Acylaminocinnamic derivatives, processes for their preparation and pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to acylaminocinnamic derivative of the formula (I), where R denotes phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, R1is hydrogen, alkyl, R2is hydrogen, alkyl or phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, R3is phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, or represents naphthyl, lH-indol-3-yl or 1-alcheringa-3-yl, R4' and R4"is hydrogen, alkyl, and one of the radicals R4' and R4"is hydrogen, and R5- cycloalkyl, D-azacycloheptan-2-he-3-yl or L-azacycloheptan-2-he-3-yl, or its salt. The compounds of formula (I) possess antagonistic activity and therefore can be used in pharmaceutical compositions as the active substance. The invention also relates to methods of obtaining new compounds of the formula (I), for example, by N-acylation of the compounds of formula (II) carboxylic acid R-C(=O)-OH, or the condensation of the carboxylic acid of formula (III) with cycloalkylation or D(+)- or L(-)-3-amino--cap the mules I

< / BR>
where R denotes phenyl which is not substituted or is substituted by 1, 2 or 3 substituents selected from the group comprising halogen, (ness.)alkyl, trifluoromethyl, hydroxy and (ness.)alkoxygroup,

R1denotes hydrogen or (ness.)alkyl, R2denotes hydrogen, (NISS. )alkyl or phenyl which is not substituted or is substituted by 1, 2 or 3 substituents selected from the group comprising halogen, (ness.)alkyl, trifluoromethyl, hydroxy and (ness.)alkoxygroup,

R3denotes phenyl which is not substituted or is substituted by 1, 2 or 3 substituents selected from the group comprising halogen, (ness.)alkyl, trifluoromethyl, hydroxy or (NISS. )alkoxygroup, or represents naphthyl, lH-indol-3-yl and 1-(ness.)alkalinty-3-Il,

R4' and R4" each independently of one another denotes hydrogen or (NISS. )alkyl, and at least one of the radicals R4' and R4" denotes hydrogen, and

R5stands WITH3-C8cycloalkyl, D-azacycloheptan-2-he-3-yl or L-azacycloheptan-2-he-3-Il,

and to their salts, to a process for the production of these compounds, to pharmaceutical compositions containing these compounds, to the use of these compounds for therapeutic treatment of human or animal or the above and below, preferably have the following meanings:

The concept of "nits." denotes a radical having not more than 7 and preferably not more than 4 carbon atoms.

(NISS. )alkyl represents, for example, WITH1-C7alkyl, preferably1-C4alkyl, particularly preferably methyl and ethyl and most preferably methyl. Examples (NISS. )alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and n-heptyl.

Halogen denotes, for example, fluorine, chlorine, bromine or iodine.

Haloethanol means, for example, fluorine-, chlorine-, bromine - or iodine-)phenyl, preferably forfinal or chlorophenyl, particularly preferably 4-forfinal or 4-chlorophenyl, and most preferably 4-chlorophenyl.

Dialogpanel means, for example, dichlorophenyl, differenl or chlorophenyl, preferably dichlorophenyl or differenl, especially 3,4-dichlorophenyl or 3,4-differenl and most preferably 3,4-dichlorophenyl.

Trialodine means, for example, tryptophanyl or trichlorophenyl.

1-(ness.)alkalinty-3-yl denotes, for example, 1-methylindol-3-yl.

WITH3-C8cycloalkyl and Ballycastle ring carbon atoms. Therefore, WITH3-C8cycloalkyl means, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, preferably cyclohexyl.

D-azacycloheptan-2-he-3-yl corresponds to the following group

< / BR>
which is obtained from D(+)-caprolactam, substituted amino group in position 3 [D-3-amino-caprolactam = (R)-3-aminohexyl-2-azepine]. Similarly, L-azacycloheptan-2-he-3-yl corresponds to the group

< / BR>
which is obtained from L (-) - caprolactam, substituted amino group in position 3 [L-3-amino-caprolactam = (S)-3-aminohexyl-2-azepine].

Salts of compounds of formula I are preferably pharmaceutically acceptable salts. The compounds of formula I having a basic group may, for example, to form the acid additive salts with suitable mineral acids, such as kaleidotrope acid, sulfuric acid or phosphoric acid, for example, hydrochloride, hydrobromide, sulphates, bisulfate or phosphates.

If the compounds of formula I contain an acid group, may also form salts with bases, for example, corresponding salts of alkali metals or alkaline earth metals, for example, salts of sodium, ka is I of formula I have valuable pharmacological properties. In particular, they act as antagonists neirokinina (PC-antagonists) and therefore have the ability to prevent the symptoms of the disease caused by, among other things, the production of substance P (NK1 receptor) and neirokinina A [NKA] (NK2-receptor).

The respiratory tract is equipped with sensitive nerves, which contain a large number of neuropeptides, in particular, tachykinins and CGRP (peptide associated with the gene of chalcedonica). Activation of sensory nerves causes local release of neuropeptides within the lungs. In particular, produced substance P and neurokinin And that trigger an acute inflammatory response, called neurogenic inflammation. This inflammatory response is mainly due to activation of NK1-receptor and, in particular, includes the dilation of blood vessels, leakage through the capillaries, the recruitment of inflammatory leukocytes and excessive secretion of mucus, and bronchostenosis [mainly due to the activation of receptor neirokinina 2 (NK2-receptor)]. Such impacts tachykinin are typical symptoms of asthma.

Pharmacological action of the compounds of formula I are based, in particular, on the fact that they are antagonists N1-prescriptions the awn to inhibit neurogenic inflammation and induced tachykinin bronchostenosis.

The effectiveness of compounds of the formula I can be demonstrated by different assessment methods in experiments in vitro or in vivo. For example, in experiments in vitro they inhibit [beta l-8]PKA(4-10) - induced flow of CA2+in transfection ovarian cells of Chinese hamsters which Express recombinant human receptors neirokinina 2, with IC50approximately 10 nm. In addition, in the experience of the binding of NK-2, in which study their ability to inhibit binding125I-NKA cells hrNK2CHO [conditions of cultivation and selection of cells hrNK2CHO see N. Subramanian and others , Biochem. Biophys. Res. Comm. 200 (1994) 1512-1520], it was found that the values of the IC50these compounds account for approximately 1 nm. In addition, they are effective in experiments in vivo, for example, in Guinea pigs, in relation to bronchostenosis induced NK1, with values ED50compounds by oral administration comprise about 0.05-1 mg/kg, when the test compound is administered at 2, 4, 12, or 24 h before intravenous injection of 3.0 mg/kg conjugate [Sar9, Met(O2) 11]-substance P [hereinafter labelled as SarSP]. Control infection SarSP induces an increase in intratracheal pressure in Guinea pigs. In addition, some of istenota, induced NK2. In this case, the increase in intratracheal pressure induce by intravenous administration of 0.8 mg/kg [beta-A1A-8] PKA(4-10), and the test compound is administered, for example, for 2 h prior to infection control.

The compounds of formula I are particularly effective as antagonists of NK1 receptors. Their action in respect of this class of receptors and their effect on the same receptor system, for example, NK2, makes the compounds of formula I therapeutically valuable substances for the prevention, treatment or diagnosis of a large number of diseases, for example diseases of the upper and lower respiratory tract, for example bronchial asthma, allergic asthma, non-allergic asthma, allergic conditions hypersensitivity and hypersecretion, such as chronic bronchitis and cystic fibrosis; pneumosclerosis of different etiology; disorders of the pulmonary and bronchial circulation, such as pulmonary high blood pressure, angiogenesis, metastases; diseases of the gastrointestinal tract, such as Crohn's disease, a disease Hirshsprung, diarrhea, symptoms of deficiency suction, inflammatory condition; emotional, traumatic or inflammatory disorders of the Central and accessories is s, vomiting; diseases of the blood vessels, such as vessels of the brain; diseases associated with capillary blood flow in various tissues, such as skin and eyes; diseases of the immune system and reticulohistiocytoma system, such as splenic and lymphatic tissue; painful conditions and other disorders, pathogenesis, pathology and etiology of which have impacts neurokinin, tachykinin or other similar substances.

As mentioned above, the compounds of formula I act as antagonists of substance P. Substance P plays an important role in various disorders, for example, in painful conditions, migraine and certain Central nervous system disorders, such as anxiety, vomiting, schizophrenia and depression, and certain movement disorders such as Parkinson's disease, and inflammatory diseases such as rheumatoid arthritis, iritis and conjunctivitis, diseases of the respiratory system such as asthma and chronic bronchitis, in disorders of the gastrointestinal system, such as ulcerative colitis and Crohn's disease, and hypertension.

Antagonistic action against substance P can be done is with bovine retina, performed using radioisotope receptor analysis according to the method of N. Bittiger, Ciba Foundation Symposium 91 (1982) 196 to 199, it was found that the concentration of the compounds causing 50% inhibition (IC50), approximately 0.2 nm.

The invention preferably relates to compounds of formula I, where

R stands for phenyl, 3,5-bistrifluormethylbenzene or 3, 4, 5-trimethoxyphenyl,

R1denotes hydrogen or (ness.)alkyl,

R2denotes hydrogen or phenyl,

R3denotes phenyl, haloethanol, dialogpanel, trihalomethanes, 2-naphthyl, lH-indol-3-yl or 1-(ness.)alkalinty-3-Il,

R4' and R4" each independently of one another denotes hydrogen or (NISS. )alkyl, and at least one of the radicals R4' and R4" denotes hydrogen, and

R5stands WITH5-C7cycloalkyl, D-azacycloheptan-2-he-3-yl or L-azacycloheptan-2-he-3-yl;

and to their salts.

Particularly preferably, the invention relates to compounds of formula I, where

R denotes a 3.5-bistrifluormethylbenzene,

R1denotes hydrogen, methyl or ethyl,

R2denotes hydrogen or phenyl,

R3denotes phenyl, 4-chlorophenyl, 4-torfin is,

R4' and R4" each independently of one another denotes hydrogen or methyl, and at least one of the radicals R4' and R4" denotes hydrogen, and

R5denotes cyclohexyl, D-azacycloheptan-2-he-3-yl or L-azacycloheptan-2-he-3-Il,

and their pharmaceutically acceptable salts.

More preferably the invention relates to compounds of formula I, where

R denotes a 3.5-bistrifluormethylbenzene,

R1denotes hydrogen or methyl,

R2denotes hydrogen or phenyl,

R3denotes phenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-naphthyl, lH-indol-3-yl or 1-methylindol-3-Il,

R4' and R4" represent hydrogen,

R5denotes cyclohexyl, D-azacycloheptan-2-he-3-yl or L-azacycloheptan-2-he-3-yl;

and their pharmaceutically acceptable salts.

It should be noted each of the following subgroups of the group of compounds of formula I:

(1) the compounds of formula I, where R5denotes a D-azacycloheptan-2-he-3-yl; (2) the compounds of formula I, where R4' and R4" represent hydrogen; (3) the compounds of formula I, where R denotes phenyl, 3,5-bistrifluormethylbenzene or 3,4,5-trimethoxyphenyl; (4) the compounds of formula I in free form, i.e. not m in the examples.

The compounds of formula I can be obtained by a well known method, for example, by

(A) N-acylation of compounds of formula II

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carboxylic acid R-C(=O)-OH or its reactive derivative, or

(B) the condensation of a carboxylic acid of the formula III

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or its reactive derivative with C3-C8cycloalkylation or D(+)- or L(-)-3-amino-caprolactam, or

(C) as the last stage by synthesizing the double bond using a Wittig reaction or its variants, for example, reaction of the Wittig-Horner, and, if necessary, by turning the compounds of formula I into a different compound of the formula I and/or, if necessary, conversion of the resulting salt into the free compound or a different salt, and/or, if necessary, conversion of the resulting free compounds of formula I, having the ability to form salt, salt, and/or, if necessary, by separation of the resulting mixture of stereoisomers, diastereoisomers or on a separate enantiomers stereoisomers, diastereoisomers or enantiomers.

