N-[4-(heteroaromatic)phenyl]-heteroarenes

 

(57) Abstract:

The invention discloses compounds of formula (I), where R1, R2, R3, Het and described in the description, and their N-oxides, pharmaceutically acceptable salts connection and stereochemical isomeric form. Describes obtaining the pharmaceutical composition having inhibitory activity against metabolism of retinoic acid comprising a therapeutically effective amount of the compounds of formula (I) and a pharmaceutically acceptable carrier. Provides methods for obtaining the compounds of formula (I). 12 C. and 8 C.p. f-crystals, 8 PL.

The invention relates to N-[4-heteroaromatic)phenyl] heteroelement, their N-oxides and salts connection; it further relates to methods of their preparation and compositions containing them. Compounds of the present invention are powerful inhibitors of the metabolism of retinoic acid and, therefore, also described their use as pharmaceuticals.

EP-A-0260744, published March 23, 1988, discloses (1H-imidazol-1-ylmethyl)-substituted benzimidazole as inhibitors of the formation of androgen from C21-steroids as inhibitors of the biosynthesis thromboxanes June 6, 1990, opens the specified benzimidazole and similar benzotriazole as a potent suppressor of purification of plasma from retinoic acid, introduce endogenous or exogenous.

Retinoic acid (RA) is a key molecule in the regulation of growth and differentiation of epithelial tissue. However, RA is very rapidly metabolized by a series of enzymatic reactions that lead to its deactivation. Inhibition of metabolism of RA leads to increased levels of RA in plasma and tissues. Therefore, compounds with such inhibiting action, also called activity, imitating retinoids, have therapeutic and/or prophylactic potential in the field of dermatology and Oncology.

The new compounds of the present invention have activity that simulates retinoids and, moreover, have weak or have no endocrinological side effects.

The present invention relates to compounds of formula (I)

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their N-oxides, pharmaceutically acceptable salts connection and stereochemical isomeric forms, in which

R1represents hydrogen, a hydroxyl group, a C1-6alkyl or aryl;

R2represents hydrogen; C1-12alkyl; C3-7cyclogeraniol, or1-12alkyl, substituted by one or two substituents selected from C3-7-cycloalkyl, hydroxyl group, WITH1-4alkyloxy, ceanography, amino, mono - and di(C1-4alkyl)amino, mono - and di(aryl)amino groups, aryls1-4alkylamino, (C1-4alkyl)(arils1-4alkyl)amino group, pyrrolidinyl, piperidinyl, piperazinil, optionally substituted C1-4the alkyl, morpholinyl, perhydroanthracene, carboxyl, C1-4alkoxycarbonyl, aminocarbonyl, mono - and di(C1-4alkyl) aminocarbonyl, aryl, alloctype and aristocraty;

R3represents hydrogen, C1-6alkyl, aryl or C1-6alkyl, substituted aryl;

et represents an unsaturated heterocycle selected from imidazolyl, triazolyl, tetrazolyl and pyridinyl; each of these heterocycles may be optionally substituted amino group, mercaptopropyl, C1-6the alkyl, C1-6alkylthiophene or aryl;

represents an unsaturated mono - or bicyclic a heterocycle selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, chinoline, izochinolina, purinol, phthalazine, cinnoline, heatline and hiniduma or three substituents, selected from hydroxyl group, halogen, nitro, amino, C1-6of alkyl, hydroxys1-6of alkyl, Halogens1-6of alkyl, C1-6alkyloxy, C1-6allylthiourea, formyl, carboxyl, mono - and di(C1-6alkyl)amino, C1-6allyloxycarbonyl or aryl, or

represents a radical of the formula

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in which each X independently represents NR8, O, S, S(=O) or S(=O)2in which R8is hydrogen, C1-6the alkyl, aryl or arils1-6by alkyl;

R4or R5each independently represents hydrogen, hydroxyl group, halogen, a cyano, a nitro-group, an amino group, a C1-6alkyl, hydroxys1-6alkyl, Halogens1-6alkyl, C1-6alkyloxy, formyl, carboxyl, mono - or di(C1-6alkyl)amino group, a C1-6allyloxycarbonyl or aryl;

-R6-R7- represents a bivalent radical of the formula

-CR9=CR9-CR9=CR9- (b-1);

-N=CR9-CR9=CR9- (b-2);

-CR9=N-CR9=CR9- (b-3).

-CR9=CR9-N=CR9- (b-4);

-CR9=CR9-CR9=N- (b-5);

-CR9=N-N=CR9- (b-6);

-CR9=N-CR9=N- (b-7);

P>9=N- (b-11);

-CR9=N-N=N- (b-l2);

-N=CR9-N=N- (b-13);

-N=N-CR9=N- (b-14) or

-N=N-N=CR9- (b-15),

in which each R9independently represents hydrogen, hydroxyl group, halogen, a nitro-group, an amino group, a C1-6alkyl, hydroxys1-6alkyl, Halogens1-6alkyl, C1-6alkyloxy, formyl, carboxyl, mono - or di(C1-6alkyl)amino group, a C1-6-allyloxycarbonyl or aryl, and

aryl represents phenyl or phenyl substituted one, two or three substituents selected from hydroxyl group, halogen, ceanography, amino, mono - or di(C1-6alkyl)amino, C1-6of alkyl, Halogens1-6of alkyl, hydroxys1-6of alkyl, C1-6alkyloxy, formyl, carboxyl and C1-6-alkylsulphonyl, or two adjacent carbon atoms of the specified phenyl can be substituted by one bivalent radical having the formula C1-12alcander or Halogens1-12alcander.

As used in the foregoing definitions and below, the halogen is a common symbol for fluorine, chlorine, bromine and iodine; C3-7cycloalkyl is a General designation for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;<'s the ligature and having from 2 to 8 carbon atoms, such as, for example, ethynyl, 1-propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 3-heptenyl, 2-octenyl and the like; C1-4alkyl defines saturated hydrocarbon radicals, straight and branched chain, having from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C1-6alkyl includes WITH1-4alkyl and the higher homologues having 5 or 6 carbon atoms, such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; (C1-12alkyl includes C1-6alkyl and the higher homologues having from 7 to 12 carbon atoms, such as, for example, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, 2-etylhexyl, 3-etilosti and the like; (C1-12alcander denotes a bivalent saturated hydrocarbon radicals, straight and branched chain, having from 1 to 12 carbon atoms, such as, for example, 1,1-meander, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol, 1,5-pentandiol, 1,6-hexandiol, 1,2-propanediyl, 2,3-butanediyl, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,11-undecanedioic, 1,12-dodecanediol, 1,1,4,4-TETRAMETHYLBUTYL-1,4-diyl and the like; Halogens1-6alkyl denotes a polyhalogen C1-6alkyl, con is 1-12alcander denotes polyhalogen1-12alcander, specifically WITH1-12alcander, substituted 1 to 12 halogen atoms; triazolyl includes 1,2,4-triazolyl and 1,3,4-triazolyl; tetrazolyl includes 1H-tetrazolyl and 2N-tetrazolyl.

Unsaturated heteroaryl group, identified as Het, can be attached to the rest of the molecule represented by the formula (I), via any carbon or heteroatom of the ring, as desired. For example, if the heteroaryl group is imidazolium, it can be 1-imidazolium, 2-imidazolyl, 4-imidazolyl and 5-imidazolium if it is triazolium, it may be 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, 1,3,4-triazole-1-yl and 1,3,4-triazole-2-yl.

Pharmaceutically acceptable salts of the merger mentioned above, include therapeutically active non-toxic basic and acidic forms of salt accession, which may form a compound of formula (I). The acid salt form of accession of the compounds of formula (I), which in a free state is the basis, can be obtained by processing said basic form of the corresponding acid, such as an inorganic acid, for example of halogenation organic acid, such as, for example, acetic, hydroxyestra, propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, reklamowa, p-aminosalicylic, amoeba, salicylic acid and similar acids.

The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic base, i.e., a metal or amine salt form attached, by treatment with appropriate organic or inorganic bases. The corresponding basic salt forms include, for example, ammonium salts, salts of alkali and alkaline earth metals, i.e., salts of lithium, sodium, potassium, magnesium, calcium and the like, salts with organic bases, for example salts with benzathine, N-methyl-D-glucamine, geranamine, and with amino acids, such as arginine, lysine and the like.

On the contrary, these salt forms can be converted into a free form by treatment of the appropriate base or acid.

The term "salt accession", as used above, also includes a solvate, which is capable of clicks and the like.

Have in mind that the N-oxide forms of the compounds of formula (I) include those compounds of formula (I) in which one or more atoms of nitrogen oxidized to the so-called N-oxide.

The term "stereochemical isomeric forms" as used previously and hereinafter, includes all possible isomeric forms, in which there may be compounds of formula (I). If not mentioned or stated otherwise, the chemical name of the compounds denotes the mixture, in particular a racemic mixture of all possible stereochemical isomeric forms, with the specified mix containing all diastereomers and enantiomers of the basic structure of the molecule. Have in mind that, stereochemical isomeric forms of the compounds of formula (I) and mixtures of such forms covered by formula (I).

In particular, the compounds of formula (I) and some of the intermediates have at least one stereogenic center in their structure. Stereogenic center can be both R-and S-configuration, the symbols R and S used in accordance with the rules described in Pure Appl. Chem., 1976, 45, 11-30.

Some of the compounds of formula (I) may also exist in tautomeric forms. Although such shape is not clearly indicated in the formula above, it is understood, hydrogen, can exist in the corresponding tautomeric forms.

Wherever hereinafter used, the term "compound of formula (I), it is understood that it also includes N-oxides, pharmaceutically acceptable salts connection and all stereoisomeric forms.

