Derivatives of quinoline as antagonists nk3-receptor tachykinin

 

(57) Abstract:

A derivative of quinoline of the formula I, or MES or salt, where Ar is phenyl, optionally substituted with halogen, OH or C1-6by alkyl, benzyl, thienyl, pyridyl, C5-7cycloalkenyl group; R is C1-8alkyl, C3-7cycloalkyl, hydroxyalkyl, aminoalkyl,acylaminoalkyl, di-C1-6acylaminoalkyl, C1-6alkoxyalkyl, C1-6alkylsulphonyl, carboxy, C1-6-alkoxycarbonyl, C1-6alkoxycarbonylmethyl, alkylaminocarbonyl, halogen-C1-6alkyl; R1and R2the same or different, represent hydrogen or C1-6alkyl; (other designations radicals, see p. 1 claims), is ones antagonist NK3and represents a potential therapeutic poleznosti in the treatment of convulsive disorders, renal disorders, inflammatory pain, urinary incontinence. 5 C. and 8 C.p. f-crystals, 6 PL.

The invention relates to new quinoline derivative, process for their preparation and their use in medicine.

Peptide mammals Neurokinin B (NKB) belongs to the family of peptide Tachykinin (TC), which also includes Substance P (SP) and Neurokinin A (NKA). Pharmaco Is B>1NK2and NK3), and NKB preferably associated with NK3receptor, although he also recognizes two other receptor with lower affinity (Maggi et al, 1993, J. Auton. Pharmacol., 13, 23 - 93).

Known selective peptide antagonists NK3receptor (Drapeau, 1990 Regul. Pept., 31, 125 - 135) and findings, or discovery of peptide antagonists of NK3receptor, suggest that NKB by activating NK3receptor plays a key role in the modulation of neural input in the upper respiratory tract, skin, spinal cord and nigro-Stroitelnye ways (Myers and Undem, 1993, J. Phisiol., 470, 665 - 679; Counture et al., 1993, Regul. Peptides, 46, 426 - 429; Mccarson and Krause, 1994, J. Neurosci., 14(2), 712 - 720; Arenas et al., 1991, J. Neurosci., 11, 2332-8).

However, peptide-like character known antagonists makes them likely to be too labile with metabolic point of view, to serve as a practical therapeutic agents.

At present inventors have discovered a new class of selective ones NK3antagonists, which are much more stable with metabolic point of view, than the well-known peptide antagonists NK3receptor, and represent potential therapeutic usefulness or periactine respiratory tract, cough), skin disorders and itch or scabies (for example, atopic dermatitis and skin blisters and red dermographism), neurogenic inflammation and disorders of the Central nervous system (Parkinson's disease, disorders of the locomotor ability, anxiety or fear and psychosis). These disorders or disorders next, here referred to as primary disorders or disorders.

New antagonists NK3the present invention also represent potential therapeutic utility in the treatment of convulsive disorders (e.g., epilepsy), kidney disorders, urinary incontinence, ocular inflammation, inflammatory pain, eating disorders (inhibition of food intake), allergic rhinitis, neurodegenerative disorders (such as Alzheimer's disease), psoriasis, Huntington's disease and depression (hereinafter referred to here as secondary violations).

According to the present invention are compounds, or their solvate, or salt of formula (I):

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in which Ar represents optionally substituted phenyl, naftalina or C5-7cycloalkenyl group or an optionally substituted single or fused ring heterocyclic group, have CE or in each ring, selected from S, O, N;

R represents a linear or branched C1-8alkyl, C3-7cycloalkyl, C4-7cycloalkenyl, optionally substituted phenyl or phenyl C1-6alkyl, optionally substituted five-membered heteroaromatic ring comprising up to four heteroatoms selected from O and N, hydroxy, C1-6alkyl, amino (C1-6alkyl, C1-6acylaminoalkyl, di-C1-6acylaminoalkyl, C1-6acylaminoalkyl, C1-6alkoxyalkyl, C1-6alkylsulphonyl, carboxy, C1-6alkoxycarbonyl, C1-6alkoxycarbonyl-C1-6alkyl, aminocarbonyl, C1-6alkylaminocarbonyl, di-C1-6alkylaminocarbonyl, halogen, C1-6alkyl; or represents a group -(CH2)p- when he cycletour with Ar, where p represents 2 or 3.

R1and R2that may be the same or different, independently represent hydrogen or C1-6linear or branched alkyl, or together form a group -(CH2)n-, in which n represents 3, 4 or 5; or R1together with R forms a group -(CH2)q-, in which q is 2, 3, 4 or 5.

R3and R4that may be the same or different, represent independently in the, who and Jethro, cyano, carboxy, carboxamido, sulphonamido, C1-6alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino, mono - or di-C1-6alkylamino, -O(CH2)r-NT2in which r is 2, 3 or 4, and T represents hydrogen or C1-6alkyl, or it forms with the adjacent nitrogen group

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in which V and V1are independently hydrogen or oxygen, and u represents 0, 1 or 2; -O(CH2)s-OW2in which s is 2, 3 or 4, and W is hydrogen or C1-6alkyl; hydroxyalkyl, aminoalkyl, mono - or dialkylaminoalkyl, acylamino, alkylsulfonyl, aminoethylamino, mono - or dialkylaminoalkyl; and in the quinoline nucleus is present up to four R3substituents; or R4represents a group -(CH2)twhen he cycletour with R5as aryl, in which t is 1, 2 or 3;

R5represents a linear or branched C1-6alkyl, C3-7cycloalkyl, C4-7cycloalkenyl, optionally substituted aryl or optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four Goethe is Auda phenyl, optionally substituted by hydroxy, halogen, C1-6alkoxy or C1-6the alkyl. Examples of halogen are chlorine and fluorine, for example C1-6alkoxy is methoxy, and example C1-6the alkyl is methyl.

Examples of Ar as the heterocyclic group are thienyl and pyridyl.

Examples Ar as C5-7cycloalkenyl group is cyclohexadienyl.

Examples of R are the following:

C1-8alkyl: methyl, ethyl, n-propyl, ISO-propyl, n-butyl, heptyl;

phenyl C1-6alkyl: benzyl;

hydroxy, C1-6alkyl: -CH2OH, -CH2CH2OH, CH(Me)OH;

amino C1-6alkyl: - CH2NH2;

di-C1-6acylaminoalkyl: -CH2NMe2;

C1-6alkoxyalkyl: - CH2OMe;

C1-6alkylsulphonyl: COMe;

C1-6alkoxycarbonyl: COOMe;

C1-6alkoxycarbonyl C1-6alkyl: CH2COOMe;

C1-6alkylaminocarbonyl: CONHMe;

di-C1-6alkylaminocarbonyl: CONMe2, CO(1-pyrrolidinyl); halogen, C1-6alkyl include trifluoromethyl;

-(CH2)p- when cycletour with Ar:

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Example R1and R2in the form of C1-6the alkyl is methyl; R1together with R form a group -(CH2

Examples R5are cyclohexyl, phenyl, optionally substituted as defined above for Ar; examples R5as the heterocyclic group include furyl, thienyl, peril, thiazolyl, benzofuran and pyridyl.

A preferred group of compounds of formula (I) are compounds in which:

Ar represents phenyl, optionally substituted C1-6by alkyl or halogen; thienyl or C5-7cycloalkenyl group;

R represents a C1-6alkyl, C1-6alkoxycarbonyl, C1-6alkylsulphonyl, hydroxy, C1-6alkyl;

R1and R2are each hydrogen or C1-6alkyl;

R3marks hydrogen, hydroxy, halogen, C1-6alkoxy, C1-6alkyl;

R4represents hydrogen, C1-6alkyl, C1-6alkoxy, hydroxy, amino, halogen, aminoethoxy, mono - or dialkylaminoalkyl, mono - or dialkylaminoalkyl, ftolerance, mono - or dialkylaminoalkyl and acylamino the optimum group of compounds of formula (I) are compounds where:

Ar represents phenyl, 2-chlorophenyl, 2-thienyl or cyclohexadienyl;

R represents methyl, ethyl, n-propyl, -COOMe, -COMe;

R1and R2each represents hydrogen or methyl;

R3represents hydrogen, methoxy or hydroxy;

R4represents hydrogen, methyl, ethyl, methoxy, hydroxy, amino, chlorine, bromine, dimethylaminoethoxy, 2-(1-phthaloyl)ethoxy, aminoethoxy, 2-(1-pyrrolidinyl)ethoxy, dimethylaminopropoxy, diethylaminoethylamine, acetylamino and dimethylaminomethyl;

R5represents phenyl, 2-thienyl, 2-furyl, 2-perril, 2-thiazolyl and 3-thienyl; and

X represents oxygen.

A preferred subgroup of compounds within the scope of formula (I) above are compounds of formula (Ia):

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in which R, R2, R3and R4have the meanings given for formula (I), and Y and Z, which may be the same or different, each represents Ar is as defined for formula (I).

Especially preferred group of compounds of formula (Ia) are compounds of formula (Ib), in which the group R is oriented in a downward direction, and H - up.

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The compounds of formula (I) or their salts or solvate presents predpochtitelnei mean, along with others, connection pharmaceutically acceptable level of purity, excluding normal pharmaceutical additives such as diluents and carriers, and does not include substances that are considered toxic at normal dosage levels. Essentially pure form typically contains at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and even more preferably 95% of the compounds of formula (I) or its salt or MES. One of the preferred pharmaceutically acceptable form is a crystalline form, including a form of the pharmaceutical composition. In the case of salts and solvate secondary ion and solvent should be non-toxic.

Examples of pharmaceutically acceptable salts of the compounds of formula (I) include acid additive salts with conventional pharmaceutical acids such as maleic, hydrochloric, Hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, almond, tartaric, succinic, benzoic, ascorbic acid and methanesulfonic acid.

Examples of pharmaceutically acceptable solvate of the compounds of formula (I) include hydrates.

Connection pneu stereoisomeric form. The invention encompasses all such forms and mixtures thereof, including racemates.

This invention also provides a method of obtaining compounds of formula (I), which involves the reaction of the compounds of formula (III)

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in which R', R'1, R'2and Ar' represent R, R1, R2and Ar are as defined for formula (I), or a group or atom capable of being converted into R, R1, R2and Ar, with a compound of formula (II)

< / BR>
or its active derivatives, in which R'3, R'4, R'5and X' represent R3, R4, R5and X are as defined for formula (I), or a group capable of being converted into R3, R4, R5and X, to obtain the compounds of formula (Ic)

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and not necessarily occur after one or more of the following stages:

(a) when R', R'1- R'5, Ar' and X' are other than R, R1-R5, Ar and X, the transformation of any one of R', R'1- R'5, Ar' and X' in R, R1- R5, Ar and X to obtain the compounds of formula (I),

(b) when R', R'1- R'5, Ar' and X' are R, R1- R5, Ar and X, the transformation of any one of R, R1- R5, Ar and X other R, R1- R5, Ar and X to obtain the compounds of formula (I),

(Vodnyi compounds of the formula (II) are galodamadruga acids (preferably the acid chlorides), azides acids or anhydrides of the acids. Another suitable derivative is mixed anhydride formed between the acid and alkylchlorosilanes; another suitable derivative is an activated ester, such as cinematology, tofinally, n-nitrophenyloctyl, n-nitrodiphenylamine esters, 2,4,6-trichloranisole ether, pentachlorphenol, pentafluorophenyl ester, N-hydroxy-phthalimido ether, N-hydroxypiperidine ether, N-hydroxysuccinimidyl ester, N-hydroxy-benzotriazolyl ether; or a carboxy group can be activated using a carbodiimide or N,N'-carbonyldiimidazole.

For example, according to standard methods well known to specialists in this field, the compounds of formula (III) can be combined:

(a) with the acid chloride of the acid in the presence of an inorganic or organic base in a suitable aprotic solvent such as dimethylformamide (DMF or DMF) at a temperature in the range from -70 to 50oC (preferably in the range from -10 to 20oC)

(b) with an acid in the presence of a suitable condensing agent, such as, for example, N,N'-carbonyldiimidazole (GDI) or carbodiimide, such as dicyclohexylcarbodiimide (DCC) or N-dimethylene the Oba to avoid racemization processes (Synthesis, 453, 1972) in an aprotic solvent such as a mixture of acetonitrile (MeCN) and tetrahydrofuran (TGF or THF) in a ratio of from 1:9 to 7:3, respectively, at a temperature in the range from -70 to 50oC (preferably in the range from -10 to 25oC) (see scheme 1),

(C) with the mixed anhydride obtained on site (in situ) of the acid and alkyl (for example isopropyl)chloroformate in a suitable aprotic solvent such as dichloromethane, at a temperature in the range from -70 to 50oC (preferably in the range from -20 to 20oC). Obviously, it is clear that the compound of formula (Ic) can turn into a compound of formula (I), or one compound of formula (I) may be converted into another compound of formula (I) by interconversion of suitable substituents. Thus, some compounds of formula (I) and (Ic) are useful intermediate compounds in the formation of other compounds of the present invention.

For example, R'2may represent hydrogen and become R2alkyl group, e.g. methyl, using conventional procedures amide alkylation (Zabicky, The chemistry of amides; Interscience, London, 1970, page 749). When X' is oxygen, may be transformed into X sulfur using Lawesson (Tetrahedron, 41, 5061, 1985). When Ar' or R'5represents a methoxy-substituted phenyl, he can turn into another Ar' or R'5hydroxy-substituted phenyl using standard techniques demethylation using Lewis acids, such as trichromacy boron (Synthesis, 249, 1983), or mineral acids such as Hydrobromic or itestosterone acid. When R is alkoxycarbonyl group, for example methoxycarbonyl, he can turn into a different R such as etoxycarbonyl using complex transesterification corresponding alcohol at a temperature in the range from 0 to 120oC, carboxy using hydrolysis in an acidic or basic environment, aminocarbonyl, alkylaminocarbonyl or dialkylaminoalkyl using transaminirovania ammonia, primary amine or secondary amine in methanol as solvent at a temperature in the range from 10 to 120oC, optionally in the presence of catalytic amount of NaCN (J. Org. Chem., 52, 2033, 1987) or through the use of trimethylaluminum (Me3Al) (Tetrahedron Letters, 48, 4171, 1977), hydroxymethyl using selective reduction with metal hydride, such as restoring lithium borohydride (Tetrahedron, 35, 567, 1979) or restore the borohydride Natrii subsequent reaction with alkylpolyglucoside in THF as solvent at a temperature in the range from -78 to 30oC (Tetrahedron Letters, 4303, 1979) or with alkylcyclopentanes or dialkylamines in the presence of MgCl2or lithium chloride (J.Org. Chem., 47: 2590, 1982). Another group of R' as methoxycarbonyl can turn into substituted heterocyclic ring, such as oxadiazole (J. Med. Chem., 34: 2726, 1991), heteroaromatic ring, such as oxadiazole (J. Med. Chem. , 34, 2726, 1991).

