Quinazoline derivatives

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as an antipruritic agent in case of atopic disease such as atopic dermatitis when a steroid medicinal agent is ineffective. In formula R is C1-6 alkoxy, optionally substituted methyoxy, or an amine which is monosubstituted with C1-6 alkyl, where the R-C(=O)- group is bonded in the meta or para-position.

EFFECT: high efficiency of using said compounds.

21 cl, 16 dwg, 4 tbl, 30 ex

 

The technical field to which the invention relates

The present invention relates to new compounds derived from 4-(3-benzoylamino)-6,7-dimethoxy-2-methylaminophenol.

The level of technology

To treat itching caused by atopic disease, such as atopic dermatitis, as a therapeutic agent used anti-inflammatory drugs, such as steroid, antihistamine agent, or the like.

However, steroid drug has almost no immediate antipruritic action, and the weakening of itching the above agent is only a side effect resulting from inhibition of skin inflammation action. Accordingly, it requires a certain period of time, until it reaches such antipruritic effect. In addition, the effectiveness of the antihistamine agent is controversial, and there is no message, clearly demonstrates its effectiveness in irritation.

Itching is a common symptom of atopic dermatitis. Constant itching causes loss of concentration or insomnia and, thereby, significantly impairs quality of life (QOL). As described above, because steroid drugs require some time for the manifestation of his antipruritic actions and antihistamines the Gent in many cases is ineffective itching is still not completely eliminated these drugs.

In addition, not yet open antipruritic agent, is effective not only for itching caused by atopic disease, but also itching, resistant to steroid drug and/or antihistaminic agent (see non-patent documents 1-3).

Incidentally, the compound of the present invention, which is represented by formula (I), included in the scope of compounds of the invention described in patent document 1.

However, the compound represented by formula (I), in particular, is not described in the above patent document 1. The compound described in patent document 1, which has a structure similar to the structure of the compound represented by formula (I)is a compound represented by the following structural formula:

It also describes that the connection of the patent document 1 has an inhibiting PDE4 activity, and therefore, the above compound has anti-inflammatory action, based on the inhibiting PDE4 activity. So, in patent document 1 describes that the above compound is effective for the treatment of psoriasis based on anti-inflammatory action, but in the above publication, there is described, not the proposed use of the above compounds is La eliminate itching, called atopic disease.

Further, patent document 1 does not describe, does not imply that the connection is described in publication 1, is effective to eliminate the itching, for which the steroid drug or antihistamine agent is ineffective.

[Non-patent document 1] Lancet 2003; 361: 690-694.

[Non-patent document 2] Lancet 2003; 361: 151-160.

[Non-patent document 3] Arch. Dermatol. 1999; 135: 1522-1525.

[Patent document 1] WO 99/37622.

Description of the invention

Problems that are resolved by the invention of

The present invention is the provision of a secure connection, which is effective for itch caused by atopic disease, or itching, which from an early stage is ineffective steroid medicine or the like.

The only way of resolving problems

As a result of intensive studies, the authors present invention has created the present invention. That is, the present invention relates to:

(1) the compound represented by formula (I), its salt or its hydrate:

where R represents hydroxyl,1-6alkoxy, optionally substituted C1-6alkoxy, or amino, optionally substituted C1-6by alkyl;

(2) the compound, its salt or its hydrate according to the but the above paragraph (1), in which R-C(=O)-, where R represents hydroxyl,1-6alkoxy, optionally substituted C1-6alkoxy, or amino, optionally substituted C1-6the alkyl is in the meta - or para-position;

(3) the compound, its salt or its hydrate according to the above item (1) or (2)where R represents hydroxyl,1-3alkoxy, optionally substituted C1-3alkoxy, or amino, optionally substituted C1-3by alkyl;

(4) the compound, its salt or its hydrate according to the above item (1) or (2)where R represents hydroxyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, methoxyethoxy, amino, methylamino, dimethylamino, ethylamino or diethylamino;

(5) methyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid, its salt or its hydrate;

ethyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid, its salt or its hydrate;

N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]-N'-methyltryptamine, its salt or its hydrate;

isopropyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid, its salt or its hydrate;

isopropyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]isophthalic acid, its salt or its hydrate;

2-methoxyethylamine ether, N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid, its salt or its hydrate or

2-methoxyethylamine ether, N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]isophthalamide acid, its salt or its hydrate;

(6) methyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid, its salt or its hydrate;

(7) ethyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid, its salt or its hydrate;

