,8 (m), 2,73 (C) of 2.15 (C) of 1.85 (C).

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Example 56:

A mixture of 3-methylbiphenyl (5,23 g, and 31.1 mmol), N-bromosuccinimide (5,56 g, and 31.2 mmol), benzoyl peroxide (135 mg, 0,56 mmol) and carbon tetrachloride (150 ml) is refluxed for 17 hours. The mixture was concentrated in vacuo and the residue purified column flash chromatography (hexane) to give 3-phenylendiamine.

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-(3-phenylphenyl)alanine (obtained from 3-phenylbenzoate in accordance with the General method B according to scheme III) hydrochloride difficult methyl ester (L)-tryptophan according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-(3-phenylphenyl)alanyl-(L)-tryptophan as a mixture of 2 diastereoisomers; FAB-MS m/e 574 (M+H)+.

Example 57:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-(3-diphenyl)alanine (obtained from commercially available diphenylmethane in accordance with the General method B according to scheme III) hydrochloride stylowego ester in accordance with Example 1 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D,L)-(3-diphenyl)-alanyl-(L)-tryptophan as a mixture of 2 diastereoisomers; FAB-MS m/e 572 (M-H)-.

Example 58:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-(4-chinolin)alanine [obtained from 4-(bromomethyl)quinoline (4-(hydroxymethyl)quinoline in accordance with the procedure described in Example 52) in accordance with the General method B according to scheme III] hydrochloride difficult methyl ester (L)-tryptophan according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D,L)-(4-chinolin)alanyl-(L)-tryptophan as a mixture of 2 diastereoisomers; FAB-MS m/e 547 (M-H)-.

Example 59:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-(2-course)alanine (obtained from commercially available 2-chlorobenzylamino in accordance with the General method B according to scheme III) hydrochloride difficult methyl ester (L)-tryptophan in accordance with Example 1 followed by hydrolysis of part of a complex methyl ester in accordance with Example 12 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-(2-course)alanyl-(L)-tryptophan as a mixture of 2 diastereoisomers; FAB-MS m/e 530 (M-H)-.

Example 60:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-(3-course)alanine (obtained from commercial datafire (L)-tryptophan in accordance with Example 1 followed by hydrolysis of part of a complex methyl ester in accordance with Example 12 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-(3-course)alanyl-(L)-tryptophan as a mixture of 2 diastereoisomers; FAB-MS m/e 532 (M+H)+.

Example 61:

The interaction of N-(3,5-dimethylbenzoyl)-1-methyl- (D, L)-(4-course)alanine (obtained from commercially available 4-chlorobenzylchloride in accordance with the General method A according to scheme II) hydrochloride difficult methyl ester (L)-tryptophan in accordance with Example 1 followed by hydrolysis of part of a complex methyl ester in accordance with Example 12 results (3,5-dimethylbenzoyl)-N-methyl-(D, L)-(2-course)alanyl-(L)-tryptophan as a mixture of 2 diastereoisomers; FAB-MS m/e 530 (M-H)-.

Example 62:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-[(4-2 - pyridyl)phenyl] alanine [obtained from 4-(2-pyridyl)benzylbromide (4-(2-pyridyl)toluene in accordance with the procedure described in Example 56) in accordance with the General method B according to scheme III] hydrochloride difficult methyl ester (L)-tryptophan in accordance with Example 1 followed by hydrolysis of part of a complex methyl ester in accordance with Example 12 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl- (D, L)-[(4-(2-pyridyl)phenyl] alanyl-(L)-tryptophan as a mixture of 2 diastereoisomers; FAB-MS m/e 575 (M+H)+.

Example 63:

Vzaimodeystviya in accordance with the General method B according to scheme III) hydrochloride difficult methyl ester (L)-tryptophan in accordance with Example 1 followed by hydrolysis of part of a complex methyl ester in accordance with Example 12 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D,L)-(3-phenyl-prop-1-yl)glycyl-(L)- tryptophan as a mixture of 2 diastereoisomers; FAB-MS m/e 524 (M-H)-.

Example 64:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-tyrosine (obtained from (D)-tyrosine in accordance with the procedure described in Example 55) with the hydrochloride difficult methyl ester (L)-tryptophan in accordance with Example 1 followed by hydrolysis of part of a complex methyl ester in accordance with Example 12 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D)- tyrosyl-(L)-tryptophan; FAB-MS m/e 512 (M-H)-.

Example 65:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-O-methyl-(D)-tyrosine (obtained O-methylation of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-tyrosine (Example 64)) hydrochloride difficult methyl ester (L)-tryptophan in accordance with Example 1 followed by hydrolysis of part of a complex methyl ester in accordance with Example 12 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-O-methyl-(D)-tyrosyl-(L)-tryptophan; FAB-MS m/e 528 (M+H)+.

Example 66:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-O-benzyl-(D)-tyrosine (obtained O-benzilidene N-(3,5-dimethylbenzoyl)-N-methyl-(D)-tyrosine (Example 64)) hydrochloride difficult methyl ester (L)-tryptophan in accordance with Example 1 followed by hydrolysis of part of a complex methyl ester in accordance with Example="ptx2">

Example 67:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine (derived from the corresponding complex methyl ester, described in Example 78 by hydrolysis with lithium hydroxide in methanol/water: []D= + 88o(c = 1.0, ethanol)) with the hydrochloride difficult methyl ester (L)-phenylalanine in accordance with Example 1 followed by hydrolysis of part of a complex methyl ester in accordance with Example 12 leads to the production of N-(3,5-dimethylbenzoyl)- N-methyl-(D)-i.e. phenylalanyl-(L)- phenylalanine; FAB-MS m/e 457 (M-H)-.

Example 68:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine (derived from the corresponding complex methyl ester, described in Example 78 by hydrolysis with lithium hydroxide in methanol/water: []D= + 88o(c = 1.0, ethanol)) with the hydrochloride difficult methyl ester (L)-(1-naphthyl)alanine in accordance with Example 1 followed by hydrolysis of part of a complex methyl ester in accordance with Example 12 leads to the production of N-(3,5-dimethylbenzoyl)- N-methyl-(D)-i.e. phenylalanyl-(L)-(1-naphthyl) alanine; FAB-MS m/e 509 (M+H)+.

Example 69:

The interaction of N-(3,5-dimethylbenzoyl)-methyl-(D)-(4-phenylphenyl)alanine (Example 55) with the hydrochloride complex Geniu N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)alanyl-(L)-(1-naphthyl)alanine; FAB-MS m/e 585(M+H)+.

Example 70:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine (derived from the corresponding complex methyl ester, described in Example 78 by hydrolysis with lithium hydroxide in methanol/water: []D= + 88o(C = 1.0, ethanol)) with the hydrochloride difficult methyl ester (L)-(2-naphthyl)alanine, followed by hydrolysis of part of a complex methyl ester leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-i.e. phenylalanyl-(L)-(2-naphthyl)alanine; FAB-MS m/e 509 (M+H)+.

Example 71:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine (derived from the corresponding complex methyl ester, described in Example 78 by hydrolysis with lithium hydroxide in methanol/water: []D= + 88o(C = 1.0, ethanol)) with the hydrochloride difficult methyl ester (L)-Homo-phenylalanine in accordance with Example 1 followed by hydrolysis of part of a complex methyl ester in accordance with Example 12 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-i.e. phenylalanyl-(L)-Homo-phenylalanine; FAB-MS m/e 473 (M+H)+.

Example 72:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine (derived from the corresponding complex methyl ester, OPIE,0; ethanol)) with the hydrochloride difficult methyl ester (D,L)-Nind-methyl-tryptophan and subsequent hydrolysis of part of a complex methyl ester leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-i.e. phenylalanyl-(D, L)-Nind-methyltryptophan in the form of a mixture of 2 diastereoisomers; FAB-MS m/e 512 (M+H)+.

Example 73:

3-[N-[N-Dimethylbenzoyl)-N-methyl-(D)-i.e. phenylalanyl] - (2-amino-ethyl)]indole-4-carboxylic acid

Synthesis of methyl 3-(2-amino-ethyl)indole-4-carboxylate:

A solution of methyl indole-4-carboxylate (1.1 g, 6.2 mmol) and Eschenmoser salt [N, N-dimethylmethyleneammonium iodide] (1.3 g, 7 mmol) in acetonitrile (15 ml) is refluxed for 3 hours. The reaction mixture was concentrated, re-dissolved in dichloromethane (400 ml) and washed with 1 M sodium hydroxide solution (200 ml) and water (200 ml). The organic layer is dried in the presence of magnesium sulfate, filter and concentrate. The obtained methyl 3-(dimethylaminomethyl)indole-4-carboxylate (1.2 g) was identified in using methyl iodide (0.7 ml) in a mixture of dichloromethane (25 ml) and simple ether (13 ml). The reaction mixture is concentrated and the product is dissolved in DMSO (7 ml) and treated with potassium cyanide (700 mg, 10 mmol). After stirring at room temperature overnight, the reaction mixture razbavlenija, filtered and concentrated in vacuo. Chromatography of the crude substances on silica using ethyl acetate/hexane, 2 : 3, leads to the production of methyl 3-(cyanomethyl)indole-4-carboxylate in the form of a dark oil. Hydrogenation in acetic acid in the presence of a catalyst in the form of platinum oxide gives the desired intermediate substance in the form of a solid orange color.

Interaction:

The solution of the above 3-(2-amino-ethyl)indole-4-carboxylate (50 mg, 0.23 mmol), hydroxybenzotriazole (37 mg, 0.27 mmol) and N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine (70 mg, 0.23 mmol; obtained from the corresponding complex methyl ether, added in Example 78 by hydrolysis with lithium hydroxide: []D= + 88o(c = 1.0, ethanol)) in DMF (1 ml) at a temperature of 0oC is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.05 ml, 0.27 mmol). The reaction mixture is slowly warmed to room temperature and stirring is continued for 2 hours. Homogeneous mixture is diluted with ethyl acetate (100 ml) and washed with three portions of water (70 ml). The organic layer is dried in the presence of magnesium sulfate, filtered and concentrated in vacuo. Chromatography of the crude substances on silica using ethyl is oxalate in the form of a white foam. This substance is hydrolized at room temperature using lithium hydroxide (7 mg, 0.15 mmol) in a mixture of MeOH (3 ml), THF (1 ml) and water (2 ml). After 72 hours the reaction mixture was diluted with simple ether (200 ml) and washed with three portions of water (100 ml). The combined aqueous layers are acidified to pH 2 using 1 M hydrochloric acid and extracted with two portions of ethyl acetate (200 ml). An ethyl acetate extracts are dried in the presence of magnesium sulfate, filtered and concentrated in vacuo to obtain specified in the title compound as a white foam; FAB-MS m/e 498 (M+H)+.

Example 74:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine [obtained from the corresponding complex methyl ester, described in Example 78 by hydrolysis with lithium hydroxide in methanol/water: []D= + 88o(c = 1.0, ethanol)] hydrochloride difficult methyl ester (D,L)-(2-pyridyl)-alanine (obtained in accordance with Example 54 in accordance with the General method A according to scheme III) in accordance with Example 1 with subsequent preparative GHUR-division 2 diastereoisomeric esters and hydrolysis of complex parts methyl ester in accordance with Example 12 leads to the production of N-(3,5-dimethylbenzoyl)-(2-pyridyl)alanine; FAB-MS m/e 460 (M+H)+.

Example 75:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine (derived from the corresponding complex methyl ester, described in Example 78 by hydrolysis with lithium hydroxide in methanol/water: []D= + 88o(c = 1.0, ethanol)) with the hydrochloride difficult methyl ester (D,L)-(4-phenylphenyl)-alanine (obtained from commercially available 4-phenylbenzyl-chloride according to General method A according to scheme III) in accordance with Example 1 followed by hydrolysis of part of a complex methyl ester in accordance with Example 12 leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-i.e. phenylalanyl-(D,L)-(4-phenylphenyl)alanine in the form of a mixture of 2 diastereoisomers; FAB-MS m/e 533 (M-H)-.

