Substituted derivatives of diamino-1,3,5-triazine, methods for their production, intermediate product, pharmaceutical composition and method of reception

 

(57) Abstract:

Describes substituted derivatives of diamino-1,3,5-triazine of General formula I or their pharmaceutically acceptable salts adding acids or their stereochemical isomeric form, where R1and R2each, independently, represent hydrogen; hydroxy; amino; C1-6alkyloxy; C1-6alkylsulphonyl; C1-6allyloxycarbonyl; phenyl substituted by cyano; mono - or di(C1-6alkyl)aminocarbonyl; dihydro-2 (3H)furanone; C1-6alkyl, unsubstituted or substituted by one or two substituents, each of which is independently selected from amino, imino, aminocarbonyl, aminocarbonyl, hydroxy, hydroxy1-6alkyloxy, carboxyl, mono - or di(C1-6alkyl)amino, C1-6allyloxycarbonyl and tanila; or R1and R2taken together, may form azido or mono - or di (C1-6alkyl) amino WITH1-4alkylidene; R3represents hydrogen; phenyl substituted by cyano; C1-6alkylsulphonyl; C1-6allyloxycarbonyl; C1-6alkyl, unsubstituted or substituted C1-6allyloxycarbonyl; R4and R8each represent hydrogen; R5and R7denote hydrogen or cyano; R6oz the I Vice, independently selected from C3-7cycloalkyl, indolyl, substituted with halogen, phenyl, unsubstituted or substituted by 1-5 substituents, each of which is independently selected from halogen, hydroxy, C1-6of alkyl, C1-6alkyloxy, trihalomethyl, trihalomethane,1-6alkylcarboxylic. Intermediate compounds of formula VII used in the synthesis of a pharmaceutical composition inhibiting the replication of human immunodeficiency virus, its preparation and methods of making the compounds I. 11 C. and 6 C.p. f-crystals, 7 PL.

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The invention relates to new compounds of the formula (I) with any abscopal HIV replication properties. The invention also relates to methods of producing such novel compounds, pharmaceutical compositions containing these novel compounds and to the use of these compounds as medicines.

Compounds similar in structure to the present new compounds known from the prior art. DE-2121694, published on 25 November 1971, describes some s-triazine used as anti-inflammatory, sedative, antiviral, antispasmodic, hypoglycemic, diuretic and in the La 1973, described derivatives of diamino-1,3,5-triazine with increase hormonal secretion activity and anti-inflammatory action. Substituted triazine having diuretic activity, published in Guioca, Ann. Pharm. Fr., 31: 283-292 (1973). A series of 2,4-diamino-triazines obtained Kelarev and other Chem. A heterocycle. Conn. , 1392-1397 (1987) and Kelarev and other Chem. A heterocycle. Conn., 1395-1399 (1992). Obtaining 2-amino-4-benzyl-6-o-toluidino-s-triazine described Yuki Y. et al., Kobunshi Depending, 26:141-147 (1969). The use of aralkylamines, in particular 2-amino-4-aniline-6-benzyl-s-triazine, for the production of resins described in US-2817614, issued December 24, 1957.

It has been unexpectedly found that the compounds of formula (I) effectively inhibit the replication of human immunodeficiency virus (HIV) and, therefore, can be used to treat individuals infected with HIV.

The present invention concerns the use of compounds of the formula

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and their pharmaceutically acceptable additive salts with acid and stereochemical isomeric forms, where

R1and R2each independently selected from hydrogen, hydroxy, amino, C1-6of alkyl, C1-6alkyloxy, C1-6alkylsulphonyl, C1-6allyloxycarbonyl, AG1mono - or di(C1-61-6alkyloxy, carboxyl, mono - or di(C1-6alkyl) amino, C1-6allyloxycarbonyl and tanila, or R1and R2taken together, may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono - or di (C1-6alkyl) amino WITH1-4alkylidene;

R3denotes hydrogen, AG1C1-6alkylsulphonyl, C1-6alkyl, C1-6allyloxycarbonyl, C1-6alkyl, substituted C1-6alkyloxy-carbonyl, and

R4, R5, R6, R7and R8each independently selected from hydrogen, hydroxy, halogen, C1-6of alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalomethane;

L represents C1-10alkyl, C3-10alkenyl,3-10quinil,3-7cycloalkyl or L represents C1-10alkyl, substituted by one or two substituents, independently selected from C3-7cycloalkyl; indolyl or indolyl substituted one, two, three or four substituents, each of which is independently selected from halogen, C1-6of alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, adwuma, three, four, or five substituents, each of which is independently selected from halogen, hydroxy, C1-6of alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethane, C1-6alkylcarboxylic, and

Ar1is phenyl or phenyl substituted one, two or three substituents, each of which is independently selected from halogen, C1-6of alkyl, C1-6alkyloxy, cyano, nitro or trifloromethyl;

to obtain medicines for the treatment of subjects suffering from HIV (human immunodeficiency virus).

The invention also relates to new compounds of the formula

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their pharmaceutically acceptable additive salts with acid and stereochemical isomeric forms, where the substituents are the same as defined for formula (I), provided that the compounds (a) through (o) (see tab. A) not included.

The condition is intended to exclude compounds (a) to (f), which are described in DE-2121694 and DE-2226474; compounds, (g), described in DE-2226474; compounds (h) to (k) described Guioca, Ann. Pharm. Fr., 31:283-292 (1973); compound (1) described Kelarev Century. And. etc., Chem. A heterocycle. Conn. , 1392-1397 (1987); connect (m), described in Kelarev Century. And. etc., Chem. A heterocycle. Conn. , 1395-1399 (19 used in the foregoing definitions and hereinafter referred to here, halogen denotes fluorine, chlorine, bromine and iodine, C1-2alkyl includes methyl and ethyl, C1-3alkyl refers to saturated hydrocarbon radical with a linear or branched chain, having from 1 to 3 carbon atoms, such as, for example, methyl, ethyl, propyl, etc.;1-4alkyl refers to saturated hydrocarbon radical with a linear or branched chain, as defined for C1-3of alkyl, as well as their higher homologues containing 4 carbon atoms, such as, for example, butyl, etc.; C1-6alkyl refers to saturated hydrocarbon radical with a linear or branched chain, as defined for C1-4the alkyl and the higher homologues of them containing 5 or 6 carbon atoms, such as, for example, pentyl or hexyl;3-6alkyl refers to saturated hydrocarbon radical with a linear or branched chain, having from 3 to 6 carbon atoms, such as, for example, propyl, butyl, pentyl, hexyl and so on;2-6alkyl refers to saturated hydrocarbon radical with a linear or branched chain, as defined for C3-6the alkyl and ethyl; C1-10alkyl refers to saturated hydrocarbon radical with a linear or branched chain, as defined for C1-6of alkyl,silt, and decyl; WITH1-4alkyliden denotes a divalent hydrocarbon of linear or branched chain, having from 1 to 4 carbon atoms, such as, for example, methylene, ethylidene, propylidene, butylidene and so on;3-7cycloalkyl is an umbrella term for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C3-10alkenyl is a hydrocarbon radical with a linear or branched chain, containing one double bond and having from 3 to 10 carbon atoms, such as, for example, 2-propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 3-heptenyl, 2-octenyl, 2-nonenal, 2-decenal and so on, with the carbon atom attached to the triazine ring is preferably an aliphatic carbon atom; WITH3-10quinil is a hydrocarbon radical with a linear or branched chain containing one triple bond and having from 3 to 10 carbon atoms, such as, for example, 2-PROPYNYL, 2-butynyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 3-heptenyl, 2-octenyl, 2-nonenal, 2-decenal and so on, with the carbon atom attached to the triazine ring is preferably an aliphatic carbon atom; C1-6alcander characterizes bivalent nasishennie, the methylene, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol, 1,5-pentandiol, 1,6-hexandiol and their branched isomers.