Scheme 2 summarizes some of the above methods of transformation of compounds of formula (Ic) or (I) in which X' is oxygen, R' is COOMe, Ar' and R'1-R'5have the meanings described for formula (I) into another compound of formula (I) (scheme 2, see the end of the description).

The compounds of formula (I) can turn into their pharmaceutically acceptable acid additive salts by reaction with suitable or appropriate organic or mineral acids.

The solvate of the compounds of formula (I) can be formed using the crystallization or recrystallization from an appropriate solvent. For example, the hydrate can be obtained through crystallization or recrystallization from aqueous solutions or solutions in organic solvents containing water.

Salt or solvate of the compounds of formula (is ineni when receiving a pharmaceutically acceptable salt or solvate. Accordingly such salts and solvate are also part of this invention.

As mentioned above, the compounds of formula (I) can exist in more than one stereoisomeric form, and the process of this invention can give the racemates as well as enantiomerically pure form. To obtain pure enantiomers corresponding enantiomerically pure primary or secondary amines of the formula (IIId) or (IIIe)

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are reacted with compounds of the formula (II) to obtain the compounds of formula (I d) or (I e).

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The compounds of formula (I d) or (I (e) can be subsequently converted into compounds of formula (Id) or (Ie) using transformation methods mentioned above.

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The compounds of formula (II) are known or can be obtained from known compounds by known methods.

For example, the compound of formula (II) in which X' is oxygen, R'3, R'4and R'5represent hydrogen, as described in Pfitzinger, J. Prakt. Chem. , 38, 582, 1882, and in the work Pfitzinger, J. Prakt. Chem., 56, 293, 1897; a compound of formula (II) in which X' is oxygen, R'3and R'4represent hydrogen and R'5represents 2-pyridyl, described in Risaliti, Ric. Scient. , 2 R'5represents o-, m - and p-chlorophenyl, o-forfinal and 3,4-dichlorophenyl described in Brown et al. J. Am. Chem. Soc., 68, 2705, 1946; a compound of formula (II) in which X' is oxygen, R'3and R'4represent hydrogen, and R'5is p-methoxyphenyl, described in Ciusa and Luzzatto, Gazz. Chim. Ital., 44, 64, 1914; a compound of formula (II) in which X' is oxygen, R'3and R'4represent hydrogen, and R'5is m-triptoreline described in Shargier and Lalezari, J. Chem. Eng. Data, 8, 276, 1963; a compound of formula (II) in which X' is oxygen, R'3and R'4represent hydrogen, and R'5is p-forfinal described in Bu Hoi et al., Rec Trav. Chim. , 68, 781, 1949; a compound of formula (II) in which X' is oxygen, R'3and R'4represent hydrogen, and R'5is p-were described by Prevost et al., Compt. Rend. Acad. Sci., 258, 954, 1964; a compound of formula (II) in which X' is oxygen, R'3and R'4represent hydrogen, and R'5is p-bromophenyl described in the work of Nicolai et al. , Eur. J. Med. Chem., 27, 977, 1992; compound of formula (II) in which X' is oxygen, R'4and R'5represent hydrogen, and R'3is 6-methyl, described by Buchmann and Howton, the t hydrogen, and R'3is 8-nitro described by Buchmann et al, J. Am. Chem. Soc., 69, 380, 1947; a compound of formula (II) in which X' is oxygen, R'4represents hydrogen, R'3is 6-chloro, R'5is p-chlorophenyl, described in Lutz et al., J. Am. Chem. Soc., 68, 1813, 1946; a compound of formula (II) in which X' is oxygen, R'3and R'4represent hydrogen, and R'5is 2-thiazolyl described in European patent application EP 112776; the compounds of formula (II) in which X' is oxygen, R'3is 8-trifluoromethyl, R'4represents hydrogen and R'5represents phenyl, o - and p-forfinal, 3,4-dichlorophenyl, p-methoxyphenyl, described in the work of Nicolai et al. , Eur. J. Med. Chem., 27, 977, 1992; compounds of the formula (II) in which X is oxygen, R'3is 6-bromo, R'4represents hydrogen and R'5represents phenyl or p-forfinal are described in the work of Nicolai et al., Eur. J. Med. Chem., 27, 977, 1992; other compounds of formula (II) are described in German laid application DE 3721222 and in European patent application EP 384313.

Compounds of formula (III), (IIId) and (IIIe) are industrially available compounds or can be obtained from known compounds using isostress hydrogen and Ar' matter defined for compounds of formula (I) are described in Liebigs Ann. der Chemie, 523, 199, 1936).

The activity of compounds of the formula (I) as antagonists of NK3receptor in standard tests indicates that they have potential therapeutic utility in the treatment of both primary and secondary disorders, for which there had previously given link. Finding that antagonists NK3receptor is a potential therapeutic usefulness in the treatment of secondary disorders, is new, and in accordance with the following aspect of the present invention is the use of antagonists of NK3receptor in the treatment of secondary disorders. There is also the use of antagonists of NK3receptor in the manufacture of medicaments for the treatment of any of the secondary disorders.

The present invention also provides compounds of formula (I) or their pharmaceutically acceptable salt or solvate for use as an active therapeutic substance.

The present invention further provides pharmaceutical compositions comprising a compound of formula (I) or its pharmaceutically acceptable salt or MES the compounds of formula (I) or their pharmaceutically acceptable salts or solvate in the manufacture of medicaments for the treatment of primary and secondary disorders.

Such medicaments and compositions of this invention can be obtained by mixing the compounds of the invention with an appropriate carrier. They may contain conventional diluents, binders, fillers, dezintegriruetsja agents, flavoring or flavoring agents, coloring agents, lubricant or preservative agents.

Data common excipients are the same as those that can be applied, for example, upon receipt of the compositions with known agents for the treatment of these conditions.

Preferably the pharmaceutical composition of the invention is in the form of a unit dosage form, suitable for use in medical or veterinary fields. For example, such preparations may be packaged form, accompanied by written or printed instructions for use as an agent for the treatment of these conditions.

The interval of suitable doses of the compounds of the invention depends on the connection and condition of the patient. It also depends on the communication activity or strength and ability to absorb and frequency and method of assignment to the drug.

The compound or composition of izobretena single dose or in the form which man himself can take the form of a dose at once. The composition may be in a form suitable for oral, rectal, topical or local, parenteral, intravenous or intramuscular administration. Preparations can be made in such a way as to provide slow release of the active ingredient.

The composition can be, for example, in the form of tablets, capsules, sachets, vials or tubes, powders, granules, pellets, reconstituirea or perelistyvaem powders or liquid preparations, for example solutions or suspensions, or in the form of medical candles or suppository.

Compositions, for example, those that are suitable for oral purposes, and may contain conventional excipients such as binding agents, for example syrup, gum acacia, gelatin, sorbitol, tragakant or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants agents, for example magnesium stearate; dezintegriruetsja agents, for example starch, polyvinyl-pyrrolidone, matrikamantra or microcrystalline cellulose; or pharmaceutically acceptable agents for curing such right, filling, tabletting or similar. Re-blending operation can be used to distribute or distribution of the active agent in compositions that use huge amounts of fillers. When the composition is in the form of tablets, powder or pellet, may use any media suitable for the formation of solid pharmaceutical compositions, and examples are magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular enterococci coating. The composition may also be in the form of a swallow capsules, e.g. of gelatin-containing compound, optionally with a carrier or other excipients.

Compositions for oral assignments in the form of liquids can be in the form of, for example, emulsions, syrups or Alexiou, or they can be presented as a dry product intended for rekonstruirovaniya with water or other suitable vehicle before use. Such liquid compositions may contain conventional additives such as suspendresume agents, for example sorbitol, si is rowanne edible fats; emulsifying agents, for example lecithin, servicemanual or gum acacia; aqueous or non-aqueous media, which include edible oils, for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine or propylene glycol, or ethyl alcohol, glycerine, water or normal saline or saline; preserving agents such as methyl - or propyl-p-hydroxybenzoate or ascorbic acid; and, if desired, conventional flavoring or coloring agents.

The compositions of this invention can also be assigned to receive not oral way. In accordance with conventional pharmaceutical procedures compositions can be formulated for rectal destination in the form of medical candles. They may also be formed or prepared for submission in injectable form in an aqueous or nonaqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid such as sterile, free of pyrogens water or parenterally acceptable oil or a mixture of liquids. The liquid may contain antibacterial agents, antioxidants or other preservative agents, buffers or the solute is e pharmaceutically acceptable additives. Such forms shall be submitted in the form of a unit dose, such as ampoules or disposable products for injection or in the form of many doses, such as a bottle or vial, which can be taken right dose, or solid form or concentrate that can be used for the preparation of injectable ready-made forms.

The compounds of this invention can also be administered via inhalation through the nose or mouth. This medication may be carried out using the prepared spray, comprising a compound of the invention and a suitable carrier, optionally suspended, for example, in hydrocarbon jet fuel substance.

The preferred form in the form of spray include the smallest (micronized) particle compounds in combination with surface-active agent, solvent or dispersing agent to prevent settling of the suspended particles. The particle size of the compound is preferably from about 2 to 10 microns.

For more of the compounds of the invention includes a transdermal delivery using the finished form of the drug in the form of a skin patch. Preferred are ready prep is that adheres to the skin, thereby allowing the connection to diffusivity of the adhesive through the skin for delivery to the patient. For a constant extent or rate of absorption through the skin can be used pressure-sensitive adhesives known in the art, such as natural rubber or silicone.

As mentioned above, an effective dose of a compound used depends on the specific compound, the condition of the patient and on the frequency and method of appointment. A single dose usually contains from 20 to 1000 mg, and preferably from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg of the Composition may be eligible to receive one or more times per day, for example, 2, 3 or 4 times a day and the total daily dose for an adult weighing 70 kg is usually in the range from 100 to 3000 mg Alternative unit dose contains from 2 to 20 mg of the active ingredient and is made repeatedly, if necessary, to give the specified daily dose.

In the case of compounds of the invention, when they are taken in accordance with the invention, it is not anticipated no unacceptable Toxicological effects.

The present invention also provides a method of treatment and/or prevention of primary and secondary restrictee and/or prevention, effective amounts of compounds of formula (I) or its pharmaceutically acceptable salt or MES.

The invention further provides a method of treatment and/or prevention of secondary disorders in mammals, particularly humans, which includes the appointment of a mammal in need of such treatment and/or prevention, an effective amount of the antagonist NK3the receptor.

The activity of the compounds of the present invention as ligands NK3is determined by their ability to inhibit the binding of radioactively labeled ligands NK3, [125I]-[Me-Phe7]-NKB or [3H]-Sentido, with NK3receptors of Guinea pigs and humans (Renzetti et al., 1991. Neuropeptide, 18, 104 - 114; Buell et al, 1992. FEBS, 299 (1), 90 - 95; Chung et al, 1994, Biochem. Biophys. Res. Commun., 198(3), 967 -972). Used analyses linking allows to determine the concentration of the individual compound required to reduce by 50% the specific binding of [125I]-[Me-Phe7]-NKB and [3H]-Sentida with NK3receptor in equilibrium (IC50). Analyses bindings make for each tested compound average IC50from 2-5 separate experiments performed with two-or three-fold repetition. The most and is byte with the cerebral cortex of Guinea pigs with substitution (displacement) [3H] -Sentido compounds of examples 22, 47, 48 and 85 show KiS (nm), respectively, 5.6, 8.8, 12.0 and 4.8 (n=3). NK3-antagonistic activity of the compounds of the present invention is determined by their ability to inhibit induced sanction contraction of the ileum of the Guinea pig (Maggi et al, 1990, Br. J Pharmacol., 101, 996 - 1000) and isolated sphincter muscle of the iris rabbit (Hall et al., 1991, Eur. J. Pharmacol. , 199, 9-14) and mediated NK3receptors Ca++mobilization (Mochizuki et al. , 1994, J. Biol. Chem., 269. 9651 - 9658). Functional analyses in vitro on Guinea pigs and rabbits given for each test compound average KBfrom 3-8 separate experiments, where KBrepresents the concentration of the individual compound required to obtain a 2-fold shift to the right on the curve sentida concentration - response. Functional analysis with receptors person allows to determine the concentration of the individual compound required to reduce by 50% (the value of the IC50Ca++mobilization induced by antagonist NKB. In this analysis, the compounds of the present invention act as antagonists.

therapeutic potential of the compounds of this izaberete the ptx2">

The following descriptions illustrate the production of intermediate compounds, while the examples illustrate the formation of compounds of the present invention. Connection examples are shown in tables 1 - 6.

DESCRIPTION 1

The acid chloride 2-phenylindolin-4-carboxylic acid

to 11.7 ml (136,3 mmole) of oxalicacid was dissolved in 150 ml of methylene chloride. The solution was cooled at -10oC, and portions were added 20 g (an 80.2 mmole) industrial available 2-phenylindolin-4-carboxylic acid. The reaction mixture was left overnight at room temperature and then was evaporated to dryness, giving 22 g specified in the title compound, used without further purification.

C16H10ClNO

M. C. = 267,76

DESCRIPTION 2

7-methoxy-2-phenylindolin-4-carboxylic acid

5 g (28.2 mmole) of 6-methoxyisatin, 4 ml (33.8 mmole) of acetophenone and 5.2 g (92,6 mmole) of potassium hydroxide was dissolved 22.9 ml of absolute ethanol, and the suspension was heated at 80oC for 42 hours. After cooling, the reaction mixture was added 50 ml of water, and the solution was extracted with 50 ml diethyl ether. Chilled with ice water phase was padillas to pH 1 with 37% HCl, and the precipitate was collected by filtration and promyvaniya.

C17H13NO3< / BR>
So pl. = 226 - 228oC

M. C.= 279,30

Elemental analysis: Calculated C 73,11; H 4,69; N 5,01

Found C 72,07; H 4,59; N 4,90.

IR (KBr): 3420, 1630 cm-1< / BR>
DESCRIPTION 3

The acid chloride 7-methoxy-2-phenylindolin-4-carboxylic acid

of 2.8 ml (32,3 mmole) of oxalicacid was dissolved in 60 ml of methylene chloride. The solution was cooled at -10oC, and portions were added 6 g (19.0 mmol) 7-methoxy-2-phenylindolin-4-carboxylic acid. The reaction mixture was left overnight at room temperature and then was evaporated to dryness, yielding 7 g specified in the title compound, used without further purification.

C17H12ClNO2< / BR>
M. C. = 297,74

DESCRIPTION 4

Hydroiodide 7-hydroxy-2-phenylindolin-4-carboxylic acid

1.5 g (5.4 mmole) of 7-methoxy-2-phenylindolin-4-carboxylic acid were added in portions to 50 ml of 57% aqueous HI. The reaction mixture was heated under reflux and vigorously stirred for 5 hours; then it was evaporated in vacuum to dryness, giving 2.1 g specified in the connection header.