Example 76:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine (derived from the corresponding complex methyl ester, described in Example 78 by hydrolysis with lithium hydroxide in methanol/water: []D= + 88o(c = 1.0, ethanol)) with the hydrochloride complex ethyl ester (D,L)-(4-chinoline)-alanine (obtained as described in Example 58 in accordance with the General method B according to scheme III) in accordance with Example 1 followed by hydrolysis of part of the complex et(4-chinoline)alanine in the form of a mixture of 2 diastereoisomers; FAB-MS m/e 508 (M-H)-.

Example 77:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine (derived from the corresponding complex methyl ester, described in Example 78 by hydrolysis with lithium hydroxide in methanol/water: []D= + 88o(c = 1.0, ethanol)) with methyl 3-(3-indolyl)-2-hydroxypropionate (obtained from 3-intolerate recovery using sodium borohydride) in accordance with Example 1 followed by hydrolysis of part of a complex methyl ester in accordance with Example 12 yields a complex ethyl ester N-(3,5-dimethylbenzoyl)-N-methyl-(D)-i.e. phenylalanyl-1-carboxy-2-(3-indolyl) in a mixture of 2 diastereoisomers; FAB-MS m/e 499 (M+H)+.

Example 78:

5-(R)-[N-(3,5-Dimethylbenzoyl)-N-methyl] amino-2-(R)-(3-indolyl)methyl - 4-oxo-6-fenilcetonuria acid

The mixed solution of N-BOC-N-methyl-(D)-phenylalanine (3 g, 10.5 mmol) in methylene chloride (25 ml) is treated at a temperature of 0oC using a slight excess of diazomethane simple ether (25 ml). The reaction mixture is stirred at a temperature of 0oC and concentrated in vacuo to obtain a complex of methyl ester of N-BOC-N-methyl-(D)-phenylalanine in the form of a colorless oil. The above venturato temperature for 1 hour. Add 4 M solution of hydrogen chloride in dioxane (3.6 ml). The hydrochloride is precipitated by adding a simple ether (400 ml) and hexane (300 ml), filtered and washed with simple ether to obtain the hydrochloride complex of methyl ester of N-methyl-(D)-phenylalanine (2.4 g) as a white powder. The solution of the above hydrochloride complex of methyl ester of N-methyl-(D)-phenylalanine (2.4 g, 10 mmol) and 3,5-dimethylbenzoic acid (1.8 g, 11 mol) in DMF (15 ml) at a temperature of 0oC is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.2 ml, 11 mmol). The reaction mixture is slowly warmed to room temperature and stirring is continued over night. Homogeneous mixture is diluted with ethyl acetate (500 ml) and washed with three portions of water (200 ml). The organic layer is dried in the presence of magnesium sulfate, filtered and concentrated in vacuo. The crude substance chromatographic on silica using ethyl acetate/hexane, 1 : 2, receiving the methyl ester of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine in the form of a colorless oil. []D= + 111o(c = 0,94; ethanol).

Chilled (- 70oC) a solution of dimethyl methylphosphonate (800 mg, 6.4 mmol) in dry THF (15 ml) under nitrogen atmosphere is treated with 1.5 M solution of utility in hexm solution of the above-mentioned complex of methyl ester of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine (850 mg, 2.6 mmol) in dry THF (5 ml). The colorless reaction mixture is stirred at -70oC for 2 hours. The reaction mixture was cooled by adding 1 ml of acetic acid, diluted with ethyl acetate (400 ml) and washed with three portions of water (300 ml). The organic layer is dried in the presence of magnesium sulfate, filtered and concentrated in vacuo. Chromatography of the crude substances on silica using ethyl acetate leads to the production of dimethyl 3-(R)-[N-(3,5-dimethylbenzoyl)-N-methyl]amino-2-oxo-4-phenyl-1-butylphosphonate in the form of a colorless oil. []D= + 145o(c = 0,99; ethanol).

To a cooled (0oC) suspension of sodium hydride (20 mg, 60% in oil, 0.5 mmol) in dry THF (1 ml) under nitrogen atmosphere was added dropwise dimethyl 3-(R)-[N-(3,5-dimethylbenzoyl)-N-methyl] amino-2-oxo-4 - phenyl-1-butylphosphonate (200 mg, 0.5 mmol) in dry THF (0.5 ml). Stirring is continued for 30 minutes. Added dropwise benzyl indole-3-pyruvate (140 mg, 0.5 mmol; obtained from commercially available indole-3-pyruvic acid and benzylbromide) in 0.5 ml dry THF. The reaction mixture is slowly warmed to room temperature and stirring is continued over night. The yellow reaction mixture was diluted with ethyl acetate (100 ml) and about irout in vacuum. Chromatography of the crude substances on silica using ethyl acetate yields a mixture of E/Z product (105 mg). This substance is subjected to hydrogenolysis under pressure of 5 atmospheres of hydrogen in ethanol at a temperature of 50 - 60oC in the presence of a catalyst Wilkinson (chloride Tris-(triphenylphosphine)-rhodium(I)). Chromatography on silica using ethyl acetate/hexane, 1 : 2, leads to the production of benzyl 5-(R)-[N-(3,5-dimethylbenzoyl)-N-methyl]amino-2-(R,S)-(3 - indolyl)methyl-4-oxo-6-phenylhexanoic in the form of a mixture 2 : 3 diastereoisomers. Division of diastereoisomers using preparative GHUR (silica, hexane/isopropanol, 30 : 1), followed gidrodinamicheskim removal (Pd/C, hydrogen (1 ATM) part of a complex benzyl ether leads to the production of 5-(R)-[N-(3,5-dimethylbenzoyl)- N-methyl] amino-2-(R)-(3-indolyl)methyl-4-oxo-6-fenylopropanol acid, de > 98% ee > 92% (IHVR, chiralcel, OD), FAB-MS m/e 497 (M+H)+and 5-(R)-[N-(3,5-dimethylbenzoyl)-N-methyl]amino-2-(S)-(3-indolyl)methyl - 4-oxo-6-phenyl-Caproic acid, de > 98% ee > 92% (IHVR, chiralcel, OD), FAB-MS m/e 497 (M+H)+.

Example 79:

4-[N-(3,5-Dimethylbenzoyl)-N-methyl] amino-2-(3-indolyl)methyl - 5-phenylpentane acid

To a suspension of sodium hydride (9 mg, 0.22 mmol) in THF (1 ml) add rasteau at a temperature of 0oC for 30 minutes. To the mixture was added a solution of 2-(R)-[N-(3,5-dimethylbenzoyl)-N-methyl] -amino-3-phenyl-1-propanal (50 mg, 0,169 mmol) in THF (0.3 ml), and all this was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo. The remainder chromatographic on silica gel using ethyl acetate/hexane, 1 : 2, receiving methyl 4-[N-(3,5-dimethylbenzoyl)-N-methyl] amino-2-(3-indolyl)methyl-5 - finalment-2-ENOAT in the form of a white foam. A solution of methyl 4-[N- (3,5-dimethylbenzoyl)-N-methyl] amino-2-(3-indolyl)methyl-5-finalment-2-enoate (40 mg, 0.08 mmol) in methanol (2 ml) hydronaut in the presence of palladium carbon (5 mg) in a nitrogen atmosphere at room temperature for 24 hours. The catalyst is filtered off and the filtrate was concentrated in vacuo. The remainder chromatographic on silica gel using ethyl acetate/hexane, 1 : 2, receiving methyl 4-[N-(3,5-dimethylbenzoyl)-N-methyl] amino-2-(3-indolyl)-methyl-5-phenylpentane. Hydrolysis of methyl 4-[N-(3,5-dimethylbenzoyl)-N-methyl] amino-2-(3 - indolyl)methyl-5-phenylbutanoate in accordance with Example 1 leads to the production of 4-[N-(3,5-dimethylbenzoyl)-N-methyl] amino-2-(3 - indolyl)methyl-5-phenyl-pentane the measures as follows:

Synthesis of 2-(R)-[N-(3,5-dimethylbenzoyl)-N-methyl]amino-3-phenyl-1-propanol:

To a solution of complex methyl ester N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine (obtained according to Example 78) (895 mg, of 2.75 mmol) in THF (15 ml) is added L-selectride (11 ml, 11 mmol) at a temperature of 0oC and the reaction mixture was stirred at the same temperature throughout the night. The mixture is diluted with diethyl ether, washed with water, dried in the presence of magnesium sulfate and concentrated in vacuo. The remainder chromatographic on silica gel (ethyl acetate) to obtain 2-(R)-[N-(3,5-dimethylbenzoyl)-N-methyl]amino-3-phenyl-1-propanol.

To a mixed solution of dimethyl sulfoxide (0,12 ml) in methylene chloride (4 ml) under nitrogen atmosphere add oxalicacid (0,132 ml of 1.52 mmol) at a temperature of 35oC and the reaction mixture is stirred for 30 minutes. To the mixture was added a solution of 2-(R)-1-(3,5-dimethylbenzoyl)-N-methyl]amino-3-phenyl-1-propanol (410 mg, 1.38 mmol) in methylene chloride (4 ml) and stirring is continued at a temperature of - 35oC for 30 minutes, then added triethylamine (0.7 ml, 5 mmol) at a temperature of 35oC. the Reaction mixture is heated to room temperature, diluted with water (10 ml) and extracted with mechaniem 2-(R)-[N-(3,5-dimethylbenzoyl)-N-methyl]amino-3-phenyl-1-propanol in the form of a yellow oil.

Synthesis of 3-(3-indolyl)-2-(dimethylphosphino)propionate:

To a stirred solution of indole (5.6 g, of 47.8 mmol) in acetonitrile (130 ml) was added Eschenmoser salt (10 g, 54 mmol) under nitrogen atmosphere and the mixture is stirred for 30 minutes. The mixture was concentrated in vacuo and the residue diluted with 1 M sodium hydroxide solution and extracted with methylene chloride. The organic layer is dried in the presence of sodium carbonate and concentrated in vacuo to obtain 3-(dimethylaminomethyl)indole as a brown oil. To a solution of 3-(dimethylaminomethyl)indole in methylene chloride (200 ml) was added dropwise methyliodide (5 ml, 80 mmol). The mixture is heated at room temperature for 6 hours and concentrated in vacuo to obtain (3-indolylmethane)ammonium iodide in the form of a brown foam. To a cooled (0oC) suspension of sodium hydroxide (1.5 g, 37 mmol) in DMF (100 ml) was added trimethyl phosphonoacetate (6,7 ml, 41 mmol) and the mixture is stirred at a temperature of 0oC for 30 minutes. To the mixture was added (3-indolylmethane) ammonium iodide and all this was stirred at room temperature overnight. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo. The remainder of HGO oil.

To a suspension of sodium hydride (9 mg, 0.22 mmol) in THF (1 ml) add a solution of methyl 3-(3-indolyl)-2-(dimethylphosphino)propionate (80 mg, 0.25 mmol) in THF (0.7 ml) at a temperature of 0oC in nitrogen atmosphere and the mixture is stirred at a temperature of 0oC for 30 minutes. To the mixture was added a solution of 2-(R)-[N-(3,5-dimethylbenzoyl)-N-methyl] -amino-3-phenyl-1-propanal (50 mg, 0,169 mmol) in THF (0.3 ml), and all this was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo. The remainder chromatographic on silica gel using ethyl acetate/hexane, 1 : 2, receiving methyl 4-[N-(3,5-dimethylbenzoyl)-N-methyl]amino-2-(3-indolylmethane)-5-phenyl - Penta-2-ENOAT in the form of a white foam. A solution of methyl 4-[N-(3,5-dimethylbenzoyl)-N-methyl] amino-2-(3-indolyl)-methyl-5-finalment - 2-enoate (40 mg, 0.08 mmol) in methanol (2 ml) hydronaut in the presence of palladium carbon (5 mg) in a nitrogen atmosphere at room temperature for 24 hours. The catalyst is filtered off and the filtrate was concentrated in vacuo. The remainder chromatographic on silica gel using ethyl acetate/hexane, 1 : 2, receiving methyl 4-[N-(3,5-dimethylbenzoyl)-N-methyl]amino-2-(3-indole in accordance with Example 1 leads to the production of 4-[N-(3,5-dimethylbenzoyl)-N-methyl]amino-2-(3-indolyl)methyl - 5-phenylpentane acid.