A separate group of compounds includes compounds of formula (I), in which

R1represents hydrogen, C1-6alkyl or aryl;

R2represents hydrogen, C1-12alkyl; C3-7cycloalkyl; C2-8alkenyl; aryl or1-12alkyl, substituted by one or two substituents selected from C3-7cycloalkyl, hydroxyl group, WITH1-4alkyloxy, ceanography, amino, mono - and di(C1-4alkyl)amino, mono - and di(aryl)amino groups, aryl-C1-4alkylamino, (C1-4alkyl)(arils1-4alkyl)amino group, pyrrolidinyl, piperidinyl, piperazinil, morpholinyl, perhydroanthracene, carboxyl,1-4allyloxycarbonyl, aminocarbonyl, mono - and di(C1-4alkyl)aminocarbonyl, aryl, alloctype and aristocraty;

represents an unsaturated mono - or bicyclic a heterocycle selected from the group consisting of 2-pyridinyl, 3-pyridazinyl, 2-pyrimidinyl, is alinia, 4-hintline and 2-khinoksalinona, each of these unsaturated mono - or bicyclic heterocycles may be optionally substituted by one, two or three substituents selected from hydroxyl group, halogen, nitro, amino, C1-6of alkyl, hydroxys1-6of alkyl, Halogens1-6of alkyl, C1-6alkyloxy, formyl, carboxyl, mono - or di(C1-6alkyl)amino, C1-6allyloxycarbonyl or aryl, or

represents a radical of formula (a) or (b) in which R4or R5each independently represents hydrogen, hydroxyl group, halogen, a nitro-group, an amino group, a C1-6alkyl, hydroxys1-6alkyl, Halogens1-6alkyl, C1-6alkyloxy, formyl, carboxyl, mono - or di(C1-6alkyl)amino group, a C1-6allyloxycarbonyl or aryl.

A group of preferred compounds includes those compounds of formula (I), in which

R1represents hydrogen, a hydroxyl group, a C1-6alkyl;

R2represents hydrogen, C1-12alkyl, C3-7cycloalkyl, pyrrolidinyl, optionally substituted C1-4the alkyl or C1-4allyloxycarbonyl, aryl or C1-12alkyl, substituted one is)amino, (C1-4alkyl)(arils1-4alkyl)amino, C1-4allyloxycarbonyl, morpholinyl, piperidinyl, piperazinil, optionally substituted C1-4the alkyl, and alloctype;

R3represents hydrogen, C1-6alkyl;

Het represents imidazolyl, optionally substituted C1-6by alkyl; pyridinyl or thiazolyl;

represents 2-pyridinyl, optionally substituted hydraxis1-6the alkyl, formyl or C1-6allyloxycarbonyl; 2-honokalani; 1-ethenolysis; 2-chinoline; 3-pyridazinyl, optionally substituted C1-6by alkyl; purinol; 2-pyrazinyl; 1-phthalazine; 4-hintline, optionally substituted by aryl; 2-pyrimidinyl; 4-pyrimidinyl, optionally substituted C1-6alkylthiol, or

represents a radical of formula (a) or (b) in which

X represents NH, O or S;

R4or R5each independently represents hydrogen, a hydroxyl group, a nitrogroup, cyano, amino, C1-6alkyl or aryl;

-R6-R7- represents a bivalent radical of formula (b-1), (b-2) or (b-10), in which each R9independently represents hydrogen, C1-6alkyl, hydroxychlorides the compounds of formula (I), in which Het is imidazolyl or triazolyl, optionally substituted, in particular 1-imidazolium, optionally substituted C1-6the alkyl or aryl, 2-imidazolyl, optionally substituted C1-6the alkyl, 5-imidazolyl, optionally substituted C1-6the alkyl, 1,3,4-triazole-1-yl and 1,2,4-triazole-1-yl.

Also of particular interest are compounds of formula (I) in which a represents a radical of formula (b), especially those in which

X represents O or S and

-R6-R7- represents a bivalent radical of formula (b-1).

Other compounds of particular interest are the compounds of formula (I) in which R2represents a C1-12alkyl; C3-7cycloalkyl; aryl or1-12alkyl, substituted mono - and di(C1-4alkyl)amino group, WITH1-4allyloxycarbonyl or arroceros.

Deserving special attention are compounds of special interest, in which Het is 1-imidazolyl, optionally substituted C1-6the alkyl or aryl; 2-imidazolium, optionally substituted C1-6by alkyl; 5-imidazolium, optionally substituted C1-6by alkyl; 1,3,4-triazole-1-yl/SUB>alkyl, substituted mono - or di(C1-4alkyl)amino group, and

represents a radical of the formula

in which X represents O or S.

The preferred compounds are the compounds of formula (I) in which R1is hydrogen and R2is3-7-cycloalkyl or C1-6the alkyl, optionally substituted di(C1-6alkyl)amino group.

Most preferred are compounds

N-[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl]phenyl]-2-benzothiazole;

N-[4-[2-ethyl-1-(1H-1,2,4-triazole-1-yl)butyl]phenyl]-2-benzoxazolone;

N-[4-[2-ethyl-1-(1H-1,2,4,-triazole-1-yl)butyl]phenyl]-2-benzothiazole;

N-[4-[2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl] phenyl] -2-benzothiazole;

N-[4-[2-(dimethylamino)-1-(1H-1,2,4-triazole-1-yl)propyl] phenyl] -2-benzothiazole;

N-[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl]phenyl]-2-benzoxazolone;

N-[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl] phenyl] -6-methoxy-2-benzothiazole;

N-[4-[2-(dimethylamino)-1-(1H-imidazol-1-yl)-2-methylpropyl] phenyl] -2-benzothiazole;

N-[4-[2-(dimethylamino)-2-methyl-1-(1H-1,2,4-triazole-1-yl)propyl] phenyl]-2-benzothiazole;

N-[4-[cyclohexyl(1H-imidazol-1-yl)methyl]phenyl]-2-benzothiazole;

N-[4-[cyclohexyl(1H-1,2,4-triazoline salt accession.

Wherever hereinafter are used, the symbols R1-R3, Het, aryl, and denote the same as in the formula (I), unless otherwise indicated.

In General, the compounds of formula (I) can be obtained by the reaction of intermediate compounds of formula (II), in which1is the corresponding leaving group such as, for example, halogen, hydroxyl or alkylsulfonates, with an intermediate compound of formula (III) or its functional derivatives. For example, functional derivatives of imidazole may be 1,1'-carbonyldiimidazole.

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This reaction can be carried out in an inert towards the reaction solvent, such as, for example, acetonitrile or tetrahydrofuran, in the presence of a suitable base, such as, for example, potassium carbonate. In the case when W1is a hydroxyl group, it may be convenient to carry out the above reaction in the presence of triphenylphosphine and diethylazodicarboxylate or a functional derivative of any of these reagents.

In this and subsequent reactions, the reaction products can be separated from the reaction medium and, if necessary, subjected to further purification in accordance with the techniques widely lime.

Alternative compounds of formula (I) can be obtained by N-alkylation of the intermediate compounds of formula (IV) an intermediate compound of formula (V), where W2is the corresponding leaving group such as, for example, fenoxaprop, inert to the reaction solvent, such as, for example, N,N-dimethylformamide.

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The compounds of formula (I) in which a is a radical of formula (a), in which X represents S, and the above compounds represented by formula (I-a-1) can be obtained by the reaction of intermediate compounds of formula (VI) with an intermediate compound of formula (VII), in which W3is the corresponding leaving group, in an inert towards the reaction solvent, such as, for example, tetrahydrofuran.

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Suitable intermediate compounds of formula (VII) can be replaced by a functional derivative, such as, for example, catalinae derived. When the carbonyl group in the intermediate compound of formula (VII) detalizirovano, the reaction is appropriately carried out in the presence of acid, such as hydrochloric acid.

The compounds of formula (I) in which R3is hydrogen and alloy (I-b-1), can be obtained by the reaction of intermediate compounds of formula (VIII) with an intermediate compound of formula (IX-1) in an inert towards the reaction solvent, such as, for example, tetrahydrofuran or 1-methyl-2-pyrrolidinone.

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In the above reaction intermediate compound (IX-1) can be replaced by an intermediate compound of formula (IX-2) forming thus the compounds of formula (I-a-1) in which R3is hydrogen and R4is an amino group, and these compounds are represented by formula (I-a-2).

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Instead of intermediate compound (VIII) in the reaction can also use an intermediate compound of formula (X). The above reaction is then carried out in an inert towards the reaction solvent, such as, for example, dimethyl sulfoxide, in the presence of a suitable base, such as, for example, sodium hydroxide.

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The compounds of formula (I) in which R1is a hydroxyl group, can be obtained by the reaction of intermediate compound corresponding to the compound of formula (I) in which R1and R2together with the carbon atom to which they are attached, form a carbonyl group with Het-H (III) or its functionality is compared to the reaction solvent, such as tetrahydrofuran, and optionally in the presence of chlorotrimethylsilane.

The compounds of formula (I) in which R2is C1-4alkalosis1-12the alkyl can be obtained by the reaction of intermediate compound corresponding to the compound of formula (I) in which R2is L-C1-12the alkyl, where L is an appropriate leaving group, such as, for example, alkylsulfonates, with C1-4alkyla-M+where M+an appropriate metal ion, such as, for example, Na+, in an appropriate solvent such as methanol.

The compounds of formula (I) in which R3is optionally substituted C1-12the alkyl can be obtained by reduction of an intermediate compound corresponding to the compound of formula (I), wherein said R2attached to the carbon atom bearing the substituent R2, a double bond, using the appropriate reducing agent, such as, for example, borohydride sodium, in an appropriate solvent such as methanol.

The compounds of formula (I) can also be transformed into each other, adhering to the known methods of transformation of functional groups.

3different from hydrogen.

Also the compounds of formula (I) containing C1-6allyloxycarbonyl Deputy, can be converted into compounds of formula (I) where the specified Deputy restore to hydroxymethyl, and, if required, specified hydroxymethylene Deputy may further be converted into a formyl group.

The compounds of formula (I-a-2) in which R5is cyano, can then be introduced into reaction with HN=CH-NH2or its functional derivatives, thus forming a corresponding compound of formula (I-b-1) in which R6-R7is-N=CH-N=C(NH2)-.

The compounds of formula (I) in which R1is a hydroxyl group can be converted into compounds of formula (I) in which R1is hydrogen, using an appropriate reagent, such as chloride of tin.