The following more detailed description of methods, unless otherwise indicated, each of the symbols R, R1-R3, R4', R41-COCl, for example, chloride of 3,5-bistrifluormethylbenzene acid, for example, in the presence of triethylamine and optional 4-dimethylaminopyridine (DMAP).

The compounds of formula II have the following manner: as the original product is used as a compound of formula IV

< / BR>
where Pr denotes aminosidine group [e.g., BOC represents tert-butoxycarbonyl (-COO-tert-butyl)] , a Alk represents C1-C7alkyl. Alkilany ester hydrolyzing to obtain the carboxylic acid radical other5introduced by reacting with the appropriate amine N2N5[education-C(=O)-other5] and finally removing the protective group Pr.

The compound of formula IV can be obtained, for example, using as starting product derivative-amino acids of formula V

< / BR>
(for example, R2denotes H, R3denotes phenyl, D-phenylalanine), by protecting the amino group SUB> for example, by N-alkylation and esterification of the carboxylic acid radical (preferably with the formation of ether (ness.)the alkyl, especially methyl ether). If necessary, the introduction of the group R1and esterification of the carboxylic acid radical can also be carried out in one stage, for example, by interacting with methyliodide and Ag2O in DMF. Ether carboxylic acids are reduced to the corresponding aldehyde Va

< / BR>
(for example, using hydride diisobutylaluminum in toluene at -78oC) and finally subjected to interaction with obtaining the compounds of formula IV by reaction of the Wittig-Horner. It can be done, for example, by interacting with trialkylsilyl ether Postnikova acid of the formula (AlkO)2P(=O)-CH2-COOAlk (where Alk denotes a1-C7alkyl).

In a preferred embodiment, receiving the above-described compounds of formula IV as the original product instead of the carboxylic acids of formula V using the known esters of formula Vb (where Alk denotes (NISS. )alkyl, preferably methyl)

< / BR>
and then work in the same way as described above, i.e., again to protect the free amino group with a protective group "RG", nobreaks Wittig-Horner subjected to interaction with trialkylsilyl ether Postnikova acid of the formula (AlkO)2P(=O)-CH(-Alk)-COOAlk (Alk denotes a1-C7alkyl), we obtain the compounds of formula IV, where R4" means (ness.)alkyl.

If you want to obtain the compounds of formula IV, where R4' means (NISS. )alkyl, for example, the aldehyde of formula Va may be subjected to interaction with (ness.)alkylhalogenide magnesium, for example, methyliodide magnesium, with the formation of a secondary alcohol, which can then be converted, for example by oxidation will Roll (oxalicacid, DMSO) in a ketone of the formula Vc

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Then the product obtained in a similar way is subjected to interaction with aldehyde Va by the reaction of the Wittig-Horner obtaining the compounds of formula IV (where R4' means (ness.)alkyl).

Method (B)

The interaction according to the method (B) corresponds to a well-known method for obtaining the amides of carboxylic acids from the corresponding carboxylic acids or their reactive derivatives and primary amines. Among the large number of possible ways we can mention the following: (1) the interaction of the carboxylic acid of formula III with a primary amine H2NR5for example, in the presence of hydrochloride of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC) and 4-dimethyl what lorida N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide in the presence of DMAP to obtain the corresponding N-hydroxysuccinimide ether and then with the appropriate amine H2NR5; (3) the interaction of the carboxylic acid of formula III with an amine H2NR5in the presence of anhydride 1-papapostolou acid.

The compounds of formula III have the following manner:

using as starting product the compound of the formula IV, remove aminosidine group, for example, in the case of VOS by interacting with triperoxonane acid, the amino group acelerou carboxylic acid R-COOH (for example, 3,5-bistrifluormethylbenzene acid) or its reactive derivative [analogously to method (A)] and finally hydrolyzing the group Olkiluoto ether, for example, using LiOH in methanol and THF.

Method ()

Possible source product for the reaction of the Wittig-(Horner) is, for example, the aldehyde of formula Va, in which remove aminosidine group and which is then N-acelerou carboxylic acid R-COOH (for example, 3,5-bistrifluormethylbenzene acid) or its reactive derivative [analogously to method (A)] . This aldehyde may be, for example, be subjected to interaction with Amida dialkylamide ether Postnikova acid of the formula (AlkO)2P(= O)-CO-OTHER5the reaction of the Wittig-Horner obtaining the compounds of formula I.

tx2">

For example, the compounds of formula I, where R1means (ness.)alkyl, can be obtained by N-alkylation of compounds of formula I, where R1denotes hydrogen, with compounds of Y3-R1where Y3denotes a hydroxy-group or a reactive esterified with the hydroxy-group. Reactive esterified with the hydroxy-group is, for example, halogen, especially bromine, iodine or chlorine, or sulfonyloxy, for example, methylsulfonylamino - or para-toluensulfonate. Another possible method consists in the interaction of compounds of formula I, where R1denotes hydrogen, with a compound Y4-R1'where Y4denotes formyl, a R1' denotes the radical R1where there is no group of CH2[R1=-CH2-R1'], in reducing conditions (reductive amination).

If any of the intermediate products contain able to interact reactive group, for example, carboxy-, hydroxy-, mercapto - or amino groups, these groups may be temporarily protected by easily removable protective groups. The selection of suitable protective groups and methods for their introduction and removal is the Li compounds of formula I can be obtained by a well-known manner. For example, the acid additive salts of compounds of formula I are obtained by processing suitable acid or a suitable ion exchange reagent, and salts with bases are obtained by processing suitable base or a suitable ion exchange reagent. Salts of compounds of formula I can be converted into the free compounds of formula I accepted way: acid additive salts, for example, can be obtained by treatment with a suitable basic agent or a suitable ion exchange reagent, and salts with bases, for example, by treatment with a suitable acid or a suitable ion exchange reagent.

The compounds of formula I, including their salts (compounds of formula I can form salts) can also be obtained in the form of their hydrates and/or may include other solvents, for example solvents which can be used for the crystallisation of compounds in solid form.

Depending on the variable nature of substances and the corresponding number of centers of asymmetry, as well as from the selected source products and methods of the compounds of formula I can be obtained in the form of mixtures of stereoisomers, for example, mixtures of diastereoisomers or mixtures of enantiomers, such as the rat is by the method according to the invention or in any other way, can be separated by the usual method on a mixture of enantiomers, such as racemates, or on a separate diastereoisomer, for example, on the basis of the physicochemical differences between the components, the conventional method using a fractionated crystallization, distillation and/or chromatography. Mainly emit more active isomers.

Mixtures of enantiomers, in particular racemates obtained according to the method according to the invention or in any other way, may be separated into individual enantiomers by known methods, for example by recrystallisation from an optically active solvent, with the aid of microorganisms, by chromatography and/or interaction with an optically active auxiliary compound, for example, a base, acid or alcohol, to obtain mixtures of salts of diastereoisomers or funktsionalnostey derivatives, such as esters, their division and separation of the desired enantiomer. Mainly emit more active enantiomers.

The invention also relates to such variants of the method, in accordance with which the connection is obtained as an intermediate product at any stage of the method used to is or salt, or, in particular, it is formed under the reaction conditions. The invention also relates to end-products, which are (4S)-configuration, described in the following examples, and also have some activity as N1/N2-antagonists.

In the method according to the present invention, it is preferable to apply such starting materials and intermediates, in each case in free form or in salt form, which can lead to compounds of the formula I or their salts, which are previously described as the most valuable. The invention also relates to new source products and intermediate products, in each case in free form or in salt form, intended for the production of compounds of the formula I or their salts, to their use and to processes for their preparation, and the radical R has the meaning indicated for the compounds of formula I.

The invention also relates to the use of compounds of the formula I and their pharmaceutically acceptable salts for the treatment of allergic conditions and diseases, preferably in the form of pharmaceutically acceptable compositions, particularly intended for a method of therapeutic treatment of an animal or person, and to the way that the formula I or its pharmaceutically acceptable salt as an active ingredient, and to methods for their manufacture. Such pharmaceutical compositions are compositions for enteral administration, such as oral and rectal administration, for parenteral administration, for local application and particularly for administration by inhalation warm-blooded animal, especially a human, the composition or contain only one pharmacologically active ingredient, or in addition to it contain conventional pharmaceutical excipients. Pharmaceutical compositions include (wt.%), for example, from about 0,001% to 100%, preferably from about 0.1% to about 50% active ingredient.

Pharmaceutical compositions for enteral and parenteral administration, for example, represent a standard dosage forms, such as pills, tablets, capsules or suppositories, and also ampoules. They are made well-known method, for example, using conventional methods of mixing, granulation, packing (mixing with sweet filling), dissolution or lyophilization. For example, pharmaceutical compositions for oral administration can be obtained by combining the active substance with solid wear the e adding of suitable excipients to obtain tablets or dragee cores.

Suitable carriers are in particular fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, preparations based on cellulose and/or calcium phosphates, for example tricalcium phosphate or secondary acidic calcium phosphate, and also binders, such as starch pastes, obtained using, for example, corn, wheat, rice or potato starch, gelatin, tragakant, methylcellulose and/or polyvinylpyrrolidone, and, if necessary, leavening agents, such as the abovementioned starches, and carboxymethylate starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or its salt, such as sodium alginate. Excipients preferably are substances that improve the fluidity, and the oil, for example, silicic acid, talc, stearic acid or its salts, such as magnesium stearate or calcium, and/or polyethylene glycol. On the kernel drops causing suitable, optional intersolubility, cover, with, among other things, apply concentrated sugar solutions, which may include gum Arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating applied from a solution pripodnjat solutions suitable compositions based on cellulose, such as cellulose acetate phthalate or phthalate of hydroxypropylmethylcellulose. In the coating of tablets or pills may be added dyes or pigments, for example for identification purposes or to indicate different doses of active ingredient.

Other pharmaceutical compositions for oral administration are capsules with solid floor and a sealed capsule with a soft coating consisting of gelatin and a plasticizer, such as glycerol or sorbitol. Gelatin capsules with a hard surface may include the active substance in the form of granules, for example, in a mixture with fillers, such as lactose, binders, such as starches, and/or substances that improve the slip, such as talc or magnesium stearate, and, if necessary, with stabilizers. Capsules, soft coated active substance is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it is also possible to add stabilizers.

Suitable pharmaceutical compositions for rectal injection are, for example, suppositories, which are a combination of loads is emer, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is also possible to use gelatin capsules for rectal administration, which represents the combination of the active substance by substance basis. Suitable substances bases are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

For parenteral administration are especially suitable aqueous solutions of the active ingredient in water-soluble form, and also suspensions of the active ingredient, such as corresponding oily suspension for injection, when used suitable lipophilic solvents or carriers, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example, etiloleat or triglycerides, or aqueous suspension for injection, which include increasing the viscosity of the substance, for example, sodium carboxymethyl cellulose, sorbitol and/or dextran, and optionally also stabilizers.