Pharmaceutically acceptable additive salts with an acid, above, indicate therapeutically active non-toxic salt forms accession acids, which can give the compounds of formula (I) or (I'). The compounds of formula (I) or (I'), which have properties of bases can be converted into their pharmaceutically acceptable additive salts with acid by processing the basic form of a suitable acid. Suitable acids include, for example, inorganic acid, such as halogen acids, for example hydrochloric or gidropony acid; sulfuric; nitric; phosphoric and the like acids; or organic acids, such as, for example, acetic, propanoic, hydroxyestra, lactic, pyruvic, oxalic, malonic, succinic (i.e. batandjieva acid), maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, reklamowa, salicylic, p-aminosalicylic, AMOVA and similar acids.

The term additive salt also includes a hydrate and solvate additive form to olati etc.

The term stoichiometric isomeric forms of the compounds of formula (I) or (I') above, refers to all possible connections received from the same atoms connected in the same sequence of relationships, but having different three-dimensional structures which are not interchangeable, which may be of the compounds of formula (I) or (I'). If not specified or as otherwise indicated, the chemical designation of compounds comprises a mixture of all possible stereochemical isomeric forms, which may be of the specified connection. This mixture may contain all of the diastereomers and/or enantiomers basic molecular structure of the compounds. All stereochemical isomeric forms of the compounds of formula (I) or (I') both in pure form and in mixtures with each other are included in the scope of the present invention.

Some of the compounds of formula (I) or (I') may also exist in tautomeric forms. Such forms, although it is not stated specifically in the formula above, are included in the scope of the present invention.

When used hereinafter the term "compounds of formula (I) or (I')" imply that it also includes all pharmaceutically acceptable additive salts with acid and all stereoisomeric forms.

1and R2each independently selected from hydrogen, C1-6of alkyl, AG1or mono - or di(C1-6alkyl) aminocarbonyl; or

R1and R2taken together, may form pyrrolidinyl, piperidinyl or morpholinyl;

R3denotes hydrogen, C1-6alkyl or AG1;

AG1denotes phenyl or phenyl substituted with 1, 2 or 3 substituents, each of which is independently selected from halogen, C1-6of alkyl, C1-6alkyloxy, cyano, nitro or trifloromethyl; and L is a radical of the formula

< / BR>
where Alk represents C1-6alcander;

Rand, Rb, Rc, Rd, Re, R4, R5, R6, R7and R8each, independently, selected from hydrogen, halogen, C1-6of alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalomethane; or

Raand Rbtaken together may form a bivalent radical of the formula

-CH=CH-NR9(a-1),

-NR9-CH=CH- (a-2),

where R9denotes hydrogen or C1-4alkyl.

Another specific group of compounds is formed by compounds of formula (I-P), from which are excluded the compounds (a) to (o), the compound represented by the P>R2has a different meaning than amino.

Other interest compounds are those compounds of formula (I'), where L represents C1-10alkyl, C3-10alkenyl,3-10quinil,3-7cycloalkyl; or L represents C1-10alkyl, substituted by one or two substituents, independently selected from C3-7cycloalkyl; indolyl or indolyl substituted with one, two, three or four substituents, each of which is independently selected from halogen, C1-6of alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethane, C1-6alkylcarboxylic; phenyl substituted one, two, three, four, or five substituents, each of which is independently selected from halogen, C1-3of alkyl, C3-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethane, C1-6alkylcarboxylic.

Still some interest compounds are those compounds of formula (I), which applies one of the following constraints:

1) R4denotes hydroxy, halogen, C2-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, amino, trihalomethyl or trihalomethane; or

2) R
3) R6stands WITH2-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, trihalomethyl or trihalomethane; or

4) R7denotes hydroxy, halogen, C1-3alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalomethane; or

5) R8denotes hydroxy, halogen, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalomethane.

Particular cases of such compounds are the compounds of formula (I) or (I'), where L denotes a3-10alkenyl or C1-2alkyl, substituted by one or two substituents, independently selected from C3-7cycloalkyl; indolyl or indolyl substituted with one, two, three or four substituents, each of which is independently selected from halogen, C1-6of alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethane, C1-6alkylcarboxylic; phenyl or phenyl substituted one, two, three, four, or five substituents, each of which is independently selected from halogen, hydroxy, C1-6of alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, UB>alkyl, substituted by one or two substituents, independently selected from cyclopropyl; indolyl or indolyl substituted with one, two, three or four substituents, each of which is independently selected from halogen, hydroxy, C1-6of alkyl, C1-6alkyloxy, trihalomethyl, trihalomethane, C1-6alkylcarboxylic.

Also particular cases of the compounds are the compounds of formula (I) or (I'), where R4, R7and R8denotes hydrogen, and R5and R6each, independently, represents hydrogen, cyano, halogen or aminocarbonyl; more specifically, where R4, R5, R7and R8represent hydrogen, and R6denotes cyano.

Other particular cases of the compounds are the compounds of formula (I) or (I'), where R1and R2each independently selected from hydrogen; hydroxy; amino; C1-6of alkyl, C1-6alkyloxy; C1-6alkylcarboxylic; AG1; mono - or di(C1-6alkyl) aminocarbonyl; dihydro-2(3H)-furanone; C1-6of alkyl, substituted by one or two substituents, each of which is independently selected from amino, imino, aminocarbonyl, aminocarbonyl, hydroxy, hydroxy (C1-6alkyloxy, carboxyl, mono - or di(C1-6and mono - or di (C1-6alkyl) amino1-4alkylidene; more specifically, where R1denotes hydrogen and R2denotes hydrogen; hydroxy; amino; C1-6alkyl, C1-6alkyloxy; C1-6alkylsulphonyl; C1-6allyloxycarbonyl; AG1; mono - or di (C1-6alkyl) aminocarbonyl; dihydro-2(3H)-furanone; C1-6alkyl, substituted by one or two substituents, each of which is independently selected from amino, imino, aminocarbonyl, aminocarbonyl, hydroxy, hydroxy (C1-6alkyloxy, carboxyl, mono - or di(C1-6alkyl) amino, C1-6allyloxycarbonyl or tanila.

A preferred group of compounds are those compounds of formula (I) or (I'), where L denotes 2,6-dichlorophenylethyl.

Another preferred group of compounds forming such compounds of formula (I) or (I'), where R3denotes hydrogen, R4, R5, R7and R8denotes hydrogen and R6denotes cyano.

Another group of preferred compounds form such compounds of formula (I) or (I'), where R1denotes hydrogen and R2denotes hydrogen or hydroxy.

More preferred are such compounds of formula (I) or (I'), where L denotes 2,6->denotes cyano.

The most preferred compounds are 4-[[4-amino-6-[(2,6-dichlorophenyl)methyl] -1,3,5-triazine-2-yl] amino]benzonitrile; 4-[[4-[(2,6-dichlorophenyl)methyl]-6-(hydroxyamino)-1,3,5-triazine-2-yl] amino]benzonitrile and their pharmaceutically acceptable additive salts with acids.

Usually the compounds of formula (I) can be obtained in accordance with the methods described in DE-2121694 and DE-2226474 and Guioca, Ann. Pharm. Fr., 31:283-292 (1973).

The compounds of formula (I-a), which are compounds of formula (I), where R1and R2denote hydrogen, can be obtained by reacting the intermediate compounds of formula (II) with an intermediate compound of formula (III) in a reaction-inert solvent such as, for example, N,N-dimethylformamide (see diagram 1 at the end of the description).

The compounds of formula (I-b), which are compounds of formula (I), where R3denotes hydrogen, can be obtained by reacting the intermediate compounds of formula (IV) with an intermediate compound of formula (V) in a reaction-inert solvent such as, for example, N,N-dimethylformamide (see diagram 2 at the end of the description).