C16H11NO3HI

M. C. = 393,17

IR (KBr): 3120; 1650; 1620 cm-1.

DESCRIPTION 5

2-(2-thienyl)quinoline-4-carbon which was extended

in 40 ml of absolute ethanol, and the suspension was heated at 80oC for 16 hours. After cooling, the reaction mixture was added 50 ml of water, and the solution was extracted with 50 ml diethyl ether. Chilled with ice water phase was padillas to pH 1 with 37% HCl, and the precipitate was collected by filtration and rinsed with water. The resulting crude product was dried in vacuum at 40oC and were pulverized with ethyl acetate, giving 4.8 g specified in the connection header.

C14H9NO2S

So pl. = 181 - 183oC

M. C. = 255,29

IR (KBr): 1620 cm-1< / BR>
300 MHz1H-NMR (DMSO-d6): 8,60 (D., 1H); 8,45 (S., 1H); 8,10 (m, 2H); for 7.78 (m, 2H); to 7.68 (t, 1H); 7,22 (m, 1H).

DESCRIPTION 6

2-(2-furyl)quinoline-4-carboxylic acid

5 g (34,0 mmole) of isatin, 4 ml (40,8 mmole) of 2-acetylfuran and 6.3 g (to 112.2 mmole) of potassium hydroxide was dissolved in of 40.9 ml of absolute ethanol, and the suspension was heated at 80oC for 12 hours. After cooling, the reaction mixture was added 50 ml of water, and the solution was extracted with 50 ml diethyl ether. Chilled with ice water phase was padillas to pH 1 with 37% HCl, and the precipitate was collected by filtration and rinsed with water. The resulting crude product was dried in vacuum at 40oC, giving 8.5 g pointed to by edred 2-(2-furyl)quinoline-4-carboxylic acid and 5.2 ml (60,4 mmole) of oxalicacid was dissolved in 70 ml of methylene chloride. The solution was cooled at -10oC, and portions were added 8.5 g (35.5 mmol) of 2-(2-furyl)quinoline-4-carboxylic acid. The reaction mixture was left overnight at room temperature and then was evaporated to dryness, yielding 9.2 grams specified in the title compound, used without further purification.

C14H8ClNO2< / BR>
M. C. = 257,78

DESCRIPTION 8

The acid chloride of 2-(4-pyridyl)quinoline-4-carboxylic acid

5 g (34,0 mmole) of isatin, and 4.5 ml (40,8 mmole) of 4-acetylpyridine and 6.3 g (to 112.2 mmole) of potassium hydroxide was dissolved in 40 ml of absolute ethanol, and the suspension was heated at 80oC for 12 hours. After cooling, the reaction mixture was added 50 ml of water, and the solution was extracted with 50 ml diethyl ether. Chilled with ice water phase was padillas to pH 1 with 37% HCl, and the precipitate was collected by filtration and rinsed with water.

The aqueous solution was evaporated in vacuum to dryness, the residue was pulverized with ethanol and filtered. Evaporation of the solvent gave 6.0 g of crude specified in the connection header. This product was combined with the previously obtained precipitate was precrystallization from toluene containing a trace of methanol, giving 4.5 g specified in the connection header.

>

300 MHz1H-NMR (DMSO-d6): 8,90 (D., 2H), 8,70 (m, 2H), 8,50 (S., 2H), 8,28 (D., 1H), 7,89 (dt., 2H).

DESCRIPTION 9

The hydrochloride of the acid chloride of 2-(4-pyridyl)quinoline-4-carboxylic acid

1.3 ml (or 10.4 mmole) of oxalicacid was dissolved in 60 ml of methylene chloride. The solution was cooled at 10oC and portions were added 3.0 g (14.4 mmole) of the hydrochloride of 2-(4-pyridyl)quinoline-4-carboxylic acid. The reaction mixture was left for 72 hours at room temperature and then was evaporated to dryness, giving 4.0 g specified in the title compound, used without further purification.

C15H9ClN2O HCl

M. C. = 305,22

Example 1

(R, S)-N-(-methylbenzyl)-2-phenylindolin-4-carboxamid 1.2 ml (9.4 mmole) of (R, S)(-methylbenzylamine and 1.6 ml (about 11.7 mmole) of triethylamine (TEA) were dissolved under nitrogen atmosphere in a 50 ml 1:1 mixture of dry methylene chloride and CH3CN. It chilled with ice to a solution of amine was added dropwise 2.0 g (7,8 mmole) 2-phenylphenol-4-carbonylchloride dissolved in 50 ml of 1:4 mixture of dry methylene chloride and DMF, and the reaction mixture was stored at 0 - 5oC for 1 h and left overnight at room temperature. The reaction mixture was evaporated in vacuum to dryness, the residue was dissolved in ethyl acetate, the sodium atom, filtered and evaporated in vacuum to dryness. The residual oil was crystallized from ethyl acetate, giving 1.1 g of the target compound as a white solid.

C24H20N2O

So pl. = 156 - 157oC

M. C. = 352,43

Elemental analysis: Calculated C 81,79; H 5,72; N OF 7.95

Found C 81,99; H 5,69; N 7,89

IR (KBr): 3240, 1645 cm-1.

300 MHz1H-NMR (DMSO-d6): 9,29 (D., 1H), 8,32 (D., 2H), 8,13 (D., 1H), 8,13 (S., 1H), 8,06 (D., 1H), 7,81 (DDD., 1H), 7.68 per-7,52 (m, 4H), 7,47 (D., 2H), 7,39 (DD., 2H), 7,27 (DD., 1H), and 5.30 (DQC., 1H), 1,52 (D., 3H).

MC (EI; source 200oC, 70 V, 200 mA): 352 (M+.), 337, 232, 204, 77.

Example 2

S-(+)-N-( - methylbenzyl)-2-phenylindolin-4 - carboxamid

The result was, as in example 1, 1.2 ml (9.4 mmole) of S-(-)- - methylbenzylamine, 1.6 ml (11,7 mmole) TEA, 2.0 g (7,8 mmole) 2-phenylphenol-4-carbonylchloride in 100 ml of a mixture of methylene chloride, CH3CN and DMF. Processing of the reaction mixture was carried out in the same manner as described in example 1. The residual oil was crystallized from ethyl acetate, giving 1.1 g of the target compound.

C24H20N2O

So pl. = 161 - 162oC

M. C. = 352,43

[]2D0= +25 (C = 0.5 DMF) IR (KBr): 3240, 1645 cm-1< / BR>
300 MHz1H-NMR (DMSO-d6): 9,29 (D., 1H), 8,32 (doctor, 2 the ptx2">

MS spectrum was identical to the spectrum of example 1.

Example 3

R-(-)-N-( - methylbenzyl)-2-phenylindolin-4 - carboxamid

The result was, as in example 1, from 1, 2 ml (9.4 mmole) of R-(+)- - methylbenzylamine, 1.6 ml (11,7 mmole) TEA, 2.0 g (7,8 mmole) 2-phenylphenol-4-carbonylchloride in 100 ml of a mixture of methylene chloride, CH3CN and DMF. Processing of the reaction mixture was carried out in the same manner as described in example 1. The residual oil was crystallized from ethyl acetate, giving 1.1 g of the target compound.

C24H20N2O

So pl. = 158 - 160oC

M. B. = 352,43

[]2D0= -25 (C=0.5 DMF) IR (KBr): 3240, 1645 cm-1< / BR>
1H-NMR and MS spectra were identical to the spectra of examples 1 and 2.

Example 4

(R,S)-N-[ - (methoxycarbonyl)benzyl]-2-phenylindolin - 4-carboxamid

2.0 g (8.0 mmol) of 2-phenylphenol-4-carboxylic acid were dissolved under nitrogen atmosphere in 130 ml of dry THF and 100 ml of CH3CN. Was added 2.0 g (to 9.9 mmole) of the hydrochloride (D, L) methylphenylglycidate and 1.5 ml (10.7 mmole), TEA, and the reaction mixture was cooled at 5oC. was added dropwise 2.5 g (12,1 mmole) dicyclohexylcarbodiimide (DCC) dissolved in 10 ml of dry methylene chloride, and the solution was given the opportunity to reach room temperature, was revivals, and the solution was evaporated in vacuum to dryness. The residue was dissolved in methylene chloride, and then was rinsed with water. The organic layer was separated, dried over sodium sulfate and evaporated in vacuum to dryness, giving 6.0 g of crude product, which was dissolved in 20 ml of methylene chloride and was left overnight. Some more of dicyclohexylamine precipitated and was filtered off.

The solution was evaporated in vacuum to dryness, and the residue was subjected to pleskrestore 230 - 400 mesh silica gel with elution by the mixture hexane/ethyl acetate 3/2 containing 0.5% ammonium hydroxide. The resulting crude or crude solid was pulverized with a warm diisopropyl ether, filtered, rinsed and dried, yielding 1.1 g of the target compound.

C25H20N2O3< / BR>
So pl. = 170 - 172oC

M. C. = 396,45

Elemental analysis: Calculated C 75,74; H 5,09; N 7,07

Found C 75,88; H 5,12; N 7,06

IR (nujol): 3240, 1750, 1670 cm-1.

300 MHz1H-NMR (DMSO-d6): 9,72 (D., 1H), 8,28 (DD., 2N), to 8.20 (DD., 1H), 8,13 (DD. , 1H), 8,11 (S. , 1H), 7,83 (DDD., 1H), 7,66 (DDD., 1H), 7,60 is 7.50 (m, 5H), 7,47-7,37 (m, 3H), 5,78 (D., 1H), 3.72 points C., 3H).

MS (EI; source 200oC, 70 V, 200 mA): 396 (M+.), 337, 232, 204.

Example. 5

(+)-(S)-N-[-(metavariables in nitrogen atmosphere in 70 ml of dry THF and 30 ml of CH3CN. Was added 1.7 g (8.4 mmole) of the hydrochloride (L) methylphenylglycidate, 1.1 ml (9,9 mmole) N-methylmorpholine and 2.1 ml (15.5 mmol) of N-hydroxybenzotriazole (NOVT), and the reaction mixture was cooled at 0oC. was dropwise added 1.85 g (9.0 mmol) of DCC, dissolved in 10 ml of methylene chloride, and the solution was stored at 0 - 5oC for 1 hour and then at room temperature for 2 hours. Precipitated in the sediment dicyclohexylamine filtered, and the solution was evaporated in vacuum to dryness. The residue was dissolved in methylene chloride and was washed with water, saturated sodium bicarbonate solution, 5% citric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was separated, dried over sodium sulfate and evaporated in vacuum to dryness, the residue was dissolved in 20 ml of methylene chloride and was left overnight. Some more of dicyclohexylamine precipitated and was filtered off. The solution was evaporated in vacuum to dryness, and was obtained 2.6 g of crude product, which was pulverized with petroleum ether, dissolved were washed diisopropyl ether, and then precrystallization of 70 ml isopropanol, giving 1.7 g of the target compound.

C25H20N2SUB>0= +42 (C=0.5 in methanol).

1H-NMR and MS spectra were identical to the spectra of example 4.

Example 6

(-)-(R)-N-[ - (methoxycarbonyl)benzyl]-2-phenylindolin-4 - carboxamid

The result was, as in example 5, 2.0 g (8.0 mmol) of 2-phenylphenol-4-carboxylic acid, 1.7 g (8.4 mmole) of the hydrochloride (D) methylphenylglycidate, 1.1 ml (9,9 mmole) N-methylmorpholine, 2.1 g (15.5 mmol) NOWT and 1.85 g (9.0 mmol) DCC in 70 ml of dry THF and 30 ml of CH3CN. Processing of the reaction mixture was carried out in the same manner as described in example 5. The resulting crude product (3.5 g) were pulverized twice with warm diisopropyl ether, filtered, rinsed, and then precrystallization of 80 ml of isopropanol, giving 2.3 g of the target compound.

C25H20N2O3< / BR>
So pl. = 180 - 181oC

M. C. = 396,45

IR (nujol): 3300, 1750, 1640 cm-1.

[]2D0= -42,0 (C=0.5 in methanol).

1H-NMR and MS spectra were identical to the spectra of examples 4 and 5.

Example 7

(R, S)-N-[-(methoxycarbonyl)benzyl] -7-methoxy-2 - phenylindolin-4-carboxamid

1.0 g (5.0 mmol) of hydrochloride (D,L) methylphenylglycidate was dissolved under nitrogen atmosphere in 30 ml of dry DMF. Was added 2.5 g (18,1 mmole) anhydrous carb is Oronogo in 25 ml of dry DMF, and the solution was stored at 0 - 5oC for 1 hour and at room temperature over night. The reaction mixture was evaporated in vacuum to dryness, and the residue was dissolved in ethyl acetate and was washed twice with water. The organic layer was separated, dried over sodium sulfate, filtered and evaporated in vacuum to dryness. The residual oil was subjected to pleskrestore on 230-400 mesh mesh silica gel with elution with a mixture of hexane and ethyl acetate 3:2 containing 0.5% ammonium hydroxide, yielding 0.1 g of the crude product, which was pulverized with diisopropyl ether, yielding 0.08 g of the target compound.

C26H22N2O4< / BR>
So pl. = 187 - 190oC

M. C. = 426,48

IR (KBr): 3220, 1750, 1660, 1620 cm-1.

300 MHz1H-NMR (CDCl3): 8,13-8,08 (m, 3H), 7,80 (S., 1H), 7,55 -7,38 (m , N), 7,21 (DD., 1H), 7,02 (D. broad, N), 5,88 (D., 1H), 3,97 (C., 3H), 3,80 (C., 3H).

MS (EI; source 200oC, 70 V, 200 mA): 426 (M+.), 367, 262, 234, 191, 77.

Example 8

(R, S)-N-[-(methoxycarbonyl)benzyl] -7-hydroxy-2-phenylindolin - 4-carboxamid

The result was, as in example 5, from 2.1 g (5.3 mmole) of the compound of description 4, 1.08 g (5.3 mmole) of the hydrochloride (D, L) methylphenylglycidate, 1.5 ml (10.7 mmole), TEA, 1.7 g (12.5 mmol) NOWT and 1.2 g (5.8 mmole) of DCC in 70 ml of dry THF and 30 ml of CH3the SPS were pulverized with diisopropyl ether, and then precrystallization twice from isopropanol, yielding 0.06 g of target compound.

C25H20N2O4< / BR>
So pl. = 256 - 257oC

M. C. = 412,45

IR (KBr): 3270, 1750, 1650, 1620 cm-1< / BR>
300 MHz1H-NMR (DMSO-d6): 10.30 a.m. (C. broad, 1H), for 9.64 (D., 1H), they were 8.22 (D. , 2H), 8,04 (D., 1H), 7,85 (S., 1H), 7,60-7,34 (m, N), 7,21 (DD., 1H), 5,74 (D., 1H), 3,71 (C., 3H).