Example 80:

The reaction Horner-Wittig in accordance with Example 78 between dimethyl 3-[N-(3,5-dimethylbenzoyl)-N-methyl] amino-2-oxo-4 - phenyl-1-butylphosphonate (obtained according to Example 78) and methyl 1-naphthyl pyruvate and subsequent catalytic hydrogenation of the double bond in the presence of Wilkinson catalyst in accordance with Example 78 by hydrolysis part of a complex methyl ester in accordance with Example 12 leads to the production of 5-[N-(3,5-dimethylbenzoyl)-N-methyl]amino-2-(1-naphthyl)methyl-4-oxo-6 - fenylopropanol acid in the form of a mixture of isomers; FAB-MS m/e 506 (M-H)-.

The original substance can be obtained, for example, as follows:

Synthesis of methyl 1-naphthyl pyruvate:

Sodium (677 mg, 29.4 mmol) is dissolved in ethanol (48 ml). To the solution was added 1-naphthylacetamide (5,07 g, 30.3 mmol), then after 20 minutes, diethyl oxalate (4,1 ml, 30.3 mmol) at room temperature, and the mixture is stirred at room temperature for 2 hours and refluxed for 1 hour. After cooling to room temperature was added acetic acid (2 ml). The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried in the presence of magnesium sulfate and evaporated in vacuum with paml) is heated at a temperature of 100oC for 2 hours. After cooling, the mixture is extracted with ethyl acetate. The organic layer is dried in the presence of magnesium sulfate and evaporated in vacuo to obtain 3-(1-naphthyl)pyruvic acid. To a solution of 3-(1-naphthyl)pyruvic acid (1.86 g, 8,7 mmol) in simple diethyl ether (20 ml) was added a solution of diazomethane diethyl ether (25 ml). The mixture was concentrated in vacuo and the residue chromatographic on silica gel using hexane and ethyl acetate (3 : 2) to give methyl 3-(1-naphthyl)pyruvate.

Example 81:

Reductive alkylation of the hydrochloride difficult methyl ester (L)-tryptophan using 2-(R)-[N-(3,5-dimethylbenzoyl)-N-methyl]amino-3-phenyl-1-propanol (obtained according to Example 79) in methanol in the presence of cyanoborohydride sodium in accordance with Example 14, followed by hydrolysis of part of a complex methyl ester in accordance with Example 12 leads to the production of N-{2-(R)-[N-(3,5-dimethylbenzoyl)-N-methyl]-amino-3-phenyl-prop-1-yl}-(L)- tryptophan; FAB-MS m/e 484 (M + N)+.

Example 82:

100 mg benzyl-5-(R)-[N-(3,5-dimethylbenzoyl)-N-methyl]amino-2-(R)-(3-indolyl)methyl - 4-oxo-6-(4-biphenylyl)hexanoate, which is obtained as described in Example 84, dissolved in 750 μl tetrahydrofuranyl at a temperature of 0oC for one hour and at room temperature for one hour. Then add 280 ál of a saturated aqueous solution of ammonium chloride, stirred for 30 minutes and the mixture is extracted with simple ether. Evaporation of the ether phase yields a crude product, which was purified flash chromatography on silica gel using mixtures of ethyl acetate and hexane (2 : 1) as eluent. 15 mg of the obtained lactone is then treated with 2 mg of lithium hydroxide in a mixture of 500 μl of methanol and 250 μl of water for 12 hours at ambient temperature. Evaporation of the solvent leads to the production of lithium 5-(R)-[N-(3,5-dimethylbenzoyl)-N-methyl] amino-2-(R)-(3-indolyl)methyl-4 - hydroxy-6-(4-biphenylyl)-hexanoate.

Example 83:

The reaction Horner-Wittig in accordance with Example 78 between dimethyl 3-[N-(3,5-dimethylbenzoyl)-N-methyl]amino-2-oxo-4-(2 - thienyl)-1-butylphosphonate [complex methyl ester N-(3,5-dimethylbenzoyl)-N-methyl-(D,L)-(2-thienyl)alanine obtained in accordance with Example 52), as described in Example 78] and methyl 3-indole pyruvate and subsequent catalytic hydrogenation of the double bond in the presence of Wilkinson catalyst in accordance with Example 78 by hydrolysis of the part with the 2-(3 - indolyl)methyl-4-oxo-6-(2-thienyl)Caproic acid in the form of a mixture of isomers; FAB-MS m/e 501 (M-H)-.

Example 84:

The reaction Horner-Wittig in accordance with Example 78 between dimethyl 3-(R)-[N-(3,5-dimethylbenzoyl)-N-methyl] amino-2-oxo-4-(4-phenylphenyl)-1 - butylphosphonate [complex methyl ester N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)alanine obtained in accordance with Example 55), as described in Example 78] and benzyl 3-indole pyruvate and subsequent catalytic hydrogenation of the double bond in the presence of Wilkinson catalyst according to Example 78, preparative GHUR-division 2 diastereoisomers and hydrogenolysis part of a complex benzyl ester in accordance with Example 78 leads to the production of 5-(R)-[N-(3,5-dimethylbenzoyl)-N-methyl]amino-2-(R)-(3-indolyl)methyl-4-oxo - 6-(4-phenylphenyl)Caproic acid; FAB-MS m/e 573 (M+H)+and 5-(R)-[N-(3,5-dimethylbenzoyl)-N-methyl]-amino-2-(S)-(3-indolyl)methyl-4-oxo - 6-(4-phenylphenyl)Caproic acid; FAB-MS m/e 573 (M+H)+.

Example 85:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)- 3-phenyl-3-(4-phenylphenyl)alanine (obtained according to Example 108) hydrochloride difficult methyl ester (L)-tryptophan according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads is somerow; FAB-MS m/e 650 (M+H)+.

Example 86:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)- (5-dibenzosuberyl)alanine (obtained from commercially available 5-chlorodibenzofuran in accordance with the General method B according to scheme III) hydrochloride difficult methyl ester (L)-tryptophan according to Example 12 followed by hydrolysis of part of a complex methyl ester in accordance with Example 1 leads to the production of N-(3,5-dimethylbenzoyl)- N-methyl-(D,L)-(5-(dibenzosuberyl) alanyl-(L)-tryptophan as a mixture of 2 diastereoisomers; FAB-MS m/e 600 (M+H)+.

Example 87:

N-(5-Methyl-2-thienylboronic)-N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan

Interaction hydrochloride complex of methyl ester of N-methyl-(D)-i.e. phenylalanyl(L)-tryptophan 5-methyl-thienyl-2-carboxylic acid in accordance with Example 1 followed by hydrolysis of part of a complex methyl ester in accordance with Example 12 leads to the production of N-(5-methyl-2-thienylboronic)-N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan: FAB-MS m/e (M-H)-.

Example 88:

N-(3,5-Dimethylbenzoyl)-1,2,3,4-tetrahydro-3-athinaikon-(L)-tryptophan

A solution of the hydrochloride of methyl 1,2,3,4-tetrahydro-3-ethanolinduced (2.0 g, 9 mmol) and 3,5-dimethylbenzoic acid (1.6 g, 10 mmol) varavut to room temperature and stirring is continued for 2 hours. Homogeneous mixture is diluted with ethyl acetate (500 ml) and washed with three portions of water (200 ml). The organic layer is dried in the presence of magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica using ethyl acetate/hexane, 1 : 3, leads to the production of methyl N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro-3-ethanolinduced in the form of a colorless oil. This substance is hydrolized with 1 M sodium hydroxide solution in THF to obtain dimethylbenzoyl)-1,2,3,4-tetrahydro-3-ethinlestradiol acid as a white solid.

To a stirred solution of N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro-3-ethinlestradiol acid (350 mg, 1.1 mmol) in dry DMF (2 ml) was added the hydrochloride difficult methyl ester (L)-tryptophan (290 mg, 1.1 mmol) and hydroxybenzotriazole (180 mg, 1.3 mmol). The mixture is cooled to a temperature of 0oC and added dropwise 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.25 ml, 1.3 mmol). The reaction mixture is slowly warmed to room temperature and stirring is continued over night. Homogeneous mixture is diluted with ethyl acetate (100 ml) and washed with three portions of water (70 ml). The organic layer is dried in the presence of magnesium sulfate, filtered and concentrated in vacuo. Diastereoisomeric methyl esters of N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro-3 - athinaikon-(L)-tryptophan in the form of a white foam.

This substance hydrolyzing at a temperature of 0oC using 1 M sodium hydroxide solution in THF. The reaction mixture was diluted with simple ether and washed with three portions of water. The combined aqueous layers are acidified to pH 2 using 1 M hydrochloric acid and extracted with two portions of ethyl acetate. An ethyl acetate extracts are dried in the presence of magnesium sulfate, filtered and concentrated in vacuo to obtain specified in the title compound as a white foam; melting point 119 - 126oC. FAB-MS m/e 496 (M+H)+.

Example 89:

The reaction Horner-Wittig in accordance with Example 78 between dimethyl 3-[N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro-3 - ethanolinrequirements [methyl N-(3,5-dimethylbenzoyl)- 1,2,3,4-tetrahydro-3-ethanolinduced obtained in accordance with Example 88), as described in Example 78] and methyl 3-indole pyruvate and subsequent catalytic hydrogenation of the double bond in the presence of Wilkinson catalyst in accordance with Example 78 by hydrolysis part of a complex methyl ester in accordance with Example 12 leads to the production of 3-[N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro - 3-athinaikon] -2-(3-indolyl)methyl-propionic acid as a mixture isopinocampheol acid (obtained according to Example 88) hydrochloride difficult methyl ester (L)- (1-naphthyl)alanine with subsequent hydrolysis of part of a complex methyl ester in accordance with Example 12 leads to the production of N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro-3-athinaikon- (L)-1-naphthylamine in the form of a mixture of 2 diastereoisomers; FAB-MS m/e 507 (M+H)+.

Example 91:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-3-[4-(3-thienyl)phenyl] alanine (obtained from 4-(3-thienyl)benzylbromide in accordance with the General method B according to scheme III) hydrochloride difficult methyl ester (L)-tryptophan with subsequent separation of the two diastereoisomers using GHUR results in (D,L)-isomer and (L,L)-isomer. Hydrolysis of (D,L)-isomer according to Example 1 to obtain N-(3,5-dimethylbenzoyl)-N-methyl-D)-3-[4-(3-thienyl)phenyl] alanyl- (L)-tryptophan; FAB-MS m/e 578 (M-H)+.

The original substance can be obtained, for example, as follows:

Synthesis of 4-(3-thienyl)benzylbromide:

A solution of 4-bromothymol (0.9 ml, 7,3 mmol) in THF (3 ml) was added to the dry magnesium filings (0,815 g, 33.5 atom) in a nitrogen atmosphere. After initiating an exothermic reaction in the reaction mixture is added dropwise a solution of 4-bromothymol (3,16 ml of 25.7 mmol) in THF (3 ml). Stirring is continued for 10 minutes. The mixture is added dropwise to a suspension of 3-bromothiophene (2.8 ml, and 29.9 mmol) and chloride [1,2-bis(diphenylphosphino)-ethane] Nickel (II) (0,72 g, 1.4 mmol) in a simple diethyl ether (50 ml), which was stirred for 10 minutes. The reaction mixture is cooled to 1 N. the solution chloritoid sodium and salt solution, dried in the presence of magnesium sulfate and concentrated in vacuo. The residue is recrystallized from ethanol to obtain 4-(3-thienyl)-toluene. To a solution of 4-(3-thienyl)toluene (of 3.56 g of 20.5 mmol) in carbon tetrachloride (100 ml) was added N-bromosuccinimide (of 3.64 g of 20.5 mmol) and benzyl peroxide (80 mg, 3.3 mmol). The reaction mixture is heated under reflux for 24 hours and concentrated in vacuo. The reaction mixture is recrystallized from ethanol to obtain 4-(3-thienyl)benzyl bromide.