The compounds of formula (I), where L denotes a1-10alkyl, substituted indolium or Indigena, C1-6of alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethane, C1-6alkylcarboxylic, and these substituents represented by (R')n, where n is from 1 to 4, and these compounds are represented by formula (I-C), can be obtained by removing the protection of the intermediate compounds of formula (IV), where P is a suitable protecting group, such as, for example, toluensulfonate or the like, according to known methods for the removal of the protective groups, such as boiling under reflux in a reaction-inert solvent, such as water, methanol or mixtures thereof, in the presence of a base, for example, potassium carbonate or the like (see diagram 3 in the end of the description).

The compounds of formula (I), where R1denotes hydrogen, represented by formula (I-d) can be obtained by reacting the intermediate compounds of formula (VII), where W1denotes a suitable leaving group, such as, for example, halogen, amino derivatives of formula (VIII) in a reaction-inert solvent such as, for example, 1,4-dioxane and the like, in the presence of a suitable base, such as, for example, sodium hydroxide, triethylamine or N,N-diisopropylate the PPU, you appropriately implement the above interaction with a protected form of intermediate compound (VIII), the hydroxy-group which has a suitable protective group P, which is, for example, a group trialkylsilyl, with the subsequent removal of the protective group according to known methods.

The compounds of formula (I), where R1and R3denotes hydrogen, and R2and part of the molecule WITH6(R4R5R6R7R8) are identical, represented by formula (I-e) can be obtained by reacting the intermediate compounds of formula (IX), where W2denotes a suitable leaving group, such as, for example, halogen or the like, with an intermediate compound of formula (X) in a reaction-inert solvent such as, for example, 1,4-dioxane (see figure 5 at the end of the description).

The compounds of formula (I), where R1and R2other than hydrogen, and they are represented by R1and R2accordingly, with the above compounds represented by formula (I-f-1) can be obtained by reacting the intermediate compounds of formula (XI) with an intermediate compound of formula (XII), where W3is a suitable leaving group such as, e.g. the and in the presence of a suitable base, such as, for example, sodium hydride or potassium carbonate (see diagram 6 in the end of the description).

In the case when the intermediate compound (XII) is bounded for W3- Ar1(XII-b) and R3is hydrogen, the reaction time can be set by the formation of disubstituted analogues represented by the formula (I-f-2) (see scheme 7 at the end of the description).

The compounds of formula (I) can also be obtained by converting compounds of the formula (I) into each other according to well-known in this field reactions of transformation groups.

For example, the compounds of formula (I-a) can be subjected to interaction with the anhydride of the formula (XIII) where R has a value such that-C(=O)-R is part of the definition of R1or R2according to the method described in Arch. Pharm. (Waldheim) 1986, 319, 275, obtaining thus compounds of formula (I-g). In this reaction by boiling under reflux is significant; over long periods of time lead to lower output monosubstituted end products and increased formation of di - and, where possible, tizamidine end products (see figure 8 at the end of the description).

The compounds of formula (I-a) can also be subjected to interaction with realencoder Foundation, such as, for example, sodium hydride (see chart 9 in the end of the description).

Some of the intermediates mentioned above, are commercially available or can be obtained according to known methods, while other intermediate compounds are considered new. Intermediate compounds of formula (II) can be obtained by reacting cyanoderivatives formula (XV) with ammonium chloride (XVI) or its functional derivative in a reaction-inert solvent such as, for example, toluene, in the presence of a suitable catalyst, such as, for example, trimethylaluminum (see figure 10 at the end of the description).

Intermediate compounds of formula (III) can usually be obtained by reacting diphenyl-N-cyanocarbonimidate formula (XVII), which can be obtained according to Webb R. L. et al., J. Heterocyclic Chem., 19:1205-1206 (1982), with an aniline derivative of the formula (XVIII) in a reaction-inert solvent such as, for example, N,N-dimethylformamide ( see figure 11 at the end of the description).

Intermediate compounds of formula (VII) can be obtained by making the beginning of the Grignard reagent of the intermediate compounds of formula (XIX), where W4is a suitable leaving group, such as, n is a simple diethyl ether, and the subsequent interaction of the specified Grignard reagent with an intermediate compound of formula (XX), where W5is a suitable leaving group, such as, for example, halogen, for example chlorine, in a reaction-inert solvent such as, for example, benzene, obtaining thus the intermediate compounds of formula (XXI). It may be convenient to conduct the above interaction in an inert atmosphere, such as, for example, an argon atmosphere. The intermediate compound (XXI) can be isolated from the reaction medium or can be further subjected to interact in situ with an intermediate compound of formula (XXII) in a reaction-inert solvent such as, for example, 1,4-dioxane, and in the presence of a suitable base, such as, for example, diisopropylethylamine or so on, obtaining thus the intermediate compounds of formula (VII). Intermediate compounds of formula (VII) are new (see figure 12 at the end of the description).

Intermediate compounds of formula (XI) can be obtained by reacting the intermediate compounds of formula (XXIII) with an intermediate compound of formula (XXIV) in a reaction-inert solvent such as, for example, N,N-dimethylformamide (see figure 13 in the end of the description). the reasoning centers in its structure, presents R or S configuration.

The compounds of formula (I) obtained by the methods described above can be synthesized as a mixture of stereoisomeric forms, in particular in the form of racemic mixtures of enantiomers which can be separated from each other by the following known methods of separation. Racemic compounds of the formula (I) can be converted into the corresponding diastereomeric salt form by reacting with a suitable chiral acid. These diastereomeric salt forms are then separated, for example, by selective or fractional crystallization, and the enantiomers release with alkali. An alternative way of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. These pure stereochemical isomeric forms may also be derived from the corresponding pure stereochemical isomeric forms suitable source products provided that the reaction proceeds in a stereospecific. If desired specific stereoisomer, it would be appropriate to synthesize the specified connection stereochemical methods of getting them. In these methods should preferably the viral properties, in particular against human immunodeficiency virus (HIV), which is etiologichesky agent of acquired immunodeficiency syndrome (AIDS) in humans. The HIV virus primarily infects cells of the T-4 people and destroys them or change their normal function, particularly the coordination of the immune system. In the infected patient has a constantly decreasing number of cells T-4, which, moreover, behave abnormally. Thus, the immune system is unable to fight infections and tumors, and HIV infected subject usually die from infection by opportunistic microorganisms, such as pneumonia, or cancer. Other conditions associated with HIV infection include thrombocytopenia, Kaposi's sarcoma and infection of the Central nervous system characterized by progressive demyelination, resulting in dementia and symptoms such as progressive articulation disorder, ataxia and disorientation. HIV infection is also associated with peripheral neuropathy, progressive widespread lymphadenopathy (PGL) and complex related to AIDS (ARC).

These compounds also show activity against stammwitz. They also have a small but non-binding affinity to -1 acid glycoprotein person.

Due to their antiretroviral properties, particularly their properties against HIV, especially their anti-HIV-1 activity, the compounds of formula (I), their pharmaceutically acceptable salts and stereochemical isomeric form can be used in the treatment of individuals infected with HIV, and to prevent these individuals. Typically, compounds of the present invention can be used in the treatment of warm-blooded animals infected with viruses, the existence of which is mediated by the enzyme reverse transcriptase or depends on it. Conditions that can be prevented or treated by the compounds of the present invention, particularly conditions associated with HIV and other pathogenic retroviruses, include AIDS-related AIDS complex (ARC), progressive disseminated lymphadenopathy (PGL), and chronic CNS diseases caused by retroviruses, such as, for example, mediated HIV dementia and multiple sclerosis.

Therefore, compounds of the present invention can be used as drugs against the above-mentioned conditions. Specified the number of examples, effective to combat the conditions associated with HIV and other pathogenic retroviruses, particularly HIV-1.