The compounds of formula (I) can also be converted into the corresponding N-oxide forms, following known methods of transformation of trivalent nitrogen into its N-oxide form. This reaction N-oxidation can usually be carried out by introducing into the reaction educt of the formula (I) with 3-phenyl-2-(phenylsulfonyl)oxazin rockside include, for example, hydrogen peroxide, peroxides of alkali metals or alkaline earth metals, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may include peroxyacids, such as, for example, benzoperylene acid or substituted with halogen benzoperylene acid, such as 3-chlorobenzophenone acid; phenoxyalkanoic acid, for example peroxidasa acid; alkylhydroperoxide, for example tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alcohols such as ethanol and the like, hydrocarbons such as toluene, ketones, such as 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

Some of the compounds of formula (I) and some of the intermediate compounds of the present invention may have asymmetric carbon atom. Pure stereochemical isomeric forms of these compounds and these intermediate compounds can be obtained using known techniques. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter-current separation, sideromecanica transformations specified racemic mixture using a suitable separating agent, such as, for example, chiral acid, a mixture of diastereomeric salts or compounds, then the physical separation of this mixture of the diastereomeric salts or compounds with, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods, and, finally, transformation of these separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemical isomeric forms may also be obtained from pure stereochemical isomeric forms of the appropriate intermediates and starting compounds, provided that the intermediate reactions are stereospetsifichno.

An alternative method of separating the enantiomeric forms of the compounds of formula (I) and intermediates include liquid chromatography, in particular liquid chromatography with chiral stationary phase.

Some of the intermediates and starting compounds are known compounds and can be commercially available or can be obtained according to known methods.

In particular, the intermediate compounds of formula (II) in which R1and R3are hydrogen, W represented by formula (II-b-1), can be obtained by the reaction of intermediate compounds of formula (IX) with an intermediate compound of formula (XI-1) or (XI-2) and subsequent restoration of the educated thus intermediate compounds.

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The first reaction is carried out according to the same technique as used above to obtain compounds of formula (I-b-1) from the intermediate compounds of formula (IX) and intermediate compounds of the formula (VIII) or (X). The recovery may be carried out in the presence of a suitable reducing agent in an appropriate inert to the reaction solvent, such as, for example, sodium borohydride in methanol or alumoweld lithium in tetrahydrofuran and water.

In some cases it may be convenient to replace the hydroxyl group in the intermediate compound of formula (II-b-1) to another leaving group, such as, for example, halogen or sulfonylurea derived, for example p-toluensulfonate-group or alkylsulfonates, and thus, the intermediate compound (II-b-2) and (II-b-3). This reaction can be carried out in an inert towards the reaction solvent, such as, for example, chloroform, and in the presence of a suitable reagent, such as, for example, lionelrichie intermediate compounds of formula (XII), in which R is a protective group such as, for example, WITH1-4alkylsulphonyl, benzoyl or1-4allyloxycarbonyl, with an intermediate compound of formula (III) and subsequent reaction of the formed thereby amide derivative with an acid, such as, for example, hydrochloric acid. The intermediate amide derivative can be carried out using the same methodology that was used to obtain the compounds of formula (I) from the intermediate compounds of formula (II) and (III).

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Intermediate compounds of formula (VI) can be obtained by further reaction of the intermediate of formula (IV) with a combination of two suitable reagents, such as, for example, NH4SCN in combination with benzoyl chloride or a functional derivative of any of these reagents in an inert towards the reaction solvent, such as, for example, 2-propanone. With educated thus intermediate compounds may be unsecured by using a suitable base, such as, for example, sodium hydroxide.

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Intermediate compounds of formula (IV) in which R3is hydrogen, and these intermediate compounds represented by formula (IV-a), maissade, in an inert towards the reaction solvent and in the presence of a suitable base, such as, for example, sodium hydroxide, thus giving the intermediate compounds of formula (VIII).

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Intermediate products of the formula (IV-a) can be further used to obtain intermediates of formula (X). The specified receiving involves the reaction of the intermediate compound (IV-a) CS2and CH3-I or a functional derivative of any of these reagents in an inert towards the reaction solvent and in the presence of a base, such as, for example, sodium hydroxide.

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The compounds of formula (I) inhibit the destruction of the plasma retinoids such as all-TRANS-retinoic acid, 13-CIS-retinoic acid and derivatives thereof, which leads to a more stable concentration of retinoic acid in plasma and tissues and improved control of differentiation and growth of various cell types. This action of the compounds of the present invention is also referred to as activity, imitating retinoids, because the introduction of the compounds of formula (I) causes the same effect as with the introduction of retinoids. As such, the compounds of the present invention can be used to pin the material or mesenchymal; will they ectodermal, endodermal or mesoderm origin.

The ability to delay the metabolism of retinoic acid can be confirmed by various experiments in vitro and in vivo. Specific in vitro method described in example C. 1 and shows the inhibitory activity of the compounds of formula (I) on the metabolism of retinoic acid in cancer cells human mammary gland. Compounds of the present invention is also effective in suppressing the stimulated effect vaginal keratinization in ovariectomized rats as described in example C. 2.

In addition, the compounds of formula (I) show weak or completely missing endocrinological side effects and have good accessibility by oral administration.

In connection with the above-described pharmacological properties, particularly their activity, imitating retinoids, compounds of the present invention are useful for the treatment and/or prevention of diseases characterized by abnormal proliferation and/or abnormal differentiation of cells, particularly cells, for which growth and differentiation are sensitive to the action of retinoids. Such diseases are related to the field of Oncology, for example cancer of gologo bladder, prostate cancer and similar diseases, and dermatology, such as diseases associated with keratinization, such as acne rosacea, acne vulgaris, psoriasis, severe psoriasis, lamellar ichthyosis, plantar warts, amosulalol, acanthosis nigricans, planus, molluscum, an excess of black pigment in the skin, corneal epithelial abrasion, landkarten language, disease, Fox-Fordyce, cutaneous metastatic melanoma and keloids, epidermolizei hyperkeratosis, disease Darier, pytilias rubra pilaris, congenital Ichtiofauna erythroderma, hyperkeratosis palmaris and planaris, the excess of the black pigment in the skin, hyperpigmentation and similar diseases.

Further, the compounds of formula (I) are suitable for suppressing metabolism of the introduced exogenous or educated endogenous 1, 25-dihydroxyvitamin D3(calcitriol). The inhibitory activity of the compounds of formula (I) on the metabolic destruction of calcitriol can be shown by measuring the effect of these compounds on the destruction of calcitriol in the foreskin keratinocytes, the cells of the kidney pig cells and human hepatoma. Due to their inhibitory effect on the metabolism of calcitriol compounds of formula (I) can the blast metabolic bone diseases. Also describes the effect of calcitriol on the effects and/or production of interleukins. Furthermore, calcitriol is used in the treatment of diseases characterized by abnormal proliferation and/or differentiation of cells, particularly diseases associated with keratinization, such as described above (Bouillon et al. Endocrine Reviews, 1995, 16, 200-257).

From the above-described applications of the compounds of formula (I), it follows that the present invention relates to a method of treating warm-blooded animals suffering from diseases that are characterized by abnormal proliferation and/or abnormal differentiation of normal, precancerous, and cancer cells, whether they are epithelial or mesenchymal; will they ectodermal, endodermal or mesoderm origin. This method comprises the systemic or local injection of simulating retinoid amount of the compounds of formula (I), is effective in treating above-described diseases, especially diseases associated with keratinization, such as psoriasis, optionally in the presence of an effective amount of retinoic acid, its derivative or its stereochemical isomeric form. The present invention further relates to a method of treatment of patients, suffering is alacarte, especially conditions associated with a keratinization, such as psoriasis, and this method includes the introduction of the patient (a) an effective amount of calcitriol or its prodrugs and (b) an effective amount of the compounds of formula (I).

Thus, the present invention also relates to the use of compounds of formula (I) defined above, as a medicine, in particular for use in the manufacture of medicaments for the treatment of diseases associated with keratinization, such as psoriasis. The present invention further relates to the use of compounds of formula (I) as defined above, in combination with retinoic acid, its derivative or a stereochemical isomeric form or in combination with calcitriol or a prodrug as a medicine.

For convenience, the introduction of the compounds of the invention can be presented in various pharmaceutical forms. As appropriate compositions can specify all compositions commonly used for systemic or local administration of drugs. To obtain pharmaceutical compositions of this invention simulates the retinoid effective amount of a particular compound, optionally in formley filler, which can have many different forms, depending on the form of the composition desired for administration. Preferably, these pharmaceutical compositions were in the form of single dose suitable for oral, rectal, subcutaneous or parenteral injection. For example, to obtain a composition in the form of doses for oral administration may be used any conventional pharmaceutical environment, such as, for example, water, glycol, oil, alcohol and the like, in the case of oral liquid preparations such as suspensions, syrups,

elixirs and solutions, or solid media, such as starches, sugars, kaolin, lubricants, binders, dezintegriruetsja agents and the like in the case of powders, pills, capsules and tablets. Because of the convenience in use of tablets and capsules represent the most preferred form a single oral dose, in this case, obviously, apply solid pharmaceutical carriers. For parenteral compositions, the carrier typically includes sterile water, at least for the most part, although there may be other components, for example, to facilitate solubility. Can be prepared, for example, solutions for injection, to the positions, suitable for spokojnego introduction, the carrier optionally includes improving the penetration of the agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor quantities, and these additives have no significant adverse effects on the skin. These supplements can facilitate the introduction on the skin and/or may be useful in the preparation of the desired composition. These compositions can be applied in various ways, such as transcutaneous patch, as a label or as an ointment. Salt accession compounds of formula (I) due to the increased solubility compared to the respective basic form, obviously, are more suitable for the preparation of aqueous compositions.

As appropriate compositions for the local introduction you can specify all compositions usually employed for topically injected drugs, for example creams, gels, dressings, shampoos, tinctures, pastes, ointments, salves, powders and the like. You can use the compositions in aerosol form, for example with a propellant such as nitrogen, carbon dioxide, freon, or without propellant, as a spray, drops, lotions, or semi-solid substances, such as zag is the substance of semi-solid composition, such as balms, creams, gels, ointments and the like.

Especially useful to make the above pharmaceutical composition in the form of a unit dose, for ease of administration and uniformity of dosage. The form of a unit dose, as this term is used here in the description and in the claims refers to physically discrete units suitable as unit doses, each unit contains a specified quantity of active ingredient calculated to produce the desired therapeutic effect together with the required pharmaceutical carrier. An example of this form of unit doses are tablets (including tablets groove or coated tablets), capsules, pills, packets of powder, pills, solutions or suspensions for injection, teaspoons, tablespoons, and the like, and the same combined dosage forms.

Other such compositions are cosmetic preparations such as toilet water, tampons, lotions, lotion, skin milk lotions. These preparations contain, besides the active components, the components are usually used in such preparations. Examples of such components are oils, fats, waxes, surface the coefficients, buffers, preservatives, fragrances, dyes, lower alcohols and the like. If required, the composition may include other components, such as anti-inflammatory agents, antibacterial, antifungal, disinfectants, vitamins, means to protect from sunburn, antibiotics or other agents against acne.