Example 92:

Hydrolysis of (L, L)-isomer obtained in Example 91, in accordance with the Example 1 to obtain N-(3,5-dimethylbenzoyl)- N-methyl-(L)-3-[4-(3-thienyl)phenyl]alanyl-(L)-tryptophan; FAB-MS m/e 578 (M-H)+.

Example 93:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-3-[4-(2-thienyl)phenyl] alanine (obtained from 4-(2-thienyl)benzylbromide [obtained as described in Example 91) according to General method b according to scheme III] hydrochloride difficult methyl ester (L)-tryptophan in accordance with Example 1 with the subsequent separation of the two diastereoisomers using GHUR results in (D,L)-isomer and (L,L)isomer. Hydrolysis of (D,L)-isomer according to Example 1 to obtain N-(3,5-dimethylbenzoyl)-N-matino, for example, as follows:

4-(2-Thienyl)benzylbromide obtained from 4-bromothymol and 2-bromothiophene according to Example 91.

Example 94:

Hydrolysis of (L, L)-isomer obtained in Example 93, in accordance with the Example 1 to obtain N-(3,5-dimethylbenzoyl)-N-methyl-(L)-3-[4-(2-thienyl)phenyl]alanyl-(L)-tryptophan; FAB-MS m/e 578 (M-H)+.

Example 95:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-3-[4-(5- isoxazolyl)phenyl]alanine (obtained from 4-(5-isoxazolyl)-benzylbromide in accordance with the General method B according to scheme III) hydrochloride difficult methyl ester (L)-tryptophan in accordance with Example 12, followed by separation of the two diastereoisomers using column chromatography medium pressure results in (D,L)-isomer and (L,L)-isomer. Hydrolysis of (D,L)-isomer according to Example 1 to obtain N-(3,5-dimethylbenzoyl)-N-methyl-D)-3-[4-(5- isoxazolyl)-phenyl]alanyl-(L)-tryptophan; FAB-MS m/e 565 (M-H)+.

The original substance can be obtained, for example, as follows:

In accordance with Example 56 4-(5-isoxazolyl)toluene [Lin et al., J. Org. Chem. 45, 4857 (1980)] brainrot obtaining 4-(5-isoxazolyl)benzyl bromide.

Example 96:

Hydrolysis of (L, L)-isomer, polucen the phenyl]alanyl- (L)-tryptophan; FAB-MS m/e 563 (M-H)+.

Example 97:

The hydrolysis of complex ethyl ester 1-(3,5-dimethylbenzoyl)-(D,L)-3-[4-(5-isoxazolyl)phenyl] alanine (obtained in accordance with Example 56) in accordance with Example 1 and the interaction hydrochloride difficult methyl ester (L)-tryptophan in accordance with Example 1 allows to obtain N-(3,5-dimethylbenzoyl) -(D,L)-3-[4-(5-isoxazolyl)phenyl]alanyl-(L)-tryptophan; FAB-MS m/e 549 (M-H)+.

Example 98:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)- 3-(4-cyanophenyl)alanine [obtained from 4-cyanobenzyl bromide (4-ceanataur, as described in the methods according to Example 56) in accordance with the General method B according to scheme III] hydrochloride difficult methyl ester (L)-tryptophan in accordance with Example 1 with the subsequent separation of the two diastereoisomers using column chromatography medium pressure results in (D,L)-isomer and (L, L)isomer. Hydrolysis of (D,L)-isomer according to Example 1 to obtain N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-(4 - cyanophenyl)alanyl-(L)-tryptophan; FAB-MS m/e 521 (M-H)+.

Example 99:

Hydrolysis of (L,L)-isomer obtained in Example 98, in accordance with the Example 1 to obtain N-(3,5-dimethylbenzoyl)-N-methyl-(L)-3-(4- (cyanophenyl)Alani obtained in Example 98] (500 mg, 0,932 mmol) and azide tetrabutyrate (464 mg, 1.4 mmol) in toluene (50 ml) is refluxed for 20 hours under nitrogen atmosphere. To the mixture was added methylene chloride (50 ml), methanol (30 ml) and ammonium hydroxide (1 ml). All this was stirred at room temperature for 1 hour, then concentrated in vacuo. The obtained residue chromatographic on silica using hexane/ethyl acetate (1 : 4 to + 0.5% acetic acid) to obtain the derived tetrazole. Hydrolysis of the compounds obtained in accordance with Example 1 to obtain N-(3,5-dimethylbenzoyl)-N-methyl-D)-3-[4-(5-tetrazolyl)-phenyl]alanyl- (L)-tryptophan; FAB-MS m/e 564 (M-H)+.

Example 101:

In accordance with the procedure described in Example 100, the formation of rings tetrazole of complex methyl ester [(L,L)-isomer: obtained in Example 98] with subsequent hydrolysis of complex methyl ester in accordance with Example 1 to obtain N-(3,5-dimethylbenzoyl)-N-methyl-(L)-3-[4-(5-tetrazolyl)-phenyl]alanyl-(L)- tryptophan; FAB-MS m/e 564 (M-H)+.

Example 102:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl- (D,L)-3-[4-(3-isoxazolyl)phenyl] alanine (obtained from 4-(3-isoxazolyl)- benzylbromide in accordance with the General method B according to scheme III) with the hydrochloride of Komarov using column chromatography medium pressure results in (D,L)-isomer and (L,L)-isomer. Hydrolysis of (D,L)-isomer according to Example 1 to obtain N-(3-dimethylbenzoyl)-N-methyl-(D)-[4-(3 - isoxazolyl)-phenyl]alanyl-(L)-tryptophan; FAB-MS m/e 565 (M-H)+.

The original substance can be obtained, for example, as follows:

4-(3-Isoxazolyl)benzyl bromide is obtained from 4-(3-isoxazolidinone [derived from p-tolualdehyde in accordance with the method of synthesis of 2-(3-isoxazolyl)mesitylene: L. D. Nunno et al., Tetrahedron, 43, 2181 (1987)] in accordance with Example 56.

Example 103:

Hydrolysis of (L, L)-isomer obtained in Example 102, in accordance with the Example 1 to obtain N-(3,5-dimethylbenzoyl)-N-methyl-(L)-3-[4-(5-isoxazolyl)phenyl]alanyl- (L)-tryptophan; FAB-MS m/e 565 (M-H)+.

Example 104:

Complex ethyl ester of N-(3,5-dimethylbenzoyl)-N-methyl-(D,L)-3-[4-(5-isoxazolyl)phenyl] alanine (obtained in Example 95) treated with 3 equivalents of lithium hydroxide to obtain N-(3,5-dimethylbenzoyl)-N-methyl-(D,L)-3-[4-(2-cyanoacetyl)-phenyl] alanine. Interaction obtained above connection hydrochloride difficult methyl ester (L)-tryptophan in accordance with Example 1 with the subsequent separation of the two diastereoisomers using column chromatography medium pressure results in (D,L)-isomer [soderm 1 allows to obtain N-(3,5-dimethylbenzoyl)-N-methyl-D)-3- [4-(2-cyanoacetyl)phenyl] alanyl-(L)-tryptophan; FAB-MS m/e 563 (M-H)+.

Example 105:

Hydrolysis of (L,L)-isomer obtained in Example 104, in accordance with the Example 1 to obtain N-(3,5-dimethylbenzoyl) -N-methyl-(L)-3-[4-(2-cyanoacetyl)phenyl]alanyl-(L)-tryptophan; FAB-MS m/e 563 (M-H)+.

Example 106:

To a solution of the monohydrate (D)-3-(4-nitrophenyl)alanine (4,56 g, 20 mmol) in MeOH (80 ml) in an atmosphere of nitrogen was slowly added thionyl chloride (24 ml, 320 mmol). The reaction mixture is heated at the temperature of reflux distilled over night and concentrated in vacuo. The residue is taken in a simple ether, then filtered. The obtained precipitation was washed with several portions of simple ether and dried in vacuum to obtain hydrochloride difficult methyl ester (D)-3-(nitrophenyl)alanine.

To a cooled to a temperature of 0oC to the above solution of ester (2,60 g, 10 mmol) and 3,5-dimethylbenzoic acid (1,95 g, 13 mmol) in DMF (60 ml) under nitrogen atmosphere was added 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (2.38 ml, 13 mmol) under stirring. The reaction mixture is slowly warmed to room temperature and stirring is continued for 3 days. The reaction mixture was diluted with ethyl acetate and washed with 1 N. a solution of hydrochloric acid and a saturated solution of the drug complex of methyl ester of N-(3,5-dimethylbenzoyl)-(D)-3-(4-nitrophenyl)alanine.

To a cooled to a temperature of 0oC to the above solution of ester (2.5 g, 7.0 mmol) and methyl iodide (1.3 g, 21,0 mmol) in DMF (26 ml) was slowly added sodium hydride (60% in oil, 0.28 g, 7.0 mmol) with stirring. After 30 minutes the reaction mixture was cooled water and extracted with ethyl acetate.

The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo to obtain a complex of methyl ester of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-(4-nitrophenyl)alanine.

The above ester hydrolyzing at room temperature using lithium hydroxide (323 ml, 7.7 mmol) in MeOH/water, 10 : 1, (55 ml). After 2 hours the reaction mixture was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with 1 n hydrochloric acid and extracted with ethyl acetate. The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo to obtain N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-(4-nitrophenyl)alanine.

The interaction of the compound, obtained above, with the hydrochloride difficult methyl ester (L)-tryptophan in accordance with Example 1 allows to obtain methyl ester of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-(4-nitrophenyl)alanyl-(L)-tryptophan. Hydroly is)-3-(4 - nitrophenyl)alanyl-(L)-tryptophan; FAB-MS m/e 541 (M-H)+.

Example 107:

A solution of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-(4-nitrophenyl)alanyl-(L)-tryptophan (20 mg) obtained in Example 106, in MeOH (1 ml), hydronaut in the presence of platinum oxide (1 mg) under hydrogen pressure of 3.8 ATM. After 1 hour, the catalyst was removed by filtration and the filtrate concentrated in vacuo. The crude substance is purified preparative thin-layer chromatography on silica using acetate/MeOH/acetic acid, 90 : 10 : 1, to obtain N-(3,5-dimethylbenzoyl)-N-methyl-(D)- 3-(4-AMINOPHENYL)alanyl-(L)-tryptophan; FAB-MS m/e 511 (M-H)+.

Example 108:

The interaction of N-(3,5-dimethylbenzoyl)-N-methyl-3-(4 - biphenyl)-3-phenyl-(D, L)-alanine [obtained from bromo-(4-biphenyl)-methylmethane in accordance with the General method B according to scheme III] hydrochloride difficult methyl ester (L)-tryptophan in accordance with Example 1 with the subsequent separation of the four diastereoisomers using column chromatography medium pressure results in (R,D,L)-isomers, (S,D,L)-isomers, (R,L,L)-isomer and (S,L,L)-isomer. Hydrolysis of (R,D,L)-isomer according to Example 1 allows to obtain (3R)-N-(3,5-dimethylbenzoyl)-N-methyl-3-(4-biphenyl)-3-phenyl- (D)-alanyl-(L)-tryptophan; FAB-MS m/e 648 (M-H)+.

The original substance of dimethyl sulfoxide (3.9 ml, to 54.4 mmol) in methylene chloride (70 ml) under nitrogen atmosphere was added triperoxonane acid (5.7 ml, of 40.8 mmol) under stirring at a temperature of 70oC. After 10 minutes, was added 4-biphenylmethanol (5 g, to 27.2 mmol) and after stirring for 30 minutes added triethylamine (30 ml, 218 mmol). The reaction mixture is heated to room temperature, diluted with water and extracted with methylene chloride. The organic layer is washed successively 1 N. a solution of hydrochloric acid and saturated sodium bicarbonate solution, dried in the presence of magnesium sulfate and concentrated to obtain 4-biphenylmethanol.