(8) N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]-N'-methyltryptamine, its salt or its hydrate;

(9) isopropyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid, its salt or its hydrate;

(10) isopropyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]isophthalic acid, its salt or its hydrate;

(11) 2-methoxyethylamine ether, N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid, its salt or its hydrate or

(12) 2-methoxyethylamine ether, N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]isophthalamide acid, its salt or its hydrate;

(13) a pharmaceutical composition comprising as active ingredient a compound, its salt or its hydrate according to any of the above items (1) to (12);

(14) antipruritic agent for atopic disease, comprising as active ingredient a compound, its salt or its hydrate according to any of the above items (1) to (12);

(16) antipruritic agent for itching, for which the steroid drug and/or antihistaminic agent are inefficient, comprising as active ingredient a compound, its salt or its hydrate according to any of the above items (1) to (12);

(17) the antipruritic agent according to any of the above items (14) to (16), where the dosage form is a preparation for external use.

The present invention also applies to

(P1) the compound represented by formula (II), its salt or its hydrate:

where RPrepresents hydroxyl,1-6alkoxy or amino, optionally substituted C1-6by alkyl;

(P2) the compound, its salt or its hydrate according to the above item (P1), in which RP-C(=O)-, where RPrepresents hydroxyl,1-6alkoxy or amino, optionally substituted C1-6the alkyl is in the meta - or para-position;

(P3) the compound, its salt or its hydrate according to the above item (P1) or (P2), where RPrepresents hydroxyl,1-3alkoxy or amino, optionally substituted C1-3by alkyl;

(P4) the compound, its salt or its hydrate according to the above item(P1) or (P2), where RPrepresents hydroxyl, methoxy, ethoxy, amino, methylamino, dimethylamino, ethylamino or diethylamino;

(P5) methyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid, its salt or its hydrate;

ethyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid, its salt or its hydrate or

N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]-N'-methyltryptamine, its salt or its hydrate;

(P6) pharmaceutical compositions comprising as active ingredient a compound, its salt or its hydrate according to any of the above clauses from (P1) to (P5);

(P7) antipruritic agent for atopic disease, comprising as active ingredient a compound, its salt or its hydrate according to any of the above clauses from (P1) to (P5);

(R8) the antipruritic agent according to the above item (P7), where atopic disease is atopic dermatitis;

(P9) antipruritic agent for itching, for which the steroid drug and/or antihistaminic agent is ineffective, comprising as active ingredient a compound, its salt or its hydrate according to any of the above clauses from (P1) to (P5);

(P10) the antipruritic agent according to any of the above items is t (P7) to (P9), where the dosage form is a preparation for external use.

The effect of the invention

Based on the results described below tests found that the compound of the present invention has excellent antipruritic effect and also has excellent activity against metabolism. According to this connection of the present invention is useful as an antipruritic agent for itching caused by atopic disease, inter alia, atopic dermatitis or itching, for which the steroid drug and/or antihistaminic agent is ineffective.

A brief description of graphic materials

The figure 1 shows the number of pokusyvanii (Carpani) in mice induced by oxazolone (examples 1, 4 and 5).

The figure 2 shows the performance assessment of skin symptoms (after 1 day) mice induced by oxazolone (examples 1, 4 and 5).

The figure 3 shows the powder x-ray crystal obtained in example 22.

The figure 4 shows the powder x-ray crystal obtained in example 23.

The figure 5 shows the powder x-ray crystal obtained in example 24.

The figure 6 shows the powder x-ray crystal obtained in example 25.

The figure 7 shows the powder x-ray crystal is in, obtained in example 26.

The figure 8 shows the powder x-ray crystal obtained in example 27.

The figure 9 shows the number of pokusyvanii (Carpani) in mice induced by oxazolone (examples 7, 14 and 21).

The figure 10 shows the performance assessment of skin symptoms (after 1 day) mice induced by oxazolone (examples 7, 14 and 21).

The figure 11 shows the performance assessment of skin symptoms (4 days) of mice induced by oxazolone (examples 7, 14 and 21).

The figure 12 shows the number of pokusyvanii (Carpani) in mice induced by oxazolone (example 20).

The figure 13 shows the performance assessment of skin symptoms (after 1 day) mice induced by oxazolone (example 20).

The figure 14 shows the performance assessment of skin symptoms (4 days) of mice induced by oxazolone (example 20).

The figure 15 shows the efficiency of the connection A of example 1 in comparison with the connection of betamethasone.

The best way of carrying out the invention

The present invention will be described in detail below.