These compounds can be formulated into various pharmaceutical forms for administration. These pharmaceutical forms or compositions are new and, therefore, constitute another aspect of the present invention. And obtaining these compositions is another aspect of the present invention. As appropriate compositions can be stated all compositions usually employed for systemically injected drugs. To obtain pharmaceutical compositions of this invention, an effective amount of a particular compound, possibly in the form of additive salts with an acid, as the active ingredient together in a thin mixture with a pharmaceutically acceptable carrier, which may have a wide variety of forms depending on the form of preparation desired for administration. Such pharmaceutical compositions are desirable in the form of a suitable standard dosage forms, in particular for administration orally, rectally, transdermally, or by parenteral injection. For example, upon receipt of the compositions in oral dosage form is s and the like, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, loosening means and the like, in the case of powders, pills, capsules and tablets. Because of the ease of their administration tablets and capsules represent the most preferred standard oral dosage forms, in this case, be sure to use solid pharmaceutical carriers. For parenteral compositions, the carrier will typically contain sterile water, at least in the most part, although there may be other ingredients, for example, to facilitate solubility. Can be obtained, for example, solutions for injection, in which the medium contains saline solution, glucose solution or a mixture of saline and glucose solution. Can also be prepared suspension for injection in this case can be used suitable liquid carriers, suspendresume substances, etc., Also included are solid formulation that is designed to convert directly before use in a liquid formulation. In the compositions suitable for percutaneous call the CTB, possibly together with suitable additives of any nature in very small quantities, such additives do not have a significant harmful impact on the skin.

It is particularly convenient to obtain the above pharmaceutical composition in the form of a standard dosage form for easy administration and uniformity of dosage. Standard dosage form, as used here, refers to physically discrete units suitable as unit doses, each unit contains a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including tablet core or coated tablets), capsules, pills, powder packing, pills, solutions or suspensions for injection and the like and separated sets.

Specialists for the treatment of HIV infection in the state to determine the effective daily amount based on the results presented here tests. It is generally assumed that the effective daily amount should be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg DGB-doses at appropriate intervals throughout the day. These sub-doses may be in the form of standard dosage forms, for example, containing from 1 to 1000 mg, in particular from 5 to 200 mg of active ingredient in a unit dosage form.

The exact dosage and frequency of injection depends on the specific compounds of formula (I), the severity of the condition being treated, age, weight and basic physical condition of the particular patient, and other medication, which may be subjected to an individual that is well known to specialists in this field. Moreover, it is obvious that the effective daily amount may be reduced or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds according to this invention. Intervals effective daily amounts shown above are therefore only indicative and should not be interpreted as limiting the scope or application of the invention in any way.

Combination antiretroviral compounds and compounds of the formula (I) can also be used as a drug. Thus, the present invention also relates to the preparation for simultaneous, separate or sequential use in the treatment of HIV. Various medications can be combined in a single preparation together with pharmaceutically acceptable carriers. These other antiretroviral compounds may be known antiretroviral compounds such as nucleoside reverse transcriptase inhibitors such as zidovudine (3'-azido-3'-deoxythymidine, AZT), didanosine (dideoxyinosine, ddI), zalcitabine (dideoxycytidine, ddC) or lamivudine (3'-thia-2'-3'-dideoxycytidine, 3TC), etc.; non-nucleoside reverse transcriptase inhibitors, such as suramin, pentamidine, thymopentin, castanospermine, dextran (dextran sulfate), foscarnet-sodium (phosphonoformate trisodium), nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6N-dipyrido[3,2-b: 2', 3'-e][1,4]diazepin-6-he, takin (tetrahydroaminoacridine), etc.; connection type TIBO (tetrahydro-imidazo[4,5,1-jk] [1,4] benzodiazepine-2(1H)-he tion), for example (S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)-imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-tion); connection type-APA (-anilinoquinazoline), for example -[(2-nitrophenyl)amino] -2,6-dichlorobenzoate etc.; TAT-inhibitors, e.g. P0-5-3335.and so on; protease inhibitors such as indinavir, ritonavir, saquinavir and t is in to illustrate but not to limit the scope of the present invention.

Experimental part

Below "CT" means room temperature, "DHM" means dichloromethane, "DMF" means N,N-dimethylformamide and "atsn" refers to acetonitrile.

A. the production of intermediate compounds

Example A. 1

a) a Mixture of 4-cyano-aniline (2,48 g) and diphenyl-N-cyano-carbonamide (5.0 g) in DMF (25 ml) is stirred for 20 hours at 110oWith in a stream of argon. Add water and the precipitate is filtered off with getting brownish solid. This fraction is recrystallized from atsn. The precipitate is filtered off and dried, obtaining a rate of 1.67 g (30%) phenyl-N'-cyano-N-(4-cyanophenyl)carbanilide (intermediate compound 1). In this way receive phenyl-N'-cyano-N-(3-cyano-phenyl)carbamimidoyl (intermediate compound 2); phenyl-N'-cyano-N-(4-chlorophenyl)carbamimidoyl (intermediate compound 3) and O-phenyl-N'-cyano-N, N-dimethylcarbamate (intermediate compound 7).

b) a Mixture of intermediate compound (7) (0,01746 mol) and 2,6-dichlorobenzonitrile (0,01746 mol) in DMF (30 ml) is stirred for 24 hours at 85oC. After cooling, the reaction mixture was quenched with H2O and the precipitate is filtered off and SUSAT">

Example A. 2

a) a Mixture of NH4Cl (2.55 g) in toluene (100 ml) is stirred and cooled in an ice bath in a stream of argon. Add Al(CH3)3/toluene (23.9 ml; 2.0 M) and the resulting mixture is stirred for 1.5 hours at RT. Add 5-Chloro-1[(4-were-sulfonyl] -1H-indol-4-acetonitrile, which can be obtained according to Matsumoto et al., Heterocycles, 24(11), 31 57-3162 (1986), (3,0 g) and the reaction mixture is stirred for 24 hours at 80oC. Then the reaction mixture is poured into a suspension of 96 g of silica gel in DHM (200 ml), stirred, filtered and the filter cake washed with methanol (400 ml) and evaporated to obtain 5.35 g of white solid product. The solid product is dissolved in DHM, washed 3 N. NaOH, dried with potassium carbonate, filtered and the filtrate is evaporated, getting 2,80 g (89%, white solid product) 5-chloro-1[(4-were-sulfonyl] -1H-indol-4-ethane-imidated (intermediate compound 4).

b) a Mixture of intermediate soedineniya (4) (2,61 g) and intermediate (1) (1.89 g) in DMF (25 ml) is stirred for 24 hours at 65oWith in a stream of argon. Slowly add water and the precipitate is filtered to obtain 3.55 g not quite white solid product. The solid product was stirred at the boil under reflux in atsn, ogladac filtered off and dried, getting 0.28 g (62%, white solid) 4-[[4-amino-6-[(4-cyanophenyl)amino]-1,3,5-triazine-2-yl]methyl] -5-chloro-1-[(4-

were)sulfonyl]-lH-indole (intermediate compound 5).

Table 1 lists the intermediate compounds that receive according to the method described in example A. 2A.

Example A. 3

To 4-cyanophenyl-thiourea (5.0 g) in acetone (100 ml) add itmean (1,76 ml). The reaction mixture was stirred over night at RT. The precipitate is filtered off, dried and dissolved in DHM. The organic solution was washed with NH3(aq. ) (excess), dried over potassium carbonate, filtered and the solvent evaporated, receiving a 4.53 g (84%, white solid product) methyl-N'-(4-cyanophenyl) carbamimidoyl (intermediate compound 6).