Pharmaceutical compositions for local application are, for example, compositions for topical application to the skin: lotions, creams and ointments, i.e., liquid or semi-solid emulsion type wt is you, the absorbent products of secretion; gels, which may be water, to have a small water content, or not to contain water and consist of nabukenya, gelling agents; foam, i.e., liquid emulsion of the type oil-in-water in aerosol form, which are applied from a container under pressure; and infusions with an aqueous-ethanolic base; each of these components, in addition, may include conventional pharmaceutical excipients such as preservatives. Pharmaceutical compositions for local application is made well-known manner by mixing the active substance with pharmaceutical excipients, for example, by dissolution or suspension of the active substance in matter basis or, if necessary, in a certain part of it. To obtain emulsions in which the active substance is dissolved in one of the liquid phases, the active ingredient, as a rule, is dissolved in this phase before emulsification; to obtain suspensions, in which the active substance is suspended in the emulsion, the active ingredient is mixed with part of the substance and basis after emulsification and then added to the remaining portion of the composition.

The dose of active ingredient may depend on lesne, be disinfected, and its symptoms, the form of administration, species, gender, age and weight warm-blooded animal and/or individual condition. In the normal case, the daily dose for administration, for example, for oral administration of a warm-blooded animal weighing approximately 75 kg is set to approximately 1 mg to approximately 1000 mg, preferably from about 5 mg to about 200 mg, the dose may be, for example, as a single dose or as multiple divided doses, for example, from 10 to 100 mg.

Below the invention is illustrated in the examples. When this temperature is indicated in degrees Celsius; DMSO means dimethyl sulfoxide; THF refers to tetrahydrofuran; EtOH means ethanol; carbarnoyl represents-CONH2; hexane indicates a mixture of isomers of different hexanol (for example, supplied by the company Fluka); TCX refers to thin layer chromatography; CT denotes room temperature.

Example 1: N-[(R) - caprolactam-3-yl] amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino-5-(1-methylindol-3-yl)Penta-2-ene acid

To a solution containing 0,976 g of N-[(R) - caprolactam-3-yl]amide (4R)-(N'-methylamino)-5-(1-methylindol-3-yl)Penta-2-ene acid and 1.1 ml of triethylamine in 20 ml Meiling who live in the 20oC for 30 min and concentrated by evaporation. The residue is dissolved in ethyl acetate and extracted once with water and twice with brine. The combined organic phases are dried over magnesium sulfate and concentrated by evaporation. The residue is subjected to rapid chromatography (85 g of silica gel, ethyl acetate/acetone in a ratio of 3/1). The result is indicated in the title compound in the form of a colorless solid foam. Rf(ethyl acetate/acetone in a ratio of 1/1)=0,4. GHUR: Chiracel OD, heptane/isopropyl alcohol in a ratio of 80/20 +0,1% triperoxonane acid, 1 ml/min, Rt=24,39 min []D20= +54,2o3,8o(C=0,26, tO).

Original products can be obtained in the following way:

a) N-[(R) - caprolactam-3-yl] amide (4R)-(N'-methylamino)-5-(1-methylindol-3-yl)Penta-2-ene acid

To 1.24 g of N-[(R) - caprolactam-3-yl]amide (4R)-(N'-methyl-N'-tert-butyloxycarbonyl)-5-(1-methylindol-3-yl)Penta-2-ene acid added at 0oWith 27 ml of 4 N. hydrochloric acid in dioxane. The resulting suspension is stirred at room temperature for 15 min and concentrated by evaporation. The residue is dissolved in a small amount of a mixture of ice/water; add 2 n sodium carbonate solution and three times what hatom magnesium and concentrated by evaporation. The residue is twice dissolved in methylene chloride and again concentrated by evaporation. The result is indicated in the title compound in the form of a yellow foam. Rf(ethyl acetate)=0,05.

b) N-[(R) - caprolactam-3-yl] amide (4R)-(N'-methyl-N'-tert-butyloxycarbonyl)-5-(1-methylindol-3-yl)Penta-2-ene acid

A mixture containing 1.07 g of (4R)-(N-methyl-N-tert-butyloxycarbonyl)-5-(1-methylindol-3-yl)Penta-2-ene acid, 0,42 g D-3-amino-caprolactam, 0,63 g of the hydrochloride of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, of 0.48 g of 4-dimethylaminopyridine and 15 ml of methylene chloride, stirred at room temperature for 4 h and then concentrated by evaporation. The residue is dissolved in ethyl acetate and extracted twice with water, once 1 N. hydrochloric acid and twice with brine. The combined organic phases are dried over magnesium sulfate and concentrated by evaporation. The result is indicated in the title compound in the form of a colorless foam. Rf(methylene chloride/methanol in a ratio of 9/1)=0,45.

C) (4R)-(N-methyl-N-tert-butyloxycarbonyl)-5-(1-methylindol-3-yl)Penta-2-ene acid

To a solution containing 5,56 g ethyl ester (4R)-(N-methyl-N-tert-butyloxycarbonyl)-5-(1-met is lithium hydroxide in 27 ml of water and the mixture is stirred at room temperature for 45 min, neutralize with approximately 25 ml of 4 N. hydrochloric acid and concentrated by evaporation. The residue is dissolved in water, acidified with 4 N. hydrochloric acid to pH 2 and extracted with ethyl acetate. The combined organic phases are washed with water and saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation. The residue is dissolved three times in methylene chloride and again concentrated by evaporation. The result is indicated in the title compound in the form of a solid foam. Rf(ethyl acetate/hexane in a ratio of 1/1)=0,07.

d) Ethyl ester (4R)-(N-methyl-N-tert-butyloxycarbonyl)-5-(1-methylindol-3-yl)Penta-2-ene acid

To a solution of a 4.86 g teeterboro ether fastnesses acid in 50 ml of absolute acetonitrile is added at 0oWith 0,848 g anhydrous LiCI, 1.77 g of 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) and a solution of 5.75 g (R)-N-methyl-N-tert-butyloxycarbonyl-3-(1-methylindol-3-yl)propanol in 100 ml of acetonitrile. After complete addition, the mixture is stirred at room temperature for 45 minutes Then the resulting suspension was poured onto water and extracted twice, using each time with 500 ml of diethyl ether. The combined organic phases are washed with water three times is using chromatography (330 g of silica gel, hexane/ethyl acetate in a ratio of 2/1). The result is indicated in the title compound in the form of a colourless resin.f(hexane/ethyl acetate in a ratio of 2/1)=0,25.

d) (R)-N-methyl-N-tert-butyloxycarbonyl-3-(1-methylindol-3-yl)propanal

The solution 6,28 g of methyl ester of (R)-N-methyl-N-tert-butyloxycarbonyl-3-(1-methylindol-3-yl)propenylboronic acid in 117 ml of toluene is cooled to -78oIn argon atmosphere, and thereto are added dropwise to 41.6 ml of 20% aqueous solution of hydride diisobutylaluminum in toluene (40 min). After completion of adding dropwise, the mixture was stirred at -78oEven for 90 minutes Then add to 5.9 ml of methanol and 200 ml of diethyl ether at -74oAnd 10 g of citric acid dissolved in 190 ml of water, so that the temperature did not exceed -10oC. the Mixture is intensively stirred at 0oC for 2 h the Resulting suspension is filtered under vacuum. Then, the filtrate separated phase and the aqueous phase is once again extracted with diethyl ether. The combined organic phases are washed with water and saturated NaCl solution, dried (sodium sulfate) and concentrated by evaporation. The result is indicated in the title compound in the form of a viscous is carbylamine-3-(1-methylindol-3-yl)propenylboronic acid

To a solution of 14.3 g of methyl ether of tert-butyloxycarbonyl-D-tryptophan in 90 ml of N,N-dimethylformamide added under stirring at 5oWith 55 g of silver oxide(I). Then when 5oTo add 44 ml of methyliodide and 2 ml of acetic acid (absolute). The reaction mixture was stirred at room temperature for 72 h, then diluted with 1 l of diethyl ether, filtered and concentrated by evaporation. The residue is dissolved in diethyl ether, washed with water and with brine, dried over magnesium sulfate and concentrated by evaporation. After chromatography of the residue on 1 kg of silica gel (hexane/ethyl acetate in a ratio of 2/1) get mentioned in the title compound in the form of a resin light yellow color. Rf(hexane/ethyl acetate in a ratio of 2/1)=0,27.

f) Methyl ether tert-butyloxycarbonyl-D-tryptophan

To a suspension of 12.12 g of the hydrochloride of the methyl ester of D-tryptophan in 80 ml of absolute tetrahydrofuran at 0oWith add 10 g of tert-butanol, to 10.1 g of BOC-anhydride and 12,27 g diisopropylethylamine dissolved in 30 ml of tetrahydrofuran. After stirring for 2 h at room temperature actionnow mixture was poured onto a mixture of ice/470 ml of 0.3 N. model HC1 and extracted three times with ethyl acetate. Volume will contentresult by evaporation. The residue is converted into a suspension in a mixture of diethyl ether/petroleum ether and filtered under vacuum. The result is indicated in the title compound in the form of colourless crystals having a PL148-149oC. Rf(methylene chloride) =0,24.

Working similarly to the method described in example 1, but using instead of D-3-amino-caprolactam appropriate amines, the following compounds:

Example 2: N-[(S) - caprolactam-3-yl] amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-5-(1-methylindol-3-yl)Penta-2-ene acid

When using L-3-amino-caprolactam. Solid foam. Rf(ethyl acetate/acetone in a ratio of 1/1) = 0,31. GHUR: Chiralpack OD, heptane/isopropyl alcohol in a ratio of 80/20 +0,1% triperoxonane acid, 1 ml/min, Rt=29,96 min []D20=+67o2,3o(C=0,44, EtOH).

Example 3: N-cyclohexylamine (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-5-(1-methylindol-3-yl)Penta-2-ene acid

When using cyclohexylamine. Rf(ethyl acetate) =0,41.

Example 4: N-cyclohexylamine (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-5-(1-methylindol-3-yl)-2-methylpent-2-ene acid

Specified in the title compound can be obtained strictly in the place of the ether triethylphosphate acid. Specified in the title compound is obtained in the form of colorless amorphous solid. Rf(ethyl acetate) =0,46.

Working similarly to the described method, it is also possible to obtain the following products:

Example 5: N-[(R) - caprolactam-3-yl] amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-5-(1-methylindol-3-yl)-2-methylpent-2-ene acid

Colorless foam, Rf(ethyl acetate/acetone in a ratio of 1/1)=0,46; []D20= -24.4o2,8o(C=0,352, EtOH).

Example 6: N-[(S) - caprolactam-3-yl] amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-5-(1-methylindol-3-yl)-2-methylpent-2-ene acid

Colorless foam, Rf(ethyl acetate/acetone in a ratio of 1/1) = 0,46. When using L-3-amino-caprolactam.

Working similarly to the method described in example 5, but using benzoyl chloride instead of 3,5-bistrifluormethylbenzene, you get the following product:

Example 5/1: N-[(R) - caprolactam-3-yl]amide (4R)-[N'-methyl-N'-benzoylamine]-5-(1-methylindol-3-yl)-2-methylpent-2-ene acid

Colorless foam, Rf(ethyl acetate/acetone in a ratio of 1/1)=0,23; []D20= -10,7o3,5o(C=0,283, EtOH).

Example 7: N-[(R) - caprolactam-3-yl] amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene the-5-(naphthas-2-yl)Penta-2-ene acid in 6 ml of methylene chloride add to 78.3 mg D-3-amino-caprolactam, 116,9 mg of the hydrochloride of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide and 88 mg of 4-dimethylaminopyridine. The reaction mixture is stirred at 20oC for 3.5 h and concentrated by evaporation. The residue is subjected to rapid chromatography (40 silicagel, ethyl acetate). The result is indicated in the title compound in the form of a solid of light yellow color.f(methylene chloride/methanol in the ratio of 15/1)=0,28.