In the present description structural formula of the compound may mean for the convenience of a certain type of isomer. The present invention includes all isomers formed on the basis of the connection structure, such as a geometric isomer, optical isomer, stereoisomer or t is atomer, and isomeric mixture. Thus, the connection of the present invention is not limited to the descriptions of the formulas are provided for the convenience, but it can be any of such isomers or mixtures thereof. According to this connection of the present invention may exist in optically active forms and racemic forms. The present invention includes any such optically active forms and racemic forms and is not limited to any of them. In addition, in the compound of the present invention may also be a polymorphism. Such crystalline polymorphism is not limited to any of the polymorphs, and the connection of the present invention may be either individual crystalline form, or mixtures thereof. In addition, the present invention also includes an amorphous form, and the compound of the present invention includes anhydrate (anhydrous form) and hydrate. In addition, the present invention also includes so-called metabolite, which is formed as a result of metabolism in vivo (oxidation, recovery, hydrolysis, conjugation, etc.) of compound (I) of the present invention. Further, in the present invention also includes a compound (a so-called prodrug), which forms the compound (I) of the present invention as a result of metabolism in vivo (oxidation, recovery, guide is Alisa, conjugation and so on).

Definitions of terms, symbols, and other values used in the present description, will be explained below, and the present invention will be described in detail below.

The term "C1-6alkyl" used in this description to denote alkyl groups with unbranched or branched chain containing 1-6 carbon atoms. Concrete examples of C1-6the alkyl may include methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 2-methyl-1-propyl (isobutyl), 2-methyl-2-propyl (tert-butyl), 1-butyl (n-butyl), 2-butyl (sec-butyl), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-methyl-3-pentyl, 3-methyl-3-pentyl, 2,3-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2,2-dimethyl-1-butyl, 2-ethyl-1-butyl, 3,3-dimethyl-2-butyl and 2,3-dimethyl-2-butyl.

Preferred examples may include With1-3alkyl, such as methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 2-methyl-1-propyl (isobutyl), 2-methyl-2-propyl (tert-butyl), 1-butyl (n-butyl or 2-butyl (sec-butyl). More preferred examples may include methyl and ethyl.

The term "C1-6alkoxy" used in this description to denote actigraphy with which the light is an above "C 1-6alkyl". Concrete examples of C1-6alkoxy may include methoxy, ethoxy, 1-propoxy, 2-propoxy, 2-methyl-1-propoxy, 2-methyl-2-propoxy, 1-butoxy, 2-butoxy, 1 pentox, 2-pentyloxy, 3-pentyloxy, 2-methyl-1-butoxy, 3-methyl-1-butoxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 2,2-dimethyl-1-propoxy, 1-hexyloxy, 2-hexyloxy 3 hexyloxy, 2-methyl-1-pentox, 3-methyl-1-pentyloxy, 4-methyl-1-pentox, 2-methyl-2-pentox, 3-methyl-2-pentox, 4-methyl-2-pentox, 2-methyl-3-pentyloxy, 3-methyl-3-pentyloxy, 2,3-dimethyl-1-butoxy, 3,3-dimethyl-1-butoxy, 2,2-dimethyl-1-butoxy, 2-ethyl-1-butoxy, 3,3-dimethyl-2-butoxy and 2,3-dimethyl-2-butoxy.

Preferred examples may include With1-3alkoxy, such as methoxy, ethoxy, 1-propoxy and 2-propoxy. More preferable example is methoxy.

In addition, examples of the "C1-6alkoxy, optionally substituted C1-6alkoxy" or "C1-3alkoxy, optionally substituted C1-3alkoxy" in the definitions of R may include methoxyethoxy, ethoxyethoxy, methoxyethoxy, ethoxyethoxy.

Examples of "amino, optionally substituted C1-6by alkyl" in the present description can include amino, mono-C1-6alkylamino, which replaced the above With1-6the alkyl (for example, methylamino, ethylamino, tert-butylamino etc) and di-C1-6alkylamino (EmOC is emer, dimethylamino, diethylamino, methylethylamine etc).

Preferred examples may include amino, mono-C1-3alkylamino and di-C1-3alkylamino. More preferred examples may include amino, monomethylamine.

Type "salt"used in the present description, is not specifically limited if it is a salt formed with the compound of the present invention, and is pharmacologically acceptable. Examples of such salts can include a salt of an inorganic acid, salt with organic acid, salt with inorganic base, a salt with organic base, salts of acidic or basic amino acids.