MS (EI; source 200oC, 70 V, 200 mA): 412 (M+.), 353, 248, 220, 77.

Example 9

Hydrochloride (R, S)-N-[-(carboxy)benzyl] -7 - methoxy-2-phenylindolin-4-carboxamid

0.18 g (0.4 mmole) of the product of example 7 was dissolved in 10 ml of 10% HCl and 5 ml of dioxane. The reaction mixture was heated under reflux and stirred for 3 hours and then evaporated in vacuum to dryness. The crude product was pulverized with warm ethyl acetate (containing a few drops of ethanol) to give 0.16 g of the target compound.

C25H20N2O4HCl

So pl. = 228-230oC

M. C. = 448,91

IR (KBr): 3180, 1735, 1655, 1630 cm-1.

300 MHz1H-NMR (DMSO-d6): 9,6 (D., 1H), compared to 8.26 (DD., 2H), 8,14 (D., 1H), 7,98 (S., 1H), 7,63-7,52 (m, 6N), 7,46 and 7.36 (m, 3H), 7,33 (DD., 1H), 5,66 (D., 1H), 3,98 (C., 3H).

MS (EI; source 200oC, 70 V, 200 mA): 412 (M+.), 368, 262, 234, 191, 77.

Example 10

(R,S)-N-[-(methylenedi 33% MeNH2/EtOH, was added a catalytic amount of NaCN, and the reaction mixture was heated at 70oC for 1 hour in a Parr apparatus. The internal pressure was raised to 40 lb/in2(2,812 kg/cm2). The solution was evaporated in vacuum to dryness, and the residue was pulverized with water, filtered and precrystallization from a mixture of isopropanol (50 ml) and ethanol (30 ml), giving 0.2 g of the target compound.

C25H21N3O2< / BR>
So pl. = 261 - 263oC

M. C. = 395,47

Elemental analysis: Calculated C 75,93; H 5,35; N 10,63

Found C 75,65; H of 5.34; N 10,55

IR (KBr): 3300, 3270, 1660, 1635 cm-1< / BR>
300 MHz1H-NMR (DMSO-d6): 9,48 (D., 1H), 8,33-of 8.25 (M, 3H), 8,18-8,10 (m, 3H), 7,80 (DDD., 1H), 7.68 per-7,50 (m, 6N), 7,40-7,28 (m, 3H), 5,75 (D., 1H), 2.63 in (D., 3H).

MS (EI; source 200oC, 70 V, 200 mA): 395 (M+.), 337, 232, 204, 77.

Example 11

(R,S)-N-[-(methoxycarbonyl)benzyl]-2-(2 - thienyl)quinoline-4-carboxamide

The result was, as in example 5, 2.0 g (7.3 mmole) of 2-(2-thienyl)quinoline-4-carboxylic acid, 1.7 g (8.4 mmole) of the hydrochloride (D,L) methylphenylglycidate, 1.1 ml (10 mmol) N-methylmorpholine, 2.1 g (15.5 mmol) NOWT and 1.85 g (9.0 mmol) DCC in 70 ml of dry THF, 30 ml of methyl cyanide and 10 ml of methylene chloride. Processing of the reaction mixture was carried out in the same manner as opis absolute ethanol, giving 0.9 g of the target compound.

C23H18N2O3S

So pl. = 178 - 180oC

M. C. = 402,47

Elemental analysis: Calculated C 68,64; H 4,51; N OF 6.96

Found C 67,50; H 4,99; N 7,43

IR (KBr): 3300, 1745, 1645 cm-1.

300 MHz1H-NMR (DMSO-d6): 9,70 (D., 1H), 8,12 (D., 1H), 8,08 (S., 1H), 8,04 (D. , 1H), 8,02 (D., 1H), 7,19 (t, 1H), 7,76 (D., 1H), 7.62mm (t, 1H), 7,53 (D. , 2H), 7,46-7,37 (m, 3H), and 7.3 (DD., 1H), 5,68 (D., 1H), 3,68 (C., 3H).

MC (EI; source 200oC, 70 V, 200 mA): 402 (M+.), 343, 238, 210, 77.

Example 12

(R,S)-N-[-(methoxycarbonyl)benzyl]-2-(2-furyl)quinoline - 4-carboxamide

The result was, as in example 1, from 7.2 g (35.5 mmol) of hydrochloride (D,L) methylphenylglycidate, and 12.4 ml (88.8 mmol) TEA and 9.1 g (35.5 mmol) of crude 2-(2-furyl)quinoline-4-carbonylchloride in 350 ml of a mixture of methylene chloride, methyl cyanide and DMF. Processing of the reaction mixture was carried out in the same manner as described in example 1. The resulting crude product was pulverized with methanol, yielding 3.3 g of the target compound.

C23H18N2O4< / BR>
So pl. = 178 - 180oC

M. C. = 386,405

Elemental analysis: Calculated C 71,49; H 4,70; N 7,25

Found C 71,67; H 4,74; N 7,17.

IR (KBr): 3300, 1750, 1650 cm-1.

300 MHz1H-NMR (DMSO-d6): 9,72 (D., 1H), 8,12 (D., 1H), 8,06 (D., 1H; the source 200oC, 70 V, 200 mA): 386 (M+.), 327, 222, 194, 77.

Example 13

(R,S)-N-[-(methoxycarbonyl)benzyl]-2-(4-pyridyl)quinoline-4 - carboxamide

The result was, as in example 1, from 3.4 g (16.7 mmol) of hydrochloride (D,L) methylphenylglycidate, of 3.9 ml (up 27.8 mmole) TEA and 3.0 g (11.1 mmole) of 2-(4-pyridyl)quinoline-4-carbonylchloride in 100 ml of a mixture of methylene chloride, methyl cyanide and DMF. Processing of the reaction mixture was carried out in the same manner as described in example 1. The resulting crude product was precrystallization three times from ethyl acetate, giving 1.9 g of the target compound.

C24H19N3O3< / BR>
So pl. = 172 - 174oC,

M. C. = 397,43

Elemental analysis: Calculated C 72,53; H 4,82; N 10,57

Found C 71,87; H to 4.87; N 10,44

IR (KBr): 3240, 1750, 1670 cm-1.

300 MHz1H-NMR (DMSO-d6): 9,74 (D., 1H), 8,79 (DD., 2H), 8,27-8,17 (m , 5H), 7,89 (DDD., 1H), 7,74 (DDD., 1H), 7,54 (DD., 2H), 7,47-7,38 (m, 3H), 5,8 (D., 1H), 3,75 (C., 3H).

MS (EI; source 200oC, 70 V, 200 mA): 397 (M+.), 338, 233, 205, 77.

Example 14

(R, S)-N-[-(methoxycarbonyl)-2-thienylmethyl] -2 - phenylindolin-4-carboxamid

The result was, as in example 1, was 1.94 g (9.4 mmol) of hydrochloride (D,L) methylphenylglycidate with 2.7 ml (19.5 mmol) TEA and 2.0 g (7,8 mmole) 2-phenylphenol-4-carbonylchloride in 100 ml of a mixture of METI is the iMER 1. The resulting crude product was precrystallization three times from ethyl acetate, yielding 0.66 g of the target compound.

C23H18N2O3S

So pl. = 144 - 145oC

M. C. = 402,47

Elemental analysis: Calculated C 68,64; H 4,51; N OF 6.96

Found C 68,81; H 4,46; N Of 6.96.

IR (KBr): 3295, 1745, 1640 cm-1.

300 MHz1H-NMR (DMSO-d6): of 8.25 (DD., 1H), they were 8.22 (DD., 1H), 8,17 (DD., 2H), 7,95 (S. , 1H), 7,78 (DDD., 1H), 7,60 (DDD., 1H), 7,56 was 7.45 (m, 3H), 7,35 (DD. , 1H), 7,20 (m, 1H), 7,05 (DD., 1H), 7,05 (S. broad, 1H), 6.22 per (D., 1H), 3,9 (C., 3H).

MS (EI; source 200oC, 70 V, 200 mA): 402 (M+.), 343, 232, 204.

Example 15

(R,S)-N-[-(methoxycarbonylmethyl)benzyl]-2 - phenylindolin-4-carboxamid

The result was, as in example 5, from 1.39 g (the ceiling of 5.60 mmole) 2-phenylphenol-4-carboxylic acid, 1.2 g (the ceiling of 5.60 mmole) of the hydrochloride of (R,S) methyl-3-amino-3-phenylpropionate, 0,78 ml (ceiling of 5.60 mmole) TEA, 1.51 g (11.2 mmole) NOWT and 2,31 g (11.2 mmole) of DCC in 10 ml of THF, 4 ml of CH3CN and 7 ml of methylene chloride. Processing of the reaction mixture was carried out in the same manner as described in example 5. The resulting crude product was dissolved in methylene chloride and was left overnight at 0oC. to precipitate a number of dicyclohexylamine and filtered. The solution was evaporated in vacuum to dryness, and the target compound as a white solid.

C26H22N2O3< / BR>
So pl. = 156 - 158oC

M. C. = 410,47

Elemental analysis: Calculated C 76,07; H of 5.40; N 6,82

Found C 75,77; H 5,38; N 6,94.

IR (KBr): 3295, 1755, 1645, 1590, 1530 cm-1.

300 MHz1H-NMR (DMSO-d6): 9,40 (D., 1H), 8,29 (DD., 2H), 8,14 (D., 1H), 8,07 (D., 1H), 8,04 (S., 1H), 7,83 (DDD, 1H), 7,66 - 7,52 (m, 4H), 7,50 (D. , 2H), 7,40 (DD, 2H), 7,31 (DDD., 1H), ceiling of 5.60 (dt., 1H), 3,65 (C., 3H), 3,40-2,89 (m, 2H).

MS (EI; source 200oC, 70 V, 200 mA): 410 (M+.), 337, 233, 205.

Connection examples 16-49 General formula (I) (see table 2) was synthesized on the basis of relevant acylchlorides compounds (II) and amines (III), are shown in the table and following the synthesis procedure described in example 1. Acylchlorides was synthesized on the basis of the appropriate acid of the formula (II) and following the description of 1. Outputs the result of the reaction is calculated on the cleared, but supercriticalities material. Analytical and spectroscopic data of the compounds of examples 16-49 are given in table 5.

Connection examples 50-88 General formula (I) (see table 3) was synthesized on the basis of appropriate reagents (II) and (III) shown in the table, and following the synthesis procedure described in example 5. The reaction outputs calculated for purified, but supercrystal is.

Connection examples 89-92 General formula (I) (see table 4) was synthesized on the basis of other compounds of formula (I) (i.e., compounds of formula Ic) and following the procedure of synthesis described in example 10 (for compounds of examples 89, 90 and 91) and in example 9 (compound of example 92). The reaction outputs calculated on the cleared, but supercriticalities material. Analytical and spectroscopic data of the compounds of examples 89-92 are given in table 5.

Available in Table 5 legend have the following meanings:

IR = IR (infrared)

cm = cm

MHz = MHz

1H NMR = NMR

DMSO = DMSO

Calcd. = calculated

Found = found

d = D. (doublet or double)

dd = DD (double doublet)

s = S. (singlet)

br = broad

m = m (multiplet)

q = square (Quartet)

t = T. (triplet)

Example 93

(R, S)-N-[-(methoxycarbonyl)benzyl] -2-(p-chlorophenyl) quinoline-4-carboxamide

2 g (7.0 mmol) of 2-(p-chlorophenyl)quinoline-4-carboxylic acid and 1.7 ml (15.4 mmole) of N-methylmorpholine was dissolved under nitrogen atmosphere in 50 ml of dry THF. The solution was cooled to -20oC, and added of 0.91 ml (7.0 mmol) of isobutylacetate. After 20 minutes was added 2,12 g (10.5 mmole) of the hydrochloride of methyl (R,S)phenylglycinate and 1.3 the th temperature during the night. 3 Quiroga was added 5 ml of H2O, and the reaction mixture was evaporated in vacuum to dryness. The residue was dissolved in Et2O were washed with saturated solution of NaHCO3was separated, dried over sodium sulfate and evaporated in vacuum to dryness. The residual oil was subjected to instant flash-chromatography on silicagel column (230-400 mesh mesh with elution by the mixture hexane/isopropyl ether 7: 3, giving 0.9 g of the crude product, which was precrystallization three times with a mixture of ISO-PrO2/toluene, giving 0.5 g of the target compound.

C25H19ClN2O3< / BR>
So pl. = 170-172oC

M. C. = 430,90

Elemental analysis: Calculated 69,72; H of 4.45; N, 6.50

Found C 69,82; H 4,47; N 6,48

I. K. (KBr): 3280; 1740; 1670; 1635; 1590; 1530 cm-1.

300 MHz1H-NMR (DMSO-d6): 9,71 (d, 1H); 8,32 (d, 2H); 8,21 (d, 1H); 8,13 (d, 1H); 8,13 (s, 1H); a 7.85 (DD, 1H); to 7.67 (DD, 1H); 7,63 (d, 2H); 7,53 (DD, 2H); 7,46-7,38 (m, 3H); 5,79 (d, 1H); 3,74 (s, 3H).

MS (EI; source 200oC; 70 eV; 200 ľa): 430(M+.); 371; 266; 238; 203.

Example 94

(R)-N-[-(methoxycarbonyl)-4-methoxybenzyl]-2-phenylindolin-4-carboxamid

of 0.62 g (1.5 mmole) of (R)-N[-(methoxycarbonyl)-4 - hydroxybenzyl]-2-phenylindolin-4-carboxamide (compound of example 83) was dissolved in 30 ml of dry acetone and 2 ml of dry Dei room temperature was added 0,093 ml (1.5 mmole) of methyliodide and the reaction mixture was heated at 40oC for 4 hours. 3 Quiroga was again added in 0.104 g (0.75 mmole) K2CO3and 0,093 ml (1.5 mmole) of methyliodide, and the mixture was heated under reflux for an additional 6 hours. The mixture was evaporated in vacuum to dryness, dissolved in EtOAc and washed with water. The organic layer was dried over sodium sulfate and evaporated in vacuum to dryness. The residue was precrystallization of Et2O, giving 0.45 g of the target compound.

C26H22N2O4< / BR>
So pl. = 160-162oC

M. C. = 426,48

Elemental analysis: Calculated C 73,22; H 5,20; N 6,57

Found C 73,01; H 5,20; N 6,48

I. K. (KBr): 3210; 1750; 1635; 1625; 1590; 1530; 1515 cm-1< / BR>
300 MHz1H-NMR (DMSO-d6): 9,65 (d, 1H); of 8.28 (d, 2H); 8,21 (d, 1H); to 8.14 (d, 1H); 8,10 (s, 1H); to 7.84 (DD, 1H); to 7.67 (DD, 1H); to 7.61-7,49 (m, 3H); 7,44 (d, 2H); 6,98 (d, 2H); 4,70 (d, 1H); 3,79 (s, 3H); 3,76 (s, 3H).