The present invention also relates to certain pharmaceutical or cosmetic compositions which comprise an inert carrier, an effective amount of the compounds of formula (I) and an effective amount of retinoic acid, its derivative or its stereochemical isomeric form. These compositions, containing retinoic acid, is particularly useful for the treatment of acne ordinary or to slow down the effect of aging of the skin and significantly improve the quality of the skin, especially the skin of the person. Further, the invention also relates to certain pharmaceutical or cosmetic compositions which comprise an inert carrier, an effective amount of the compounds of formula (I) and an effective amount of calcitriol or its prodrugs. The last composition is particularly useful in the treatment of diseases associated with keratinization.

The invention tonirovannogo preparation for simultaneous, separate or sequential use in dermatological or cancer. The invention also relates to a product containing calcitriol or its prodrug and a compound of formula (I), as a combined preparation for simultaneous, separate or sequential use in diseases in which beneficial effect of calcitriol. Such products may include, for example, the set containing vessel with an appropriate composition comprising the compound of formula (I), and another container with a composition comprising calcitriol or retinoid. Such a product may have the advantage that the physician can select on the basis of diagnosis treated the patient the appropriate amounts of each component and the sequence and timing of their introduction.

Specialists in the treatment of the above diseases can define an effective therapeutic daily amount from the results of the experiments are given in the experimental part. Effective therapeutic daily amount is from about 0.1 mg/kg to about 40 mg/kg body weight, more preferably from about 0.1 mg/kg to about 10 mg/kg of body weight. more parts doses at appropriate intervals throughout the day. Specified parts of a dose can be made in the form of a unit dose, for example, containing from 0.1 mg to 500 mg of active component in a unit dose.

The exact dosage and frequency of injection depends on the specific selected compounds of formula (I), and must be taken into consideration a specific disease, severity of disease, age, weight and General physical condition of the patient, as well as other treatment, as is well known to experts in this field. Moreover, it is obvious that the effective daily amount may be reduced or increased depending on the response of the patient being treated, and/or depending on the evaluation of the physician prescribing the compounds of the present invention. Therefore, the above-mentioned ranges effective daily amounts are a guide only.

The following examples are intended to illustrate and not limit the scope of the present invention.

The experimental part.

In some compounds of formula (I) absolute stereochemical configuration of the stereogenic atom(atoms) of carbon is not determined experimentally. In these cases, the stereochemical isomeric form, which was the separation is. the shown form "a" and "b" of these compounds of formula (I), in which there are two stereogenic carbon atom, were divided into pure stereochemical isomeric forms, designated as "A1" and "A2", "B1" and "B2", without further reference to the exact stereochemical configuration.

Below "THF" means tetrahydrofuran, "EtOAc" means ethyl acetate, "DIPE" means diisopropyl ether and "RT" refers to room temperature.

A. the production of intermediate compounds

Example A-1.

a) benzoyl chloride (0,067 mol) are added to a solution aminonicotinate (5,09 g) in 2-propanone (150 ml), the mixture is stirred and refluxed for 20 minutes, Add a solution of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl] aniline (0,0557 mol) in 2-propanone (150 ml) and the mixture is stirred and refluxed at 80oWith all night. The mixture is cooled, filtered through celite and the filtrate evaporated. The rest move to CH2Cl2. The organic layer is dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE/NH4HE 98/2/0,1). Collect the pure fractions and evaporated the solvent, receiving 15.2 g (72%) ()-N-Bestemianova connection (1) in NaOH (300 ml; 3 N.) is stirred and refluxed for 2 hours. The solution is cooled, poured into ice, neutralized concentratewanna Hcl and extracted with CH2CL2. The organic layer is separated, dried, filtered and evaporated the solvent, getting to $ 7.91 g (88%) of N'-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]thiourea (intermediate compound 2).

Example A-2.

a) second-Utility (298 ml; 1.3 M) is added dropwise at -60oWith the current N2to a solution of N-(4-bromophenyl)ndimethylacetamide (0,1892 mol) in THF (400 ml) and the mixture was stirred at -70oC for 2 hours. Added dropwise a solution of 1-cyano-1-methyl-N,N-dimethylethanamine (0,075 mol) in THF (60 ml), the mixture was brought to RT and then stirred at RT for 12 hours. The mixture was poured into ice and extracted with EtOAc. Evaporated the solvent, the residue is transferred in Hcl (3 BC ) and EtOAc, extracted with EtOAc, alkalinized with help from2CO3(10%) and extracted with CH2Cl2. The organic layer is separated, dried, filtered and evaporated the solvent. The residue is recrystallized from (C2H5)2O and DIPE. The precipitate is filtered off and dried, obtaining 6.8 g (36%) of N-[4-[2-(dimethylamino)-2-methyl-1-oxopropyl] ѡl (180 ml; 6 N. ) is stirred and heated to 100oC for 2 hours. The solution was poured into ice, washed with EtOAc, alkalinized NH4OH and extracted with EtOAc. The organic layer is separated, dried, filtered and evaporated the solvent, obtaining of 5.1 g (94%) of 1-(4-AMINOPHENYL)-2-(dimethylamino)-2-methyl-1-propanone (intermediate compound 4).

c) Dichlorohydrin Topolino acid (2,45 ml) is added dropwise at 0oTo a solution of intermediate compound (4) (0,0247 mol) in NaOH (10,7 ml; 3 N.) and l3(200 ml) and the mixture was stirred at 0oC for 4 hours. The mixture was poured in TO a2CO3(10%) and extracted with CH2Cl2. The organic layer is separated, dried, filtered and evaporated the solvent, obtaining of 6.1 g (99%) of 2-(dimethylamino)-2-methyl-1-(4-isothiocyanatobenzene)-1-propanone (intermediate compound 5).

d) a Mixture of intermediate compound (5) (0,0247 mol) and 2-aminothiophenol (0,0298 mol) in THF (60 ml) is stirred and refluxed for 2 hours and then stirred at RT for 72 hours. The mixture was poured into water and extracted with EtOAc. The organic layer is separated, dried, filtered and evaporated the solvent. The residue is crystallized from (C2H5)2ethyl-1-propanone (intermediate compound 6).

e) NaBH4(and 3.72 g) added in portions at 10oTo a solution of intermediate compound (6) (0,0164 mol) in methanol (60 ml) and the mixture was stirred at RT for 24 hours. The mixture was poured into water and extracted with CH2Cl2. The organic layer is separated, dried, filtered and evaporated the solvent, getting 5,2 g(93%) 1-[4-(2-benzothiazolylthio)phenyl]-2-dimethylamino)-2-methyl-1-propanol (intermediate compound 7).

Example A-3.

a) a Solution of lithium aluminum hydride (0,1107 mol) in THF (100 ml) is added dropwise at 0oWith the current N2to a suspension of ethyl-4-(2-benzothiazolylthio)benzoate (0,1107 mol) in water. The mixture was brought to RT and stirred for 30 minutes hydrolyzing the Mixture, adding water (8 ml) dropwise, and then add CH2Cl2(50 ml) and a bit of CH3HE. The precipitate was filtered and evaporated the solvent. The residue is crystallized from 2-propanone and DIPE. The precipitate is filtered off and dried, obtaining 8 g (86%) of 4-(2-benzothiazolylthio)benzoimidazole (intermediate compound 8).

b) thionyl chloride (10 ml) is added dropwise at 0oTo a solution of intermediate compound (8) (0,039 mol) in CH2CL2(100 ml) and stirred the mixture at 0oC for 2 hours. Evaporated LASS="ptx2">

a) a Mixture of intermediate (8) (0,0312 mol) and carbon dioxide magnesium (0,115 mol) in CH2Cl2(200 ml ) in N,N-dimethylformamide (10 ml) was stirred at RT for 12 hours. Dioxide, magnesium (0,115 mol) is added again and stirred the mixture at RT for 12 hours. The mixture is filtered through celite, washed with CH2Cl2and the solution evaporated. Add water (100 ml), evaporated, filtered, crystallized, filtered and dried, obtaining 7 g (89%) of 4-(2-benzothiazolylthio)benzaldehyde (intermediate compound 10).

b) a Solution of 1-bromo-3-fervently (0,213 mol) in THF (60 ml) is added dropwise at RT in the current of the N2to a suspension of magnesium (0,213 mol) in THF (60 ml) and the mixture is stirred for 30 minutes the Mixture is cooled to 0oC, a solution of intermediate compound (10) (0,071 mol) in THF (60 ml) is added dropwise and the mixture is stirred for 15 minutes the Mixture was poured into water and NH4C1 and extracted with EtOAc. The organic layer is separated, dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE/NH4HE from 100/0/0 to 90/10/0,1). Collect the pure fractions and evaporated the solvent, getting 22,4 g(90%) ()--[4-(2-benzothiazolylthio)phenyl] -3-UP>oWith the current N2to a solution of N-(1-methylethyl)-2-propanamine (0,1836 mol) in THF (60 ml). The mixture is stirred for 20 minutes, then allow the mixture to warm to -30oC. Add a solution of ethylpropylamine (0,1836 mol) in THF (100 ml) at -78oC. Allow the mixture to warm to -30oC and then cooled to -78oC. is Added dropwise a solution of intermediate compound (10) (0,0875 mol) in THF (60 ml). The mixture was stirred at -60oC for 20 min, then poured into water and NH4Cl and extracted with EtOAc. The organic layer is separated, dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE/NH4HE 97/3/0,5). Collect the pure fractions and evaporated the solvent. The remainder crystalized from 2-propanone and diethyl ether. The precipitate is filtered and dried, obtaining 18 g (the)-ethyl-4-(2-benzothiazolylthio)--hydroxy--methylbenzophenone (intermediate compound 12).