Original products can be obtained in the following way:

a) (4R)-[N-methyl-N-(3,5-bistrifluormethylbenzene)amino] -5-(naphthas-2-yl)Penta-2-ANOVA acid

To a solution containing 0,325 g ethyl ester (4R)-[N-Methyl-N-(3,5-bistrifluormethylbenzene)amino] -5-(naphthas-2-yl)Penta-2-ene acid in 3 ml of tetrahydrofuran and 3 ml of methanol, add at 0oTo a solution of 0.18 g of lithium hydroxide in 1.18 ml of water and the mixture is stirred at room temperature for 45 min, neutralized with a small amount 4 N. hydrochloric acid and concentrated by evaporation. The residue is dissolved in water, acidified to pH 2 with 4 N. hydrochloric acid and extracted with ethyl acetate. The combined organic phases are washed with water and saturated NaCl solution, dried (magnesium sulfate) and concentrated by perivan is specified in the title compound in the form of a colorless solid foam. Rf(ethyl acetate/hexane in a ratio of 1/1)=0,15.

b) Ethyl ester of (4R)-[N-methyl-N-(3,5-bistrifluormethylbenzene)amino]-5-(naphthas-2-yl)Penta-2-ene acid

To a solution containing 0,327 g ethyl ester (4R)-N-methylamino-5-(naphthas-2-yl)Penta-2-ene acid and of 0.48 ml of triethylamine in 5 ml of methylene chloride, at 0oWith added dropwise 0,229 ml 3.5-bistrifluormethylbenzene. The reaction mixture is stirred at 20oC for 60 min and concentrated by evaporation. The residue is dissolved in ethyl acetate and extracted once with water and twice with brine. The combined organic phases are dried over magnesium sulfate and concentrated by evaporation. The residue is subjected to rapid chromatography (40 g silica gel, hexane/ethyl acetate in a ratio of 2/1). The result is indicated in the title compound in the form of a hard orange foam. Rf(ethyl acetate/hexane in the ratio 2/1)=0,59.

b) Ethyl ester of (4R)-N-methylamino-5-(naphthas-2-yl)Penta-2-ene acid

To 0,30 g ethyl ester (4R)-(N-methyl-N-tert-butyloxycarbonyl-5-(naphthas-2-yl)Penta-2-ene acid added at 0oWith 8 ml of 4 N. hydrochloric acid in dioxane. The resulting suspension is stirred at room temperature in the course is T. 2 N. the sodium carbonate solution and extracted three times with ethyl acetate. The combined organic phases are washed twice with brine, dried over magnesium sulfate and concentrated by evaporation. The residue is twice dissolved in methylene chloride and again concentrated by evaporation. The result is indicated in the title compound in the form of a yellow foam. Rf(ethyl acetate) =0,65.

d) Ethyl ester (4R)-(N-methyl-N-tert-butyloxycarbonyl-5-(naphthas-2-yl)Penta-2-ene acid

To the solution was 7.08 g teeterboro ether fastnesses acid in 80 ml of absolute acetonitrile is added at 0oA 1.34 g of dried LiCl, 4,37 g of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and a solution of 9.0 g (R)-N-methyl-N-tert-butyloxycarbonyl-3-(naphthas-2-yl)propanal in 150 ml of acetonitrile. After complete addition, the mixture is stirred at room temperature for 45 minutes Then the resulting suspension was poured onto water and extracted twice, using each time in 600 ml of diethyl ether. The combined organic phases are washed three times with water and twice with saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation. The residue is purified via chromatography (800 g silica gel, hexane/ethyl acetate in a San/acetate in a ratio of 8/1)=0,09. GHUR: Chiralcel OJ, hexane/isopropyl alcohol in a ratio of 90/10+0,1% triperoxonane acid, 1 ml/min, Rt=15,86 minutes

d) (R)-N-methyl-N-tert-butyloxycarbonyl-3-(naphthas-2-yl)propanal

A solution of 21.8 g of methyl ester of (R)-N-methyl-N-tert-butyloxycarbonyl a melamine-3-(naphthas-2-yl)propenylboronic acid 497 ml of toluene is cooled to -78oIn argon atmosphere, and thereto are added dropwise 146 ml of 20% aqueous solution of hydride diisobutylaluminum (DIBAH) in toluene (60 min). After completion of adding dropwise, the mixture was stirred at -78oEven within 60 minutes Then add to 17.8 ml of methanol at -74oWith 35 g of citric acid dissolved in 665 ml of water, so that the temperature did not exceed -10oC. the Mixture is intensively stirred at 0oC for 2 h the Resulting suspension is filtered under vacuum. Then, the filtrate separated phase and the aqueous phase is once again extracted with diethyl ether. The combined organic phases are washed with water and saturated NaCl solution, dried (sodium sulfate) and concentrated by evaporation. The result is indicated in the title compound in the form of beige crystals with tPL98-100oC. Rf(hexane/ethyl acetate in cootes is sloty

To a solution of 20.1 g (R)-N-tert-butyloxycarbonyl-3-(naphthas-2-yl)propenylboronic acid (for example, company Bachem) and 191 ml of N,N-dimethylformamide added under stirring at 5oFrom 76.4 g of silver oxide(I). Then when 5oWith add 12.5 ml of methyliodide. The reaction mixture was stirred at room temperature for 24 h, then diluted with 1 l of diethyl ether, filtered and concentrated by evaporation. The residue is dissolved in diethyl ether, washed with water and with brine, dried over magnesium sulfate and concentrated by evaporation. The result is indicated in the title compound in the form of oil is light yellow in color. Rf(hexane/ethyl acetate in a ratio of 4/1)= 0,47. GHUR: Chiralcel OJ, hexane/isopropyl alcohol in a ratio of 90/10+0,1% triperoxonane acid, 1 ml/min, Rt=11,32 minutes

Working similarly to the method described in example 7, but using on stage 7b) benzoyl chloride instead of 3,5-bistrifluormethylbenzene receive the following connection:

Example 7/1: N-[(R) - caprolactam-3-yl] amide (4R)-[N'-methyl-N'-benzoyl)amino] -5-(naphthas-2-yl)Penta-2-ene acid

Rf(ethyl acetate/acetone in a ratio of 9/1)=0,13.

Example 8: N-[(R) - caprolactam-3-yl] amide (4R)-[N'-methyl-N'-(3,5-bestafter the-3-yl]amide (4R)-(N'-methylamino)-5-(naphthas-2-yl)-2-methylpent-2-ene acid and 0.3 ml of triethylamine in 6 ml of methylene chloride, dropwise at 0oTo add 0,153 ml 3.5-bistrifluormethylbenzene. The reaction mixture is stirred at 20oC for 90 min and concentrated by evaporation. The residue is dissolved in ethyl acetate and extracted once with water and twice with brine. The combined organic phases are dried over magnesium sulfate and concentrated by evaporation. The residue is subjected to rapid chromatography (150 g silica gel, ethyl acetate/hexane in a ratio of 4/1). The result is indicated in the title compound in the form of a colorless solid foam. Rf(ethyl acetate) =0,43. GHUR: AD column, hexane/isopropyl alcohol in a ratio of 90/10+0,1% triperoxonane acid, 1 ml/min, Rt=17,87 minutes

Original products can be obtained in the following way:

a) N-[(R) - caprolactam-3-yl]amide (4R)-(N-methylamino)-5-(naphthas-2-yl)-2-methylpent-2-ene acid

To 0,342 g of N-[(R) - caprolactam-3-yl]amide (4R)-(N'-methyl-N'-tert-butyloxycarbonyl)-5-(naphthas-2-yl) -2-methylpent-2-ene acid added at 0oWith 7.0 ml of 4 N. hydrochloric acid in dioxane. The resulting suspension is stirred at room temperature for 20 min and concentrated by evaporation. The residue is dissolved in a small amount of a mixture of ice/water; daywalt twice with brine, dried over magnesium sulfate and concentrated by evaporation. The residue is twice dissolved in methylene chloride and again concentrated by evaporation. The result is indicated in the title compound in the form of a yellow foam. Rf(methylene chloride/methanol in a ratio of 95/5)=0,33.

b) N-[(R) - caprolactam-3-yl] amide (4R)-(N'-methyl-N'-tert-butyloxycarbonyl)-5-(naphthas-2-yl)-2-methylpent-2-ene acid

A mixture containing 500 mg of (4R)-(N-methyl-N-tert-butyloxycarbonyl)-5-(naphthas-2-yl)-2-methylpent-2-ene acid, 0,183 g D-3-amino-caprolactam, 0,265 g of the hydrochloride of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, 0,200 g of 4-dimethylaminopyridine and 16 ml of methylene chloride, stirred at room temperature for 1 h and then concentrated by evaporation. The residue is dissolved in ethyl acetate and extracted twice with water, once 1 N. hydrochloric acid and twice with brine. The combined organic phases are dried over magnesium sulfate and concentrated by evaporation. The residue is subjected to rapid chromatography (80 g silica gel, ethyl acetate/hexane in a ratio of from 7/3 to 9/1). The result is indicated in the title compound in the form of a colorless foam. Rf (ethyl acetate) =0,39.

C) (4R)-(N-metal-N-tert-Buti is about ester (4R)-(N-methyl-N-tert-butyloxycarbonyl)-5-(naphthas-2-yl)-2-methylpent-2-ene acid in 40 ml of tetrahydrofuran and 40 ml of methanol, add at 0oTo a solution of 2.6 g of lithium hydroxide in 17 ml of water and the mixture is stirred at room temperature for 45 min, neutralized approximately 15 ml of 4 N. hydrochloric acid and concentrated by evaporation. The residue is dissolved in water, acidified with 4 N. hydrochloric acid to pH 2 and extracted with ethyl acetate. The combined organic phases are washed with water and saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation. The residue is dissolved three times in methylene chloride and again concentrated by evaporation. The result is indicated in the title compound in the form of a solid foam. Rf(ethyl acetate/hexane in a ratio of 1/1)=0,26.

d) Ethyl ester (4R)-(N-methyl-N-tert-butyloxycarbonyl)-5-(naphthas-2-yl)Penta-2-ene acid

To a solution 7,52 g teeterboro ether 2-phosphonopropionic acid in 80 ml of absolute acetonitrile is added at 0oWith 1,36 g of dried LiCl, 4,37 g of 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) and a solution of 9 g of (R)-N-methyl-N-tert-butyloxycarbonyl-3-(naphthas-2-yl)propanal in 150 ml of acetonitrile. After complete addition, the mixture was stirred at 10oC for 40 minutes Then the resulting suspension was poured onto water and extracted twice, icolysedum NaCl, dried (magnesium sulfate) and concentrated by evaporation. The residue is purified via chromatography (600 g silica gel, hexane/ethyl acetate in a ratio of from 95/5 to 93/7). The result is indicated in the title compound in the form of a colourless resin. Rf(hexane/ethyl acetate in a ratio of 7/3)=0,53.

Working similarly to the method described in example 8, but using 3,4,5-trimethoxybenzoate instead of 3,5-bistrifluormethylbenzene, you may get the following connection:

Example 8/1: N-[(R) - caprolactam-3-yl] amide (4R)-[N'-methyl-N'-(3,4,5-trimethoxybenzoyl)amino]-5-(naphthas-2-yl)-2-methylpent-2-ene acid

Rf(methylene chloride/methanol in a ratio of 95/5)=0,42.