MS (EI; source 200oC; 70 eV; 200 ľa): 426 (M+.); 367; 232; 204.

Example 95

Hydrochloride (R,S)-N-[-(methoxycarbonyl)- - (methyl) benzyl]-N-methyl-2-phenylindolin-4-carboxamide

0.50 g (1.3 mmole) of (R,S)-N-[ - (methoxycarbonyl)benzyl]-2-phenylindolin-4 - carboxamide (compound of example 4) was dissolved in 10 ml of dry DMF under nitrogen atmosphere. The solution was cooled to 0oC and added 0,052 g (1.3 mmole) of NaH (60%); after 20 minutes p which was at room temperature during the night, then the procedure was repeated by adding additional 0,052 g (1.3 mmole) of NaH (60%) and 0.1 ml (1.6 mmole) of MeI. After 6 hours at room temperature was added 10 ml of a saturated solution of NH4Cl, and the reaction mixture was evaporated in vacuum to dryness. The residue was dissolved in CH2Cl2and was rinsed with water; the organic layer was separated, dried over sodium sulfate and evaporated in vacuum to dryness. The residual oil was subjected to instant chromatography on silicagel column (230-400 mesh mesh, loirevalley a mixture of hexane/ethyl acetate 3:2 containing 0.5% conc. NH4OH, giving 0.18 g of the crude product, which was dissolved in Et2O, and is treated with a mixture of HCl/Et2O, yielding 0.15 g of the target compound.

C27H24N2O3HCl

M. C. = 460,96

I. K. (KBr): 1745; 1640; 1610 cm-1.

MS (EI; source 200oC; 70 eV; 200 ľa): 424 (M+.); 365; 232; 204.

Example 96

(R,S)-N-[-(methylcarbamoyl)benzyl]-2-phenylindolin-4-carboxamid

with 0.27 ml (3.1 mmole) of oxalicacid was dissolved in 2.3 ml of dry CH2Cl2in nitrogen atmosphere. The solution was cooled to -55oC, and dropwise added to 0.22 ml (3.1 mmole). DMSO, dissolved in 0.7 ml of dry CH2Cl2with maintaining the temperature below -50oproxetil)benzyl] -2-phenylindolin-4-carboxamide (compound of example 17), dissolved in 25 ml of dry CH2Cl2maintaining the temperature between -50 and -55oC. After 30 minutes at -55oC was added 1.9 ml (to 13.6 mmole) TEA without exceeding -40oC, then the reaction mixture was given to reach room temperature and it is stirred an additional 15 minutes. The reaction mixture was extinguished 5 ml of water and was extracted CH2Cl2; the organic layer was washed with water, 20% citric acid, saturated solution of NaHCO3and brine; the organic layer was separated, dried over sodium sulfate and evaporated in vacuum to dryness. The residual oil was subjected to instant chromatography on silicagel column (230-400 mesh mesh, loirevalley a mixture of hexane/ethyl acetate 70:30, containing 0.5% conc. NH4OH, yielding 0.64 g of the crude product, which was pulverized with a warm mixture of ISO-Pr2O/ISO-D 2: 1, was filtered and dried, yielding 0.5 g of the target compound.

C25H20N2O2< / BR>
So pl. = 160-161oC

M. C. = 380,45

Elemental analysis: Calculated C 78,93; H and 5.30; N OF 7.36

Found C 79,01; H 5,31; N, 7.27

I. K. (KBr): 3400; 3265; 1725; 1660; 1640; 1592 cm-1.

300 MHz1H-NMR (DMSO-d6): 9,60 (d, 1H); 8,29 (d, 2H); 8.17 and (d, 1H); to 8.14 (d, 1H); to 8.12 (s, 1H); of 7.82 (DD, 1H); the 7.65 (DD, 1H); to 7.61-7,51 (m, 5 the
(R,S)-N-[-(2-hydroxyethyl)benzyl]-2-phenylindolin-4-carboxamid

0.7 g (1.7 mmole) of (R,S)-N-[-(methoxycarbonylmethyl)benzyl]-2-phenylindolin-4-carboxamide (compound of example 15) was dissolved in 50 ml of tert-BuOH and 2 ml MeOH under nitrogen atmosphere. To the boiling solution for 15 minutes was added 60 mg (1.6 mmole) of NaBH4. The reaction mixture was heated under reflux for 6 hours, it was extinguished 5 ml of a saturated solution of NH4Cl and then was evaporated in vacuum to dryness. The residue was dissolved in CH2Cl2and was filtered salt solution; the organic layer was separated, dried over sodium sulfate and evaporated in vacuum to dryness. The crude product was subjected to instant chromatography on silicagel column (230-400 mesh mesh, elyuirovaniya Et2O containing 0.5% conc. NH4OH, and then crystallized from ISO-D, giving 0,19 g of target compound.

C25H22N2O2< / BR>
So pl. = 167-169oC

M. C. = 382,47

Elemental analysis: Calculated C 78,52; H 5,80; N 7,32

Found C 78,49; H 5,79; N 7,29

I. K. (KBr): 3360; 1650; 1592 cm-1.

300 MHz1H-NMR (DMSO-d6): of 9.30 (d, 1H); 8,31 (d, 2H); 8,13 (d, 1H); 8,10 (s, 1H); 8,03 (d, 1H); 7,81 (DD, 1H); to 7.64-7,51 (m, 4H); 7,46 (d, 2H); 7,39 (DD, 2H); 7.29 trend (DD, 1H); and 5.30 (dt, 1H); br4.61 (t, 1H); 3,61-to 3.41 (m, 2H); 2,11-1,86 (MP-(active compounds)-3-(2 - dimethylaminoethoxy)-2-phenylindolin-4-carboxamide

of 0.62 g (1.6 mmole) of (S)-N-(-active compounds)-3-hydroxy-2-phenylindolin-4-carboxamide (compound of example 85) was dissolved in 30 ml dry DMF. 3 Quiroga was added 0,58 g (4.0 mmole) of the hydrochloride of diethylaminoethylamine and 0.56 g (4.0 mmole) K2CO3and the reaction mixture was heated under reflux for 20 hours. K2CO3filtered, and the mixture was evaporated in vacuum to dryness, dissolved in AcOEt and washed with water and 20% citric acid. The aqueous layer was podslushivaet 2 standards. NaOH and was extracted EtOAc; the organic layer was washed brine, separated, dried over sodium sulfate and evaporated in vacuum to dryness. The residue was subjected to instant chromatography on silicagel column of 230-400 mesh holes, elyuirovaniya a mixture of CH2Cl2/MeOH 98: 2, containing 0.4% conc. NH4OH, and then a mixture of CH2Cl2/MeOH 86: 10, containing 0.6% conc. NH4HE, giving 85 mg of the crude product, which was dissolved in EtOAc and treated with a mixture of HCl/Et2O to obtain 75 mg of the target compound.

C29H31N3O2HCl

So pl. = 70oC Razlog.

M. C. = 490,05

I. K. (nujol): 3600; 3100; 1650: 1550 cm-1.

300 MHz1H-NMR (DMSO-d6): 10,28 (Shir.s, 1H); 9,50 (d, 1H)1,85 (m, 2H); to 0.97 (t, 3H).

MS (FAB, POS. , migliarina matrix, Xe gas, 8 Kev, the source 50oC): 454 (MH+).

Example 99

(S)-N-(-active compounds)-3-acetylamino-2-phenylindolin-4-carboxamid

0.40 g (1.05 mmole) of (S)-N-( - active compounds)-3-amino-2-phenylindolin-4 - carboxamide (compound of example 69) was heated in 25 ml of acetic anhydride at 70oC for 1 hour and then at 100oC for an additional 3 hours. The reaction mixture was then evaporated in vacuum to dryness, and the residue was dissolved in EtOAc, the solution was washed with water, saturated solution of NaHCO3, saline solution, dried over sodium sulfate and evaporated in vacuum to dryness. The crude product (0.39 g) was purified using instant chromatography on silicagel column, elyuirovaniya a mixture of hexane/EtOAc/conc. NH4OH 70: 30: 0.5, respectively, giving 0.2 g of pure compound, which was precrystallization from acetone, yielding 0.14 g of the target compound.

C27H25N3O2< / BR>
So pl. = 268-269oC

M. C. = 423,52

Elemental analysis: Calculated C 76,57; H 5,95; N 9,92

Found C 76,38; H 5,98; N 9,90.

I. K. (KBr): 3230, 1670, 1640, 1555, 1525 cm-1< / BR>
300 MHz1H-NMR (DMSO-d6): 9,65 (S., 1H), 9,05 (D., 1H), 8,10 (D., 1H), 7,80 (t, 1H), 7,70-to 7.50 (m, 4H), 7,45 to 7.2 261, 247, 218.

Example 100

The hydrochloride of (-)-(S)-N-(-active compounds)-3-(3 - dimethylaminopropoxy)-2-phenylindolin-4-carboxamide

1.2 g (3.1 mmole) of (-)-(S)-N-(-active compounds)-3-hydroxy-2-phenylindolin-4-carboxamide (compound of example 85) was dissolved in 15 ml of dry THF. Was added 1.0 g (8.2 mmole) 3-dimethylaminopropylamine dissolved in 10 ml of Et2O, 1.3 g (9.4 mmole)2CO3and 0.16 g of KI, and the reaction mixture stirred at room temperature for 30 minutes and then was heated under reflux for 2 hours. Then every 12 hours was added 0,77 g (6.3 mmole), 1.0 g (8.2 mmole), 0.6 g (4.9 mmole) and an additional 0.6 g (4.9 mmole) of 3-dimethylaminopropylamine, each time dissolved in 10 ml of Et2O, and a bit of KI, and the reaction mixture was heated under reflux. K2CO3filtered, and the mixture was evaporated in vacuum to dryness, dissolved in EtOAc and was washed with water and 20% citric acid. The aqueous layer was podslushivaet 2 standards. NaOH and was extracted EtOAc; the organic layer was washed brine, separated, dried over sodium sulfate and evaporated in vacuum to dryness. The residue was subjected to instant chromatography on silicagel column 230 - 400 mesh, elyuirovaniya a mixture of CH2Cl2/camping mixture of HCl/Et2O giving of 0.62 g of the target compound.

C30H33N3O2HCl,

So pl. = 108oC decomp.

M. C. = 504,08

[]2D0= - 16,0 (C = 0.5, MeOH)

I. K. (KBr): 3400, 3080, 1655, 1545 cm-1.

300 MHz1H-NMR (DMSO-d6): 10,55 (Shir.S., 1H), 9,35 (D., 1H), 8,09 (D., 1H), 7,92 (DD. , 2H), 7,76 (DDD., 1H), 7,65-7,51 (m, 5H), of 7.48-7,40 (m, 4H), 7,31 (DD., 1H), 5,10 (dt., 1H), 3.72 points-3,62 (m, 2H), 2,75-2,60 (m, 2H), 2,58 (D., 3H), 2,56 (D., 3H), 1,90-to 1.67 (m, 4H), and 1.00 (t, 3H).

MS (EI; source 180oC, 70 V, 200 mA): 467 (M+.), 466, 395, 58.

Example 101

The hydrochloride of (-)-(S)-N-(-active compounds)-3-[2-(1- phthaloyl)-ethoxy]-2-phenylindolin-4-carboxamide

to 1.9 g (5.0 mmol) of (-)-(S)-N-( - active compounds)-3-hydroxy-2-phenylindolin-4-carboxamide (compound of example 85) was dissolved in 20 ml of dry THF. 3 Quiroga was added 3.8 g (14.9 mmole) of 2-phthalimidopropyl dissolved in 15 ml of THF, 2.0 g (14.5 mmole) K2CO3and 0.25 g of KI, and the reaction

the mixture is stirred at room temperature for 2.5 hours and then was heated under reflux for 2 hours. 3 Quiroga was added to 1.9 g (7.4 mmole) of 2-phthalimidopropyl and a bit of KI, and the reaction mixture was heated under reflux additional 3.5 hours. Again, was added 0.5 g (2.0 mmole) of 2-phthalimidopropyl and the mixture was evaporated in vacuum to dryness, was dissolved in CH2Cl2and rinsed with water. The organic layer was dried over sodium sulfate and evaporated in vacuum to dryness. The residue was subjected to instant chromatography on silicagel column 230 - 400 mesh, elyuirovaniya a mixture of hexane/EtOAc 80:20, containing 0.5% conc. NH4OH and then hexane/EtOAc 60:40, containing 0.5% conc. NH4OH, giving 2.6 g of the pure product, which was pulverized with ISO-Pr2O, giving 2.5 g of the target compound.

C35H29N3O4< / BR>
So pl. = 172 - 175oC

M. C. = 555,64

[]2D0= -16,3 (C = 0.5 in MeOH)

I. K. (KBr): 3280, 3060, 2960, 1780, 1715, 1660, 1530 cm-1.

300 MHz1H-NMR (DSMO-d6): 9,27 (D., 1H), 8,03 (D., 1H), 7,92-to 7.84 (m, 4H), 7,78-of 7.69 (m, 3H), 7,60-7,53 (m, 2H), 7,46 - 7,38 (m, 4H), 7,27 (DD., 1H), 7,13? 7.04 baby mortality (m, 3H), 4,96 (dt., 1H), 3,92-of 3.78 (m, 2H), 3.72 points-3,55 (m, 2H), 1,78 (D. square, 2N), of 0.93 (t, 3H).

MS (EI; source 180oC, 70 V, 200 mA): 555 (M+.), 526, 421, 174.

Example 102

The hydrochloride of (-)-(S)-N-(-active compounds)-3-(2-aminoethoxy)-2 - phenylindolin-4-carboxamide

2.2 g (3.9 mmole) of the hydrochloride of (-)-(S)-N-[ - active compounds)-3- [2-(1-phthaloyl)ethoxy]-2-phenylindolin-4-carboxamide (compound of example 101) was dissolved in 150 ml of 96% EtOH, and the boiling solution was added to 0.38 ml (7,8 mmole) of hydrazine hydrate is added, and the solution Naga is (4.1 mmole), 0.2 ml (4.1 mmole), 0.4 ml (8.2 mmole) and 0.4 ml (8.2 mmole) of hydrazine hydrate is added and the reaction mixture was maintained at reflux. The reaction mixture was then evaporated in vacuum to dryness, dissolved in 20 ml of water, cooled and padillas 10 ml conc. Model HC1. The mixture was boiled for 1 hour and cooled, phthalhydrazide filtered. The aqueous layer was washed EtOAc and then podslushivaet 2 standards. NaOH and was extracted EtOAc, the organic layer was washed brine, separated, dried over sodium sulfate and evaporated in vacuum to dryness. The residue was subjected to chromatography on silicagel column 230 - 400 mesh, elyuirovaniya a mixture of EtOAc/MeOH 96:4, containing 1.2% conc. NH4OH, yielding the purified product, which was dissolved in EtOAc and treated with a mixture of HCl/Et2O, giving 1.2 g of the target compound.