Preferred examples of salts of inorganic acids may include hydrochloride, hydrobromide, sulfate, nitrate and phosphate. Preferred examples of salts of organic acids may include acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, methanesulfonate, aconsultant, p-toluensulfonate and bansilalpet.

Preferred examples of salts of inorganic bases include alkali metal salts such as sodium salt or potassium salt; salts of alkaline earth metals such as calcium salt or magnesium salt; aluminum salt and ammonium salt. Preferred examples of salts of organic bases may include all the I salt diethylamine, salt diethanolamine salt of meglumine and salt N,N of dibenziletilendiaminom.

Preferred examples of salts with acidic amino acids may include aspartate and glutamate. Preferred examples of salts of basic amino acids may include salt, arginine salt and lysine salt of ornithine.

In the present description R-C(=O) in the formula (I) (where R represents a hydroxyl,1-6alkoxy, optionally substituted C1-6alkoxy, or amino, optionally substituted C1-6the alkyl may be associated with any of the provisions of substitution, namely ortho-, meta - or para-position of the benzene ring to which it is linked. It is preferably bound in the meta - or para-position. Thus, the connection represented by the following formula (I') or (I”)is preferred

[where R has the same values as the values described above]. Preferred examples of such compounds may include

methyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid, its salt or its hydrate;

ethyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid, its salt or its hydrate and

N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]-N'-methyltryptamine, its salt or its hydrate.

The term "atopic disease" used in the present about what Isani to indicate atopic dermatitis, urticaria, bronchial asthma, allergic rhinitis, allergic conjunctivitis, etc.

When the compound of this invention should be applied as a drug, it is usually mixed with suitable pharmaceutical ingredients for pharmaceutical products for use. However, one should not reject the use of medicinal substances compounds of the invention in the form of a medicinal product.

Pharmaceutical ingredients may include excipients, binders, lubricants, dezintegriruetsja agents, coloring agents, agents, corrective taste, emulsifiers, surfactants, agents that promote dissolution, isotonic agents, buffering agents, preservatives, antioxidants, stabilizers, agents that enhance the adsorption, and the like, all of which are commonly used in medicines. When you desire to apply these agents can be combined.

Excipients may include, for example, lactose, white unsteady sugar, glucose, corn starch, mannitol, sorbitol, starch, alpha-starch, dextrin, crystalline cellulose, fine silicic anhydride, aluminum silicate, calcium silicate, aluminometasilicate magnesium, calcium phosphate and the like.

Connect the s substances may include, for example, polyvinyl alcohol, methylcellulose, ethylcellulose, Arabian gum, tragakant, gelatin, shellac, hypromellose, hydroxypropylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, macrogol and the like.

Lubricants may include, for example, magnesium stearate, calcium stearate, sodium fumarate, talc, polyethylene glycol, colloidal silicon oxide, and the like.

Dezintegriruetsja agents may include, for example, crystalline cellulose, agar, gelatin, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, slabosalenuyu hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium salt croscarmellose, carboximetilkrahmal, sodium carboxymethyl cellulose and the like.

Coloring agents may include a single iron oxide, yellow Queen-size iron oxide, Carmine, burnt sugar, beta-carotene, titanium oxide, talc, sodium salt of Riboflavin phosphate, yellow aluminum lacquer and the like, which were allowed as additives for medicines.

Agents, corrective taste, can include cocoa powder, menthol, aromatic powder, peppermint oil, borneol, powdered bark of the cinnamon tree, and so on is one.

Emulsifiers or surfactants can include steartrimonium, sodium lauryl sulfate, lauramidopropyl acid, lecithin, glycerol monostearate, sucrose esters and fatty acid ester of glycerol and fatty acids, and the like.

Agents that promote the dissolution, may include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate, Polysorbate 80, nicotinamide, and the like.

Suspendresume agents may include surfactants, hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxymethylcellulose, hydroxyethyl cellulose and hydroxypropylcellulose.

Isotonic agents may include glucose, sodium chloride, mannitol, sorbitol and the like.

Buffering agents may include phosphate, acetate, carbonate, citrate buffers, and the like.

Preservatives may include methylparaben, propylparaben, chlorobutanol, benzyl alcohol, finitely alcohol, along with dehydroacetic acid, sorbic acid and the like.

Antioxidants can include sulfite, ascorbic acid, alpha-tocopherol, and the like.

The stabilizers may include stabilizers, usually p is imename in medicines.