Working similarly to the method described in example 8, but using instead of D-3-amino-caprolactam appropriate amines, the following compounds:

Example 9: N-[(S) - caprolactam-3-yl] amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-5-(naphthas-2-yl)-2-methylpent-2-ene acid

When using L-3-amino-caprolactam, Rf(ethyl acetate) =0,44.

Example 10: N-cyclohexylamine (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-5-(naphthas-2-yl)-2-methylpent-2-ene acid

When using cyclohexylamine, Rf(hexane acid, 1 ml/min, Rt=6,25 minutes

Example 11: N-[(S) - caprolactam-3-yl]amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-5-(1-methylindol-3-yl)Penta-2-ene acid (another way of obtaining compounds of example 2).

Specified in the title compound can also be obtained using as starting product is racemic methyl ester hydrochloride (D, L-tryptophan (instead of methyl ester hydrochloride (D-tryptophan). The hydrochloride of the methyl ester of D,L-tryptophan is subjected to interact in a manner analogous to the method described in example 1. Stage 1B) using L-3-amino-caprolactam. The resulting mixture diastereoisomers then share at the final stage using chromatography on silica gel (ethyl acetate). In this way we obtain a pure N-[(S) - caprolactam-3-yl]amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-5-(1-methylindol-3-yl)Penta-2-ene acid (Rf=0.31, ethyl acetate/acetone in a ratio of 1/1) and N-[(S) - caprolactam-3-yl] amide (S)-4-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino] -5-(1-methylindol-3-yl)Penta-2-ene acid {Rf=0,35, ethyl acetate/acetone in a ratio of 1/1; []D20=-44,3o4,5o(C=0,221, EtOH)}.

Example 12: N-[(R) - caprolactam-3-yl]amide (4R)-[N'-met is) - caprolactam-3-yl]amide (4R)-(N'-methylamino)-4-(4-chlorbenzyl)but-2-ene acid and 0.75 ml of triethylamine in 35 ml of methylene chloride, added dropwise at 0oTo a solution of 0.71 g of 3,5-bistrifluormethylbenzene (in 5 ml of methylene chloride). The reaction mixture was stirred at room temperature for 2 hours Then add 3 ml of methanol and the reaction mixture is diluted with 50 ml of methylene chloride. The solution was washed with Hcl 0.1 N., water (twice) and saturated

NaCl, dried (MgSO2) and concentrated by evaporation. The residue is subjected to rapid chromatography (85 g of silica gel, ethyl acetate/methanol in a ratio of 98/2). Specified in the title compound is obtained in the form of an amorphous solid white.f=0,12 (ethyl acetate), []D20= +42o1o(C= 1, EtOH). Rt=20,38 min (Chiralcel-OJ, 0,4625 cm, detection at 210 nm, hexane:ethanol in a ratio of 90:10+0.1% of TFA, flow rate 1.0 ml/min 30 bar).

Original products can be obtained in the following way:

a) N-[(R) - caprolactam-3-yl] amide (4R)-(N'-methylamino)-4-(4-Chlorobenzyl)but-2-ene acid

A solution containing 1.2 g of N-[(R) - caprolactam-3-yl]amide (4R)-(N'-methyl-N'-tertbutyloxycarbonyl)-4-(4-chlorbenzyl)but-2-ene acid and 8 ml triperoxonane acid in 30 ml of methylene chloride, is stirred in an argon atmosphere at room temperature for 2 h Then the reaction smetana sodium hydroxide and a saturated solution of NaCl, dried (sodium sulfate), concentrated by evaporation and subjected to further interaction without additional purification.

b) N-[(R) - caprolactam-3-yl] amide (4R)-(N'-methyl-N'-tert-butyloxycarbonyl)-4-(4-chlorbenzyl)but-2-ene acid

Mixture of 1.53 g of (4R)-(N'-methyl-N'-tert-butyloxycarbonyl)-4-(4-chlorbenzyl)but-2-ene acid, of 0.58 g of D-3-amino-caprolactam, of 0.94 g of the hydrochloride of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, of 0.60 g of 4-dimethylaminopyridine, 0,725 g of hydroxybenzotriazole and 80 ml of methylene chloride, stirred at room temperature for 16 h, and then concentrated by evaporation. The residue is subjected to chromatography (silica gel, hexane/ethyl acetate in a ratio of 1/1). The result is indicated in the title compound, tPL154-156oC.

C) (4R)-(N'-methyl-N'-tert-butyloxycarbonyl) -4-(4-chlorbenzyl)but-2-ANOVA acid

The solution containing 1.64 g of ethyl ester of (4R)-(N'-methyl-N'-tert-butyloxycarbonyl)-4-(4-chlorbenzyl)but-2-ene acid and 1,72 g of lithium hydroxide in a mixture of tetrahydrofuran/methanol/water in the ratio 3/3/1, stirred at room temperature for 1 h and then poured into 150 ml of water. The mixture is acidified to pH 2 by dobavleniya water and saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation, receiving a colorless oil.1H-NMR, 400 MHz, CDCl3d (part./million): 7,30 (d, 2H), 7,20 (d, 2H), 6,80 (dd, 1H), of 5.81 (d, 1H), around 4.85 (m, 1H), 2,75 (d, 2H), 2.63 in (s, 3H), of 1.35 (s, 9H).

d) Ethyl ester (4R)-(N'-methyl-N'-tert-butyloxycarbonyl)-4-(4-chlorbenzyl)but-2-ene acid

To a solution of 2.37 g teeterboro ether phosphonooxy acid in 40 ml of absolute acetonitrile is added at room temperature 0,453 g of dried LiCl and of 1.46 g of DBU. Then it added dropwise a solution of 2.86 g of (R)-N'-methyl-N'-tert-butyloxycarbonyl-(4-chlorophenyl) alanines (10 ml acetonitrile). After completion of adding dropwise, the mixture is stirred at RT for 2 h Then the reaction mixture was poured onto water and extracted twice, using each time with 100 ml of diethyl ether. The combined organic phases are washed three times with water and once with saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation. The residue is purified via chromatography (silica gel, hexane/ethyl acetate in a ratio of 3/1). The result is indicated in the title compound in the form of a colorless oil.1H-NMR, 200 MHz, CDCl3d (part./million): 7,35-7,05 (m, 4H), 6.90 to (dd, 1H), to 5.85 (d, 1H), 5,15 (m, 0.5 H), the 4.90 (m, 0.5 H), to 4.17 (q, 2H), 2,90 (m, 2H),95 g of methyl ester of (R)-N'-methyl-N'-tert-butyloxycarbonyl-(4-chlorophenyl)alanine in 75 ml of toluene is cooled to -78oC in argon atmosphere. At this temperature, to it is slowly added dropwise 17 ml of 1 M solution of DIBAH in toluene). After completion of adding dropwise, the mixture is stirred at this temperature for 2 hours Then added to the mixture of 2 ml of methanol and 50 ml (18 g) of an aqueous solution of tartrate of sodium/potassium. The mixture is intensively stirred for 2 h at 0oC. Then divide phase and the aqueous phase is extracted again with diethyl ether. The combined organic phases are washed with water and saturated NaCl solution, dried (sodium sulfate) and concentrated by evaporation. The residue is subjected to further interaction without additional purification (colorless oil).1H-NMR, 200 MHz, D13d (frequent. /million): 7,30-7,05 (m, 4H), 4,16 (m, 0.5 H), 3,93 (m, 0.5 H) at 3.25 (dd, 2H), 2,90 (m, 1H), 2,70, and 2,62 (2s, 3H), 1,40 (2s, 9H).

e) Methyl ester of (R)-N'-methyl-N'-tert-butyloxycarbonyl-(4-chlorophenyl)alanine

To a solution of 3.1 g of methyl ester of (R)-tert-butyloxycarbonyl-(4-chlorophenyl)alanine in 45 ml of N,N-dimethylformamide added under stirring 9.5 g of silver oxide(I). Then add 23 g methyliodide and 1 ml of acetic acid (absolute). The reaction mixture was stirred at RT for 72 h, then diluted with 150 ml of diethyl ether, filtered and concentrate rezultate get mentioned in the title compound in the form of a colorless oil.1H-NMR: of 7.25 (d, 2H), 7,11 (d, 2H), 4,90 (bs, 0.5 H), 4,47 (bs, 0.5 H), and 3.72 (s, 3H), of 3.25 (m, 1H), 3,00 (dd, 1H), 2,70 (s, 3H), of 1.35 (s, 9H).

f) Methyl ester of (R)-tert-butyloxycarbonyl-(4-chlorophenyl)alanine

To a suspension of 2.5 g of methyl ester of D-4-chlorophenylalanine (for example, company Bachem) in 40 ml of absolute THF add 4 ml of tert-butanol, 2,12 g of BOC-anhydride and 2.57 g of diisopropylethylamine. After stirring for 4 h at room temperature the reaction mixture was poured onto a mixture of ice/Hcl 0.1 N. and extracted twice with diethyl ether. The combined organic phases are washed with water (three times) and saturated NaCl solution, dried (MgSO4) and concentrated by evaporation, getting an oil, which crystallizes upon maturation. Rf=0,19 (hexane:ethyl acetate =5:1).

Getting D-3-amino-caprolactam

A solution of 12.8 g of D,L-3-amino-caprolactam in 200 ml of absolute ethanol is mixed with a solution of 12.9 g of D-pyroglutamic acid (200 ml absolute ethanol) and allowed to stand at room temperature for 20 hours the Resulting crystals filtered off and dissolved at approximately 65-70oWith in a mixture of ethanol:water (in the ratio 9:1), cooled to room temperature and again allowed to stand for 20 hours Formed Krista is their free base 1 N. solution MN3) get mentioned in the title compound in the form of a free amine. Colorless crystals, []D20=+41o(=2,2, water).

Working similarly to the method described in example 12, but using in stage 12B) corresponding amines (instead of D-3-amino-caprolactam), also receive the following connections:

Example 13: N-[(S) - caprolactam-3-yl]amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino] -4- (4-chlorbenzyl)but-2-ene acid

Rf=0,12 (ethyl acetate). Is obtained using L-3-amino-caprolactam (marketed, for example, Fluca 07257). Rt=35,2 minutes (Chiracel-OD, 0,h cm, detection at 210 nm, hexane:isopropanol in a ratio of 80: 20+0.1% of TFA, flow rate 1.0 ml/min 30 bar).

Example 14: N-cyclohexylamine (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-4-(4-chlorbenzyl)but-2-ene acid with tPL183-185oC.

Get using cyclohexanamine. Rt=10,5 minutes (Chiracel-AC, 0,h cm, detection at 210 nm, hexane:isopropyl alcohol in the ratio of 97: 3+0,1% TFA, flow rate 1.0 ml/min, 20 bar). []d20=+60,4o4,4o(C= 0,227, EtOH).

Working similarly to the method described in examples 12 and 14, using as initial products R> Example 14A: N-cyclohexylamine (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-4-(3,4-dichlorobenzyl)but-2-ene acid

Rf=0,24 (hexane:ethyl acetate in the ratio 1:1).

Example 14B: N-cyclohexylamine (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-4-(3,4-diferensial)but-2-ene acid

Rf=0,28 (hexane:ethyl acetate in the ratio 1:1).

Example 15: N-cyclohexylamine (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-5-(4-chlorophenyl)-2-methylpent-2-ene acid

Specified in the header of the connection get working strictly according to the method described in example 14 (example 12, respectively), but using on stage 12g) triethyl-2-phosphonopropionic instead teeterboro ether phosphonooxy acid. Specified in the title compound is obtained in the form of colorless amorphous solid. Rf=0,32 (hexane:ethyl acetate in the ratio 1:1).