Example A-5.

a) a Solution of 3-bromopentane (0,331 mol) in (C2H5)2O (200 ml) is added dropwise to a solution of magnesium shavings (0,331 mol) in (C2H5)2O, the mixture was stirred at RT for 2 hours and then cooled to 0oC. RA is the return poured into aqueous NH4C1 and extracted with EtOAc. The organic layer is dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE/NH4HE 97/3/0,1). Collect the pure fractions and evaporated the solvent, getting 13.5 g (52%) ()-N-[4-(2-ethyl-1-hydroxybutyl)phenyl] ndimethylacetamide (intermediate compound 13).

b) Methanesulfonanilide (0,114 mol) is added dropwise at 0oWith N2to a solution of intermediate (13) (0,057 mol) and triethylamine (0,114 mol) in CH2Cl2(250 ml) and the mixture was stirred at RT for 12 hours. The solvent is evaporated, getting 17,86 g (100%) methansulfonate ()-4-(acetylamino)--(1-ethylpropyl)benzoimidazole (ester) (intermediate compound 14).

c) a Mixture of intermediate (14) (0,187 mol), 1H-1,2,4-triazole (0,516 mol) and potassium carbonate (0,561 mol) in methanol (600 ml) is stirred and refluxed for 20 hours. The mixture was poured into water and extracted with CH2Cl2. The organic layer is washed with water, dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/CH3

d) a Mixture of intermediate (15) (0,0073 mol) in Hcl (10 ml; 3 N. ) was stirred at 60oWith in 12 hours. The mixture was poured into ice-cold water, alkalinized with concentrated NaOH solution and extracted with EtOAc. The organic layer is separated, dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE/NH4HE 98,5/1,5/0,1). Collect the pure fractions and evaporated the solvent. The residue is crystallized from ethyl ketone/DIPE. The precipitate is filtered and dried, obtaining 1.8 g(73%) ()-4-[2-ethyl-1-(1H-1,2,4-triazole-1-yl)butyl] aniline (intermediate compound 16). The product is shared with jhud Chiralpack AS 20 μm (eluent: hexane/S2H5HE 65/35). Pure fractions are collected, evaporated and dried, obtaining of 0.54 g (A)-4-[2-ethyl-1-(1H-1,2,4-triazole-1-yl)butyl] aniline (intermediate compound 17) and (C)-4-[2-ethyl-1-(1H-1,2,4-triazole-1-yl)butyl] aniline (intermediate compound 18).

e) a Mixture of CS2(0,0819 mol) in NaOH (3.8 mol; 20 N.) is added at RT to a solution of intermediate (16) (0,063 mol) in dimethyl sulfoxide (37 ml). The mixture is stirred for 1 hour and cooled to 0oC. Add itmean (4,9 ml). The mixture is stirred Ei RT overnight. Add EtOAc and water and extracted with a mixture with EtOAc. The organic layer was separated, washed with water, dried, filtered and evaporated the solvent, obtaining 25 g of ()-N-[bis(methylthio)methyl]-4-[2-ethyl-1-(1H-1,2,4-triazole-1-yl)butyl]aniline (intermediate compound 19a).

f) Dichlorohydrin Topolino acid (0,216 mol) is added dropwise at 0oTo a solution of intermediate (16) (0,1665 mol) in sodium hydroxide (3 N.; 72,15 ml) and CH2Cl2(400 ml). Mixture was allowed to warm to RT over a two-hour period of stirring and then poured in TO a2CO3(10%; 200 ml). The mixture is stirred for 30 minutes and then decanted. The organic layer is dried, filtered and evaporated the solvent, getting 47,7 g(100%) ()-1-[2-ethyl-1-(4-isothiocyanatobenzene)butyl] -1H-1,2,4-triazole (intermediate compound 19b).

()-1-[1-(4-isothiocyanatobenzene)-2-ethylbutyl] -1H-imidazole (intermediate compound 19s) receive as well.

Example A-6.

a) a Mixture of 1-(4-AMINOPHENYL)-2-methyl-1-propanone (0,0637 mol) and methyl 2-chloro-3-pyridinecarboxylic (0,0637 mol) in 2-methoxyethanol (200 ml) is stirred and refluxed for 90 hours. The mixture is transferred into the water and EtOAc and extracted with EtOAc. The organic layer is separated is dicarboxylate (intermediate compound 20).

b) Tetrahydroborate sodium (0,0764 mol) is added by portions at 0oTo a solution of intermediate (20) (0,0637 mol) in methanol (200 ml). The solution is stirred for 2 hours, add water and evaporated organic solvent. The concentrate is transferred to a CH2CL2, dried, filtered and evaporated the solvent, getting 18,38 g ()-methyl-2-[[4-(1-hydroxy-2-methylpropyl " phenyl]amino]-3-pyridinecarboxamide (intermediate compound 21).

Example A-7.

a) Chloride, aluminum(III) (0,666 mol) is added in portions at RT to a solution of N-phenyl-2-benzothiazolinone (0,222 mol) and 1,2-dichloro-1-propanone (0,233 mol) in 1,2-dichloroethane (500 ml) and the mixture is stirred and heated to 80oC for 2 hours. The mixture was poured into ice and extracted with CH2CL2. The organic layer is decanted, dried, filtered and evaporated the solvent, receiving 68 g()-1-[4-(2-benzothiazolylthio)phenyl] -2-chloro-1-propanone (95,7%) (intermediate compound 22).

b) a Mixture of intermediate (22) (0,0423 mol), N-methylethanamine (0,084 mol) and potassium carbonate (to 0.127 mol) in methanol (150 ml) is stirred and refluxed for 90 minutes the Mixture was poured into water, extracted with CH2Cl2and desantiruemaya on silica gel (eluent: CH2Cl2/2-propanone/NH4HE 95/5/0,1 and 90/10/0,1). Collect the pure fractions and evaporated the solvent, getting 6,85 g(54%) ()-1-[4-(2-benzothiazolylthio)phenyl] -2-ethylmethylamino-1-propanone (intermediate compound 23).

In the same way get()-1-[4-(2-benzothiazolylthio)phenyl] -2-(dimethylamino)-1-propanone (intermediate compound 24).

(C) Borohydride sodium (0,0642 mol) is added in portions at a temperature of from 0 to -5oTo a solution of intermediate (24) (0,0584 mol) in methanol (250 ml) and the mixture is stirred for 3 hours. The mixture was poured into water and extracted with CH2Cl2. The organic layer is decanted, dried, filtered and evaporated the solvent, obtaining 45 g ()-4-(2-benzothiazolylthio)--[1-(dimethylamino)ethyl]benzoimidazole (intermediate compound 25).

Example A-8.

(a) the Following reaction is carried out in an atmosphere of N2. A solution of N-(4-bromophenyl)-2-benzothiazoline (0,492 mol) in THF (2700 ml) is stirred at -70oC. Add portions utility (0,984 mol; 2.5 M in hexane) at -65oC. the Mixture is stirred for 1 hour. A solution of 2-ethylbutanal (0,492 mol) in THF (300 ml) is added by portions at -75oC. the Mixture was allowed to warm to RT over night. Add 10% aqueous RA is divided organic layer is dried, filtered and evaporated the solvent. The residue is crystallized from the mixture. The precipitate is filtered off and dried, getting 109 g(68%) ()-4-(2-benzothiazolylthio)--(1-ethylpropyl)benzoimidazole (intermediate 28).

b) a mixture of intermediate 28 (0,156 mol) and triethylamine (0,312 mol) in CH2Cl2(500 ml) stirred at 0oWith the current N2. Add portions solution methylsulfonylamino (0,314 mol) in CH2Cl2(500 ml). The mixture was stirred at 0oC for 3 hours. The solvent is evaporated, getting methanesulfonate ()-4-(2-benzothiazolylthio)--(1-ethylpropyl)benzoimidazole (ester) (intermediate compound 26).

c) Toluene (150 ml) is added to the intermediate connection 28 (0,0582 mol). The heterogeneous mixture was stirred at RT. A solution of thionyl chloride (0,0644 mol) in toluene (50 ml) is added dropwise. The reaction mixture is stirred for 2 hours at RT, then cooled to 0oC. the Residue is filtered off and dried at RT, receiving 25 g monohydrochloride ()-N-[4-(1-chloro-2-ethylbutyl)phenyl]-2-benzothiazoline (intermediate compound 29).

Example A-9.

Solution (a)--(1-ethylpropyl)-4-[2-(methylthio)-4-pyrimidinamine] benzoimidazole obtained by the method, episodesthe catalyst. After uptake of hydrogen (1 equivalent), the catalyst is filtered off through celite, washed with methanol and the filtrate evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE 95/5). Collect the desired fraction and evaporated the solvent. The residue is crystallized from diethyl ether. The precipitate is filtered and dried, obtaining 1,02 g(17%) ()--(1-ethylpropyl)-4-[4-pyrimidinamine]benzoimidazole (intermediate compound 27).

Example A. 10.

a) Connection 130 (0,009 mol) is added at 0oIn thionyl chloride (40 ml). The mixture was stirred at 0oC for 90 minutes, the Solvent evaporated, obtaining 3.5 g of N-[4-[2-(dimethylamino)-1-(1-methyl-1H-imidazol-5-yl)-1-propenyl]phenyl] -2-benzothiazolone (intermediate compound 56).

b) Using the same technique as described below in example b-12, receive N-[4-[2-ethyl-1-(1-methyl-1H-imidazol-2-yl)-1-butenyl]phenyl]-2-benzothiazolone (intermediate compound 57).

All of the following intermediate compounds (see table IA), which is the racemic mixtures, except intermediate compounds 55, which does not have a chiral carbon atoms are in accordance with one of the methods described above.

Century Polychemical (0,0584 mol) and potassium carbonate (0,0586 mol) in methanol (300 ml) is stirred and refluxed for 12 hours. The solvent is evaporated and transfer the residue in water and CH2Cl2. The organic layer is separated, dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE/NH4HE 96,5/3,5/0,2). Collect the pure fractions and evaporated the solvent. The residue is crystallized from 2-propanone and DIPE. The precipitate is filtered off and dried, obtaining of 1.65 g (28%) of N-[4-(1H-imidazol-1-ylmethyl)phenyl]-2-benzothiazoline (compound 24).

Example B-2.

Triphenylphosphine (4.8 g) and 1H-1,2,4-triazole (0.018 mol) is added to the current of the N2when 5oTo a solution of intermediate compound (7) (0,00732 mol) in THF. Then add a solution of diethylazodicarboxylate (2,88 ml) in THF, bring the mixture to RT and then stirred overnight. Add water, solvent evaporated, acidified with Hcl (3 BC) and separate the layers. The aqueous layer was washed with EtOAc, alkalinized with NH4OH and extracted with EtOAc.

The organic layer is separated, dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0,25). Collect the pure fractions and uparivaetsya 1 g (49%) ()-N-[4-[2-(dimethylamino)-2-methyl-1-(1H-1,2,4-triazole-1-yl)propyl]phenyl]-2-benzothiazoline (compound 38).