To a cooled to a temperature of 0oC to a solution of 4-biphenyl-methanal in THF (50 ml) in an atmosphere of nitrogen was slowly added a 3 M solution of bromide vinylmania in diethyl ether (5,7 3l, 15.7 mmol) under stirring. The reaction mixture is heated to room temperature and stirring is continued for 15 hours. The mixture is diluted with water and extracted with diethyl ether. The organic layer was washed with a saturated solution of ammonium chloride, dried in the presence of magnesium chloride and concentrated in vacuo. The residue is purified column flash chromatography on silica gel using 15% diethyl mmol) in methylene chloride (40 ml) under nitrogen atmosphere is added thienylboronic (3,7 ml, to 47.8 mmol) at room temperature with stirring. After 2 hours the reaction mixture was taken in methylene chloride and then washed with water. The organic layer is dried in the presence of sodium sulphate and concentrated in vacuo to obtain bromo-(4-biphenyl)-phenylmethane.

Example 109:

The hydrolysis of (S, D, L)-isomer obtained in Example 108, in accordance with the Example 1 to obtain (3S)-N-(3,5-dimethylbenzoyl)-N-methyl-3- (4-biphenyl)-3-phenyl-(D)-alanyl-(L)-tryptophan; FAB-MS m/e 648 (M-H)+.

Example 110:

Hydrolysis of (R, L, L)-isomer obtained in Example 108, in accordance with the Example 1 to obtain (3S)-N-(3,5-dimethylbenzoyl) -N-methyl-3-(4-biphenyl)-3-phenyl-(L)-alanyl-(L)-tryptophan; FAB-MS m/e 648 (M-H)+.

Example 111:

The hydrolysis of (S, L, L)-isomer obtained in Example 108, in accordance with the Example 1 to obtain (3S)-1-(3,5-dimethylbenzoyl)-N-methyl-3-(4-biphenyl)-3-phenyl-(L)-alanyl- (L)-tryptophan; FAB-MS m/e 648 (M-H)+.

Example 112:

To a stirred solution of the hydrochloride difficult methyl ester 3-(4-biphenyl)alanine (755 mg, 2.6 mmol) and di-tert-butyl dicarbonate (680 mg, 3.1 mmol) in methylene chloride (10 ml) was added drop wise addition of triethylamine (0,432 ml, 3.1 mmol) at a temperature of 0oC in nitrogen atmosphere. The reaction sesaot 0.1 N. a solution of hydrochloric acid, saturated sodium bicarbonate solution and brine, then dried in the presence of magnesium sulfate and concentrated in vacuo. The remainder chromatographic on silica using ethyl acetate/hexane, 1 : 2, receiving the methyl ester of N-BOC-3-(4-biphenyl)alanine in the form of a yellow oil.

To a cooled to a temperature of 0oC to a solution of the compound obtained above (953 mg) and methyl iodide (0,486 ml, 7.8 mmol) in DMF (8 ml) was added sodium hydride (60%; 104 mg, 2.6 mmol) under nitrogen atmosphere. The reaction mixture is slowly warmed to room temperature and extracted with ethyl acetate (10 ml x 2). The organic layer was washed with water (5 ml x 2), saturated sodium chloride solution and dried in the presence of magnesium sulfate and concentrated in vacuo to obtain a complex of methyl ester of N-BOC-3-(4-biphenyl)alanine. Hydrolysis of the above complex methyl ester (855 mg, 2.3 mmol) using a hydrate of lithium hydroxide (146 mg, 3.5 mmol) leads to the production of N-BOC-3-(4-biphenyl)alanine.

Interaction BOC-3-(4-biphenyl)alanine (750 mg, 2.1 mmol) according to General method B shown in scheme III, hydrochloride difficult methyl ester (L)-tryptophan (642 mg, 2.5 mmol) in Pris is igodit difficult to obtain methyl ester of N-BOC-N-methyl-3-(4-biphenyl)alanyl-(L)-tryptophan (1,16 g, 95%). The mixed solution of complex methyl ester of N-BOC-N-methyl-3-(4-biphenyl)alanyl-(L)- tryptophan (1.0 g, 1.8 mmol) in toluene (10 ml) is treated with Lawesson reagent (364 mg, 0.9 mmol) at room temperature under nitrogen atmosphere overnight. The resulting mixture was diluted with ethyl acetate and washed with water and brine, then dried in the presence of magnesium sulfate and concentrated in vacuo. The remainder chromatographic on silica using ethyl acetate/hexane, 1 : 2, to obtain a mixture of two diastereoisomers (590 mg, 57%) who share with GHUR (silica, hexane/isopropanol, 30 : 1) to obtain the complex methyl ester BOC-N-methyl-(D)-3-(4-biphenyl)toolani- (L)-tryptophan complex and methyl ester of N-BOC-N-methyl-(L)-3- (4-biphenyl)toolani-(L)-tryptophan.

The mixed solution of complex methyl ester of N-BOC-N-methyl-(D)--3(4-biphenyl)toolani-(L)-tryptophan (145 mg, 0.25 mmol) and dithiothreitol (77 mg, 0.05 mmol) in 1,4-dioxane (of 0.64 ml) was added to 4 N. the solution of hydrogen chloride in 1,4-dioxane (2.6 ml) at room temperature under nitrogen atmosphere. The mixture is stirred for 4 hours, concentrated in vacuo and washed with simple ether to obtain the hydrochloride complex of methyl ester of N-methyl-(D)-3-(4-biphenyl)toolani-(L)-Tr the Nile-(L)-tryptophan (150 mg) is treated with 3,5-dimethylbenzoic acid (50 mg, 0.33 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol) and 1-(dimethylaminopropyl)-3-ethylcarbodiimide (60 μl, 0.33 mmol) in DMF (1 ml) at room temperature under nitrogen atmosphere overnight. The mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and water, then dried in the presence of magnesium sulfate and concentrated in vacuo. The remainder chromatographic on silica using ethyl acetate/hexane, 1 : 2, to obtain the complex methyl ester N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-(4 - biphenyl)toolani-(L)-tryptophan.

The hydrolysis of complex methyl ester N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-(4-biphenyl)toolani-(L)-tryptophan (40 mg, of 0.066 mmol) using a hydrate of lithium hydroxide (4 mg, 0,099 mmol) gives N-(3,5-dimethylbenzoyl)-N-methyl- (D)-3-(4-biphenyl)toolani-(L)-tryptophan; FAB-MS m/e 590 (M-H)+.

Example 113:

In accordance with the procedure described in Example 112, methyl ester of N-BOC-N-methyl-(L)-3-(4-biphenyl)toolani-(L)-tryptophan (obtained in Example 112) BOC-unlocks, N-3,5-dimethylbenzoyl and hydrolyzing in accordance with Example 1, obtaining N-(3,5-dimethylbenzoyl)-N-methyl-(L)-3-(4-biphenyl)toolani-(L)-tryptophan; FAB-MS m/e 590 (M-H)+.

Example 114:

To a solution of hlog ml) was added dropwise 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (5,46 M solution) (5,77 ml, to 31.5 mmol) at a temperature of 0oC in nitrogen atmosphere. The reaction mixture is stirred at a temperature of 0oC for 1 hour, then at room temperature overnight. The mixture is diluted with 250 ml of ice water and extracted with ethyl acetate twice. The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo. The remainder chromatographic on silica using ethyl acetate/hexane, 1 : 1, obtaining the methyl ester of N-3,5-dimethylbenzoyl-tyrosine.

To a solution of complex methyl ester of N-3,5-dimethylbenzoyl-tyrosine (4.11 g, 12.6 mmol) and pyridine (5 ml) in methylene chloride (25 ml) was added anhydride triperoxonane acid (2.2 ml, 13,2 mmol) at a temperature of 0oC in nitrogen atmosphere. After stirring at room temperature for 4 hours, the reaction mixture was washed successively H2O 0,5 N. NaOH, H2O, 1 N. HCl and H2O. the Organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo. The remainder chromatographic on silica using ethyl acetate/hexane, 1 : 2, receiving the methyl ester of N-3,5-dimethylbenzoyl-O-triptorelin-sulfonyl-tyrosine.

To a suspension of complex methyl ester of N-3,5-dimethylbenzoyl-O-triptorelin what logikoi: W. Thompson et al., J. Org. Chem., 1984, 49, 5237), potassium carbonate (0,83 g, 6 mmol) and toluene (50 ml) was added tetrakis(triphenylphosphine)palladium (O) (0.14 g, 0.12 mmol) under nitrogen atmosphere. The mixture is heated to a temperature of 90oC for 2 hours, then diluted with ethyl acetate and washed sequentially with saturated solution of NaHCO3H2O, 10% citric acid and H2O. the Organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo. The remainder chromatographic on silica using ethyl acetate/hexane, 1 : 1, obtaining the methyl ester of N-3,5-dimethylbenzoyl-[4-(2-furyl)phenyl]alanine.

Then add methyl iodide (0,55 ml, 8,82 mmol), sodium hydride (without oil: 70,6 mg, to 2.94 mmol) in DMF (3 ml) at a temperature of 0oC in nitrogen atmosphere. The reaction mixture is stirred at a temperature of 0oC for 1 hour, then at room temperature overnight. The mixture is diluted with water and extracted with ethyl acetate twice. The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo. The remainder chromatographic on silica using ethyl acetate/hexane, 1 : 1, obtaining the methyl ester of N-3,5-dimethylbenzoyl-N-methyl-[4-(2-furyl)phenyl]alanine, which is hydrolized with guide

To a solution of N-3,5-dimethylbenzoyl-N-methyl-[4-(2-furyl)phenyl]alanine (0.64 g, 1.7 mmol) in DMF sequentially added hydrochloride difficult methyl ester of tryptophan (0.56 g, 2.2 mmol), 1-hydroxybenzotriazole (0,504 g, 3.73 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (5,46 M solution) (0,37 ml, 2.03 mmol) at a temperature of 0oC in nitrogen atmosphere. The reaction mixture is stirred at a temperature of 0oC for 2 hours, then at room temperature overnight. The mixture is diluted with ethyl acetate and washed twice with 10% citric acid. The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo. The remainder chromatographic on silica using ethyl acetate/hexane, 1 : 1, obtaining the methyl ester of N-3,5-dimethylbenzoyl-N-methyl-3-[4-(2-furyl)phenyl] alanyl-tryptophan as a mixture of diastereoisomers who share GHUR on (D,L)-isomer. Hydrolysis of (D, L)-isomer (102 mg, 0.18 mmol) using a hydrate of lithium hydroxide (7.8 mg, 0.185 mmol) leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-D)-3-[4-(2-furyl)phenyl)-alanyl-(L)- tryptophan.

Example 115:

Hydrolysis of (L,L)-isomer (20 mg, 0.035 mmol) obtained in Example 114, using a hydrate of lithium hydroxide (1,52 mg, being 0.036 mmol) gives N-(3,5-diretiva (60% in oil: 0,82 g, of 20.5 mmol) in dry DMF (4.5 ml) under nitrogen atmosphere is added imidazole (1,37 g of 20.1 mmol) under stirring at room temperature. After stirring for 20 minutes was added 4-bromobenzaldehyde dimethylacetal (4,63 g, 20 mmol) and copper powder (of 0.13 g, 2.0 mmol), after which the reaction mixture is stirred at a temperature of 130oC for 2 hours, then at a temperature of 150oC for 2.5 hours. The solution is stirred for 1 hour and filtered to celite. The organic layer was separated, washed with water, dried in the presence of sodium sulphate and concentrated in vacuo. The residue is dissolved in 1 N. the solution of hydrochloric acid (20 ml) and stirred at room temperature for 4 hours. The reaction mixture is diluted with 5 N. NaOH solution (4 ml) and extracted with ethyl acetate. The organic layer is washed with saline, dried in the presence of sodium sulphate and concentrated in vacuo. The obtained solid was washed with hexane and dried in vacuum to obtain 4-(1-imidazolyl)benzaldehyde.