Working similarly to the method described in example 15, it is also possible to obtain the following connections:

Example 16: N-[(R) - caprolactam-3-yl]amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-5-(4-chlorophenyl)-2-methylpent-2-ene acid

Rf=0,14 (ethyl acetate). Get with the use of D-3-amino-caprolactam. Rt= 6,24 minutes (Chiracel AD, 0,h cm ,7o4,4o(C=0,225, EtOH).

Example 17: N-[(S) - caprolactam-3-yl]amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-4-(4-Chlorobenzyl)-2-methylbut-2-ene acid

Rf=0,14 (ethyl acetate). Is obtained using L-3-amino-caprolactam.

Example 18: N-[(S) - caprolactam-3-yl] amide (4R)-[N'-ethyl-N'-(3,5-bistrifluormethylbenzene)amino]-5-(4-chlorophenyl)Penta-2-ene acid

Specified in the header connection receive, using as the source of the product methyl ester (R)-N-ethyl-N-tert-butyloxycarbonyl-(4-chlorophenyl)alanine and working strictly according to the method described in example 12 (using L-3-amino-caprolactam). Rf=0,18 (ethyl acetate).

The original product, methyl ester (R)-N-ethyl-N-tert-butyloxycarbonyl-(4-chlorophenyl)alanine can be obtained in the following way.

To a solution of 1.4 g of methyl ester of N-tert-butyloxycarbonyl-(4-chlorophenyl)alanine in 25 ml DMF added by portions at 0oC in an atmosphere of argon 118 mg of sodium hydride (net). The mixture was stirred at 0oC for 30 min and at RT for 30 min Then added 1.07 g of ethylbromide and the reaction mixture is stirred at 50oC for 16 h Then the reaction mixture was poured onto 200 ml of water and the aqueous phase was EXT orida sodium, dried (MgSO4) and concentrated by evaporation. The residue is subjected to chromatography (hexane/ethyl acetate in the ratio of 5/1). The result is indicated in the title compound in the form of a colorless oil.

Example 19: N-cyclohexylamine (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-5-(4-chlorophenyl)-3-methylpent-2-ene acid

Specified in the header of the connection get working strictly according to the method described in example 12, but using tert-butyl ether (R)-[1-(4-Chlorobenzyl)-2-oxopropyl] carbamino acid instead of methyl ester of (R)-tert-butyloxycarbonyl-(4-chlorophenyl)alanines. Rf= 0,41 (hexane:ethyl acetate in the ratio 1:1).

The original product, tert-butyl ester (R)-[1-(4-Chlorobenzyl)-2-oxopropyl]carbamino acid, can be obtained in the following way.

To a solution of 0.45 ml of oxalicacid (10 ml methylene chloride) at -60oC for 5 min in an atmosphere of argon is added dropwise a solution of 0.77 ml DMSO (2.5 ml of methylene chloride and the mixture is then stirred for 15 minutes Then at -60oTo the mixture are added dropwise a solution of 1.4 g of tert-butyl methyl ether (R)-[1-(4-Chlorobenzyl)-2-hydroxypropyl] carbamino acid (4 ml of methylene chloride). The reaction mixture per the round, add 25 ml of water. Separate the organic phase and the aqueous phase is extracted twice more with methylene chloride. The combined organic phases are washed with water and saturated sodium chloride solution, dried (MgS4) and concentrated by evaporation. The residue is subjected to rapid chromatography (toluene/methylene chloride/ethyl acetate in the ratio 4/4/2). The result is indicated in the title compound in the form of a colorless oil.

tert-Butyl ether (R)-[1-(4-Chlorobenzyl)-2-hydroxypropyl]carbamino acid

To a solution of 1.19 g (R)-N'-methyl-N'-tert-butyloxycarbonyl-(4-chlorophenyl)alanines in 25 ml of THF is added dropwise a solution of Grignard reagent (obtained from 0,64 ml methyliodide and 0,244 g of magnesium turnings in 20 ml of diethyl ether and then stirred for 30 minutes and Then the reaction mixture was poured onto 100 ml of water and extracted twice with diethyl ether. The combined organic phases are washed with water and saturated sodium chloride solution, dried (MgSO4) and concentrated by evaporation. The residue is subjected to rapid chromatography (hexane/ethyl acetate in a ratio of 1/1). The result is indicated in the title compound in the form of a colorless oil.

Working similarly to the method described in example 19, but use the 20: [(R) - caprolactam-3-yl] amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-4-(4-Chlorobenzyl)-3-methylbut-2-ene acid

Is obtained using L-3-amino-caprolactam. Rf=0,16 (ethyl acetate).

Example 21: N-[(R) - caprolactam-3-yl]amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino] -4-(4-chlorbenzyl)but-2-ene acid (another way of obtaining compounds of example 12)

Specified in the title compound can also be obtained using as starting product is racemic methyl ester of 4-chlorophenylalanine (instead of the methyl ester of D-4-chlorophenylalanine). Racemic methyl ester of 4-chlorophenylalanine subjected to interaction according to the method described in example 12. At the stage b) use of D-3-amino-caprolactam by the method described in 12B). Then at the final stage the resulting mixture diastereoisomers separated using chromatography on silica gel (ethyl acetate). The result in pure form N-[(R) - caprolactam-3-yl] amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino] -4-(4-chlorbenzyl)but-2-ene acid [Rf= 0,12, ethyl acetate, Rt= 20,38 min (Chiracel-OJ, 0,h cm, detection at 210 nm, hexane:ethanol in a ratio of 90: 10+0.1% of TFA, flow rate 1.0 ml/min 30 bar)] and N-[(R) - caprolactam-3-yl] amide of (4S)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino]-4-(4-chlorbenzyl)but-2-ene acid [Rf=0,09, Etihad flow 1.0 ml/min, 30 bar)].

Example 22: Working similarly to the method of obtaining the compounds described in example 21, it is also possible to obtain N-4-[(R) - caprolactam-3-yl]amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino] -4-(3,4-dichlorobenzyl)but-2-ene acid

Specified in the header of the connection can be obtained using as starting product is racemic methyl ester of 3,4-dichlorophenylamino. Racemic methyl ester of 3,4-dichlorophenylamino subjected to interaction according to the method described in example 12 [g)]. At the stage b) use of D-3-amino-caprolactam in accordance with the method described in 12B). Then at the final stage the resulting mixture diastereoisomers separated using chromatography on silica gel (ethyl acetate). The result in pure form N-[(R) - caprolactam-3-yl]amide (4R)-4-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino] -4-(3,4-dichlorobenzyl)but-2-ene acid [Rf=0,12, ethyl acetate, tPL115-120oC []D20=+39,4o(C=0,97, ethanol and N-[(R) - caprolactam-3-yl] amide of (4S)-4-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino] -4-(3,4-dichlorobenzyl)but-2-ene acid [Rf=0,09, ethyl acetate).

Working similarly to the method described in examples 21 and 22, but using CC the following connections:

Example 22: N-[(R) - caprolactam-3-yl] amide (4R)- and (4S)-4-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino] -4-(3-fluoro-4-chlorbenzyl)but-2-ene acid: 1st diastereoisomer: Rf=0,24 (ethyl acetate) and 2nd diastereoisomer: Rf=0,28 (ethyl acetate).

Example 22B: N-[(R) - caprolactam-3-yl] amide (4R)- and (4S)-4-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino] -4-(3,4-diferensial)but-2-ene acid: 1st diastereoisomer: Rf=0,4 (ethyl acetate:acetone in the ratio 1:1) and 2nd diastereoisomer: Rf=0,34 (ethyl acetate:acetone in the ratio 1:1).

Example 22B: N-[(R) - caprolactam-3-yl] amide (4R)- and (4S)-4-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino] -4-(3,4-dibromobenzyl)v-2-ene acid: 1st diastereoisomer: Rf=0,17 (ethyl acetate) and 2nd diastereoisomer: Rf=0,11 (ethyl acetate).

Example 22G: N-[(R) - caprolactam-3-yl] amide (4R)- and (4S)-4-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino] -4-(3,4,5-triptorelin)but-2-ene acid: 1st diastereoisomer: Rf=0,11 (ethyl acetate) and 2nd diastereoisomer: Rf=0,076 (ethyl acetate).

Example D: N-[(R) - caprolactam-3-yl] amide (4R)- and (4S)-4-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino] -4-(4-terbisil)but-2-ene acid: 1st diastereoisomer:f= 0,175 (ethyl acetate) and 2nd diastereoisomer: Rf=0,14 (ethyl acetate).

Primality [expected what compound is (4R)-derived]

To a suspension of 207 mg (0.40 mmole) of (4R)- or (4S)-[N-(3,5-bistrifluormethylbenzene)-N-methylamino] -5,5-diphenylene-2-ene acid in 5 ml of methylene chloride successively added 58 mg (0,47 mmole) of 4-dimethylaminopyridine (DMAP), 85 mg (of 0.44 mmole) of the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (l) and 58 mg (of 0.44 mmole) of (S)-3-aminohexyl-2-azapirone. After stirring at room temperature for 16 h the mixture is concentrated by evaporation and the residue is subjected to chromatography on silica gel using a mixture of methylene chloride/methanol (95:5). Specified in the title compound is obtained in the form of a cream solid color. TLC: methylene chloride/methanol (ratio 95:5) Rf= 0,32; ESI(+)-MC (M+H)+=632; []D20=+41,9o(C=1, methanol).

The original product is obtained in the following way:

a) Methyl ester of 2-(N-tert-butoxycarbonyl-N-methylamino)-3,3-diphenylpropanoic acid

To a solution of 34.2 g (of 0.10 mole) of 2-tert-butoxycarbonylamino-3,3-diphenylpropanoic acid, J. Med. Chem. 35, 3364, 1992) in 250 ml of N,N-dimethylformamide successively added in one portion 121,9 g (0.52 mole) of silver oxide(I) dropwise and 26 ml (0,41 mole) of methyliodide within 20 minutes After PE is omashu filter type Hyflo and then washed with ethyl acetate. The organic phase is concentrated by evaporation at first using a rotary evaporator and then under high vacuum. The residue is dissolved in ethyl acetate, washed three times with water and once with brine, dried over sodium sulfate and concentrated by evaporation. Specified in the title compound is obtained in the form of a solid beige color. TLC: methylene chloride/methanol (ratio 95:5) Rf=0,28; FAB-MS (M+H)+=370.

b) tert-Butyl methyl ether (1-hydroxymethyl-2,2-diphenylether)methylcarbamate acid

To a solution of 32.0 g (86,6 mmole) of the methyl ester of 2-(N-tert-butoxycarbonyl-N-methylamino)-3,3-diphenylpropanoic acid in 400 ml of simple ether successively added in several portions of 3.0 g (130,0 mmol) of lithium borohydride and dropwise with 5.3 ml (130 mmol) of methanol (foaming!). The reaction mixture was stirred at the temperature of reflux distilled for 3 h, then cooled in an ice bath and add 40 ml of 0.5 N. hydrochloric acid (foaming! ). After further dilution with water the mixture is extracted twice with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated by evaporation, getting mentioned in the title compound in the form of a white foam. Diformyl-2,2-diphenylether)methylcarbamate acid:

To a solution of 14.5 g (42.5 mmole) of tert-butyl methyl ether (1-hydroxymethyl-2,2-diphenylether)methylcarbamate acid in 80 ml of dimethyl sulfoxide successively added to 17.8 ml (127 mmol) of triethylamine and a solution of 22.8 g (127 mmol) of a complex of a sulfur trioxide-pyridine in 100 ml of dimethyl sulfoxide. After 45 min the reaction mixture was poured onto a mixture of ice-water and completely extracted with simple ether. The combined organic phases are washed twice in 1 M potassium bisulfate, twice with water and once 1 M sodium bicarbonate, dried over sodium sulfate and concentrated by evaporation, getting mentioned in the title compound in the form of a yellow oil. TLC: methylene chloride/methanol (ratio 95:5) Rf=0,88.

d) Ethyl ester of 4-(N-tert-butoxycarbonyl-N-methylamino)-5,5-diphenylene-2-ene acid:

To a solution of 3.7 g (84 mmole) 55-65% dispersion of sodium hydride (washed three times with pentane) in 130 ml of tetrahydrofuran added at 0oTo a solution of 14 ml (68 mmol) teeterboro ether phosphonooxy acid in 130 ml of tetrahydrofuran. After 1 h the mixture added dropwise a solution of 13.6 g (40 mmol) of tert-butyl methyl ether (1-formyl-2,2-diphenylether)methylcarbamate acid in 130 ml of tetrahydrofuran. After 4 h the reaction mixture it is an ode, dried over magnesium sulfate and concentrated by evaporation. The remainder chromatographic on silica gel using a mixture of methylene chloride/methanol (99: 1-98:2). Specified in the title compound is obtained in the form of a yellow oil. TLC: methylene chloride/methanol (in the ratio 98:2) Rf=0,45.

d) Ethyl ester of 4-methylamino-5,5-diphenylene-2-ene acid:

To a solution of 14.2 g (to 34.7 mmole) ethyl ester of 4-(tert-butoxycarbonylmethylene)-5,5-diphenylene-2-ene acid in 100 ml of methylene chloride are added dropwise 22 ml (0,28 mol) triperoxonane acid. After 5 h the reaction mixture is concentrated by evaporation and then double-add toluene and the mixture is concentrated by evaporation. The residue is dissolved in methylene chloride, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and again concentrated by evaporation. Specified in the title compound is obtained in the form of a yellow oil. TLC: methylene chloride/methanol (ratio 95:5) Rf=0,26.

e) Ethyl ester of 4-[N-(3,5-bistrifluormethylbenzene)-N-methylamino]-5,5-diphenylene-2-ene acid:

To a solution of 6.7 ml (36.0 mmol) of 3,5-bistrifluormethylbenzene in 110 ml of methylene chloride through the cannula was added at 0oThis add 5.8 ml (41,1 mmole) of triethylamine and 0.4 g (3.4 mmole) of 4-dimethylaminopyridine. After 1 h the reaction mixture was diluted with ethyl acetate and washed twice with water and once with brine. The aqueous phase is once again extracted with ethyl acetate. Then the combined organic phases are dried over magnesium sulfate and concentrated by evaporation. The remainder chromatographic on silica gel using a mixture of methylene chloride/methanol (in a ratio of from 100:0 to 98:2). Specified in the title compound is obtained in the form of foam a light yellow color. TLC: methylene chloride/methanol (in the ratio 98:2) Rf=0,38; FAB-MS (M+N)+=550.

W) Ethyl ester (4R)- and (4S)-[N-(3,5-bistrifluormethylbenzene)-N-methylamino]-5,5-diphenylene-2-ene acid

of 4.38 g (7.95 mmole) ethyl ester 4-[N-(3,5-bistrifluormethylbenzene)-N-methylamino] -5,5-diphenylene-2-ene acid is subjected to chromatography on a preparative column type ChiracelOD using a mixture of hexane/isopropanol (99: 1). Divided specified in the title compound is obtained in the form of foam a light yellow color. GHUR (ChiracelOD g,6 mm): hexane/isopropanol (ratio 980: 20) Rt(enantiomer 1)= 5,28 min, Rt(enantiomer 2)=EUR 7.57 min

C) (4R)- and (4S)-[N-(3,5-bistrifluormethylbenzene)-N-methylamino]-5,5-diphenylene-2-ANOVA sour is nipent-2-ene acid (enantiomer 2) in 30 ml of a mixture of tetrahydrofuran/methanol (2:1 ratio) type of 6.7 ml of 1 N. of sodium hydroxide. After 4 h the reaction mixture is concentrated by evaporation, diluted with water and acidified with cold 2 N. hydrochloric acid. The precipitated white filtered off, washed with water and dried in high vacuum at 60oC. Specified in the title compound is obtained in the form of a solid white color. TLC: methylene chloride/methanol (ratio 95:5) Rf=0,22; ESI(-)-MC (M-H)=520; []D20=+38,5o(C=1, methanol).

In a similar way [using as the source of the product (4S)- or (4R)-[N-(3,5-bistrifluormethylbenzene)-N-methylamino] -5,5-diphenylene-2-envoy acid obtained from enantiomer 1 of example I)] can be obtained N-[(S) - caprolactam-3-yl] amide of (4S)- or (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino] -5,5-diphenylene-2-ene acid [it is assumed that the compound is (4S)-derivative]; TLC: methylene chloride/methanol (ratio 95:5) Rf=0,36; ESI(+)-MC (M+H)+=632; []D20=-31,2o(C=1, methanol).

Examples a-D: a Pharmaceutical composition

Example: Tablets, each containing 50 mg of active substance:

Ingredients (for 10,000 tablets)

active substance - 500.0 g

lactose - 500.0 g

potato starch - 352,0 g

gelatin - 8 q.s.

The active substance is mixed with the lactose and 292 g of potato starch, the mixture is moistened ethanol solution of gelatin and granularit through a sieve. After drying, the product is mixed with the remainder of the potato starch, the magnesium stearate, talc and silicon dioxide and the mixture is pressed to form tablets, each of which has a mass of 145 mg and containing 50 mg of active substance; if necessary, the tablets can be provided with dividing grooves for a more subtle dose selection.

Example B: the Tablets are film-coated, each of which contains 100 mg of active ingredient:

Composition (per 1000 film-coated tablets)

active substance - 100.0 g

lactose - 100.0 g

corn starch - 70,0

talc - 8.5 g

calcium stearate 1.5 g

the hypromellose - 2,36 g

shellac - 0.64 g

water - q.s.

dichloromethane - q.s.

The active ingredient, the lactose and 40 g of corn starch are mixed together and the mixture is moistened paste obtained from 15 g of corn starch and water (with heating), and granularit. The granules are dried and mixed with granules remaining portion of the corn starch, the talc and calcium stearate. The mixture is pressed, forming the SHL and shellac in dichloromethane (final weight of each tablet film-coating: 283 mg).

Example: Gelatin capsules with solid floor, each containing 100 mg of active ingredient:

Composition (for 1000 capsules)

active substance - 100.0 g

lactose - 250,0 g

microcrystalline cellulose - 30,0 g

sodium dodecyl sulfate - 2.0 grams

magnesium stearate - 8.0 g

To liofilizirovannom current substance add sodium lauryl sulfate, sifting through a sieve with a pore size of 0.2 mm. Two components are mixed until odnorodnosti. Then first add lactose, sifting through a sieve with cell size of 0.6 mm, and after that add microcrystalline cellulose, sifting through a sieve with a pore size of 0.9 mm, Then all four components are mixed until homogeneity within 10 minutes At the end add magnesium stearate, sifting through a sieve with cell size of 0.8 mm After additional stirring (3 min) portions of 390 mg of the obtained composition contribute in gelatine capsules of size 0.

Example G: Solution for injection or infusion contains 5 mg of active ingredient per vial has a volume of 2.5 ml:

Composition (for 1000 capsules)

active substance - 5.0 g

sodium chloride - 22,5 g

a solution of phosphate buffer (pH 7.4) - 300,0 g

demineralized water up to 2500,a microfilter. To the filtrate is added a solution of phosphate buffer and the volume of the mixture was adjusted to 2500 ml with demineralized water. To obtain a standard dosage forms portions of the mixture by volume of 2.5 ml is introduced into glass ampoules, resulting in each of them contains 5 mg of active substance.

Example D: Suspension for inhalation, including propellant, and forming a solid aerosol particles with a content of active substance 0.1 wt.%:

The composition of

the active ingredient, chopped - 0,1

trioleate sorbitan - 0,5

propellant And (trichlorotrifluoroethane) - 4,4

propellant B (DICHLORODIFLUOROMETHANE and 1,2-dichlorotetrafluoroethane) - 80,0

In the absence of moisture, the active substance is suspended in trichlorotrifluoroethane with the addition of trioleate sorbitan using conventional homogenizer and suspension make in an aerosol container fitted with a measuring valve. The container is closed and is filled under pressure by a propellant B.

1. Acylaminocinnamic derivatives of the formula I

< / BR>
where R denotes phenyl which is not substituted or is substituted by 1, 2 or 3 substituents selected from the group comprising halogen, (NISS. )alkyl, trifluoromethyl, hydroxy and (NISS. )alkoxygroup, which is not substituted or is substituted by 1, 2 or 3 substituents selected from the group comprising halogen, (NISS. )alkyl, trifluoromethyl, hydroxy and (NISS. )alkoxygroup;

R3denotes phenyl which is not substituted or is substituted by 1, 2 or 3 substituents selected from the group comprising halogen, (NISS. )alkyl, trifluoromethyl, hydroxy and (NISS. )alkoxygroup, or represents naphthyl, lH-indol-3-yl or 1-(NISS. )alkalinty-3-yl;

R4' and R4" each independently of one another denotes hydrogen or (NISS. )alkyl, and at least one of the radicals R4' and R4" represents hydrogen;

R5stands WITH3-C8cycloalkyl, D-azacycloheptan-2-he-3-yl or L-azacycloheptan-2-he-3-Il,

or its salt.

2. The compound of formula I under item 1, where R denotes phenyl, 3,5-bistrifluormethylbenzene or 3,4,5-trimethoxyphenyl, R1denotes hydrogen or (NISS. )alkyl, R2denotes hydrogen or phenyl, R3denotes phenyl, haloethanol, dialogpanel, trihalomethanes, 2-naphthyl, 1H-indol-3-yl or 1-(NISS. )alkalinty-3-yl, R4' and R4" each independently of one another denotes hydrogen or (NISS. )alkyl, and at least one of the radicals R4' and R4" denotes hydrogen, and what about the salt.

3. The compound of formula I under item 1, where R denotes phenyl, 3,5-bistrifluormethylbenzene or 3,4,5-trimethoxyphenyl, R1denotes hydrogen or (NISS. )alkyl, R2denotes hydrogen or phenyl, R3denotes phenyl, haloethanol, dialogpanel, 2-naphthyl, 1H-indol-3-yl or 1-(NISS. )alkalinty-3-yl, R4' and R4" each independently of one another denotes hydrogen or (NISS. )alkyl, and at least one of the radicals R4' and R4" represents hydrogen, and R5stands WITH5-C7cycloalkyl, D-azacycloheptan-2-he-3-yl or L-azacycloheptan-2-he-3-yl, or its salt.

4. The compound of formula I under item 1, where R is 3,5-bistrifluormethylbenzene, R1denotes hydrogen, methyl or ethyl, R2denotes hydrogen or phenyl, R3denotes phenyl, 4-chlorophenyl, 4-forfinal, 3,4-dichlorophenyl, 3,4-differenl, 3-fluoro-4-chlorophenyl, 3,4,5-tryptophanyl, 2-naphthyl, 1H-indol-3-yl or 1-methylindol-3-yl, R4' and R4" each independently of one another denotes hydrogen or methyl, and at least one of the radicals R4' and R4" represents hydrogen, and R5denotes cyclohexyl, D-azacycloheptan-2-he-3-yl or L-azacycloheptan-2-he-3-yl, or its pharmaceutically acceptable salt.