Example B-3.

a) a Mixture of intermediate compound (19b) (0,1665 mol) and 2-aminothiophenol (0.2 mol) in THF (500 ml) is stirred and refluxed overnight. The mixture is cooled, poured into water, extracted with CH2Cl2and decanted. The organic layer is dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE/NH4HE 97,5/2,5/0,1). Collect the pure fractions and evaporated the solvent. The residue is crystallized from 2-butanone/diethyl ether. The precipitate is filtered and dried, obtaining and 31.2 g (49,6%) ()-N-[4-[2-ethyl-1-(1H-1,2,4-triazole-1-yl)butyl)phenyl]-2-benzothiazoline (compound 25).

b) Compound (25) (0,0265 mol) separated and purified using chiral column chromatography on a stationary phase Chiralcel OJ (eluent: hexane/ethanol 50/50). Gather need two groups of fractions and evaporated the solvent. Fraction 1 crystalized from 2-propanol. The precipitate is filtered off, washed with 2-propanol, then dried, obtaining 2 g (20%) (A) N-[4-[2-ethyl-1-(1H-1,2,4-triazole-1-yl)butyl]phenyl]-2-benzothiazoline (compound 33).

Fraction 2 crystalized from 2-propanol. The precipitate is filtered off and dried, obtaining 1,9 is otkristallizovalas faction 2 evaporated, part of the residue is dissolved in 2-propanol and converted into the salt (E)-2-butandiol acid (2:3). The precipitate is filtered off and dried, obtaining 3 g (In) N-[4-[2-ethyl-1-(1H-1,2,4-triazole-1-yl)butyl] phenyl]-2-benzothiazolyl-(E)-2-butenedioate (2:3) (compound 35).

C) 2-Methyl-2-propanol, potassium salt (0,0127 mol) is added by portions at 0oTo a solution of compound (25) (0,0106 mol) in THF (30 ml) and the mixture was stirred at 0oC for 10 minutes Slowly add a solution of iodomethane (0,0127 mol) in THF (10 ml) and stirred the mixture at RT for 12 hours. The mixture was poured into water and extracted with CH2Cl2. The organic layer is separated, dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE/NH4HE 98,5/1,5/0,1). Collect the pure fractions and evaporated the solvent. The residue is recrystallized from 2-butanone and DIPE. The precipitate is filtered off and dried. The residue is recrystallized from 2-butanone. The precipitate is filtered off and dried, obtaining 1.5 g (36%) ()-N-[4-[2-ethyl-1-(1H-1,2,4-triazole-1-yl)butyl]phenyl]-N-methyl-2-benzothiazoline (compound 32).

Example B-4.

a) NaOH (6,35 ml; 20 N.) is added at RT to a solution of 2-aminothiophenol (0,0637 mol) in denil]-N,N, -trimethyl-1H-imidazol-1-ethanamine (0,0637 mol), obtained according to the method of obtaining the intermediate compound (19a). The mixture was stirred at 110oWith overnight, then poured on ice, extracted with EtOAc and washed with Hcl (3 BC). The aqueous layer was alkalinized with concentrated solution of NH4OH and extragere with EtOAc. The organic layer is separated, dried, filtered and evaporated the solvent. The residue is separated via column chromatography on silica gel (eluent: CH2CL2/CH3HE/NH4HE 97/3/0,1 and 90/10/0,1). Two pure fractions (F1 and F2) is collected and evaporated the solvent. F1 is crystallized from 2-propanone. The precipitate is filtered off and dried. The residue is transferred in TO the2CO3(10%), filtered and evaporated the solvent, receiving 1.12 g (5%) ()-(A)-N-[4-[2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl] phenyl] -2-benzothiazoline (compound 1). F2 crystalized from 2-propanone. The precipitate is filtered off and dried. The residue is recrystallized from 2-propanone. The precipitate is filtered off and dried, obtaining 0.9 g (4%) ()- ()-N-[4-[2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]-2-benzothiazoline (compound 2).

b) Compound 2 (0,021 mol) share with jhud Chiralpack AS (eluent: HS DIPE. The precipitate is filtered off and dried, obtaining of 2.54 g (B1) N-[4-[2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl] phenyl] -2-benzothiazoline (32%) (compound 3). Fraction 2 is transferred into diethyl ether. The precipitate is filtered off and dried, getting to 2.41 g (B2) N-[4-[2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]-2-benzothiazoline (30,3%) (compound 4).

Example B-5.

a) 1,1'-Carbonyl-bis-1H-imidazole (0,122 mol) is added at 60oTo a mixture of intermediate 21 (0,0612 mol) in THF (250 ml). The mixture is stirred overnight, poured into water and extracted with EtOAc. The organic layer is separated, dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4OH 99,25/0,75/0,1). Collect the pure fractions and evaporated the solvent. Part of the residue (2 g) is crystallized from CH3IT/2-propanone/DI. The precipitate is filtered off and dried, obtaining 1.6 g (40%) ()-methyl-2-[[4-[1-(1H-imidazol-1-yl)-2-methylpropyl] phenyl] amino] -3-pyridinecarboxamide (compound 52).

b) Alumoweld lithium (0,0242 mol) is added by portions at 0oWith the current N2to THF (100 ml). A solution of compound 52 (0,022 mol) in THF (200 ml) is added by portions at 0oC. a Mixture of pen is it. The solvent is evaporated, getting 6.5 g(93%) ()-2-[[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]amino]-3-pyridinemethanol (compound 54).

(C) a Mixture of compound 54 (0.02 mol) and magnesium oxide (IV) (65 g) in CH2Cl2(200 ml) was stirred at RT for 16 hours. The mixture is filtered through celite, the solvent evaporated, getting 5,2 g(81%) ()-2-[[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]amino]-3-pyridinecarboxamide (compound 55).

Example B-6.

2 Phenoxy-1,3-benzoxazol (0,0123 mol) is added to a solution of intermediate 16 (0,0123 mol) in N,N-dimethylformamide (20 ml). The mixture is stirred and refluxed at RT for 12 hours and then overnight. Add EtOAc. The organic layer was separated, washed with water, dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (eluent: cyclohexane/2-propanol/NH4HE 90/10/0,5). Collect the pure fractions and evaporated the solvent. The residue is crystallized from DIPE. The precipitate is filtered off and dried, obtaining 2,04 g (49,5%) N-[4-[2-ethyl-1-(1H-1,2,4-triazole-1-yl)butyl] phenyl]-2-benzoxazolinone (compound 56).

Example B-7.

A mixture of intermediate compound 2 (0,0123 mol), 1-chloro-2-propanone (1.08 m is jut solvent. The residue is transferred in CH2Cl2and washed with K2CO3(10%) and water. The organic layer is dried, filtered and evaporated. The residue is crystallized from 2-propanone and (C2H5)2O getting is 3.08 g (80%) ()-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl] phenyl]-4-methyl-2-thiazoline (compound 50).

Example B-8.

A mixture of intermediate compound 2 (0,0269 mol), 2-bromo-1,1-diethoxyethane (0.035 mol) in Hcl (11.8 ml; 3 N.) and ethanol (200 ml) is stirred and refluxed for 3 hours. The mixture is cooled and evaporated. The residue is transferred in CH2CL2and K2CO3(10%) and extracted with CH2Cl2. The organic layer is washed with water and K2CO3(10%), dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0,2). Collect the pure fractions and evaporated. The residue is crystallized from 2-propanone and DIPE, obtaining 0.9 g (11%) ()-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-2-thiazoline (compound 51).

Example B-9.

Acetate methanimidamide (0,0309 mol) are added to a solution of compound 113 (0,0155 mol) in 1-methyl-2-pyrrolidinone (35 ml). A mixture of paramashiva is using CH2Cl2. The organic layer is separated, dried, filtered and evaporated the solvent. The residue (28.4 g) purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE/NH4HE 96/4/0,1). Collect the pure fractions and evaporated the solvent. The residue is crystallized from CH3HE. The precipitate is filtered off, washed with diethyl ether and dried, obtaining 1.66 g ()-N2-[4-[2-ethyl-1-(1H-1,2,4-triazole-1-yl)butyl] phenyl]thiazolo[5,4-d]pyrimidine-2,7-diamine (compound 117).

Example B-10.

A mixture of intermediate compound 43 (0,0089 mol) and CH3OPA 30% in CH3HE (0,0445 mol) in CH3HE (81 ml) is stirred and refluxed for 15 hours. The mixture is cooled, poured into water, saturated with NaCl and extracted with CH2Cl2. The organic layer is separated, dried, filtered and evaporated the solvent. The residue (3.3 g) purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE/NH4HE 95/5/0,2; 15-40 μm). Collect two pure fractions and evaporated the solvent. Fraction 1 crystalized of 2-butanone and diethyl ether. The precipitate is filtered off and dried, obtaining 0.6 g (A) N-[4-[1-(1H-imidazol-1-yl)-3-methoxy-2-methylpropyl]FeNi is s if -4oWith the current N2to a solution of intermediate 56 (0,009 mol) in methanol (100 ml). The mixture is stirred for 1 hour, then poured in TO a2CO310% and ice and exteriour using CH2Cl2. The organic layer is separated, dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE/NH4HE 95,5/4,5/0.2 to 93/7/0,3; 15-40 μm). Collect two pure fractions and evaporated the solvent. The residue is crystallized from 2-butanone. The precipitate is filtered off, washed with diethyl ether and dried, obtaining and 0.61 g (In) N-[4-[2-(dimethylamino)-1-(1-methyl-1H-imidazol-5-yl)propyl]phenyl]-2-benzothiazoline (18%) (compound 109).

Example B-12.

SnCl2(0,156 mol) and model HC1 12 N. (0,562 mol) is added to a mixture of compound 126 (0,039 mol) in acetic acid (159 ml). The mixture is stirred and refluxed overnight, then poured on ice, alkalinized with concentrated solution NH4HE and extracted with CH2Cl2. The organic layer is separated, filtered through celite, dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (E. retell. The residue is crystallized from 2-propanone and diethyl ether. The precipitate is filtered off and dried, obtaining 1.19 g (8%) ()-N-[4-[2-ethyl-1-(1-methyl-1H-imidazol-2-yl)butyl]phenyl-2-benzothiazoline (compound 110).

Example B-13.