Agents that enhance the adsorption may include amplifying the adsorption agents commonly used in medicines.

Pharmaceutical products, described above, may include oral agents such as tablets, powders, granules, capsules, syrups, lozenges and pharmaceutical forms for inhalation; preparations for external use, such as suppositories, ointments, eye ointments, plasters, ophthalmic solutions, nasal drops, eye drops, lotions and lotions and injections. The preferred drug is a drug for external use, which acts directly on the affected area.

Oral agents can appropriately be combined with the above-described auxiliary means to obtain drugs. In addition, on the surface of such agents, if necessary, can coat.

Agents for external use can suitably be combined with auxiliary means, in particular excipients, binding agents, agents, corrective taste, emulsifiers, surfactants, agents that promote dissolution, suspendresume agents, isotonic agents, preservatives, antioxidants, stabilizers or agents that increase the absorption, with the formation of products.

Injection the AI can appropriately be combined with auxiliary means, in particular, emulsifiers, surfactants, agents that promote dissolution, suspendresume agents, isotonic agents, preservatives, antioxidants, stabilizers or agents that increase the absorption, with the formation of products.

The dose of the pharmaceutical preparation of the present invention vary depending on the severity of symptoms, age, sex, body weight, dosage form, type of salts, differences in sensitivity to the agent, a specific type of disease or the like. In General, in the case of oral administration the dose of the pharmaceutical preparation of the present invention is between about 30 μg and 10 g (preferably between 0.1 mg and 100 mg) per adult person per day. In the case of the preparation for external use it is between 30 µg and 20 g (preferably between 100 μg and 10 g) per adult person per day. In the case of injections, it is between 30 mg and 1 g (preferably between 100 μg and 500 mg) per adult person per day. The above dose is used as a single injection or divided into 2 to 6 injections a day.

The crude compounds and different types of reagents used in obtaining the compounds of the present invention may be in the form of a salt, hydrate or MES. Such crude compounds and reagents differ depending on the source connection, the applied solvent or the like. Types such crude compounds and reagents, in particular, limit, if they do not inhibit the reaction. Solvents used are also different depending on the source of the crude compounds, reagents or the like. Obviously, such a solvent is not specifically limited if it does not inhibit the reaction and dissolves the original substance to a certain extent. When the compound (I) of the present invention receive a free form, such a free form can be converted into a salt, which may be formed of the above compound (I)or its hydrate according to conventional methods.

The compound (I) of the present invention are in the form of salt or hydrate of compound (I), these components can be converted into the free form of the above compound (I) by conventional methods.

Furthermore, the various isomers (for example, geometric isomer, optical isomer, rotary isomer, stereoisomer, tautomer and so on) of the compound (I) of the present invention can be cleaned and allocate conventional separation method such as recrystallization, the method diastereomeric salt, enzymatic method for the separation, various types of chromatography (e.g., thin layer chromatography, column chromatography, gas chromatography, and so on).

Next will be described a method of obtaining compounds of the present invention, which is represented by formula (I).

The compound represented by formula (I)can be obtained by method A, method b or method C, as described below. In addition, the connection can also be obtained by method D, which is described in WO 99/37622.

Method A, method b and method will be described in detail below. However, the method of obtaining the compounds of the present invention is not limited to them.

(Method A)

[where R1represents a C1-6alkyl].

Method a is the method by which the compound (a-3) provide an opportunity to interact with the compound (b-2), which is the acid chloride of the acid, in an inert solvent in the presence or in the absence of a base, to obtain the compound (I-1) of the present invention.

As such a compound (b-2) it is possible to apply well-known compound, a commercially available compound or compound that can be easily obtained from commercially available compound by a method that is commonly used specialists in this area. Examples of such compounds (b-2) may include methyl ether 4-chlororesorcinol acid and the like.

The compound (b-2) can be used in an amount of 1-10 times, preferably 1-2 times molar the th equivalent of the compound (a-3).

The type of the used solvent is not specifically limited, if it dissolves the original substance to a certain extent and does not inhibit the reaction in this stage. Examples of the solvent may include aromatic hydrocarbons such as toluene, benzene or xylene; ethers, such as diethyl simple ether, tetrahydrofuran, dimethoxyethane or dioxane; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane or carbon tetrachloride; organic bases, such as pyridine, 2-, 3 - or 4-picoline; water and mixtures of these solvents. Preferred examples are tetrahydrofuran or pyridine.