2denotes hydrogen or phenyl, R3denotes phenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-naphthyl, 1H-indol-3-yl or 1-methylindol-3-yl, R4' and R4" each independently of one another denotes hydrogen or methyl, and at least one of the radicals R4' and R4" represents hydrogen, and R5denotes cyclohexyl, D-azacycloheptan-2-he-3-yl or L-azacycloheptan-2-he-3-yl, or its pharmaceutically acceptable salt.

6. The compound of formula I under item 1, where R is 3,5-bistrifluormethylbenzene, R1denotes hydrogen or methyl, R2denotes hydrogen or phenyl, R3denotes phenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-naphthyl, 1H-indol-3-yl or 1-methylindol-3-yl, R4' and R4" represent hydrogen and R5denotes cyclohexyl, D-azacycloheptan-2-he-3-yl or L-azacycloheptan-2-he-3-yl, or its pharmaceutically acceptable salt.

7. Connection on p. 1, representing N-[(R) - caprolactam-3-yl] amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino] -5-(1-methylindol-3-yl)Penta-2-ene acid.

8. Connection on p. 1, representing N-[(S) - caprolactam-3-yl] amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino] -5-(1-methylindol-3-yl)Penta-2-ene acid.

9. With the on] -4-(4-chlorbenzyl)but-2-ene acid.

10. Connection on p. 1, representing N-[(R) - caprolactam-3-yl] amide (4R)-[N'-methyl-N'-(3,5-bistrifluormethylbenzene)amino] -4-(3,4-dichlorobenzyl)but-2-ene.

11. The compound according to any one of paragraphs. 1-10 intended for use in the treatment of diseases that are affected by the antagonism against NK1 receptor and/or N2-receptor.

12. Pharmaceutical composition having antagonistic activity against NK1 and N2 receptors and containing active substance and at least one pharmaceutically acceptable carrier, characterized in that the active substance it contains a compound according to any one of paragraphs. 1-10.

13. The method of obtaining acylaminoalkyl derivatives of the formula I on p. 1, including N-acylation of compounds of formula II

< / BR>
carboxylic acid R-C(= O)-OH or its reactive derivative, and, if necessary, conversion of the resulting free compounds of formula I, having the ability to form salt, salt, and/or transformation of the resulting salt into the free compound or a different salt, and/or, if necessary, separation of the resulting mixture of stereoisomers, diastereoisomers or enantiomers on the CTD is innych derivatives of formulas I through p. 1, including the condensation of the carboxylic acid of the formula III

< / BR>
or its reactive derivative with C3-C8cycloalkylation or D(+)- or L(-)-3-amino-caprolactam, and, if necessary, conversion of the resulting free compounds of formula I, having the ability to form salt, salt, and/or transformation of the resulting salt into the free compound or a different salt, and/or, if necessary, separation of the resulting mixture of stereoisomers, diastereoisomers or on a separate enantiomers stereoisomers, diastereoisomers or enantiomers.

 

Same patents:

The invention relates to an improved process for the preparation of 8-methyl-8-azabicyclo[3,2,1]Oct-3-silt ester of indole-3-carboxylic acid hydrochloride which is a substance tropisetrona and is used as an antiemetic, effective for vomiting caused by anticancer chemotherapy drugs

The invention relates to N-(N'-substituted glycyl)-2-cyanopyrrolidine formula I, where R denotes: a)1R1aN (CH2)m-, where R1means pyridinoline or pyrimidinyl fragment, optional one - or disubstituted independently of one another by halogen, trifluoromethyl, cyano - or nitro-group; R1adenotes hydrogen or C1-C8alkyl, m is equal to 2,3, b)3-C12cycloalkyl, optional one-deputizing in position 1 WITH1-C3hydroxyalkyl,) R2(CH2)n- where either R2denotes phenyl, optional one-, two - or tizamidine selected independently of each1-C4alkoxygroup, halogen or phenylthiourea, optional one-deputizing in the phenyl ring with hydroxymethyl; or denotes a C1-C8alkyl, [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8the alkyl, pyridinoline or nattily fragment, or cyclohexenyl, or substituted and n is 1-3, or R2denotes fenoxaprop; and n is 2; d) (R3)2CH(CH2)2-, where each R3independently represents phenyl; d) R4(CH2)p-, where R4ebony in position 1 WITH1-C3hydroxyalkyl, W) R5that means indanyl piperidinyl fragment, optionally substituted benzyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8by alkyl, substituted or1-C8alkyl, optionally one or mnogozalny independently from each other hydroxy-group, hydroxymethyl or phenyl, optional one - or disubstituted independently selected from each other WITH1-C4the alkyl, C1-C4alkoxygroup or halogen, in free form or in the form of an acid additive salt

The invention relates to 4-(allumination)-2,4-dihydropyrazol-3-Onam General formula I, where R1denotes benzyl, alkoxybenzyl with 1-3 C-atoms in the alkyl part, unsubstituted or substituted once to three - fold amino, acyl, halogen, nitro, CN, AO, carboxyla, carbamoyl, N-allylcarbamate, N, N-dialkylammonium (with 1-6 C-atoms in the alkyl part), A-CO-NH-, AND-O-CO-NH-, AND-O-CO -, NA-, SO2NR4R5(R4and R5can denote H or alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, or O, which may be substituted),-CO-NH-SO2-, A-CO-NA-SO2- (AND-SO2-)2N-, tetrazolium phenyl; or pyridyl; R2denotes alkyl with 1-5 C-atoms, ethoxycarbonylmethyl, hydroxycarbonylmethyl; R3denotes unbranched or branched alkyl with 1-5 C-atoms, unbranched or branched alkoxy with 1-5 C-atoms or CF3And denotes unbranched or branched alkyl with 1-6 C-atoms or CF3and their salts

The invention relates to new compounds of the formula (I) or their salts, where X, Y independently is hydrogen, halogen; Z is oxygen; Q is chosen among the Q1-Q9described in the claims and containing heterocycles with nitrogen, and sulfur; Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl, or pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl substituted with up to five substituents, when Q - Q3or Q6substituted phenyl is excluded

The invention relates to new derivatives of carboxylic acids of General formula I containing heterocyclic ring

The invention relates to new 1-(biphenyl-4-yl)methyl-1H-1, 2,4-triazole compounds and 1-(biphenyl-4-yl)methyl-4H-1,2,4-triazole compounds, and each of them has as a substituent in the 2'-position (2,4-dioxopyrimidine-5-ilidene)methyl or (2,4-dioxotetrahydrofuran-5-ilidene)methyl, and their salts

The invention relates to new bicyclic to carboxamide formula (i) in which (1) X represents N and (a) Z is =CR1-CR2and Y is N, Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= and Y represents CR2or (2), X represents NR4Z represents CR1= and Y is N, Q is O, R1and R2are СОR6, C(= NOR6R13, alkyl-C(=NOR6R13, NR8R9, CF3or R6, R3is1-6alkoxygroup, R4represents H or alkyl, R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted with halogen; R6represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci, R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12, R8and R9represent H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14, R10represents an alkyl, heterocycle, R11and R12represent H or alkyl, and the salts

The invention relates to a method for producing compounds of formula (I) consists in the fact that the compound of formula (IX):

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in which R1' has the abovementioned meaning and M represents a hydrogen atom or the radical R2' which has the values specified above for R2in which the possible reactive functions can be protected by a protective group, is subjected to reaction with the compound of the formula (VIII) defined above, to obtain a product of formula (X):

< / BR>
in which R1' M and R4' have the above values, the obtained compound of formula (X), if M implies R2' defined above, is subjected to a halogenation reaction, to obtain the product of formula (XI):

< / BR>
in which R1', R2', R4' and Hal have the above values, which is subjected to the reaction of the exchange of the halogen-metal, then the reaction with the compound of the formula (XII):

< / BR>
in which R9' matter referred to in paragraph 1 for R9where possible reaction ф�g/rupat4/200110/01/2174513-36t.gif" ALIGN="ABSMIDDLE">< / BR>
in which R1', R2', R4' and R9' have the above meanings and, if necessary, or interact product of formula (I2) with the compound of the formula (XV):

O=C=N-R6' (XV)

in which R6' matter referred to in paragraph 1 for R6in which the possible reactive functions can be protected by a protective group, to obtain a product of formula (I3):

< / BR>
in which R1', R2', R4', R6' and R9' have the above meanings, or the product of formula (I2) is subjected to a saponification reaction with the product of formula (I4):

< / BR>
in which R1', R2', R4' and R9' have the above meanings, is subjected to reaction with COCl2to obtain a product of formula (I5):

< / BR>
in which R1', R2', R4' and R9' have the above meanings, or the product of formula (X), provided that M denotes a hydrogen atom, is subjected to a halogenation reaction to obtain a product of formula (XIV):

< / BR>
in which R1', R4'Hal and R3" have the above values, the compound obtained is subjected to the reaction of the exchange of the halogen-metal, then the processing of the compound of formula (IVa') (IVb'), (IVc'), (IVd') or (IVe') defined above, to obtain a product of formula (I7):

< / BR>
in which R1', R4', R2and R3" have the above meanings; then the above products of formula I2, I3, I4, I5, I6, I7that are a product of the formula I, allocate or subjected, if necessary, one or more reactions of transformation to other products of the formula I, in any order:

a) esterification of the acid function,

(b) saponification functions of ester to acid functions,

C) transforming functions of ester function acyl,

d) transforming Sinopoli in an acid function,

e) conversion of the acid function to an alcohol function,

g) transforming functions alkoxy function hydroxyl or hydroxyl function in the function alkoxy,

h) oxidation of the alcohol function to the aldehyde, acid or keto-function

i) the conversion of the formyl radical in the radical carbarnoyl,

j) turning radical carbarnoyl in the nitrile radical,

k) converting the nitrile radical in tetrazolyl,

l) oxidation of ancilliary or aristocraty to the corresponding sulfoxide or sulfone,

m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,

n) the transformation function oxo function of thioxo,

a) transforming radical

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in radical

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p) conversion of the acid function in function

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q) is the transformation function of beta-keto-sulfoxide in the function of alpha-ketotioefir,

r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

s) removal of protective groups, which can protect the reaction functions,

t) salt formation using mineral or organic cisisomer, enantiomers and diastereoisomers

The invention relates to the production of aliphatic lactams from dinitriles
The invention relates to the production of caprolactam, which is used to produce polymeric products

The invention relates to the production of aliphatic lactams, in particular E-caprolactam used in the production of polyamides

The invention relates to the production of modified layered silicates and can be used in the manufacture of paints, coating of enamel, plaster, household paints, ceramic industry for obtaining anhydrous molding compounds, as active fillers in polymers and rubbers, for lubricating and cooling fluids, drilling fluids oil-based

-alkoxyalkyl)caprolactam with protecting and aerorepublica activity" target="_blank">

The invention relates to new biologically active compounds, namely N-(-alkoxyalkyl)caprolactam General formula

NH - OC6H13where R is H, CH3with insect - and aerorepublica activity

-alkoxyalkyl)caprolactam with insectrepellent activity" target="_blank">

The invention relates to new biologically active compounds, namely N-(-alkoxyalkyl)caprolactam General formula

NH - OR1where R=C3H7when R1=C2H5-C4H9with insectrepellent activity

The invention relates to derivatives of heterocyclic compounds, as well as agricultural and horticultural fungicides containing these compounds as active ingredients
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