Example A. 4

a) a Solution of 2-(methyl bromide)-1,3-dichlorobenzene (about 10% of 0,383 mol) in diethyl ether (240 ml) is added to magnesium (0,383 mol) in diethyl ether (240 ml) under argon. When the reaction begins, add the rest of the 2-(methyl bromide)-1,3-dichlorobenzene in diethyl ether. The solution is stirred at RT for 2.5 hours and then added via cannula to a solution of 2,4,6-trichloro-1,3,5-triazine (0,319 mol) in benzene (480 ml), keeping the temperature below 15oC. Reaktsionnymi-benzonitrile (0.351 mol) in N,N-diisopropylethylamine (61,0 ml) and 1,4-dioxane (500 ml) and the reaction mixture was stirred at RT for 40 hours. The solvent is evaporated. Add water and ethyl acetate. The solution is stirred, then the solid is filtered off, washed with ethyl acetate and water, getting 129, 9mm g of 4-[[4-chloro-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazine-2-yl] amino] benzonitrile (intermediate compound 27; so pl. 243-244oC).

In this way receive a 4-[[4-chloro-6-[(2,4-dichlorophenyl)methyl]-1,3,5-triazine-2-yl] amino]benzonitrile (intermediate compound 28) and 4-[[4-chloro-6-[(2-chlorophenyl)methyl] -1,3,5-triazine-2-yl] amino]benzonitrile (intermediate compound 29).

b) 2,4-dichloro-6-[(2,6-dichlorophenyl)methyl] -1,3,5-triazine (intermediate compound 30) are obtained according to the method described in example A. 4A, stop it before adding 4-amino-benzonitrile.

C. obtain the final compounds

Example B. 1

a) the Intermediate compound (1) (1.66 g) are added to a solution of 2,6-dichlorobenzene-ethanimine (1.29 g) in DMF (13 ml). The reaction mixture is stirred for three days at RT, then for two days at 60oWith in a stream of argon. Add water and the precipitate filtered off. This fraction is refluxed in atsn (500 ml), cooled and the precipitate filtered and dried, obtaining 1,58 g (67%, white solid) 4-[[4-amino-6-[(2,6-dichlorophenyl) IU is Oh acid (20 ml) are combined and heated under reflux for 10 minutes. Then the reaction mixture is removed from the oil bath and cooled to CT. The precipitate is filtered off, receiving 0.25 g (45%) of N-[4-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazine-2-yl]ndimethylacetamide (compound 22).

Longer boiling under reflux leads to disubstituted (compound 40) and trisemester (compound 41) analogue connection 22.

Example Century. 2

Methanol (120 ml) is added to a mixture of intermediate compound (5) (2.35 g) and K2CO3(9,19 g) in water (40 ml). The resulting reaction mixture is stirred and refluxed 19 hours under argon. Add water (120 ml), the precipitate is filtered off and purified by chromatography on a column of silica gel (eluent: DHM/2-propanone 90/10).

Two desired fractions are collected and the solvent is evaporated. The first fractional group suspended in atsn, cooled, filtered and dried, obtaining 0.75 g (45%, white solid) 4-[[4-amino-6-[(5-chloro-1H-indol-4-yl)methyl] -1,3,5-triazine-2-yl] amino] benzonitrile (compound 8, so pl. 267-268oC). The second column fractional group give 0.15 g of 4-[[4-amino-6-[(5-chloro-1H-indol-4-yl) methyl] -1,3,5-triazine-2-yl] amino] benzamide (compound 9). After 24 hours at RT the aqueous filtrate is filtered with obtaining 0, the methanol, filtered while hot, the filtrate is concentrated to 50 ml, cooled and filtered, then dried, obtaining 0.25 g(14%) 4-[[4-amino-6-[(5-chloro-1H-indol-4-yl)methyl]-1,3,5-triazine-2-yl]amino]benzamide (compound 9, so pl. 204-205oC).

Example Century. 3

A mixture of compound (1) (1.0 g) and sodium hydride (0.11 g) in DMF (20 ml) is stirred for 20 minutes at RT in a stream of argon. Then added dropwise 2-isocyanato-propane (0,27 ml) for 30 min and the reaction mixture was stirred at RT over night. The solvent is evaporated and water is added. The precipitate is filtered, washed with water and diethyl ether and recrystallized from 1,4-dioxane. The precipitate is filtered off and dried, obtaining 0.95 g (85.1%) are N-[4-[(4-cyano-phenyl)amino] -6-[(2,6-dichlorophenyl)methyl] -1,3,5-triazine-2-yl]-N'-(1-methylethyl)urea (compound 6, so pl. 267-268oC).

Example Century. 4

A mixture of N-[amino(methylamino)methyl] -2,6-dichlorobenzene-ndimethylacetamide (4.15 g) and intermediate 6 (3,05 g) in DMF (25 ml) is stirred and refluxed for 20 hours. The solvent is evaporated, the residue is dissolved in DMF (25 ml) and heated at 80oC for 16 hours and at 100-108oWith another 66 hours. The reaction mixture is cooled, quenched with water, extracted with diethyl ether and washed Rabaul the Lasch-chromatography on a column and recrystallized from 2-propanol and at the end of the methanol, getting 0,78 g(12,6%) 4-[[4-[(2,6-dichlorophenyl)methyl] -6-(methylamino)-1,3,5-triazine-2-yl] amino] benzonitrile (compound 7, so pl. 229-230oC).

Example Century. 5

a) the Intermediate compound (27) (0,00423 mol), 2-aminoacetate (0,00431 mol), 1,4-dioxane (20 ml) and N,N-diisopropylethylamine (0,00862 mol) are combined and stirred at RT for 16 hours under argon. The reaction mixture was quenched with H2O and filtered. The residue was washed with N2Oh, filtered and recrystallized from atsn (200 ml). The precipitate is filtered and dried, obtaining 0.75 g (41,4%) [N-[4-[(4-cyano-phenyl)amino] -6-[(2,6-dichlorophenyl)methyl] )-1,3,5-triazine-2-yl] aminoacetate (compound 14).

b) 4-[[4-[(2,6-dichlorophenyl)methyl]-6-hydrazino-1,3,5-triazine-2-yl]amino] benzonitrile (compound 15) are obtained in a similar manner as described in example 5A Century, but N,N-diisopropylethylamine do not use.

Example Century. 6

a) the Intermediate compound (27) (0,0128 mol), 1,4-dioxane (50 ml) and O-(trimethylsilyl)hydroxylamine (0,134 mol) are combined under argon. The reaction mixture was stirred at RT for 20 hours. The reaction mixture was concentrated and add DHM (50 ml), NaOH (1 ad; 50 ml) and model HC1 (1 N.; 100 ml). The solution is stirred for one hour. The precipitate is filtered off and recrystallized from methanol. Sediment ethno)-1,3,5-triazine-2-yl]amino]benzonitrile (compound 21).

b) Compound (21) (0,00227 mol) is stirred in ethyl acetate (50 ml). The mixture is washed Panso3(50 ml saturated solution), then washed with saline, dried, filtered and the solvent evaporated. The residue is crystallized from methanol, filtered and dried, obtaining 0,60 g(70,6%) 4-[[4[(2,6-dichlorophenyl)methyl] -6-(hydroxyamino)-1,3,5-triazine-2-yl] amino] benzonitrile (compound 33).

Example Century. 7

A mixture of intermediate (30) (0,068 mol) and 4-aminobenzonitrile (0,0420 mol) in 1,4-dioxane (100 ml) is stirred and refluxed for 16 hours under argon. The hot reaction mixture is filtered and the resulting filtrate concentrated. The residue is dissolved in DHM (30 ml). The precipitate is filtered and recrystallized from atsn (250 ml). After cooling to CT the filtrate concentrated. The residue is partitioned between DHM/NaOH (3 BC). The resulting solution was dried over K2CO3, filtered and the solvent evaporated. The residue is recrystallized from Sson. The precipitate is filtered off and dried, obtaining of 1.00 g (5.0%) N,N'-[6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazine-2,4-diyl]bis[4-aminobenzonitrile] (compound 11).