The type used here, the base is not specifically limited if it can be obtained of interest connection and are not formed detachable part of the by-products. Examples of the base may include inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or cesium carbonate; and organic bases, such as pyridine or triethylamine. A preferred example is pyridine.

The above can be used in an amount of 1-10 times, preferably 1 to 4 times the molar equivalent of the compound (a-3).

The reaction temperature depends on the solvent and Reagan the and. Usually it is between -30°C and 180°C and preferably between 0°C and 100°C.

The reaction time depends on the solvent and reaction temperature. It is usually between 0.5 and 200 hours and preferably between 1 and 100 hours.

(The way In)

[where R1has the same values as the values described above, and R' represents a C1-6alkoxy, optionally substituted C1-6alkoxy, or amino, optionally substituted C1-6the alkyl].

The way In is the way, which includes a stage 1 getting carboxylic acid, compound (I-2), in the reaction of hydrolysis of ester, compound (I-1), and stage 2 of esterification or amidation of the above carboxylic acid, compound (I-2)to obtain the compound (I-3) of the present invention.

<step 1: hydrolysis>

The compound (I-2) are obtained by the reaction of the basic hydrolysis of the compound (I-1) in an inert solvent.

The type of the used solvent is not specifically limited, if it dissolves the original substance to a certain extent and does not inhibit the reaction in this stage. Examples of the solvent may include aromatic hydrocarbons such as toluene, benzene or xylene; ethers, such as diethyl simple ether, tetrahydrofuran, Dimitar iatan or dioxane; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or ethylene glycol; water and mixtures of these solvents. Preferred examples are methanol or tetrahydrofuran.

The type used here, the base is not specifically limited if it can be obtained of interest connection and are not formed detachable part of the by-products. Examples of the base may include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate or an aqueous solution; and organic bases, such as pyridine or triethylamine. A preferred example is an aqueous solution of sodium hydroxide.

The above can be used in an amount of 1-100 times, preferably 1 to 20 times the molar equivalent of the compound (I-1).

The reaction temperature depends on the solvent and reagent. Usually it is between -30°C and 180°C and preferably between 0°C and 100°C.

The reaction time depends on the solvent and reaction temperature. It is usually between 0.5 and 200 hours and preferably between 1 and 100 hours.

<stage 2: esterification or amidation of the compound (I-2)>

The compound (I-3) and get the result is the condensation reaction of the compound (I-2) with an appropriate alcohol or amine with the use of a condensing agent in an inert solvent in the presence or in the absence of base.

As such the corresponding alcohol or amine can be used a known compound, a commercially available compound or compound that can be easily obtained from commercially available compound by a method that is commonly used specialists in this area. Examples of such compounds may include methanol, ethanol and methylamine.

As mentioned above, the alcohol or amine can be used in an amount of 1-10 times, preferably 1-3 times the molar equivalent of the compound (I-2).

The type of the used solvent is not specifically limited, if it dissolves the original substance to a certain extent and does not inhibit the reaction in this stage. Examples of the solvent may include aromatic hydrocarbons such as toluene, benzene or xylene; ethers, such as diethyl simple ether, tetrahydrofuran, dimethoxyethane or dioxane; esters such as methyl acetate, ethyl acetate, propyl or diethylmalonate; amides, such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide or N-organic, and a mixture of these solvents. A preferred example is dimethylformamide.

The type used here, the condensing agent is not specifically limited if it can be obtained of interest connection and not formed of audela is presented by-products. Examples of the condensing agent may include carbodiimide, such as dicyclohexylcarbodiimide (DCC) or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC:WSC); and phosphine agents condensation, such as hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (THIEF) or diethylthiophosphate (DEPC). A preferred example used here, the condensing agent is WSC.

The above-mentioned condensing agent can be used in an amount of 1-10 times, preferably 1-3 times the molar equivalent of the compound (I-2).

The type used here, the base is not specifically limited if it can be obtained of interest connection and are not formed detachable part of the by-products. Examples of the base may include aqueous solutions of inorganic bases, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or cesium carbonate; and organic bases, such as pyridine or triethylamine. A preferred example is triethylamine.

The above can be used in an amount of 1-10 times, preferably 1-3 times the molar equivalent of the compound (I-2).

If desired, as an additive to accelerate the reaction it is possible to apply 4-dimethylaminopyridine or 1-hydroxyl striatal.

The above additives can be applied in an amount of 0.1-10 times, preferably 0.1 to 3 times the molar equivalent of the compound (I-2).

The reaction temperature is not specifically limited. Usually it is between -30°C and 180°C and preferably between 0°C. and 80°C.