To a cooled to a temperature of 0oC to a solution of 4-(1-imidazolyl)benzaldehyde (1,41 g, 8.16 mol) and ethyl azidoaniline (10.6 g, to 81.7 mmol) in MeOH (50 ml) under nitrogen atmosphere is added sodium methylate (28 wt.% solution in MeOH, the first solution (100 ml) and extracted with three portions of simple ether. The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo to obtain 2-azido-3-[4-(1-imidazolyl)phenyl]-2-propenate.

A solution of 2-azido-3-[4-(1-imidazolyl)phenyl]-2-propenate (0.56 g of 2.09 mmol) in acetic acid (2 ml) and MeOH (30 ml) hydronaut in the presence of platinum oxide (0.18 g) under hydrogen pressure of 30 ATM during the night. The catalyst was removed by filtration and the filtrate concentrated in vacuo. The crude residue is dissolved in methylene chloride and washed with two portions of saturated sodium bicarbonate solution. The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo to obtain complex methyl ester 3-[4-(1-imidazolyl)phenyl]alanyl.

The complex solution of the methyl ester of 3-[4-(1-imidazolyl)phenyl]alanyl (0,69 g, 2.8 mmol) in 1 N. the solution of hydrochloric acid (2.7 ml) and water (1.8 ml) was added in just the distilled cyclopentadiene (0,50 ml, 6.1 mmol) and formaldehyde (37% aqueous solution) (0,24 ml, 30 mmol) with vigorous stirring.

After stirring for 1 hour at room temperature, the reaction mixture was washed with hexane, neutralized with saturated sodium bicarbonate solution and extracted with methylene chloride. Organic target above the crude substance (0.39 g) in chloroform (5.7 ml) in nitrogen atmosphere add to triperoxonane acid (5.7 ml) and triethylsilane (0,55 ml, of 3.42 mmol) under stirring at room temperature. The mixture is stirred for 20 hours, then concentrated under reduced pressure. The crude product is dissolved in 1 N. the solution of hydrochloric acid and washed with hexane/simple ether, 1 : 1. The aqueous layer was neutralized with saturated sodium bicarbonate solution and extracted with methylene chloride. The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo to obtain complex methyl ester 3-[4-(1-imidazolyl)phenyl]-N-methyl-alanyl.

To a cooled to a temperature of 0oC the complex solution of the methyl ester of 3-[4-(l-imidazolyl)phenyl] -N-methyl-alanyl (0.28 g) and 3,5-dimethylbenzoic acid (0,175 g at 1.17 mmol) in methylene chloride (2.0 ml) under nitrogen atmosphere was added 1-(3 - dimethylaminopropyl)-3-ethyl-carbodiimide (of 0.21 ml, 1.15 mmol) with stirring. After 30 minutes the reaction mixture is slowly warmed to room temperature and further stirred overnight. The mixture is diluted with ethyl acetate and washed with two portions of water and brine. The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo. The crude substance is purified column chromatography on silica using m is.

The above ester hydrolyzing with lithium hydroxide (19 mg, 0.45 mmol) in MeOH/THF/water 2 : 2 : 1 (2.5 ml) overnight. The reaction mixture is acidified with 1 n hydrochloric acid (0.45 ml), diluted with water and extracted with two portions of ethyl acetate. The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo to obtain N-(3,5-dimethylbenzoyl)-N - methyl-3-[4-(1-imidazolyl)phenyl]-alanine.

To a stirred solution of the above acid (60 mg, 0.16 mmol) in dry DMF (3 ml) under nitrogen atmosphere was added the hydrochloride difficult methyl ester (L)-tryptophan (61 mg, 0.24 mmol) and 1-hydroxybenzotriazole (38 mg, 0.28 mmol). The mixture is cooled to a temperature of 0oC and added dropwise 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (0,029 ml, 0.16 mmol). After stirring for 1 hour the reaction mixture is slowly warmed to room temperature and stirred over night. The mixture is diluted with ethyl acetate and washed with water and brine. The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo. The crude substance is purified preparative thin-layer chromatography using methylene chloride/MeOH, 9 : 1, obtaining the methyl complex is 3 mmol) hydrolyzing at a temperature of 0oC using lithium hydroxide (13.5 mg, 0.32 mmol) in MeOH/water, 5 : 1 (5.0 ml). After 2 hours the reaction mixture is slowly warmed to room temperature and stirred for 1 hour. The reaction mixture is acidified with 1 n hydrochloric acid (0.35 ml), diluted with water and extracted with ethyl acetate. The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo. The residue was washed with simple ether and dried in vacuum to obtain N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(1-imidazolyl)-phenyl] -(D,L)-alanyl-(L)- tryptophan: FAB-MS m/e 564 (M-H)+.

Example 117:

The complex solution of methyl ester of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-tyrosine (253 mg, of 0.74 mmol) (obtained from (D)-tyrosine in accordance with the procedure described in Example 55), Ph3Bi(OAc)2[triphenylbismuth diacetate] (895 mg, 1.6 mmol) (obtained as described in the literature methodology: N. Brunner, U. Obermann and P. Winner, Organometallics 1989, 8, 821-826) and Cu powder (43 mg, of 0.68 mmol) in methylene chloride (15 ml) was stirred at room temperature under nitrogen atmosphere overnight. This reaction mixture was concentrated in vacuo and the crude substance chromatographic on silica with hexane/ethyl acetate, 3 : 1, obtaining the methyl ester of N-(3,5-dime the th above (294 mg, 0.70 mmol) using a hydrate of lithium hydroxide (31 mg, of 0.74 mmol) leads to the obtaining of the appropriate acid.

To a solution of the above acid (215 mg, of 0.53 mmol) in DMF sequentially added hydrochloride difficult methyl ester of tryptophan (177 mg, 0.70 mmol), 1-hydroxybenzotriazole (160 mg, 1.2 mmol) and 1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide (5,46 M solution) (0,12 ml, 0.66 mmol) at a temperature of 0oC in nitrogen atmosphere. The reaction mixture is stirred at a temperature of 0oC for 2 hours, then at room temperature overnight. The mixture is diluted with ethyl acetate and washed with 10% citric acid solution and 4% sodium bicarbonate solution. The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo. The remainder chromatographic on silica using hexane/ethyl acetate, 2 : 1, receiving methyl ester (phenoxyphenyl)alanyl-tryptophan (325 mg, 98 %).

The hydrolysis of complex methyl ester obtained above (325 mg, 0.52 mmol) using a hydrate of lithium hydroxide (23 mg, 0.55 mmol) leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-(4-phenoxyphenyl)-alanyl-(L)-tryptophan.

Example 118:

To a stirred solution of the hydrochloride complex of tert-butisol) was added benzaldehyde (0,549 ml, 5.40 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 17 hours, then diluted with water (10 ml) and brine, and dried in the presence of magnesium sulfate and concentrated in vacuo to obtain complex tert-butyl ether N-(phenylmethylene)alanine as a colourless oil.

To a solution of complex tert-butyl ether N-(phenylmethylene)alanine (210 mg, 0.90 mmol), 4-(3-thienyl)phenylmethyl bromide (250 mg, 0,99 mmol) and pyridine (7 ml, 0.09 mmol) in methylene chloride (1.8 ml) was added potassium hydroxide (505 mg, 9.0 mmol) and potassium carbonate (1.24 g, 9.0 mmol). The mixture is stirred at room temperature for 2 days, then filtered and washed with methylene chloride. The filtrate and washing was concentrated in vacuo to obtain crude 3-[4-(3-thienyl)phenyl]alanine in the form of a yellow oil.

A solution of 3-[4-(3-thienyl)phenyl]alanine in methanol (2 ml) is slowly added to a solution of thionyl chloride (6.8 ml, 94 mmol) in methanol (5 ml) at a temperature of -10oC. the Mixture is slowly warmed to room temperature, then refluxed overnight. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate (10 ml) and extracted with water (10 ml x is th layer is dried in the presence of magnesium sulfate and concentrated in vacuo to obtain the crude complex methyl ester 3-[4-(3-thienyl)phenyl]alanine.

The mixed solution of complex methyl ester 3-[4-(3-thienyl)phenyl] alanine (650 mg) and triethylamine (1.64 g, and 11.8 mmol) in 1,4-dioxane (10 ml) was added to 3,5-dimethylbenzoyl chloride (517 mg, of 3.07 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, then diluted with simple ether and washed with 1 N. a solution of hydrochloric acid, saturated sodium bicarbonate solution and water. The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo. The remainder chromatographic on silica using acetate/hexane, 1 : 2, to obtain the complex methyl ester N-(3,5-dimethylbenzoyl)-2-methyl-3-[4-(3-thienyl)phenyl]alanine.

To a cooled to a temperature of 0oC the solution of the above complex ester of N-(3,5-dimethylbenzoyl)-2-methyl-3-[4-(3-thienyl)phenyl] alanine (200 mg, 0.49 mmol) and methyl iodide (0,122 ml, a 1.96 mmol) in DMF (2 ml) was added sodium hydride (60%; 39 mg, 0.98 mmol) under nitrogen atmosphere. The reaction mixture is slowly warmed to room temperature and stirred for 2 days. The mixture is diluted with water and extracted with ethyl acetate (10 ml x 2). The organic layer was washed with water (5 ml x 2), dried in the presence of magnesium sulfate and concentrated in vacuo. Osta-dimethylbenzoyl)-N-methyl-2-methyl-3-[4-(3-thienyl)phenyl]alanine.

The mixed solution of complex methyl ester N-(3,5-dimethylbenzoyl)-N-methyl-2-methyl-3-[4-(3-thienyl)phenyl] alanine (100 mg, 0,245 mmol) and potassium hydroxide (40 mg, to 0.72 mmol) in ethanol (5 ml) is refluxed overnight. The mixture is diluted with water and washed with simple ether. The aqueous layer was washed with saline, dried in the presence of magnesium sulfate and concentrated in vacuo to obtain the corresponding crude N-(3,5-dimethylbenzoyl)-N-methyl-2-methyl-3-[4-(3-thienyl)phenyl]alanine.

To a solution of N-(3,5-dimethylbenzoyl)-N-methyl-2-methyl-3-[4-(3-thienyl)phenyl] alanine (135 mg, 0.33 mmol) in DMF sequentially added hydrochloride difficult methyl ester of tryptophan (110 mg, 0.43 mmol), 1-hydroxybenzotriazole (58 mg, 0.43 mmol) and 1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide (5,46 M solution) (79 μl, 0.43 mmol) at a temperature of 0oC in nitrogen atmosphere. The reaction mixture is stirred at a temperature of 0oC for 2 hours, then at room temperature overnight. The mixture is diluted with ethyl acetate and washed twice with 10% citric acid solution. The organic layer is dried in the presence of magnesium sulfate and concentrated in vacuo. The remainder chromatographic on silica using hexane/etelaat-[4-(3-thienyl)-phenyl]alanine-tryptophan. Hydrolysis of (D,L)-isomer (55 mg, 0.09 mmol) using a hydrate of lithium hydroxide (6 mg, 0.14 mmol) leads to the production of N-(3,5-dimethylbenzoyl)-N-methyl-(L)-2-methyl-3-[4-(3-thienyl)phenyl)-alanyl- (L)-tryptophan; FAB-MS m/e 592 (M-H)+.

Example 119:

Hydrolysis of (L,L)-isomer (80 mg, 0.13 mmol) obtained in Example 118, using a hydrate of lithium hydroxide (8 mg, 0.20 mmol) gives N-(3,5-dimethylbenzoyl)-N-methyl-(L)-2-methyl-3-[4-(3-thienyl)phenyl] -alanyl- (L)-tryptophan; FAB-MS m/e 594 (M-H)+.