Example Century. 8

DMF (9.0 ml) and intermediate compound (31) (0,00295 mol) is added to sodium hydride (0,00354 mol) under Argonaut at 80oWith over 3.5 hours. After cooling to CT, the reaction mixture was quenched with H2O. the Precipitate is filtered off, dried and purified flash-chromatography on columns on silica gel (eluent: DHM). The desired fractions are collected and the solvent is evaporated, obtaining 4-[4-[(2,6-dichlorophenyl)methyl]-6-(dimethylamino)-1,3,5-triazine-2-yl]amino]benzonitrile (compound 10).

b) the Intermediate compound (31) (0,00671 mol), dimethylacetamide (20 ml), 4-perbenzoate (0,01007 mol) and2CO3(0,02685 mol) are combined and refluxed for 4 hours under argon. The reaction mixture is stirred and refluxed overnight and quenched with water and extracted with DHM. The separated organic layer was washed with brine, dried, filtered and the solvent is evaporated. The residue is purified flash-chromatography (eluent: DHM). The desired fractions are collected and the solvent evaporated. The residue is crystallized from CH3HE is recrystallized from atsn and at the end of the process SN3HE. The precipitate is filtered off and dried, obtaining 0.32g 4,4'-[[4-[(2,6-dichlorophenyl)methyl] -6-(dimethylamino)-1,3,5-triazine-2-yl] amino]bicentenary (compound 38).

Example Century. 9

A solution of sodium hydride (0,00195 mol) in DMF (7 ml) are added to link the Chloroacetic acid (0,0186 mol) and the reaction mixture is heated to 70oC for 19 hours. The reaction mixture was then quenched with water and the resulting solid product is filtered off. The residue is treated with hot atsn, then filtered while it is still hot. The remainder of the cooled filtrate is recrystallized from 1,4-dioxane. The precipitate is filtered off, getting 0.16 g (19.4%) of N-(4-cyanophenyl)-N-[4-amino-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazine-2-yl]glycine (compound 39).

Example Century. 10

Sodium hydride (0,00150 mol), atsn (5 ml), compound 1 (0,00135 mol) in 1,4-dioxane (10 ml) and atsn (10 ml) are combined under argon. The solution is stirred for 1 hour. 1-Chloro-3-isocyanatopropyl (0,00137 mol) is added. The reaction mixture is stirred for 1 hour. Add 1-methyl-pyrrolidinone (10 ml). The reaction mixture is stirred for 16 hours. The mixture is then concentrated. The concentrate is partitioned between DHM/N2O. the resulting solution is filtered, dried over K2CO3, filtered, concentrated and the residue treated with NH3in 1,4-dioxane (12 ml, 0.5 M) and heated under pressure at 55oC. the resulting solution was concentrated and further purified flash-chromatography on columns (eluent: DHM/CH3HE 95/5). Pure fractions are collected and the solvent is evaporated, obtaining 0.12 g (18,9%) N-[3-[[4-[(4-cyanophenyl)amino] -6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazine (0,0128 mol) are combined and stirred at RT for 5 minutes under argon. Then add the intermediate compound 27 (0,00128 mmol) and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was quenched with H2O and stirred. The precipitate is filtered off and the residue is stirred in boiling under reflux methanol, cooled and filtered, obtaining 0.34 g (64,3%) N-[4-[(4-cyanophenyl)amino] -6-[(2,6-dichlorophenyl)methyl] -1,3,5-triazine-2-yl]guanidine (compound 20).

Example 12 Century

A mixture of intermediate 27 (0,00256 mol) and 3-amino-1,2-propane diol (0,00563 mol) in 1,4-dioxane (10 ml) and 1-methyl-pyrrolidinone (2 ml) is stirred at RT for 48 hours under argon. The reaction mixture was concentrated, quenched DHM/N20 and stirred. The precipitate is filtered off, receiving 1.12 g(86,9%)()-4-[(4-[(2,6-dichlorophenyl)methyl] -6-[(2,3-dihydroxypropyl)amino]-1,3,5-triazine-2-yl]amino]benzonitrile (compound 26).

Example Century. 13

Connection 1 (0,0016 mol) and 1,1-dimethoxy-N,N-dimethylethanamine (21 ml) are combined and thoroughly mixed at ambient temperature for 8 hours. The reaction mixture was filtered and the collected solid product was washed with simple ether (fraction A). An additional connection is obtained by concentration of the filtrate (fraction). Fractions a and b are combined and Perekrest the l] amino] benzonitrile (compound 62).

Example Century. 14

A solution of compound 13 (0,000519 mol), LiOHH2O (0,000571 mol), methanol (5.0 ml) and H2O (5.0 ml) is stirred at RT for 16 hours under argon. The reaction mixture was concentrated, re-dissolved in H2O and acidified with 1.0 N. model HC1 (0,52 ml) and stirred for 3 days. Then the solution is filtered and to the filtrate is added an excess of 1 ad model HC1 and CH3HE and the solution is stirred for 16 hours. The precipitate is filtered off and dried, obtaining 0.18 g (72,7%) %) N-[4-[(4-cyano-phenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazine-2-yl]glycine (compound 16).

An example of 15th Century

A mixture of compound 32 (0,00378 mol) in NH3in dioxane (50 ml) is heated in a pressure vessel at 85oC for 9 days. The solvent is evaporated and the resulting residue partitioned between DHM/H2O. the Organic layer was filtered, washed with ethanol and concentrated to 25 ml and filtered, obtaining 0,54 g(30,3%) ()-2-[[4-[(4-cyanophenyl)-amino] -6-[(2,6-dichlorophenyl)amino] -6-[(2,6-dichlorophenyl)-methyl] -1,3,5-triazine-2-yl] amino-4-hydroxybutanoic (compound 34).

An example of 16th Century

A solution of intermediate 27 in dimethyl sulfoxide handle NaN3in one portion and stirred at RT for 28 hours. The reaction mixture is poured on led-dichlorophenyl)methyl]-1,3,5-triazine-2-yl] amino]benzonitrile (compound 68).

In tables 1 - 5 lists the compounds that are obtained according to one of the above examples.

In the tables. No. connection Ex. No. the example salt form/stereochem. - salt form/Stereogum. (Approx. trans.)

C. Pharmacological example

Example C. 1

To assess in vitro agents against HIV using rapid and sensitive automated analytical method. Line transformed HIV-1 T cell-4, MT-4, which, as previously found (Koyanagi et al., Int. J. Cancer, 36, 445-451, 1985), are highly susceptible and vulnerable to HIV infection, serves as a line of target cells. Inhibition of HIV-induced cytopathic effect is used as the endpoint. The viability of both HIV (HIV) and mock-infected cells analyzed spectrophotometrically by in situ recovery of bromide 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT). the 50% cytotoxic concentration (CC50in microns) describe how the concentration of a compound that reduces the optical density of the mock-infected control sample by 50%. The protection percentage, which is achieved through connections in HIV-infected cells, calculated according to the following formula:

< / BR>
where (ODT)data cells; (ODC)HIV- the optical density measured for the control untreated HIV-infected cells; (ODC)MOCK- the optical density measured for the control untreated mock-infected cells; all values of optical density is determined at 540 nm. Dose that provides 50% protection according to the above formula is defined as the 50% inhibitory concentration (IC50in microns). The ratio SS50to the IC50determine the index of selectivity (SI). It is shown that the compounds of formula (I) effectively inhibit HIV-1. Specific values CC50IC50and SI are given in Table 6; figures in parentheses in columns "IC50(μm)" and "SS50(μm)" indicate the number of experiments used to calculate averages IC50and SS50.