The reaction time is not specifically limited. It is usually between 0.5 and 200 hours and preferably between 1 and 100 hours.

It should be noted that this stage can also be carried out by the method of mixed anhydride using ethylchloride, ethyl acetate or the like.

(Method C)

[where R has the same values as the values described above].

This method is a method in which the compound (a-3) is subjected to the condensation reaction with the appropriate carboxylic acid (b-3) using a condensing agent in an inert solvent in the presence or in the absence of a base, to obtain the compound (I).

As such a compound (b-3) it is possible to apply well-known compound, a commercially available compound or compound that can be easily obtained from commercially available compound by a method that is commonly used specialists in this area. An example of such a compound (b-3) is onomatology ester of terephthalic acid, which is easy to get the C of terephthalic acid.

The compound (b-3) can be used in an amount of 1-10 times, preferably 1-3 times the molar equivalent of the compound (a-3).

The type of the used solvent is not specifically limited, if it dissolves the original substance to a certain extent and does not inhibit the reaction in this stage. Examples of the solvent may include aromatic hydrocarbons such as toluene, benzene or xylene; ethers, such as diethyl simple ether, tetrahydrofuran, dimethoxyethane or dioxane; esters such as methyl acetate, ethyl acetate, propyl or diethylmalonate; amides, such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide or N-organic, and a mixture of these solvents. A preferred example is dimethylformamide.

The type used here, the condensing agent is not specifically limited if it can be obtained of interest connection and are not formed detachable part of the by-products. Examples of the condensing agent may include carbodiimide, such as dicyclohexylcarbodiimide (DCC) or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC:WSC); and phosphine agents condensation, such as hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (THIEF) or diethylthiophosphate (DEPC). A preferred example used here and the enta condensation is WSC.

The above additives can be applied in an amount of 1-10 times, preferably 1-3 times the molar equivalent of the compound (a-3).

The type used here, the base is not specifically limited if it can be obtained of interest connection and are not formed detachable part of the by-products. Examples of the base may include aqueous solutions of inorganic bases, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or cesium carbonate; and organic bases, such as pyridine or triethylamine. A preferred example is triethylamine.

The above can be used in an amount of 1-10 times, preferably 1-3 times the molar equivalent of the compound (a-3).

If desired, as an additive to accelerate the reaction it is possible to apply 4-dimethylaminopyridine or 1-hydroxybenzotriazole.

The above additives can be applied in an amount of 0.1-10 times, preferably 0.1 to 3 times the molar equivalent of the compound (a-3).

The reaction temperature depends on the solvent and reagent. Usually it is between -30°C and 180°C and preferably between 0°C. and 80°C.

The reaction time depends on the solvent and reaction temperature. It oby is but is between 0.5 and 200 hours and preferably between 1 and 100 hours.

It should be noted that this stage can also be carried out by the method of mixed anhydride using ethylchloride, ethyl acetate or the like.

(Method of obtaining intermediate connections)

The compound (a-3), which is an intermediate compound used in methods a, b and C, can be obtained by the method described in the example of a 7 WO 99/37622. In addition to the above method, the compound (a-3) are synthesized, for example, the following method of obtaining the intermediate connection:

[where Eandindependently represents hydrogen or C1-6alkyl or two Eandtogether form2-3alkylene, optionally substituted stands].

This method of obtaining includes: stage 1, in which the compound (a-1) and the compound (B-1), acting as belmetallenergo reagent is subjected to reaction combinations, similar to the Suzuki reaction, in an inert solvent, in the presence of palladium(0) catalyst in an atmosphere of inert gas or without this atmosphere, in the presence or in the absence of a base and in the presence or in the absence of additives, to obtain the compound (a-2), and stage 2 conversion of the chlorine atom of compound (a-2) in methylaminopropyl, to obtain compound (a-3), which is an intermediate floor connection is in the connection of the present invention.

<stage 1: reaction mix>

This stage is the stage in which the compound (a-1) provide an opportunity to interact with the compound (B-1) in an inert solvent in the presence of palladium(0) catalyst, in the presence of a base, in the presence or in the absence of additives and in the atmosphere of inert gas or without such an atmosphere, so as to obtain the intermediate compound (a-2).

This stage can be performed according to the publications described in S. P. Stanforth, Tetrahedron (1998), 54, 263., N. Miyaura, A. Suzuki, Chem. Rev. (1995), 95, 2457, etc. More specifically, this stage can be performed according to the conditions of the reaction, the operations after the reaction, method of cleaning, etc. that are described in the example below, get 1.