C27H27N3O2HCl

So pl. = 119oC decomp.

M. C. = 462,00

[]2D0= -19,4 (c = 0.5 MeOH)

I. K. (KBr): 3400, 3080, 1640, 1545 cm-1< / BR>
300 MHz 1H-NMR (DMSO-d6): 9,45 (D., 1H), 8,09 (D., 1H), 8,00 (DD., 1H), 7,94 (Shir.S., 3H), 7,76 (DDD., 1H), 7,65-7,51 (m, 4H), of 7.48-7,40 (m, 3H), 7,31 (DD., 1H), 5,09 (dt., 1H), 3,83 (t, 2H), 2,72 (m, 2H), 1.93 and-of 1.80 (m, 2H), 0,99 (t, 3H).

MS (FAB, POS, migliarina matrix, Xe gas, ethoxy]-2-phenylindolin-4-carboxamide

2.0 g (5.2 mmole) of (-)-(S)-N-( - active compounds)-3-hydroxy-2 - phenylindolin-4-carboxamide (compound of example 85) was dissolved in 25 ml dry THF. Was added 1.0 g (7.5 mmole) of 2-pyrrolidineethanol and 2.2 g (15.9 mmole) K2CO3and the reaction mixture stirred at room temperature for 30 minutes and then was heated under reflux to the boiling solution was added 1.1 g (8.2 mmole) of 2-pyrrolidineethanol, and the solution was heated under reflux overnight. K2CO3filtered, and the mixture was evaporated in vacuum to dryness, dissolved in EtOAc and was washed with water and 20% citric acid. The aqueous layer was podslushivaet 2 standards. NaOH and was extracted EtOAc, the organic layer was washed brine, separated, dried over sodium sulfate and evaporated in vacuum to dryness. The residue was subjected to instant chromatography on silica gel 230 - 400 mesh, elyuirovaniya a mixture of CH2Cl2/MeOH 97:3, containing 0.5% conc. NH4OH, giving 1.8 g of the pure product, which was dissolved in EtOAc and treated with a mixture of HCl/Et2O, giving 2.0 g of the target compound.

C31H33N3O2HCl

So pl.= 110 - 115oC (decomp.)

M. C. = 516,08

[]2D0= +4,5 (c = 0.5 MeOH)

MS (EI; source 180oC, 70 V, 200 mA): 479 (M+.), 478, 383, 97,84.

Example 104

(-)-(S)-N-(-active compounds)-3-(dimethylaminomethylene)-2 - phenylindolin-4-carboxamid

1.1 g (2.8 mmole) of (-)-(S)-N-( - active compounds)-3-amino-2-phenylindolin-4-carboxamide (compound of example 69) was dissolved in 10 ml of warm toluene in a nitrogen atmosphere. To the solution was dropwise added 0.96 g (5.6 mmole) of Chloroacetic anhydride dissolved in 5 ml of toluene, and the solution was heated under reflux for 1 hour. The reaction mixture was evaporated in vacuum to dryness, suspenderbelt in 10 ml of CH2Cl2and dropwise poured into 5 ml ice mixture 28% Me2NH/EtOH. The solution is stirred at room temperature overnight, then added 15 ml of a mixture of 28% Me2NH/EtOH and the reaction mixture was heated at 60oC in a Parr apparatus. The mixture was evaporated in vacuum to dryness, dissolved in 20% citric acid and EtOAc washed. The aqueous layer was podslushivaet 2 standards. NaOH and was extracted EtOAc, the organic layer was washed brine, separated, dried over sodium sulfate and evaporated in vacuum to dryness, giving 1.4 g n is x2">

C29H30N4O2< / BR>
So pl. = 189 - 191oC

M. C. = 466,59

[]2D0= -63,1 (c = 0.5 MeOH)

I. K. (KBr): 3230, 3180, 1670, 1630, 1540 cm-1.

300 MHz1H-NMR (DMSO-d6): 9,41 (S., 1H), 8,97 (D., 1H), 8,08 (D., 1H), 7,81 (DD., 1H), 7,70-to 7.59 (m, 4H), 7,49-7,26 (m, 8H), 5,00 (dt., 1H), 2,55 (S., 2H), 1,97 (C., 3H), 1,90-of 1.65 (m, 2H), of 0.93 (t, 3H).

MS (EI; source 180oC, 70 V, 200 mA): 466 (M+.), 331, 58.

Example 105

N - (- dimethylbenzyl)-3-hydroxy-2-phenylindolin-4-carboxamid

2.0 g (7.5 mmol) of 3-hydroxy-2-phenylindolin-4-carboxylic acid in a nitrogen atmosphere was dissolved in 70 ml of dry THF and 30 ml of CH3CN. 3 Quiroga was added 1,02 g (7.5 mmole) of comellini and 1.12 g (8.3 mmole) of N-hydroxybenzotriazole (NOVT), and the reaction mixture was cooled at -10oC. was added dropwise 1,71 g (8.3 mmole) of DCC, dissolved in 20 ml of CH2Cl2and the solution was maintained at -5oC for 2 hours and then at room temperature overnight. The besieged dicyclohexylamine filtered, and the solution was evaporated in vacuum to dryness. The residue was dissolved in CH2Cl2and were washed with water, saturated solution of NaHCO3with 5% citric acid, saturated solution of NaHCO3and a salt solution. The organic layer OTDELA and was left overnight. Deposited some amount of dicyclohexylamine and filtered. The solution was evaporated in vacuum to dryness, giving 1.4 g of the crude product, which was subjected to instant chromatography on silica gel 230 - 400 mesh, elyuirovaniya first with hexane/EtOAc 9:1, then hexane/EtOAc 8:2, giving 0.4 g of the pure product, which was precrystallization twice from ISO-D, yielding 0.15 g of the target compound.

C25H22N2O2< / BR>
So pl. = 166 - 169oC (decomp.)

M. C. = 382,47

I. K. (nujol): 3200, 1650, 1580, 1535 cm-1.

300 MHz1H-NMR (DMSO-d6): 9,56 (S., 1H), 8,92 (Shir.S., 1H), 8,00-7,94 (m , 3H), 7,76 (Shir.D., 1H), 7,63 was 7.45 (m, 7H), was 7.36 (DD., 2H), 7,24 (DD., 1H), 1,72 (C., 6N).

MS (EI; source 180oC, 70 V, 200 mA): 382 (M+.), 264, 247, 219, 119.

Example 106

N - (- dimethylbenzyl)-3-amino-2-phenylindolin-4-carboxamid

2.0 g (7.6 mmole) 3-amino-2-phenylindolin-4-carboxylic acid in a nitrogen atmosphere was dissolved in 70 ml of dry THF and 30 ml of CH3CN. 3 Quiroga was added 1,02 g (7.6 mmole) of comellini and 1.12 g (8.3 mmole) of N-hydroxybenzotriazole (NOVT), and the reaction mixture was cooled at -10oC. was added dropwise 1,72 g (8.3 mmole) of DCC, dissolved in 20 ml of CH2Cl2and the solution was maintained at - 5owho was revivals, and the solution was evaporated in vacuum to dryness. The residue was dissolved in CH2Cl2and were washed with water, saturated solution of NaHCO3with 5% citric acid, saturated solution of NaHCO3and a salt solution. The organic layer was separated, dried over sodium sulfate and evaporated in vacuum to dryness, the residue was dissolved in 20 ml of CH2Cl2and was left overnight. Deposited some amount of dicyclohexylamine and filtered. The solution was evaporated in vacuum to dryness to obtain 2.0 g of the crude product, which was subjected to instant chromatography on silica gel 230 - 400 mesh, elyuirovaniya a mixture of hexane/EtOAc 6:4, containing 1% conc. NH4OH, giving 0.9 g of the pure product, which was precrystallization from a mixture of hexane/tOAc 1:1 and then from ISO-D, giving 0.45 g of the target compound.

C25H23N3O

So pl. = 166 - 168oC

M. C. = 381,48

I. K. (nujol): 3460, 3360, 3220, 1667, 1605, 1527 cm-1.

300 MHz1H-NMR (DMSO-d6): 9,05 (S., 1H), 7,87 (DD., 1H), 7,74-to 7.68 (m , 3H), 7,60-7,42 (m, 7H), 7,37 (DD., 2H), 7,24 (DD., 1H), 4,74 (S., 2H), 1,71 (C., 6N).

MS (EI; source 180oC, 70 V, 200 mA): 381 (M+.), 263, 218, 119.

Example 107

(-)-(S)-N-( - active compounds)-5-methyl-2-phenylindolin-4-carboxamid

0.8 g UB>3
CN. Added 0,43 g (3,20 mmole) of (S)-(-)- - ethylbenzylamine and 0.78 g (5.78 mmole) of N-hydroxybenzotriazole (NOVT), and the reaction mixture was cooled at -10oC. was added dropwise 0,69 g (3,34 mmole) of DCC, dissolved in 5 ml of CH2Cl2and the solution was maintained at -5oC for 2 hours and then at room temperature overnight. The besieged dicyclohexylamine filtered, and the solution was evaporated in vacuum to dryness. The residue was dissolved in CH2Cl2and were washed with water, saturated solution of NaHCO3with 5% citric acid, saturated solution of NaHCO3and a salt solution. The organic layer was separated, dried over sodium sulfate and evaporated in vacuum to dryness, the residue was dissolved in 10 ml of CH2Cl2and was left overnight. Deposited some amount of dicyclohexylamine and filtered. The solution was evaporated in vacuum to dryness obtaining of 1.15 g of the crude product, which was subjected to instant chromatography on silica gel 230-400 mesh mesh, elyuirovaniya a mixture of hexane/EtOAc 6:2 containing 0.5% conc. NH4OH, giving of 0.47 g of the pure product, which was precrystallization of ISO-Pr2O, containing a few drops of EtOAc, yielding 0.36 g of target compound in the form of a white powder which P> = -3,8 (C = 0.5 in MeOH)

I. K. (KBr): 3280, 3070, 3020, 1635, 1545 cm-1.

300 MHz1H-NMR (DMSO-d6): 9,20 (D., 1H), 8,23 (D., 2H), 7,93 (D., 1H), 7,78 (S. , 1H), 7,20-of 7.70 (m , 10H), 5,00 (dt., 1H), 2,38 (Shir.S., 3H), 1,70-1,90 (m, 2H), 0,95 (t, 3H).

MS (EI; source 180oC, 70 V, 200 mA): 380 (M+.), 246, 218.

Example 108

(R, S)-N-[ - (1-hydroxyethyl)benzyl]- 3-methyl-2-phenylindolin-4-carboxamid

Obtained as described in example 1, on the basis of 11,08 g (39,33 mmole) of the crude 3-methyl-2-phenylindolin-4-carbonylchloride, to 4.87 g (32,20 mmole) of 1-phenyl-2-hydroxypropylamino and 10,33 ml (74,14 mmole) TEA in 150 ml of a mixture 1: 1 of dry CH2Cl2and CH3CN. The precipitated hydrochloride TEA was filtered, and the filtrate was concentrated in vacuum to dryness, the residue was dissolved in CH2Cl2(100 ml) and washed with saturated solution of NaHCO3, 20% citric acid and brine. The organic layer was dried over sodium sulfate and evaporated in vacuum to dryness, giving 13,23 g of oil which crystallized from ISO-RHS2(100 ml) containing 6 ml of ISO-D, giving 9,14 g of target compound in the form of not-quite-white solid.

C26H24N2O2< / BR>
So pl. = 163-165oC

M. C. = 396,49

I. K. (nujol): 3400, 3260, 1635, 1580 cm-1< / BR>
Example 109

(stepping down from 3.25 g (25,60 mmole) of oxalicacid, 3.88 g (49,66 mmole) in DMSO, and 8.2 g (20,68 mmole) of (R,S)-N-[ - (1-hydroxyethyl)benzyl] - 3-methyl-2-phenylindolin-4-carboxamide (compound of example 108) and 15,72 ml (112,76 mmole) TEA in 230 ml of dry CH2Cl2. The reaction mixture was extinguished 40 ml of water, and the organic layer was separated and was washed with 20% citric acid, saturated solution of NaHCO3and a salt solution. The organic layer was dried over sodium sulfate and evaporated in vacuum to dryness, giving 9.4 g of the crude target compound in the form of oil. The residual oil was subjected to instant chromatography on silica gel 230 - 400 mesh, loirevalley a mixture of hexane/ethyl acetate 70:30, containing 1% conc. NH4OH, giving 7.7 g of the pure product, which was crystallized from a mixture of EtOAc/hexane 1:3, respectively, giving 6.0 g of the pure target compound.

C26H22N2O2< / BR>
So pl. = 156-158oC

M. C. = 394,48

I. K. (nujol): 3270, 3180, 1735, 1725, 1660, 1630, 1527, 1460 cm-1.

300 MHz1H-NMR (DMSO-d6): at 9.53 (D., 1H), 8,01 (D., 1H), 7,73 (DD., 1H), 7,62-7,35 (m, 12H), 5,97 (D., 1H), 2,30 (Shir.S., 3H), 2,18 (C., 3H).

MS (EI; source 180oC, 70 V, 200 mA): 394 (M+.), 352, 351, 246, 218, 217.

Example 110

(R,S)-N - [(ethyl)-4-pyridylmethyl]-2-phenylindolin-4-carboxamid

4.12 g (16,52 mmole) 2-phenyl what moose 1.50 g (11.01 mmole) of 1-(4-pyridyl)-n-Propylamine and of 2.23 g (16,52 mmole) of N-hydroxybenzotriazole (NOVT), and the reaction mixture was cooled at 0oC. was added dropwise to 3.41 g (16,52 mmole) of DCC, dissolved in 26 ml of dry CH2Cl2and the solution was maintained at 0oC for 2 hours and then stirred at room temperature for 36 hours. The besieged dicyclohexylamine filtered, and the solution was evaporated in vacuum to dryness. The residue was dissolved in 100 ml of CH2Cl2and were washed with water, 10% K2CO3with 5% citric acid and brine. The organic layer was separated, dried over sodium sulfate and evaporated in vacuum to dryness, the residue was dissolved in 30 ml of CH2Cl2and was left overnight. Deposited some amount of dicyclohexylamine and filtered. The solution was evaporated in vacuum to dryness, giving 3.5 g of the crude product, which was precrystallization three times from ISO-D, giving of 0.91 g of the target compound.