D. Examples of songs

The following recipes give examples of typical pharmaceutical compositions suitable for systemic or local injection to the animals or the people in accordance with the present invention.

"Active ingredient" (A. I.), as used in these examples relates to a compound of formula (I) or its pharmaceutically acceptable salt additive.

Example D. 1: tablets, coated PMT and then moisturize with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. Wet powder mixture is sieved, dried, and sift again. Then add 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. All this is well mixed and pressed into tablets, receiving 10,000 tablets each containing 10 mg of active ingredient.

Floor

To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. Melt 10 g of polyethylene glycol and dissolved in 75 ml of dichloromethane. The last solution is added to the previous one and then add 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated colour suspension together and homogenized. Core tablets cover the thus obtained mixture in enrobing apparatus.

1. Substituted derivatives of diamino-1,3,5-triazine of General formula (I)

< / BR>
or their pharmaceutically acceptable salts adding acids or their stereochemical isomeric forms,

where R1and R2each, independently, represent hydrogen; hydroxy; amino; C1-6alkyloxy; C1-6alkylsulphonyl; C1-6allyloxycarbonyl; phenyl, substituted and substituted by one or two substituents, each of which is independently selected from amino, imino, aminocarbonyl, aminocarbonyl, hydroxy, hydroxys1-6alkyloxy, carboxyl, mono - or di(C1-6alkyl)amino, C1-6allyloxycarbonyl and tanila; or R1and R2taken together, may form azido or mono - or di(C1-6alkyl)amino1-4alkylidene;

R3represents hydrogen; phenyl substituted by cyano; C1-6alkylsulphonyl; C1-6allyloxycarbonyl; C1-6alkyl, unsubstituted or substituted C1-6allyloxycarbonyl;

R4and R8each represent hydrogen;

R5and R7denote hydrogen or cyano;

R6means cyano or aminocarbonyl;

L denotes a3-10alkenyl or C1-10alkyl, substituted by one or two substituents, independently selected from C3-7cycloalkyl, indolyl, substituted with halogen, phenyl, unsubstituted or substituted by 1-5 substituents, each of which is independently selected from halogen, hydroxy, C1-6of alkyl, C1-6alkyloxy, trihalomethyl, trihalomethane, C1-6alkylcarboxylic.

2. Connection on p. 1, wherein R1and R2each, independently, represent vadore hydrogen; C1-6alkyl or phenyl, substituted by cyano, and L denotes a radical of the formula

< / BR>
where Alk represents a C1-6alcander;

Ra, Rb, Rc, Rd, Reeach, independently, selected from hydrogen, halogen, C1-6of alkyl, C1-6alkoxy, trihalomethyl or trihalomethane.

3. Connection on p. 1, where L represents a C3-10alkenyl or1-2alkyl, substituted by one or two substituents, independently selected from C3-7cycloalkyl, indolyl, substituted with halogen, phenyl, unsubstituted or substituted by 1-5 substituents, each of which is independently selected from halogen, hydroxy, C1-6of alkyl, C1-6alkyloxy, trihalomethyl, trihalomethane,1-6-alkylcarboxylic.

4. The compound according to any one of paragraphs.1 and 2, where L denotes 2,6-dichlorophenylethyl.

5. The compound according to any one of paragraphs.1-4, where NR1R2refers to a different group than amino.

6. Connection on p. 1, where the compound is 4-[[4-amino-6-[(2,6-dichlorophenyl)methyl] -1,3,5-triazine-2-yl] amino] -benzonitrile; 4-[[4-[(2,6-dichlorophenyl)methyl] -6-(hydroxyamino)-1,3,5-triazine-2-yl] amino] benzonitrile or its pharmaceutically acceptable additive salt with Ki the tx2">

8. The compound of formula (VII)

< / BR>
where W5denotes halogen;

L, R3, R4, R5, R6, R7and R8specified in paragraph 1.

9. Pharmaceutical composition, ingibiruet replication of human immunodeficiency virus containing a pharmaceutically acceptable carrier and a therapeutically active amount of the compound specified in any of paragraphs.1-6.

10. A method of obtaining a pharmaceutical composition specified in paragraph 9, wherein therapeutically effective amount of the compounds specified in any of paragraphs.1-6, thoroughly mixed with a pharmaceutically acceptable carrier.

11. The method of obtaining compounds of General formula (I-a)

< / BR>
where L, R3, R4, R5, R6, R7and R8specified in paragraph 1,

namely, that the intermediate compound of formula (II)

< / BR>
subjected to interaction with an intermediate compound of formula (III)

< / BR>
where R3, R4, R5, R6, R7and R8above,

in a reaction inert solvent, or, if desired, convert the compounds of formula (I-a) into each other following known reactions of conversion; and further, if desired, convert the acid compounds in the free base by treatment with alkali; and if you want, get their stereochemical isomeric form.

12. The method of obtaining compounds of General formula (I-b)

< / BR>
where L, R1, R2, R4, R5, R6, R7and R8specified in paragraph 1, namely, that the intermediate compound of formula (IV)

< / BR>
where L, R1and R2above,

subjected to interaction with an intermediate compound of formula (V)

< / BR>
where R4, R5, R6, R7and R8above,

in a reaction inert solvent, or, if desired, convert the compounds of formula (I-b) into each other following known reactions of conversion; and further, if desired, convert the compounds of formula (I-b) in salt adding acid by treatment with acid, or Vice versa, convert the salt of the added acid to the free base by treatment with alkali; and, if desirable, get their stereochemical isomeric form.

13. The method of obtaining compounds of General formula (I-C)

< / BR>
where n = 1;

R' denotes a halogen;

R1, R2, R3, R4, R5, R6, R7and R8specified in paragraph 1,

namely, that removes the protective group in the intermediate joint is P>, R4, R5, R6, R7and R8above,

or, if desired, convert the compounds of formula (1-C) into each other following known reactions of conversion; and further, if desired, convert the compounds of formula (I-C) in salt adding acid by treatment with acid, or Vice versa convert the salt of the added acid to the free base by treatment with alkali; and, if desirable, get their stereochemical isomeric form.

14. The method of obtaining compounds of General formula (I-d)

< / BR>
where L, R2, R3, R4, R5, R6, R7and R8specified in paragraph 1,

namely, that the intermediate compound of formula (VII)

< / BR>
where W1denotes halogen;

R3, R4, R5, R6, R7and R8above,

subjected to interaction with an intermediate compound of formula (VIII)

< / BR>
where R2above,

in a reaction inert solvent in the presence of a suitable base and, in the case when R2contains a protected hydroxy-group, the protective group is removed, or, if desired, convert the compounds of formula (I-d) into each other following known reactions of conversion; and Yes, what do Vice versa convert the salt of the added acid to the free base by treatment with alkali; and, if desirable, get their stereochemical isomeric form.

15. The method of obtaining compounds of General formula (I-e)

< / BR>
where AG1represents phenyl, substituted cyano;

L specified in paragraph 1,

namely, that the intermediate compound of formula (IX)

< / BR>
where W2denotes a suitable leaving group;

L listed above,

subjected to interaction with an intermediate compound of formula (X)

H2N-Ar1(X)

where Ar1above,

in a reaction inert solvent, or, if desired, convert the compounds of formula (I) into each other following known reactions of conversion; and further, if desired, convert the compounds of formula (I-e) in salt adding acid by treatment with acid, or Vice versa convert the salt of the added acid to the free base by treatment with alkali; and, if desirable, get their stereochemical isomeric form.