Example 120:

To a solution of 5-(4-were)-isoxazol (17 g) and N-bromosuccinimide (19 g) in carbon tetrachloride (500 ml) under nitrogen atmosphere was added benzoyl peroxide (0,43 g) and the mixture is heated at the temperature of reflux distilled during the night. The solvent is evaporated and the residue purified flash chromatography (silica gel, hexane/ethyl acetate, 4 : 1) to give pure 5-(4-bromomethylphenyl)-isoxazol.

NMR (CDCl3, 400 MHz): [ppm] 8,32 (d, 1.8 Hz, 1H), 7,78 (d, 8.2 Hz, 2H), 7,51 (d, 8.2 Hz, 2H), 6,54 (d, 1.8 Hz, 1H), to 4.52 (s, 2H).

5-(4-Bromomethylphenyl)-isoxazol (700 mg) and compound ethyl ester of N-diphenylmethylene-gizela (890 mg) was dissolved in dichloromethane (20 ml) and stirred vigorously with a solution of hydrogensulfate tetrabutylammonium 2.5 molar aqueous solution of hydroxide nutrigest between simple ether and water and the ether phase is washed with water and brine, dried in the presence of magnesium sulfate and evaporated to obtain the crude complex ethyl ester N-diphenylmethylene-3-[4-(5-isoxazolyl)phenyl] alanine, which is used for the next stage without additional purification.

The crude complex ethyl ester of N-diphenylmethylene-3-[4-(5-isoxazolyl)phenyl] alanine (280 mg) is treated with monohydrate p-toluenesulfonic acid (100 mg) in acetonitrile (35 ml) and water (3.5 ml) at ambient temperature for 3.5 hours. After concentration, the residue is extracted with simple ether and 1 N. a solution of sodium hydroxide, washed with brine, dried and concentrated to obtain complex ethyl ester 3-[4-(5-isoxazolyl)phenyl] alanine, which is used for the next stage without additional purification.

The crude complex ethyl ester 3-[4-(5-isoxazolyl)-phenyl]alanine (660 mg) was dissolved in chloroform (6,6 ml), vigorously stirred for 2 H. a solution of sodium carbonate (1.4 ml) and, after cooling to a temperature of 10oC, was added 3,5-dimethylbenzophenone (0.7 ml). Stirring is continued for 1 hour at a temperature of 10oC and for 2 hours at room temperature. Then extraction with a mixture of dichloromethane/water, washing with 10% aqueous solution Flash chromatography (silica gel, hexane/ethyl acetate, 4 : 1) gives pure complex ethyl ester of N-(3,5-dimethylbenzoyl)-3-[4- (5-isoxazolyl)phenyl]alanine. NMR (CDCl3, 400 MHz): [ppm] of 8.28 (d, 1.8 Hz, 1H), 7,72 (d, 8.2 Hz, 2H), 7,33 (s, 2H), 7,26 (d, 8.2 Hz, 2H), 7,15 (s, 1H), 6,65 (d, 7,3 Hz, 1H), 6,50 (d, 1.8 Hz, 1H), 5,09 (m, 1H), 4,24 (kV, a 7.1 Hz, 2H), 3,32 (m, 2H), 2,34 (s, 6H), of 1.29 (t, a 7.1 Hz, 3H).

The complex solution of ethyl ester of N-(3,5-dimethylbenzoyl)-3-[4-(5-isoxazolyl)phenyl] alanine (3.8 g) and under the conditions (1.8 ml) in dry N,N-dimethylformamide (40 ml) cooled in an ice bath, followed by portion addition of sodium hydride (60% in oil, 390 mg). The mixture is heated to room temperature for 5 hours, then poured onto water, extracted with ethyl acetate, the organic phase is washed with water, brine, dried and evaporated. Flash chromatography of the residue on silica gel (hexane/ethyl acetate, 3 : 1) gives pure complex ethyl ester of N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)phenyl]-alanine. NMR (CDCl3, 400 MHz): [ppm] 8,30 (d, broad, 1H), to 7.75 (m, 2H), 7,41 (d, broad, 1H), 7,12 (d, broad, 1H), 6,97 (s, 0.5 H), 6,93 (s, 0.5 H), 6,70 (s, 1H), 6,53 (d, broad, 1H), 6,36 (d, broad, 1H), 5.40 to (m, 0.5 H), 4,58 (m, 0.5 H), 4,27 (m, 2H), 3,54 (m, 0.5 H) at 3.25 (m, 1H), 3,05 (m, 2H), 2,78 (s, 1.5 H), of 2.23 (s, 3H), 2.13 and (s, 3H), 1.27mm (m, 3H).

Complex ethyl ester of N-(3,5-dimethylbenzoyl)-N - methyl-3-[4-(5-ISO is (0.25 ml) and water (0.25 ml) for 3 hours at room temperature. The mixture is then partitioned between water and simple ether, the aqueous phase is acidified with 1 N. a solution of hydrochloric acid and then extracted with ethyl acetate. An ethyl acetate phase is washed with saline, dried and evaporated to obtain N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)phenyl] alanine. NMR (CDCl3, 400 MHz): [ppm] 8,48 (C), 8,30 (C), 7,80 (m), 7,43 (m), 7,03 (C) 6,94 (C) 6.75 in (C), 6,69 (C), 6,36 (C) 5,16 (m) and 4.65 (m), 3,55 (m), 3,40 (m) of 3.25 (m), 3,10 (m) 2,80 (C), and 2.26 (C), and 2.14 (C).

At a temperature of 0oC N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5 - isoxazolyl)phenyl]alanine (445 mg) was stirred in N,N-dimethylformamide (24 ml) together with hydrochloride difficult methyl ester (L)-tryptophan (400 mg), hydroxybenzotriazole (330 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0,32 ml) for 1 hour and at room temperature over night. After extraction with ethyl acetate and 10% aqueous citric acid solution the organic phase is washed with 4 % aqueous sodium bicarbonate solution and brine, dried and evaporated. Flash chromatography on silica gel (hexane/ethyl acetate, 2 : 1) yields a product in the form of a mixture of diastereoisomers. Separation by medium pressure chromatography on a column of silica gel using a simple ether/dichloromethane (1 : 1) in what was solil)phenyl]-(D)- alanyl]-(L)-tryptophan. NMR (CDCl3, 400 MHz): [ppm] at 8.60 (C), 8,30 (m), of 7.70 (m), 7,55 (m), of 7.70 (m), 7,10 (m), 6.90 to (m) 6,50 (m), 5,85 (C), 5,43 (m) 4,90 (m) to 4.33 (m in), 3.75 (s), 3,70 (s) to 3.35 (m), 3,15 (m), 2,85 (C) to 2.57 (s), 2,35 (C) of 2.20 (C), 1.93 and (C) of 1.85 (C).

Methyl ester [N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5 - isoxazolyl)phenyl] -(D)-alanyl]-(L)-tryptophan (50 mg) is treated with a monohydrate of lithium hydroxide (3.8 mg) in methanol (1 ml), tetrahydrofuran (0.5 ml) and water (0.5 ml) for 1 hour at a temperature of 0oC and for 2 hours at room temperature. The mixture is then partitioned between water and simple ether, the aqueous phase is acidified with 1 N. a solution of hydrochloric acid and then extracted with ethyl acetate. An ethyl acetate phase is washed with saline, dried and evaporated to obtain [N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)phenyl] -(D)-alanyl] - (L)-tryptophan. NMR (CDCl3, 400 MHz): [ppm] 8,29 (C) to 8.12 (C), of 7.70 (m), 7,55 (m), 7,28 (m), 7,17 (m), 7,07 (m), 6,98 (m) 6,86 (m), 6,61 (C), 6,53 (C) of 6.49 (C) 5,97 (C), 5,43 (m), to 4.87 (m), and 4.40 (m), 3,90 (m) to 3.33 (m), 2,08 (m) 2,77 (C) to 2.18 (C), 1,89 ().

Example 121:

Tablets, each containing 50 mg of active ingredient, for example N-(3,5-dimethylbenzoyl)-N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan can be obtained in the following way:

Composition (for 10,000 tablets)

Active ingredient - 500.0 g

Lacquer Is R>
Silica (fine) - 20,0 g

Ethanol - as required

The active ingredient is mixed with the lactose and 292 g of potato starch, after which the mixture is moistened with using an alcohol solution of gelatin and granularit using sieves. After drying, the remaining potato starch, talc and magnesium stearate, as well as highly disperse silica are mixed and the mixture is compressed to obtain tablets weight 145,0 mg each and content of active ingredient 50.0 mg, which optionally can be provided with alignment marks for more precise adjustments of the doses.

Example 122:

Coated tablets, each containing 100 mg of active ingredient, for example N-(3,5-dimethylbenzoyl)-N-methyl-(D)-i.e. phenylalanyl- (L)-tryptophan can be obtained in the following way:

Composition (for 1000 tablets)

The active ingredient is 100.00 g

Lactose - 100,00 g

Corn starch - 70,00 g

Talc - 8,50 g

Calcium stearate - 1.50 g

The hypromellose - 2,36 g

Shellac - 0.64 g

Water - as required

Dichloromethane - as required

The active ingredient, the lactose and 40 g of corn starch are mixed and moistened, then granularit using pastel, the talc and calcium stearate is added and mixed with the granules.

The mixture is compressed to obtain tablets weighing 280 mg each and content of active ingredient 50.0 mg, which cover solution hydroxypropylmethylcellulose and Melaka in dichloromethane (final weight of the coated tablets is 283 mg).

Example 123:

Tablets and coated tablets containing another compound of formula I or pharmaceutically acceptable salt of the compounds of formula I, for example, as described in Examples 1 to 120, can also be obtained by a method similar to that described in Examples 121 and 122.

Pharmacological experiments

The reaction of binding of the receptor endothelin (ET)

The affinity of the receptor binding ET compounds of the present invention is determined in accordance with the method described below (published in Takai et al. (1992) Biochem. Biophys. Res. Commun. 184, 953-959). ET-1 and ET-3 supplied by Peptide Institute Inc. (Osaka, Japan), [125I] ET-1 and [125I] ET-3 (74 Tbq/mmol each) are supplied from the company Amersham International (Bucks, U.K.).

Plasma membrane of porcine lung (2 μg protein) are incubated at a temperature of 37oC for one hour using 30 PM [125I] ET-1 or 10 PM [125I] ET-3 in Otaniemi 145 mm NaCl, 3 mm KCl, 3 mm MgCl2, 1 mm EGTA, 1 mg/ml bovine serum albumin and 0.2 mg/ml bacitracin. After incubation the unbound [125I] ET separated by centrifugation at 20000 x g for 20 minutes at a temperature of 4oC followed by extraction of the supernatant. Radioactivity in the membrane sediment was measured in an automatic gamma counter-ray Wallac-1470 Wizard (Pharmacia). Nonspecific binding is defined as membrane-associated radioactivity in the presence of saturating concentrations of ET (100 nm). The nonspecific binding is subtracted from the total binding, and the difference is defined as specific binding. Total binding is always less than 15% of the total radioactivity.

Binding to the receptor ETAdetermine with the use of [125I] ET-1 in the presence of 1 nm unlabeled ET-3, and the binding with the receptor ETBdetermine with the help of [125I] ET-3. When using Scatchard analysis of receptor ETAshows the apparent dissociation constant (Kd), is 44 PM, and maximum binding sites (Bmax) equal to 342 fmol/mg protein, whereas the receptor for ETBhas Kdequal to 8 PM, and Bmaxequal 363 fmol/mg protein. From the curves of inhibition relative to the binding of [125 as parameter affinity receptors ETAand ETB.

Table. 1 shows the results of binding assays in percent (%) inhibition of specific receptors ETAand ETBbinding at a concentration of 10-5M and 10-7M of the tested compounds.