C24H21N3O

So pl. = 218 - 219oC

M. C. = 367,45

I. K. (KBr): 3260, 3060, 1648, 1595, 1545, 1350 cm-1.

300 MHz 1H-NMR (DMSO-d6): was 9.33 (D., 1H), 8,53 (D., 2H), 8,33 (DD., 2H), 8,15 (D., 1H), 8,14 (S., 1H), 8,03 (D., 1H), 7,82 (DD., 1H), 7,66 - 7,52 (m, 4H), 7,47 (D., 2H), of 5.05 (dt., 1H), 1,85 (DQC., 2H), and 1.00 (t, 3H).

MS (EI; source 180oC, 70 V, 200 mA): 367 is Olga) of the hydrochloride of 1-(2-thienyl)-n-Propylamine and 2.45 ml (17,60 mmole) TEA in nitrogen atmosphere was dissolved in 50 ml of dry CH2Cl2and 30 ml of CH3CN. Was added 2.0 g (8,00 mmol) 2-phenylphenol-4-carboxylic acid and 1.30 grams (9,60 mmole) of N-hydroxybenzotriazole (NOVT). Dropwise added 2,48 g (12.0 mmol) of DCC, dissolved in 30 ml of dry CH2Cl2and the solution stirred at room temperature for 36 hours. 3 Quiroga was added 50 ml of 10% HCl, and the solution further stirred for 2 hours. The besieged dicyclohexylamine filtered, and the organic layer was washed with 10% citric acid and 10% K2CO3. The organic layer was separated, dried over sodium sulfate and evaporated in vacuum to dryness. The crude product was subjected to instant chromatography on silica gel 230 - 400 mesh, elyuirovaniya a mixture of hexane/EtOAc/CH2Cl280:15:0,5, giving 2.0 g of a yellow oil, which crystallized from a mixture of toluene/hexane, yielding 0.9 g of pure target compound as white crystals.

C23H20N2OS

So pl. = 134 - 137oC

M. C. = 372,49

I. K. (KBr): 3230, 3060, 1630, 1590, 1545 cm-1.

300 MHz1H-NMR (DMSO-d6): was 9.33 (D., 1H), 8.30 to (DD., 2H), 8,15 (D., 1H), 8,13 (D., 1H), 8,08 (S., 1H), to 7.84 (DDD., 1H), 7.68 per-7,51 (m, 4H), 7,44 (DD. , 1H), 7,11 (D., 1H), 7,02 (DD., 1H), 5,33 (dt., 1H), 2,10-of 1.88 (m, 2H), 1,05 (t, 3H).

MS (EI; source 180oC, 70 V,4-carboxamide

the ceiling of 5.60 g (21,27 mmole) of 3-methyl-2-phenylindolin-4-carboxylic acid was dissolved in 100 ml of dichloroethane. Added 7,60 g (42,50 mmole) of N-bromosuccinimide and 0.52 g (2.00 mmole) of the peroxide Dibenzoyl, and the solution was heated under reflux for 24 hours. The reaction mixture was evaporated in vacuum to dryness, suspenderbelt in 100 ml of a mixture of 33% Me2NH/EtOH and stirred over night at room temperature. The solution was evaporated in vacuum to dryness, dissolved in 50 ml of 20% K2CO3and again evaporated in vacuum to dryness. To the residue was added 50 ml of water, and the solution was acidified with 37% HCl was evaporated in vacuum to dryness. The crude residue and 10.8 ml (77,20 mmole) of TEA were dissolved in 50 ml of CH2Cl2, 50 ml THF and 100 ml of CH3CN. Was added 3.00 g (22,20 mmole) of (S) - ( -) - ethylbenzylamine, 0,78 g (5.78 mmole) of N-hydroxybenzotriazole (NOVT) and 11.9 g (57,90 mmole) of DCC, and the solution stirred at room temperature overnight. The besieged dicyclohexylamine filtered, and the organic layer was evaporated in vacuum to dryness. The brown oily residue was dissolved in 100 ml of CH2Cl2and the precipitate was filtered off. The filtrate was extracted three times with 40% citric acid. The aqueous layer, podslushannyy solid K2CO3, extraheavy g of brown oil. The crude product was subjected to instant chromatography on silica gel 230 - 400 mesh, elyuirovaniya a mixture of ISO-Pr2O/CH2Cl29:1, giving 2.5 g of white solid, which was dissolved in toluene and was left overnight. The precipitated DCU was filtered off and the solution treated with ethanolic HCl was evaporated in vacuum to dryness. The crude product was precrystallization from a mixture of toluene/EtOH, giving 0.7 g of the pure target compound as colorless crystals.

C28H29N3O HCl

So pl. = 164 - 167oC

M. C. = 460,02

[]2D0= +25,3 (c = 1, MeOH)

I. K. (KBr): 3440, 3150, 3020, 2560, 2460, 1650, 1540 cm-1.

300 MHz1H-NMR (DMSO-d6, 353 K): 9,70 (Shir.S., 1H), 8,10 (D., 1H), 7,85 (DD. , 1H), 7,80 (Shir.S., 1H), 7,70-7,10 (m, N), 5,15 (dt., 1H), to 4.38-4,20 (m , 2H), 2,30 (C., 3H), 2,22 (C., 6N), 2,10-to 1.82 (m, 2H), and 1.00 (t, 3H).

MS (EI; source 180oC, 70 V, 200 mA): 423 (M+.), 380, 288.

Example 113

(S)-N-( - active compounds)-3-methyl-7-methoxy-2-phenylindolin-4 - carboxamid

Was obtained as described in example 1, on the basis of 1.27 g (4.09 to mmole) of the crude 3-methyl-7-methoxy-2-phenylindolin-4 - carbonylchloride, 0.55 g (4.09 to mmole) of (S)-(-)- - ethylbenzylamine and 1.71 ml (12,27 mmole) TEA in 24 ml of dry CH2Cl2and 1 ml of DMF to promote rasanya in vacuum to dryness, the residue was dissolved in CH2Cl2(30 ml) and was washed with 10% NaHCO3with 5% citric acid and brine. The organic layer was dried over sodium sulfate and evaporated in vacuum to dryness, giving of 1.87 g of the crude product, which was subjected to instant chromatography on silica gel 230 - 400 mesh, elyuirovaniya a mixture of hexane/EtOAc 70:30, giving 0.35 g of a yellow oil.

C27H26N2O2< / BR>
M. C. = 410,51

I. K. (KBr): 3240, 2965. 2930. 1635. 1535, 1220 cm-1< / BR>
Example 114

(S)-N-(-active compounds)-3-amino-5-methyl-2-phenylindolin-4-carboxamid

0.75 g (of 2.64 mmole) 3-amino-5-methyl-2-phenylindolin-4-carboxylic acid in a nitrogen atmosphere was dissolved in 30 ml of dry THF and 10 ml of CH3CN. Added 0,38 g and 2.83 mmole) of (S)-(-)- - ethylbenzylamine and 0.69 g (5,18 mmole) of N-hydroxybenzotriazole (NOVT), and the reaction mixture was cooled at -10oC. was dropwise added 0.61 g (2.97 mmole) of DCC, dissolved in 5 ml of CH2Cl2and the solution was maintained at -5 to 0oC for 2 hours, heated at 50oC 4 hours and then was maintained at room temperature during the night. The besieged dicyclohexylamine filtered, and the solution was evaporated in vacuum to dryness. The residue was dissolved in CH2Cl2and were washed with water, saturated solution of NaHCO3, camping over sodium sulfate and evaporated in vacuum to dryness; the residue was dissolved in 10 ml of CH2Cl2and was left overnight. Deposited some amount of dicyclohexylamine and filtered. The solution was evaporated in vacuum to dryness to obtain 0,86 g of the crude product, which was subjected to instant chromatography on silica gel 230 - 400 mesh, elyuirovaniya a mixture of CH2Cl2/MeOH/conc. NH4OH 90:10:0.5, respectively, giving 0,41 g of target compound in the form of butter.

C26H25N3O

M. C. = 395,50

I. K. (KBr): 3480; 3390; 3230; 3020; 1635; 1615; 1545 cm-1.

Example 115

(S)-N-( - active compounds) -3-methoxy-5-methyl-2-phenylindolin-4-carboxamid

1.29 g (4,40 mmole) of 3-methoxy-5-methyl-2-phenylindolin-4-carboxylic acid in a nitrogen atmosphere was dissolved in 40 ml of dry THF and 20 ml of CH3CN. Added to 0.63 g (4,62 mmole) of (S)-(-)-( - ethylbenzylamine and 1.13 g (at 8.36 mmole) of N-hydroxybenzotriazole (NOVT), and the reaction mixture was cooled at -10oC. was added dropwise 1.0 g (4,84 mmole) of DCC, dissolved in 5 ml of CH2Cl2and the solution was maintained at -5oC - 0oC for 2 hours, heated at 50oC 4 hours and then left overnight at room temperature. The besieged dicyclohexylamine filtered, and the solution was evaporated in HAC is money acid, a saturated solution of NaHCO3and a salt solution. The organic layer was separated, dried over sodium sulfate and evaporated in vacuum to dryness, the residue was dissolved in 20 ml of CH2Cl2and was left overnight. Deposited some amount of dicyclohexylamine and filtered. The solution was evaporated in vacuum to dryness, giving of 2.45 g of the crude product, which was subjected to instant chromatography on silica gel 230 - 400 mesh, elyuirovaniya a mixture of hexane/EtOAc 7:2 containing 0.5% conc. NH4OH, yielding 0.28 g of target compound in the form of butter.

C27H26N2O2< / BR>
M. C. = 410,52

I. K. (KBr): 3270; 3020; 1635; 1535 cm-1.

1. A derivative of quinoline formula I, its MES or salt

< / BR>
where Ar represents phenyl, optionally substituted with halogen, OH or C1-6by alkyl; benzyl, thienyl, pyridyl, C5-7cycloalkenyl group;

R represents a C1-8alkyl, C3-7cycloalkyl, hydroxy-C1-6alkyl, aminoalkyl, acylaminoalkyl, di-C1-6acylaminoalkyl, C1-6alkoxyalkyl, C1-6alkylsulphonyl, carboxy, C1-6alkoxycarbonyl, C1-6alkoxycarbonyl-C1-6alkyl, C1-6alkylaminocarbonyl, halogen-C1-6alkyl;

Rlinear or branched alkyl;

R3and R4that may be the same or different, independently represent hydrogen or C1-6linear or branched alkyl, phenyl, C1-6alkoxy, hydroxy, halogen, carboxamido, acyloxy, phthalimido, amino, mono - or di-C1-6alkylamino, -O(CH2)r-NT2in which r = 2, 3, or 4, and T represents C1-6alkyl;

R5represents C5-7cycloalkyl, phenyl, optionally substituted by 1 to 2 halogen atoms, or a single or benzo-condensed heterocyclic group, having aromatic character, containing from 5 to 9 ring atoms and containing 1 to 2 hetero-atoms in the ring selected from N, O and S;

X is 0.

2. Connection on p. 1, in which Ar represents phenyl, optionally substituted C1-6by alkyl or halogen; thienyl, or C5-7cycloalkenyl group.

3. Connection under item 1 or 2, in which R represents a C1-6alkyl, C1-6alkoxycarbonyl, C1-6alkylsulphonyl or hydroxy-C1-6alkyl.

4. The compound according to any one of paragraphs.1 to 3, in which R3represents hydrogen, hydroxy, halogen, C1-6alkoxy, or R1-6alkyl.

5. The compound according to any one of paragraphs.1 to 4, in which R4alkyl.

6. The compound according to any one of paragraphs.1 to 5, in which R5represents phenyl, thienyl, furyl, peril or thiazolyl.

7. Connection on p. 1 of formula I or its salt or MES, in which Ar represents phenyl, 2-chlorophenyl, 2-thienyl or cyclohexadienyl; R represents methyl, ethyl, n-propyl, -COOMe or-COMe; R1and R2are each hydrogen or methyl; R3represents hydrogen, methoxy or hydroxy; R4represents hydrogen, methyl, ethyl, methoxy, hydroxy, chlorine, bromine, dimethylaminoethoxy, 2-(1-phthaloyl)ethoxy, 2-(1-pyrrolidinyl)ethoxy, dimethylaminopropoxy; R5represents phenyl, 2-thienyl, 2-furyl, 2-perril, 2-thiazolyl or 3-thienyl; and X represents oxygen.

8. The compound according to any one of paragraphs.1 to 6, or its salt or MES formula Ia

< / BR>
where R, R2, R3and R4have the meanings given for formula I in any of paragraphs.1 - 6;

Y is phenyl, optionally substituted by 1 to 2 halogen atoms;

Z is Ar, as defined in paragraph 1.

9. Connection on p. 8 formula Ib

< / BR>
where R, R2, R3and R4, Y and Z have the meanings given in paragraph 8.