16. The method of obtaining compounds of General formula (I-f-1)

< / BR>
where R1and R2are the same as R1and R2specified in paragraph 1, HB, the intermediate compound of formula (XI)

< / BR>
where L, R1and R2above,

subjected to interaction with an intermediate compound of formula (XII)

< / BR>
where W3denotes a suitable leaving group;

R4, R5, R6, R7and R8above,

in a reaction inert solvent and in the presence of a suitable base, or, if desired, convert the compounds of formula (I-f-1) into each other following known reactions of conversion; and further, if desired, convert the compounds of formula (I-f-1) in salt adding acid by treatment with acid, or Vice versa convert the salt of the added acid to the free base by treatment with alkali; and, if desirable, get their stereochemical isomeric form.

17. The method of obtaining compounds of General formula (I-f-2)

< / BR>
where L and AG1specified in paragraph 15;

R1and R2are the same as R1and R2specified in paragraph 1, but other than hydrogen,

namely, that the intermediate compound of formula (XI-b)

< / BR>
where L, R1and R2above,

subjected to interaction with the intermediate joint is r1above,

in a reaction inert solvent and in the presence of a suitable base, or, if desired, convert the compounds of formula (I-f-2) into each other following known reactions of conversion; and further, if desired, convert the compounds of formula (I-f-2) in salt adding acid by treatment with acid, or Vice versa convert the salt of the added acid to the free base by treatment with alkali; and, if desirable, get their stereochemical isomeric form.

 

Same patents:

The invention relates to new derivatives of 2- (iminomethyl) aminobenzoyl General formula (I) where a represents either a radical represented by the formula of the invention in which R1and R2denote, independently, a hydrogen atom, a group HE, a linear or branched alkyl or alkoxy having from 1 to 6 carbon atoms, R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4, R4means a linear or branched alkyl with 1-6 carbon atoms, or radicals represented by the formula of the invention, R5means a hydrogen atom, a group HE or linear or branched alkyl or alkoxy with 1-6 carbon atoms, means thienyl, X means Z1-, -Z1-CO-, -Z1-NR3-CO, -CH=CH-CO - or a simple bond, Y represents a radical chosen from the radicals Z2-Q, piperazinil, homopiperazine, -NR3-CO-Z2-Q-, -NR3-O-Z2-, -O-Z2Q-in which Q means a simple bond, -O-Z3and-N(R3)-Z3-, Z1, Z2and Z3means independently a simple link or a linear or branched alkylene with 1-6 carbon atoms, preferably Z1, Z2and Z3means -(CH2)m-, and m is an integer, R

The invention relates to new derivatives benzoylpyridine General formula (I), where R1means alkyl with 1-8 carbon atoms, a represents a group represented by the formula of the invention, means (-CH2-)aor (-CO-)band means an integer of 0 to 8, preferably 1, 2, 3 or 4, b means of 0,1 or 2, preferably 1, R2means unsubstituted or substituted alkyl with 1-8 carbon atoms, unsubstituted phenyl, NR3R4or preferably the five-membered heterocycle represented in the claims, in which U, V, W, X and Z can mean CH, NH, O or S, R3and R4denote alkyl with 1-8 carbon atoms

The invention relates to new imidazole derivative of General formula (1), where n1is an integer from 1 to 3, a represents hydrogen, linear or branched C1-C10-alkyl, which may be optionally substituted C3-C7-cycloalkyl or lower alkoxy, or a radical selected from the group shown in the formula of the invention, Y represents a radical selected from the group described in the claims, or to his new pharmaceutically acceptable salts

The invention relates to new halogensubstituted the benzimidazole of the formula I, in which R1, R2, R3and R4mean hydrogen, halogen, alkoxy with 1 to 4 carbon atoms, a group of the formula Z - R5where R5means unsubstituted phenyl, pyridinyl which can be substituted by trifluoromethyl, and Z denotes oxygen, sulfur; R2and R3together signify unsubstituted or substituted alkylenes chain with 3 or 4 links, in which two (non-adjacent) carbon atoms may be replaced by oxygen atom; A denotes a group of the formula: - SO2- R6or

,

where Y represents oxygen or sulfur; R6, R7, R8independently of one another denote alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkenyl with 1 to 4 carbon atoms, dialkylamino, phenyl which may be substituted by nitro, stands, trifluoromethyl; 1-pyrrolidinyl, 1-piperidinyl; or thienyl, pyrazolyl, isoxazolyl, each of these residues can be substituted by chlorine, amine, stands, methoxy, trifluoromethyl, methoxycarbonyl; X represents halogen, and their acid additive salt

The invention relates to benzonitrile and benzalconium formula I, where AG - means one or twice substituted with CN and/or F phenyl residue; Q meansnH2n; n denotes 3 or 4; and their salts accession acids, except for 3-/4-(4-fluoro-phenyl)-1-piperazinil)butyl/-5-cyan-indole and 3-4-(4-(2-fluoro-phenyl)-1-piperazinil)butyl/-5-cyan-indole, but not their salts accession acids

The invention relates to substituted imidazolidin-2,4-donovin compounds, method of their production and to the use of these compounds in medicine

The invention relates to a derivative of oxazolidin-2-it General formula (I):

< / BR>
where X is O,

Y denotesor

< / BR>
R1indicatesor< / BR>
R2and R3each, independently of one another, denotes H, A or benzyl;

A denotes alkyl with 1-6 C-atoms;

D denotes amidinopropane, aminomethyl, aminohydrocinnamic, 5-methyl-1,2,4-oxadiazolidine-3-yl or guanidinate;

r and s independently of one another denote 0, 1, 2, 3 or 4;

however, if necessary, free amino - or amidinopropane can be protected partially or fully protective for the amino function groups, as well as their enantiomers, diastereomers and physiologically acceptable salts

The invention relates to the technical field of herbicides and plant growth regulators, in particular of herbicides for selective control of weeds in cultivated plants

The invention relates to a new cyclopropylamino-1,3,5-triazines and their salts of General formula

< / BR>
in which R1- alkyl, cycloalkyl, alkylsilanes; R2bis (2-hydroxyethyl)amino, 3-hydroxy-1-azetidine, 3-methoxy-1-azetidine, 3-oxo-1-azetidine, morpholine-, 4-hydroxypiperidine, thiomorpholine-, S-oxide-thiomorpholine-, S, S-dioxide-thiomorpholine-, 3-thiazolidine, S-oxide-3-thiazolidine, S, S-dioxide-3-thiazolidine or 8-oxa-3-azabicyclo/3,2,1/ Oct-3-yl

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 an improved process for the preparation of substituted N-(1,3,5-triazine-2-yl)aminocarbonyl-arylsulfonamides General formula

< / BR>
where R1= Cl, COOCH3;

R2= OCH3N(CH3)2;

R3= CH3, ON=C(CH3)2, ON=C(CH3)C2H5;

R4= H, CH3,

used in agriculture as herbicides and plant growth regulators

The invention relates to a new cyclopropylamino-1,3,5-triazines and their salts of General formula

< / BR>
in which R1- alkyl, cycloalkyl, alkylsilanes; R2bis (2-hydroxyethyl)amino, 3-hydroxy-1-azetidine, 3-methoxy-1-azetidine, 3-oxo-1-azetidine, morpholine-, 4-hydroxypiperidine, thiomorpholine-, S-oxide-thiomorpholine-, S, S-dioxide-thiomorpholine-, 3-thiazolidine, S-oxide-3-thiazolidine, S, S-dioxide-3-thiazolidine or 8-oxa-3-azabicyclo/3,2,1/ Oct-3-yl

The invention relates to new triazine derivatives and herbicides containing the derivatives as an effective ingredient

The invention relates to compounds salts of the polypeptide represented by the formula (I), where a1AND2AND3AND4X, Y and Z have the values given in the description, and the transition metal, which have high antiviral activity against human immunodeficiency virus

The invention relates to new biologically active chemical compound, specifically to 3,28-di-O-nicotinate betulin (1), formula

< / BR>
showing hepatoprotective and anti-HIV activity
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