Compound 34 (0,0053 mol) is dissolved in boiling ethyl acetate (15 ml). H3RHO4(85%; 2.5 ml) is added dropwise with stirring. The resulting oily residue. The supernatant is removed by decanting and the remaining oil was poured 2-propanone (20 ml). The mixture is vigorously stirred. The precipitate is filtered off and dried, obtaining 3.0 g (82%) monohydrate phosphate (1:3) ()-N-[4-[2-ethyl-1-(1H-1,2,4-triazole-1-yl)butyl] phenyl] -2-benzothiazoline (compound 87).

Example B-14.

A mixture of intermediate 26 (0,156 mol), 1H-1,2,4-triazole (0,313 mol) and K2CO3(0,313 mol) in CH3JV (800 ml) is stirred and refluxed for 12 hours. The solvent is evaporated, the residue is transferred in CH2CL2/N2O. the Organic layer is separated, dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE/NH4HE 98/2/0,1). Collect the pure fractions and Opera 16,8 g ()-N-[4-[2-ethyl-1-(1H-1,2,4-triazole-1-yl)butyl]phenyl]-2-benzothiazoline (26%) (compound 25).

Example B-15.

n-Utility (1.6 M; 0,0607 mol) is added dropwise at -70oWith the current N2to a solution of 1-methyl-1H-imidazole (0,0607 mol) in THF (60 ml). The mixture is stirred at -70oC for 30 minutes a Mixture of intermediate 24 (0,0243 mol) in THF (60 ml) is added dropwise. The mixture is stirred and poured into water and NH4Cl. The organic layer is separated, dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE/NH4HE 98/2/0,2). Collect two pure fractions and evaporated the solvent. The residue is crystallized from diethyl ether and methyl ethyl ketone. The precipitate is filtered off and dried, obtaining 2.4 g (24%) (A)--[4-(2-benzothiazolylthio)phenyl] --[1-(dimethylamino)ethyl]-1-methyl-1H-imidazole-2-methanol (compound 127) and 0.66 g (6%) (In)--[4-(2-benzothiazolylthio)phenyl] --[1-(dimethylamino)ethyl] -1-methyl-1H-imidazole-2-methanol (compound 128).

Example B-16.

(A)--[4-(2-benzothiazolylthio)phenyl] --[1-(dimethylamino)ethyl] -1-methyl-1H-imidazole-5-methanol (compound 130) obtained by the method described in example b-15, with the exception that chlorine-3-atysian (equimolar amount of 1-methyl-1H-imidazole) is added to the reaction cm is soedineniya 19b (0,0409 mol) in 1-methyl-2-pyrrolidinone (40 ml) added dropwise to a solution of aminoproprionitrile (0.045 mol) in 1-methyl-2-pyrrolidinone (100 ml). The mixture was stirred at RT for 15 hours, then poured into water and extracted with EtOAc. The organic layer is separated, dried, filtered and evaporated the solvent. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE/NH4HE 97/3/0,1). Collect the pure fractions and evaporated the solvent. The residue is crystallized from ethyl ketone and diethyl ether. The precipitate is filtered off and dried, obtaining 0.96 g ()-5-amino-2-[4-[2-ethyl-1-(1H-1,2,4-triazole-1-yl)butyl]phenyl]amino-4-thiazolecarboxamide (compound 113).

Tables 1 through 6 include a list of compounds of formula (I), which are in accordance with the methods of the above examples.

Table 7 summarizes the experimental (columns entitled "exp") and theoretical (columns entitled "theoretical" values of elemental analysis for carbon, hydrogen, and nitrogen compounds, obtained for the compounds of the examples described above.

C. Pharmacological examples.

Example C. 1. Inhibition of the metabolism of retinoic acid (RA).

Cancer cells human breast MCF-7 was grown as a source of culture in accordance with known techniques. For about the ment of cell suspension incubated in tissue culture medium, contains3H-RA as a substrate. Various concentrations of test compounds (dissolved in 1% DMSO) are added to the incubation mixture and at the end of the incubation nematerializiranih RA is separated from its polar metabolites. The fraction containing polar3H-labeled metabolites, collect and verify using a scintillation counter. For each experiment together with the control and blank incubation. All those compounds that were tested, i.e., compounds 1-4, 8, 10, 16-18, 24, 25, 27, 29-31, 33, 34, 35, 37, 40, 44-47, 49-51, 53, 56 and 58 have a value IC50below 1x10-8M, where the value of the IC50is defined as the concentration required to reduce the number of metabolites to 50% of control.

Example C. 2. Test for vaginal keratinization in ovariectomized rats.

Ovariectomized rats subcutaneously injected solution sesame oil, containing 100 μg of undecylate estradiol, in the amount of 0.1 ml per 100 g body weight, and control rats injected sesame oil. On the first, second and third day of the animals once a day were treated per OS dose of the investigated substances and control animals were treated with media medicine (PEG 200). The day after the last treatment of animals is Ther., 261(2), 773-779 (1992). The dose at which 50% of the investigated animals, there is complete suppression of stimulated undecylate estradiol effect of keratinization, is defined as the active dose. Connection 2-5, 8, 15-19, 25, 27-29, 31, 32, 34, 42, 46 and 56 had the lowest active dose (LAD), 2.5 mg/kg or below. The other tested compounds had the LAD above 2.5 mg/kg

D. Examples of compositions.

The following formulation is given as an example of a typical pharmaceutical compositions suitable for systemic or local injection of animals and man, in accordance with the present invention.

The term "active ingredient" (A. I.), as used in these examples refers to compounds of the formula (I) or their pharmaceutically acceptable salts accession acid.

Example D. 1. Solution for oral administration.

9 g of methyl-4-hydroxybenzoate and 1 g of propyl-4-hydroxybenzoate dissolved in 4 l of boiling purified water. In 3 l of this solution are dissolved first 10 g of 2,3-dihydroxybutanedioate acid and then 20 g of A. I. the Latter solution is combined with the remaining part of the first solution and to it add 12 l 1,2,3-propanetriol and 3 l of 70% solution of sorbitol. 40 g of saccharin sodium are dissolved in 0.5 LoDo up to a volume of 20 l, getting a solution for oral administration containing 5 mg A. I. teaspoon (5 ml). The resulting solution was poured into appropriate containers.

Example D. 2. Drops for oral administration.

500 g of A. I. dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of the polyethylene glycol at 60-80oC. After cooling to 30-40oWith added 35 l of polyethylene glycol and the mixture well stirred. Then add a solution of 1750 g of saccharin sodium 2.5 l of purified water and while stirring add 2.5 l of flavor, cocoa butter and polyethylene glycol in an amount necessary to bring the volume to 50 l, getting drops for oral administration containing 10 mg/ml A. I. the resulting solution was poured into appropriate containers.

Example D. 3. The capsule.

20 g A. I., 6 g of lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of magnesium stearate vigorously stirred together. The resulting mixture was sequentially poured into 1000 suitable hard gelatin capsules, each containing 20 mg A. I.

Example D. 4. The solution for injection.

0.5 g A. I., 1,50 mg of anhydrous glucose and of 0.332 ml of concentrated hydrochloric acid is mixed with 0.8 ml of water for injection. Doba and poured into sterile containers.

Example D. 5. Tablets, film-coated.

Obtain core tablets.

A mixture of 100 g A. I., 570 g lactose and 200 g starch is mixed well and then moisturize using a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone (Kollidon-K 90) in approximately 200 ml of water. Wet powder mixture is sieved, dried and again sieved. Add 100 g microcrystalline cellulose (Avicel) and 15 g hydrogenerating vegetable oil (Sterotex). All well mixed and pressed into tablets, receiving 10,000 tablets, each contains 10 mg of the active component.

The coating shell.

To a solution of 10 g of methyl cellulose (Methocel 60 HG) in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose (Ethocel 22 cps) in 150 ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The last solution is added to the first and then add 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated colour suspension (Opaspray K-1-2109) and all homogenized. Core tablets cover the thus obtained mixture in the coating film.

Example D. 6. 2% of kreetta placed inside the receptacle casing with double walls and heated until until the mixture is fully melted. The mixture in the prepared separately, a mixture of purified water, 200 mg of propylene glycol and 15 mg of Polysorbate 60, having a temperature of from 70 to 75oS, and the homogenizer is used for liquids. The resulting emulsion allow to cool to a temperature below the 25oWith continuously stirring. Then added to the emulsion a solution of 20 mg A. I., 1 mg of Polysorbate 80 in purified water and a solution of 2 mg of anhydrous sodium sulfite in purified water, stirring constantly. Cream, 1 g A. I., homogenized and placed into the appropriate tubes.

Example D. 7. 2% gel for local application.

To a solution of 200 mg of hydroxypropyl-b-cyclodextrin in purified water is added under stirring 20 mg A. I., add hydrochloric acid until dissolved and then add sodium hydroxide until then, until you reach a pH value of 6.0. This solution is added to a dispersion of 10 mg carrageenan PJ 50 mg of propylene glycol with stirring. Slowly stirring, the mixture is heated to 50oWith and allow to cool to approximately 35oWith, then add 50 mg of 95% ethyl alcohol (V/V). Add the remainder of the purified water to 1 g and the mixture is stirred until a homogeneous state.

Pri water added with stirring 20 mg A. I., add hydrochloric acid to dissolve and then add sodium hydroxide until then, until you reach a pH value of 6.0. With stirring, add 50 mg of glycerol and 35 mg of Polysorbate 60 and heat the mixture to 70oC. the resulting mixture was added to a mixture of 100 mg of mineral oil, 20 mg stearyl alcohol, 20 mg of cetyl alcohol, 20 mg glycerol monostearate and 15 mg sorbate 60 having a temperature of 70oWith slow stirring. After cooling below the 25oTo add the remainder of the purified water to 1 g and the mixture is stirred until a homogeneous state.

Example D. 9. 2% liposomal composition.

A mixture of 2 g of A. I. microfine, 20 g of phosphatidylcholine, 5 g of cholesterol and 10 g of ethyl alcohol is stirred and heated to 55-60oWith until dissolved and added to a solution of 0.2 g of methylparaben, 0.02 g of propyl paraben, 0.15 g disodium salt editovat acid and 0.3 g of sodium chloride in purified water, homogenizing. Add 0.15 g hydroxypropylmethylcellulose in purified water to 100 g, continue to stir until then, until the swelling.