10. Connection on p. 1, selected from the group consisting of

(R,S)-N-(alpha-methylbenzyl)-2-phenylphenol)-2-phenylindolin-4-carboxamide,

(R,S)-N-[alpha-(methoxycarbonyl)benzyl]-2-phenylindolin-4-carboxamide,

(+)-(S)-N-[alpha-(methoxycarbonyl)benzyl]-2-phenylindolin-4-carboxamide,

(-)-(R)-N-[alpha-methoxycarbonyl)benzyl]-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -7-methoxy-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -7-hydroxy-2-phenylindolin-4-carboxamide,

hydrochloride(R, S)-N-[alpha-(carboxy)benzyl]-7-methoxy-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methylaminomethyl)benzyl]-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(2-thienyl)quinoline-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(2-furyl)quinoline-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(2-pyridyl)quinoline-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)-2-thienylmethyl] -2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonylmethyl)benzyl] -2-phenylindolin-4-carboxamide,

(-)-(R)-N-[alpha-(methoxycarbonyl)-1,4-cycloheptadiene]-2-phenylindolin-4-carboxamide,

unities. diast. (R,S)-N-[alpha-(1-hydroxyethyl)benzyl]-2-phenylindolin-4-carboxamide,

(R,S)-N-(alpha-active compounds)-3-methoxy-2-phenylindolin-4-carboxamide,

(R,S)-N-(alpha-Ativ is but[1,2-b] -quinoline-8-carboxamide,

(R,S)-N-(alpha-active compounds)-3-hexyl-2-phenylindolin-4-carboxamide,

(-)-(S)-N-(alpha-active compounds)-3-methyl-2-phenylindolin-4-carboxamide,

(+)-(R)-N-(alpha-active compounds)-3-methyl-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(2-methoxyphenyl)quinoline-4-carboxamide,

(R,S)-N-(alpha-active compounds)-3-phenyl-2-phenylphenol-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(2-forfinal)quinoline-4-carboxamide,

(R,S)-N-[alpha-(ethyl)-3,4-dichlorobenzyl]-2-phenylindolin-4-carboxamide,

(R,S)-N-[alpha-(hydroxymethyl)benzyl]-2-phenylindolin-4-carboxamide,

(R,S)-N-(alpha-active compounds)-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -3-methyl-2-phenylindolin-4-carboxamide,

(R,S)-N-(alpha-active compounds)-3-methyl-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -7-chloro-2-phenylphenol-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -6-methyl-2-phenylindolin-4-carboxamide,

(R,S)-N-[alpha-(methoxymethyl)benzyl]-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -6-chloro-2-phenylphenol-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -3-ethyl-2-phenylindolin-4-carboxamide,

(R,S)-N-(alpha-n-propylbenzyl)-2-finishi nil)-3-phthalimido-2-phenylindolin-4-carboxamide,

(R,S)-N-(alpha-active compounds)-3-n-propyl-2-phenylindolin-4-carboxamide,

(-)-(S)-N-(alpha-active compounds)-6-bromo-3-methyl-2-(4-bromophenyl)quinoline-4-carboxamide,

(-)-(S)-N-(alpha-active compounds)-6-bromo-3-methyl-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -6-methoxy-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(2-benzofuran)quinoline-4-carboxamide,

(R,S)-N-[(1,2-diphenyl)ethyl]-2-phenylindolin-4-carboxamide,

(R,S)-N-(alpha-trifloromethyl)-2-phenylindolin-4-carboxamide,

(-)-(S)-N-(alpha-active compounds)-3-methoxy-2-phenylindolin-4-carboxamide,

(-)-(S)-N-(alpha-active compounds)-3-ethyl-2-phenylindolin-4-carboxamide,

(R,S)-N-[alpha-(ethyl)-4-Chlorobenzyl]-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -N-methyl-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(3-thienyl)quinoline-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl]-5,6-dihydrobenzo[a] acridine-7-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(2-peril)quinoline-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(2-thiazolyl)quinoline-4-carboxamide,

(R,S)-N-[1-indenyl]-2-phenylindolin-4-carboxamide,

(R,S)-N-(alpha-n-butylbenzyl)-2-phenylindolin is ha-heptylbenzoic)-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(2-were)quinoline-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(4-methoxyphenyl)quinoline-4-carboxamide,

N-(1-phenylcyclohexyl)-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(4-hydroxyphenyl)quinoline-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(3,4-methylenedioxyphenyl)quinoline-4-carboxamide,

N-(alpha,alpha-dimethylbenzyl)-2-phenylindolin-4-carboxamide,

(R,S)-N-[alpha-(ethyl)-4-methylbenzyl]-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(3-peril)quinoline-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(3,4-dichlorophenyl)quinoline-4-carboxamide,

(-)-(R)-N-[alpha-(aminomethyl)benzyl]-2-phenylindolin-4-carboxamide,

(-)-(S)-N-[alpha-active compounds)-3-amino-2-phenylindolin-4-carboxamide,

(-)-(S)-N-[alpha-active compounds)-3-chloro-2-phenylphenol-4-carboxamide,

(-)-(S)-N-[alpha-active compounds)-3-bromo-2-phenylindolin-4-carboxamide,

(R,S)-N-(alpha-ISO-propylbenzyl)-2-phenylindolin-4-carboxamide,

(-)-(S)-N-(alpha-active compounds)-2-phenylindolin-4-carboxamide,

(+)-(R)-N-(alpha-active compounds)-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -6-fluoro-2-phenylindolin-what the f(methoxycarbonyl)benzyl] -2-(3-chlorophenyl)quinoline-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(2-chlorophenyl)quinoline-4-carboxamide,

(R,S)-N-(alpha-active compounds)-3-hydroxy-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl]-8-atomic charges-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -8-hydroxy-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(2,4-dichlorophenyl)quinoline-4-carboxamide,

hydrochloride (-)-(R)-N-[alpha-(methoxycarbonyl)-4-hydroxybenzyl] -2-phenylindolin-4-carboxamide,

N-diphenylmethyl-2-phenylindolin-4-carboxamide,

(-)-(S)-N-(alpha-active compounds)-3-hydroxy-2-phenylindolin-4-carboxamide,

(+)-(R)-N-(alpha-active compounds)-3-hydroxy-2-phenylindolin-4-carboxamide,

(-)-(R)-N-[alpha-(methoxycarbonyl)benzyl] -3-hydroxy-2-phenylindolin-4-carboxamide,

(-)-(R)-N-[alpha-(dimethylaminomethyl)benzyl] -2-phenylindolin-4-carboxamide,

(R,S)-N-[alpha-(dimethylaminomethyl)benzyl]-2-phenylindolin-4-carboxamide,

(R,S)-N-[alpha-(aminocarbonyl)benzyl]-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(1-pyrrolidinylcarbonyl)benzyl] -2-phenylindolin-4-carboxamide,

hydrochloride (-)-(R)-N-[alpha-(carboxy)benzyl] -2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(methoxycarbonyl)benzyl] -2-(4-chlorine is Yes,

hydrochloride (R,S)-N-[alpha-(methoxycarbonyl)-alpha-(methyl)benzyl]-N-methyl-2-phenylindolin-4-carboxamide,

(R,S)-N-[alpha-(methylcarbamoyl)benzyl]-2-phenylindolin-4-carboxamide,

(R,S)-N-[alpha-(2-hydroxyethyl)benzyl]-2-phenylindolin-4-carboxamide,

hydrochloride (-)-(S)-N-(alpha-active compounds)-3-(2-dimethylaminoethoxy)-2-phenylindolin-4-carboxamide,

(-)-(S)-N-(alpha-active compounds)-3-acetylamino-2-phenylindolin-4-carboxamide,

hydrochloride (-)-(S)-N-(alpha-active compounds)-3-(3-dimethylaminopropoxy)-2-phenylindolin-4-carboxamide,

hydrochloride (-)-(S)-N-(alpha-active compounds)-3-[2-(1-phthaloyl)ethoxy] -2-phenylindolin-4-carboxamide,

hydrochloride (-)-(S)-N-(alpha-active compounds)-3-(2-aminoethoxy)-2-phenylindolin-4-carboxamide,

hydrochloride (+)-(S)-N-(alpha-active compounds)-3-[2-(1-pyrrolidinyl)ethoxy] -2-phenylindolin-4-carboxamide,

(-)-(S)-N-(alpha-active compounds)-3-(dimethylaminomethylene)-2-phenylindolin-4-carboxamide,

N-(alpha,alpha-dimethylbenzyl)-3-hydroxy-2-phenylindolin-4-carboxamide,

N-(alpha,alpha-dimethylbenzyl)-3-amino-2-phenylindolin-4-carboxamide,

(-)-(S)-N-(alpha-active compounds)-5-methyl-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(1-hydroxyethyl)benzyl] -3-methyl-2-phenylindolin-4-carboxamide,

(R, S)-N-[alpha-(METI the carboxamide,

(R,S)-N-[alpha-(ethyl)-2-thienylmethyl]-2-phenylindolin-4-carboxamide,

hydrochloride (+)-(S)-N-(alpha-active compounds)-3-dimethylaminomethyl-2-phenylindolin-4-carboxamide,

(S)-N-(alpha-active compounds)-3-methyl-7-methoxy-2-phenylindolin-4-carboxamide,

(S)-N-(alpha-active compounds)-3-amino-5-methyl-2-phenylindolin-4-carboxamide,

(S)-N-(alpha-active compounds)-3-methoxy-5-methyl-2-phenylindolin-4-carboxamide.

11. The method of obtaining the compounds of formula I described in any of paragraphs.1 - 10, or MES or salt which comprises the reaction of compounds of formula III

< / BR>
where R', R'1, R'2and Ar' have the values R, R1, R2and Ar are defined for the formula I, or a group or atom capable of being converted into R, R1, R2and Ar, with a compound of formula II

< / BR>
where R'3, R'4, R'5and X' have the values of R3, R4, R5and X, defined for formula I, or a group or atom capable of being converted into R3, R4, R5and X, or its active derivative, with the formation of the compounds of formula Ic

< / BR>
and after this optional carrying out one or more of the following stages:

(a) when R', R'1- R'5, Ar' and X' have meanings different from R, R1- R5, Ar and X, prevrange formula I,

(b) when R', R'1- R'5, Ar' and X' have the values R, R1- R5, Ar and X, the transformation of any one of the groups R, R1- R5, Ar and X to another group R, R1- R5, Ar and X to obtain the compounds of formula I,

(c) formation of salts and/or MES, the compounds of formula I.

12. The method according to p. 11, in which the active derivative of a compound of formula II is galoyanized acid.

13. The pharmaceutical composition exhibiting properties antagonist NK3receptor and containing an effective amount of the compounds of formula I according to any of paragraphs.1 - 10 or its salt or MES and a pharmaceutically acceptable carrier.

 

Same patents:

The invention relates to new derivatives of amino(thio)ethers of the formula I

< / BR>
where X represents oxygen, sulfur, sulfinil, sulfonyl or, if R0and R1together are not alkalinous chain with 1 to 3 atoms, CH2:

Z represents -(CH2)n1-(CHA)n2-(CH2)n3and

n1 = 0, 1, 2 or 3,

n2 = 0 or 1,

n3 = 0, 1, 3 or 3, provided that

n1 + n2 + n3 < 4;

R0represents hydrogen or A;

R1represents hydrogen, A, OA, phenoxy, Ph, OH, F, Cl, Br, CN, CF3, COOH, COOA, acyloxy with 1-4 carbon atoms, carboxamido, -CHNH2, -CH2NHA, -CH2NA2,

-CH2NHAc, -CH2NHSO2CH3,

or

R0and R1together represent alkylenes chain with 1 to 3 carbon atoms or alkenylamine chain with 2 to 3 carbon atoms;

R2represents hydrogen, A, Ac, or-CH2-R4;

R3represents-CH2-R4or-CHA-R4;

R4is a Ph, 2-, 3 - or 4-pyridyl (unsubstituted or monosubstituted R5) or thiophene (unsubstituted, mono - or disubstituted by A, OA, OH, F, Cl, Br, CN and/or CF3or the other what it is, di-, tri-, Tetra-, or pentamidine F, CF3partially or fully fluorinated A, A and/or OA;

R6, R7, R8and R9each independently represents H, A, OA, phenoxy, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NHA, NA2, Ac, Ph, cycloalkyl c 3-7 carbon atoms, -CH2NH2, -CH2NHA, -CH2NA2, -CH2N HAC or-CH2NHSO2CH3or two coming together constitute the remainder alkylenes chain with 3-4 carbon atoms, and/or R1and R6together predstavljaet a chain with 3 or 4 carbon atoms;

A represents alkyl with 1-6 carbon atoms;

Ac is alkanoyl with 1-10 carbon atoms or aroyl with 7 to 11 carbon atoms;

Ph represents phenyl (unsubstituted or substituted R5, 2-, 3 - or 4-pyridium or phenoxyl group);

and physiologically acceptable salts, their derivatives

The invention relates to new derivatives of phenyl-oxo-alkyl-(4-piperidinyl)benzoate of formula I, their N-oxide forms, salts and steric isomer forms, where R1- halogen, R2is hydrogen, R3- C1-6-alkyl, or R2and R3form together a bivalent radical of the formula -(CH2)2- or -(CH2)3-, Alk-C1-6-alcander, R4is hydrogen or C1-6-alkoxy, R5, R6and R7is hydrogen, halogen, C1-6-alkyl, C1-6-alkyloxy or R5and R6taken together , form a bivalent radical of the formula-NR8-C(O)-NR9- or-NH-C(NH-R10)=N-, where R8and R9is hydrogen, C1-6-alkyl, R10is hydrogen, C1-6-alkylsulphonyl, C1-6-allyloxycarbonyl

The invention relates to new N-substituted piperidinylmethyl f-ly I, their N-oxide forms, isomers, and salts, where R1- halogen, C1-6alkylsulfonamides And divalent radical-CH2-CH2; -CH2-CH2-CH2- or-CH=CH-; R2is hydrogen or C1-6alkyloxy; L is a radical of formula-Alk-R4, -Alk-OR5, -Alk-NR6R7; Alk-C1-12alcander; R4is hydrogen, cyano, C1-6alkylsulphonyl,1-6allyloxycarbonyl, etc

The invention relates to substituted azetidinone General formula I listed in the description

The invention relates to certain CIS - and TRANS-benzopyrane having substituted benzamide in position C-4, and to their use for the treatment and/or prevention (prophylaxis) of certain CNS disorders

The invention relates to an improved process for the preparation of 4-(4'-forfinal)-3-hydroxyethylpiperazine f-ly I, where R3represents hydrogen; C1-C6-alkyl or C1-C6-alkylaryl, the recovery of the corresponding piperidine 2,6-dione f-crystals II, where R3have the above values, R4- C1-C6-alkyl, in the presence of a reducing agent - DIBORANE in an inert solvent, such as tetrahydrofuran or dimethoxyethane

The invention relates to a derived aydinonat or salts thereof, useful for use as a medicine, particularly as an inhibitor of activated factor X coagulation

The invention relates to compounds that should be applied in the pharmaceutical industry as biologically active substances to obtain drugs

The invention relates to the derivatives of hintline formula (I), where n = 2 and each R2independently halogen; R3- (1-4C)alkoxy; R1di-[(1-4C)alkyl]amino(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazine-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazine-1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C)alkoxy, di-[(1-4C)-alkoxy-(2-4C)alkyl] amino-(2-4C)alkoxy, and any R1containing methylene group, which is not linked to the nitrogen atom or oxygen atom, and optionally contains in the indicated methylene group, a hydroxyl Deputy, or their pharmaceutically acceptable salts, processes for their preparation, pharmaceutical compositions containing these compounds, and the use of inhibitory activity of compounds to inhibit the receptor tyrosinekinase in the treatment of proliferative diseases, such as cancer

The invention relates to new biologically active compounds, methods of treating diseases with their use and pharmaceutical compositions based on these compounds

The invention relates to new derivatives of acetic acid, the method of production thereof, pharmaceutical preparations containing such compounds and to the use of these compounds in the manufacture of pharmaceutical preparations

The invention relates to new sulfonamide of General formula I, where R1-R8A and B have the meanings indicated in the formula, which are inhibitors of endothelin and can be used for the treatment of diseases associated with the activity of endothelin, such as high blood pressure, as well as to pharmaceutical compositions based on

The invention relates to compounds intended for use in the pharmaceutical industry as active ingredients in the manufacture of medicines

The invention relates to substituted azetidinone General formula I listed in the description

The invention relates to new heterocyclic compounds of the formula I where ring a and ring To represent optionally substituted benzene or cycloalkane ring or optionally substituted 5 - or 6-membered aromatic heterocyclic ring containing one to two heteroatoms selected from nitrogen, sulfur and oxygen
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