The reduction in coronary arteries of pigs

Analysis on the reduction is carried out in accordance with the published method (S. Shetty et al., Biochem. Biophys. Res. Commun. 191, 459-464, 1993), described below:

Fresh porcine hearts obtained from a local slaughterhouse, immediately immersed in chilled on ice aktirovannye ringer's solution and transferred to the laboratory within 30 minutes after slaughter. The left anterior descending coronary artery cut out and placed in aerated physiological salt solution. Arterial preparations cleaned of surrounding connective tissue and cut into circles ranging in length from 0.5 to 1.0, see

Two self-closing hinges for transfers stainless steel is introduced into each of the arterial circle and the received device separately suspended in 20 ml tub for bodies with a water jacket, having a constant temperature, for the registration of isometric force. Tubs are filled with physiological saline solution at a temperature of 37o

The endothelium is extracted from drugs by careful scraping with the walls of the intimate surface with a wooden applicator. Failure as 1 μm acetylcholine to relax mesenterial rings, condensed with 1 µm phenylephrine, and 0.1 ám substance P to relax coronary rings, condensed with 3 μm PGF2demonstrates the efficiency of extraction of the endothelium. Curves depending on the concentration for ET-3 in the absence (control) or in the presence of concentrations of the test compounds, equal to 10-6M, is obtained by cumulative supplements in baths bodies. The effects of the compound (Example 1) is estimated in the receptacles voltage peace.

The reduction in the trachea of Guinea pigs

Analyses on the reduction carried out basically in accordance with the published method (Takai et al., Biochem. Biophys. Res. Common. 184, 953-959, 1992). The trachea, which was isolated from male Guinea pigs breed Hartley weighing 350-500 g, cut into circles with a length of the Eski from circles. Drugs are placed in the bath for bodies containing buffered solution of Krebs-Henseleit or a solution of Tyrode, at a temperature of 37oC, a pH of 7.4, which bubbled with the use of 95% O2and 5% CO2. The voltage measured isometrically using a torque of displacement transducer (Nikhon Kohden, Tokyo, TB-612T) at an initial voltage equal to 1, the Curves depending on the concentration for ET-3 is produced by its cumulative addition. The inhibiting activity of these compounds examined by adding them with a solution of DMSO in the bath for 10 to 40 minutes before the addition of ET-3. These activities evaluate numerically the values of pA2which are the negative logarithms of the concentrations of compounds that induce a shift of the curves depending on the concentrations in the direction of the 2-fold increase of the range of concentrations of ET-3. The reduction produced with concentrations of 60 mm KCl or 10 μm carbachol use as a reference. The data presented in table. 2.

1. The compound of the formula I

< / BR>
where R1denotes phenyl, substituted C1- C4-alkyl, C1- C4-alkoxy or halogen;

R2represents C1- C4-alkyl;

R3denotes furyl-phenyl, imidazolyl-phenyl or isoxazolyl-phenyl, where the mentioned aryl and heteroaryl radicals, independently of one another, are in each case unsubstituted or substituted by a Deputy selected from the group consisting of C1- C4-alkyl, C1- C4-alkoxy, phenyl-C1- C4-alkoxy, halogen, CF3, hydroxy, cyano, cyano-C2- C5alkanoyl and nitro;

denotes hydrogen, phenyl or phenyl substituted C1- C4-alkyl, C1- C4-alkoxy, halogen, CF3, hydroxy or nitro;

denotes hydrogen;

C(=X) denotes C(=O) or C(=S);

Y represents NH or methylene,

or C(=X) denotes CHOH and Y represents methylene;

R4represents -(CH2)s-Ar', where s is the number 1 and Ar' denotes phenyl, naphthyl, biphenylyl, indol-3-yl, 1-C1- C4-alkyl-indol-3-yl, or chinoline; where mentioned aryl and heteroaryl radicals, independently of one another, are in each case unsubstituted or substituted by a Deputy selected from the group consisting of C1- C4-alkyl, C1- C4-alkoxy, halogen, CF3, hydroxy and nitro;

R5denotes COOH;

or its pharmaceutically acceptable salt.

2represents C1- C4-alkyl; (i) R3denotes 4-biphenylyl, 4-(2-thienyl)-phenyl, 4-(3-thienyl)-phenyl, 4-(2-furyl)-phenyl, 4-(3-isoxazolyl)-phenyl, 4-(5-isoxazolyl)-phenyl, 4-(1-imidazolyl)-phenyl or 4-(2-pyridyl)-phenyl; denotes hydrogen or phenyl; represents hydrogen or (ii) R3denotes phenyl or phenyl substituted cyano or cyano-C2-C5-alkanoyl; each denotes hydrogen; C(=X) denotes C(=O) or C(= S); Y represents NH; R4represents -(CH2)s-Ar', where s is the number 1 and Ar' represents indol-3-yl; and R5represents carboxy; or its pharmaceutically acceptable salt.

3. Connection on p. 1 of formula I, wherein R1denotes phenyl, substituted by halogen or C1- C4-alkyl, R2represents C1- C4-alkyl; R3denotes phenyl, which is unsubstituted or substituted with halogen, C1- C4-alkoxy, hydroxy or phenyl-C1- C4-alkoxy, biphenylyl, naphthyl, thienyl, thienyl, substituted C1- C4-alkyl, pyridyl, pyridyl-phenyl or thienyl-phenyl; denotes hydrogen or phenyl; represents hydrogen; C(=X) denotes C(=O) - and Y represents-NH - or-CH2-, or C(=X) denotes CHOH and Y denotes the stands is inil; and R5represents carboxy; or its pharmaceutically acceptable salt.

4. Connection on p. 1 of formula I, wherein R1indicates 3,5-di - C1- C4-alkyl-phenyl or 3,5-di-halophenol; R2represents C1- C4-alkyl; (i) R3denotes denotes phenyl and phenyl; or (ii) R3denotes phenyl, 4-biphenylyl, or 4-(2-pyridyl)-phenyl and represents hydrogen, represents hydrogen; C(= X) denotes C(=O) - and Y represents-NH-; R4represents -(CH2)s-Ar', where s is the number 1 and Ar' represents 3-indolyl; and R5denotes COOH; or its pharmaceutically acceptable salt.

5. Connection on p. 1 of formula I, wherein R1indicates 3,5-di - C1- C4- alkyl-phenyl; R2represents C1- C2-alkyl; R3denotes 4-biphenylyl, 4-(2-thienyl-phenyl), 4-(3-thienyl)-phenyl, 4-(2-furyl)-phenyl, 4-(3-isoxazolyl)-phenyl, 4-(5-isoxazolyl)-phenyl or 4-(1-imidazolyl)-phenyl; and each denotes hydrogen; C(=X) denotes C(=O); Y represents NH; R4represents -(CH2)s-Ar', where s is the number 1 and Ar' represents 3-indolyl; and R5denotes COOH; or its pharmaceutically acceptable salt.

6. Connection on p. 1 of formula I, otlichayas jenil-phenyl), 4-(3-thienyl)-phenyl, 4-(3-isoxazolyl)-phenyl,4-(5-isoxazolyl)-phenyl or 4-(1-imidazolyl)-phenyl; and each denotes hydrogen; C(= X) denotes C(=O); Y represents NH; R4represents -(CH2)s-Ar', where s is the number 1 and Ar' represents 3-indolyl; and R5denotes COOH; or its pharmaceutically acceptable salt.

7. The compound according to any one of paragraphs.1 - 6 of formula I, wherein Y represents-NH-, has the following stereochemistry:

< / BR>
8. The compound according to any one of paragraphs.1 - 6 of formula I, wherein Y represents methylene, has the following stereochemistry:

< / BR>
9. Connection PP.1 - 8 of formula I, characterized in that it is a compound selected from the group including:

N-(3,5-dimethylbenzoyl)-N-methyl - (D)-i.e. phenylalanyl-(L)-tryptophan;

N-(3,5-dimethylbenzoyl)-N-methyl - (D)-(4-phenylphenyl)alanyl-N-methyl-(L)-tryptophan;

N-(3,5-dichlorobenzoyl)-N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan;

N-(4-methoxybenzoyl)-N-methyl-(D)-i.e. phenylalanyl-(L)-tryptophan;

N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(2-naphthyl)alanyl-(L)-tryptophan;

N-(3,5-dimethylbenzoyl)-N-methyl - (D)-(4-phenylphenyl)alanyl-(D)-tryptophan;

N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-(3-phenylphenyl)-alanyl-(L)-tryptophan;

N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-(2-chlorophenyl)-ethylbenzoyl)-N-methyl-(D)-tyrosyl-(L)-tryptophan;

N-(3,5-dimethylbenzoyl)-N-methyl-O-methyl-(D)-tyrosyl-(L)-tryptophan;

N-(3,5-dimethylbenzoyl)-N-methyl-O-benzyl-(D)-tyrosyl-(L)-tryptophan; and

N-(3,5-dimethylbenzoyl)-N-methyl-(D, L)-(2-thienyl)alanyl-(L)-tryptophan,

or its pharmaceutically acceptable salt.

10. Connection PP.1 - 8 of formula I, characterized in that it is a compound selected from the group including:

N-(3,5-dimethylbenzoyl)-N-methyl-D)-3-[4-(2-thienyl)phenyl] -alanyl-(L)-tryptophan;

N-(3,5-dimethylbenzoyl)-N-methyl-D)-3-[4-(3-oxazolyl)phenyl] -alanyl-(L)-tryptophan;

N-(3,5-dimethylbenzoyl)-N-methyl-D)-3-[4-(2-furyl)phenyl] -alanyl-(L)-tryptophan and

N-(3,5-dimethylbenzoyl)-N-methyl-D)-3-[4-(1-imidazolyl)phenyl] -(D, L)-alanyl-(L)-tryptophan,

or its pharmaceutically acceptable salt.

11. Connection PP.1 - 8 of formula I, characterized in that it is a compound selected from the group including:

N-(3,5-dimethylbenzoyl)-N-methyl-D)-3-[4-(3-thienyl)phenyl] -alanyl-(L)-tryptophan and

N-(3,5-dimethylbenzoyl)-N-methyl-D)-3-[4-(5-isoxazolyl) phenyl]-alanyl-(L)-tryptophan,

or its pharmaceutically acceptable salt.

12. Connection PP.1 - 8 of formula I, characterized in that it is a compound selected from the group vkluchaya[4-(biphenyl)-3-phenyl-(D)-alanyl-(L)-tryptophan;

N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-(4-biphenyl)toolani-(L)-tryptophan and

N-(3,5-dimethylbenzoyl)-N-methyl-D)-3-[4-(2-furyl)phenyl]-alanyl-(L)-tryptophan,

or its pharmaceutically acceptable salt.

13. Pharmaceutical preparation containing antagonist, inhibiting the binding of endothelin to its receptor, characterized in that as antagonist use an effective amount of a compound according to any one of paragraphs.1 - 12 or its pharmaceutically acceptable salt.

14. Pharmaceutical drug on p. 13, characterized in that it contains traditional pharmaceutical adjuvant.

15. Pharmaceutical drug on p. 13, characterized in that it contains antagonist, which inhibits the binding endothelina with the receptor in cerebral and coronary vasospasm, cerebral and coronary ischemia, subarachnoid hemorrhage, various types of hypertension, pulmonary hypertension, heart failure, disease, Raynaud's disease, diabetes, atherosclerosis or restenosis due to denudate, asthma, renal failure, glomerular lesions, liver failure, stomach ulcer and duodenal ulcers, trophic ulcers, various dysfunctions of the brain, migren%.

16. The active ingredient for the manufacture of pharmaceutical compositions for the treatment of cerebral and coronary vasospasm, cerebral and coronary ischemia, subarachnoid hemorrhage, various types of hypertension, pulmonary hypertension, heart failure, disease, Raynaud's disease, diabetes, atherosclerosis or restenosis due to denudate, asthma, renal failure, glomerular lesions, liver failure, stomach ulcers and duodenal ulcers, trophic ulcers, various dysfunctions of the brain, migraine, eye diseases, benign prostatic hyperplasia or glaucoma, characterized in that it is a compound according to any one of paragraphs.1 - 12.

 

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