1. The compound of formula (I)

< / BR>
their N-oxides, pharmaceutically acceptable salts connection and stereochemical isomeric forms,
1-12
alkyl; C3-7cycloalkyl; aryl; pyrrolidinyl, optionally substituted C1-4the alkyl or C1-4allyloxycarbonyl; or (C1-12alkyl, substituted C1-4alkyloxy, amino group, mono - and di(C1-4alkyl)amino group, (C1-4alkyl)(arils1-4alkyl)amino group, piperidinyl, piperazinil, optionally substituted C1-4the alkyl, morpholinyl,1-4allyloxycarbonyl and arroceros;

R3represents hydrogen, C1-6alkyl;

Het represents an unsaturated heterocycle selected from imidazolyl, triazolyl and pyridinyl; each of the above mentioned unsaturated heterocycles may be optionally substituted C1-6by alkyl;

< / BR>
represents an unsaturated mono - or bicyclic a heterocycle selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, chinoline, izochinolina, phthalazine, heatline and khinoksalinona; each of these mono - or bicyclic heterocycles may be optionally substituted by one or two substituents selected from C1-6of alkyl, hydroxys1-6of alkyl, C1-6allylthiourea, formyl, C1-6allyloxycarbonyl or aryl is NR8, O, S, S(= O) or S= (O)2where R8is hydrogen or C1-6by alkyl;

R4or R5each independently represents hydrogen, a hydroxyl group, a cyano, a nitro-group, amino group, WITH1-6alkyl or aryl;

-R6-R7- represents a bivalent radical of the formula

-CR9= CR9-CR9= CR9- (b-1);

-CR9= CR9-CR9= N - (b-5);

-CR9= N-CR9= N- (b-7) or

-N= CR9-N= CR9- (b-10),

where each R9independently represents hydrogen, halogen, amino, C1-6alkyl or Halogens1-6alkyl, and aryl represents phenyl or phenyl substituted by halogen.

2. Connection on p. 1, in which R1represents hydrogen or C1-6alkyl; R2represents hydrogen; C1-12alkyl; C3-7cycloalkyl; aryl or1-12alkyl, substituted C1-4alkyloxy, amino group, mono - and di(C1-4alkyl)amino group, (C1-4alkyl)(arils1-4alkyl)amino group, piperidinyl, piperazinil, morpholinium,1-4allyloxycarbonyl and arroceros;

< / BR>
represents an unsaturated mono - or bicyclic a heterocycle selected from kinyinya, 3-izochinolina, 1-phthalazinone, 2-hintline, 4-hintline and 2-khinoksalinona; each of these unsaturated mono - or bicyclic heterocycles may be optionally substituted by one or two substituents selected from C1-6of alkyl, hydroxys1-6of alkyl, formyl, C1-6allyloxycarbonyl or aryl, or

< / BR>
represents a radical of formula (a) or (b), where R4or R5each independently represents hydrogen, a hydroxyl group, a nitro-group, amino group, WITH1-6alkyl or aryl.

3. Connection under item 1 or 2, in which R1represents hydrogen, a hydroxyl group or a C1-6alkyl; R2represents hydrogen, C1-12alkyl; C3-7cycloalkyl; pyrrolidinyl, optionally substituted C1-4the alkyl or C1-4allyloxycarbonyl; or (C1-12alkyl, substituted C1-4alkyloxy, mono - and di(C1-4alkyl)amino group, (C1-4alkyl)(arils1-4alkyl)amino group, a C1-4allyloxycarbonyl, morpholinium, piperidinium, piperazinil, optionally substituted C1-4the alkyl, and arroceros; R3represents hydrogen, C1-6alkyl; Het is imidazolyl, neobiazatelno substituted hydraxis1-6the alkyl, formyl or1-6aryloxyalkyl; 2-honokalani; 1-ethenolysis; 2-chinoline; 3-pyridazinyl, optionally substituted C1-6by alkyl; 2-pyrazinyl; 1-phthalazine; 4-hintline, optionally substituted by aryl; 2-pyrimidinyl; 4-pyrimidinyl, optionally substituted C1-6alkylthiol, or

< / BR>
represents a radical of formula (a) or (b) where X represents NH, O or S; R4or R5each independently represents hydrogen, a hydroxyl group, a nitrogroup, cyano, amino, C1-6alkyl or aryl; R6-R7- represents a bivalent radical of formula (b-1) or (b-10), where each R9independently represents hydrogen, C1-6alkyl, halogen, amino, Halogens1-6alkyl.

4. The compound according to any one of paragraphs. 1-3, in which Het is 1-imidazolyl, optionally substituted C1-6by alkyl; 2-imidazolium, optionally substituted C1-6by alkyl; 5-imidazolium, optionally substituted C1-6by alkyl; 1,3,4-triazole-1-yl and 1,2,4-triazole-1-yl.

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

< / BR>
represents a radical of formula (b), where X represents O or S, and-R6-R7< THE R2represents a C1-12alkyl; C3-7cycloalkyl; aryl or1-12alkyl, substituted mono - or di(C1-4alkyl)amino group, WITH1-4allyloxycarbonyl or arroceros.

7. Connection on p. 1, selected from

N-[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl] phenyl] -2-benzothiazoline;

N-[4-[2-ethyl-1-(1H-1,2,4-triazole-1-yl)butyl] phenyl] -2-benzothiazoline;

N-[4-[2-ethyl-1-(1H-1,2,4-triazole-1-yl)butyl] phenyl] -2-benzothiazoline;

N-[4-[2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl] phenyl] -2-benzothiazoline;

N-[4-[2-(dimethylamino)-1-(1H-1,2,4-triazole-1-yl)propyl] phenyl] -2-benzothiazoline;

N-[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl] phenyl] -2-benzoxazolinone;

N-[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl] phenyl] -6-methoxy-2-benzothiazoline;

N-[4-[2-(dimethylamino)-1-(1H-imidazol-1-yl)-2-methylpropyl] phenyl] -2-benzothiazoline;

N-[4-[2-(dimethylamino)-2-methyl-1-(1H-1,2,4-triazole-1-yl)-propyl] phenyl] -2-benzothiazoline;

N-[4-[cyclohexyl-(1H-imidazol-1-yl)methyl] phenyl] -2-benzothiazoline;

N-[4-[cyclohexyl-(1H-1,2,4-triazole-1-yl)methyl] phenyl] -2-benzothiazoline,

its N-oxide, stereochemical isomeric forms and pharmaceutically acceptable salts of the merger.

8. The composition having ingibiruet, the active ingredient, a therapeutically effective amount of a compound according to any one of paragraphs. 1-7.

9. A method of obtaining a composition, as claimed under item 8, wherein the pharmaceutically acceptable carrier is uniformly mixed with a therapeutically effective amount of a compound according to any one of paragraphs. 1-7.

10. The compound according to any one of paragraphs. 1-7 as drugs having inhibitory activity against metabolism of retinoic acid.

11. A method of obtaining a connection on p. 1, including the interaction of the intermediate compounds of formula (II)

< / BR>
where R1-R3and

< / BR>
defined in paragraph 1;

W1is the corresponding leaving group,

with Het-H (III) or its functional derivatives, where Het is defined in paragraph 1, in an inert towards the reaction solvent and in the presence of a suitable base and optionally in the presence of triphenylphosphine and diethylazodicarboxylate or a functional derivative of any of these reagents.

12. A method of obtaining a connection on p. 1, including N-alkylation of an intermediate product of the formula (IV)

< / BR>
where R1-R3and Het is defined in paragraph 1, the intermediate product of the formula is artnum with respect to the reaction solvent.

13. A method of obtaining a connection on p. 1, comprising the reaction of intermediate compounds of formula (VI)

< / BR>
where R1-R3and Het is defined in paragraph 1,

with an intermediate compound of formula (VII) or its functional derivative

< / BR>
where R4and R5defined in paragraph 1 and W3is the corresponding leaving group,

in an inert towards the reaction solvent, optionally in the presence of acid, forming thereby a compound of the formula (I-a-I)

< / BR>
14. A method of obtaining a connection on p. 1,

including the interaction of the intermediate compounds of formula (VIII)

< / BR>
where R1, R2and Het is defined in paragraph 1, with an intermediate compound of formula (IX-I)

< / BR>
where-R6-R7is defined in paragraph 1,

in an inert towards the reaction solvent, forming, thus, the intermediate of the formula (I-b-1)

< / BR>
15. A method of obtaining a connection on p. 1, comprising the reaction of intermediate compounds of formula (VIII)

< / BR>
where R1, R2and Het is defined in paragraph 1,

with an intermediate compound of formula (IX-2)

< / BR>
where-R5defined in paragraph 1,

in an inert towards the reaction solvent, forming, thus, the intermediate connection is inane formula (X)

< / BR>
where R1, R2and Het is defined in paragraph 1,

with an intermediate compound of formula (IX-1) in an inert towards the reaction solvent and in the presence of a suitable base, forming, thus, an intermediate compound of formula (I-b-1).

17. A method of obtaining a connection on p. 1, comprising the reaction of an intermediate compound corresponding to the compound of formula (I) in which R1and R2together with the carbon atom to which they are attached, form a carbonyl group, with Het-H (III) or its functional derivatives, where Het is defined in paragraph 1, in the presence of an appropriate reagent, in an inert towards the reaction solvent and optionally in the presence of chlorotriethylsilane, forming thereby a compound of the formula (I) in which R1is a hydroxyl group.

18. A method of obtaining a connection on p. 1, comprising the reaction of an intermediate compound corresponding to the compound of formula (I) in which R2is L-C1-12the alkyl, where L is an appropriate leaving group, with1-4alkyla-M+where M+an appropriate metal ion, in an appropriate solvent, forming, thus, the connection formoline by p. 1, including the restoration of the intermediate compound corresponding to the compound of formula (I), wherein said R2attached to the carbon atom bearing the substituent R2, a double bond using a suitable reducing agent in a suitable solvent, forming thereby a compound of the formula (I) in which R is an optionally substituted C1-12the alkyl.

20. The method according to any of paragraphs. 11-19, optionally including the conversion of compounds of formula (I) into each other, in accordance with known methods of transformation, and, further, if required, conversion of the compounds of formula (I) into a therapeutically active non-toxic salt accession acid by treatment with an acid, or into a therapeutically active non-toxic salt of attaching the base by treatment with a base or Vice versa, the transformation of salt accession acid free base by treatment with alkali or turning salt attaching the base to the free acid by treatment with an acid, and also, if required, obtaining their stereochemical isomeric forms or N-oxide forms.

 

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