The compound (a-1) is a known compound. Commercially available product can be bought and used as compounds (a-1).

The type of connection (In-1)used for combinations not specifically limited if it can be obtained of interest connection and are not formed detachable part of the by-products. Examples of compounds (B-1) may include 3-aminophenylarsonic acid, its 1/2-sulfate and its hydrate. Preferably used 1/2-sulfate 3-aminophenylarsonic acid.

The compound (B-1) can be used in an amount of 0.5 to 10 times, preferably 0.5-5 times the molar equivalent of the compound (a-1).

The type of the used solvent is not specifically limited, if it dissolves the original substance to a certain extent and does not inhibit the reaction in this stage. Specific examples of the solvent may include amides, such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide or N-organic; aromatic hydrocarbons such as toluene, benzene, xylene or mesitylene; ethers, such as diethyl simple ether, diisopropyl simple ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methylcellosolve; NITRILES, such as acetonitrile or isobutyronitrile; sulfoxidov, such as dimethylsulfoxide or sulfolane; esters such as methyl acetate, ethyl acetate, propyl or diethylmalonate; water and a mixed solvent of these solvents. Preferred examples may include toluene, tetrahydrofuran, ethyl acetate, water and a mixed solvent of these solvents.

The type of palladium(0) catalyst is not specifically limited if it can be obtained of interest connection and are not formed neocd is renewable by-products. Examples of palladium(0) catalyst may include tetrakis(triphenylphosphine)palladium, Tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, bis(tri-tert-butylphosphine)palladium, palladium black, various types of palladium complexes, which become palladievye(0) precursors, as described below, and palladium(0) catalyst, generated in the reaction system in combination with different types of ligands, as described below.

That is, various types of palladium complexes, which become palladievye(0) predecessors, is not specifically limited if it can be obtained of interest connection and are not formed detachable part of the by-products. Specific examples of such palladium complexes may include palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium, dichlorobis(tri-o-tolylphosphino)palladium, dichlorobis(tricyclohexylphosphine)palladium. The type of ligand is not specifically limited if it can be obtained of interest connection and are not formed detachable part of the by-products. Specific examples of such ligands include 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xanthos), tri-tert-butylphosphine, tri-(4-were)phosphine, tri-2-furifosmin, 2-(di-tert-butylphosphino)bi is Anil, 2-(dicyclohexylphosphino)biphenyl, tricyclohexylphosphine, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 1,1'-bis(diphenylphosphino)ferrocene, tetrafluoroborate di-tert-butylphosphine and 1,3-bis-(2,4,6-trimetilfenil)imidazol-2-ilidene. A preferred example is tetrakis(triphenylphosphine)palladium(0).

The above palladium(0) catalyst can be used in amounts as low as 0.01-5 times, preferably from 0.01 to 0.1 times the number of molar equivalents of the compound (a-1).

The type of base is not specifically limited if it can be obtained of interest connection and are not formed detachable part of the by-products. Specific examples of the base may include inorganic bases such as tribalistic, trisodium phosphate, cesium carbonate, potassium carbonate, sodium carbonate, cesium bicarbonate, potassium bicarbonate, sodium bicarbonate, sodium acetate, barium hydroxide, potassium hydroxide, potassium fluoride or cesium fluoride; alkoxides of metals such as ethoxide or sodium tert-piperonyl sodium acetates of alkali metals such as sodium acetate or potassium acetate; and organic bases such as triethylamine. The preferred base is sodium carbonate.

The above can be used in an amount of 1-100 times, preferably 1-20 times previews the molar equivalent of the compound (a-1).

The type of the used additives is not specifically limited if it can be obtained of interest connection and are not formed detachable part of the by-products. Specific examples of additives may include lithium chloride, sodium chloride, lithium bromide, sodium bromide and tetrabutylammonium bromide.

The above additives can be applied in an amount of 1-100 times, preferably 1 to 10 times the molar equivalent of the compound (a-1).

The reaction temperature is not specifically limited. Usually it is between -30°C and 180°C and preferably between 0°C and 100°C.

The reaction time is not specifically limited. It is usually between 0.5 and 200 hours and preferably between 1 and 100 hours.

When the reaction is carried out in an atmosphere of inert gas, such as inert gas is not specifically limited if it does not inhibit the reaction of this stage. Specific examples can include argon or nitrogen.

<T2>

This stage is the stage in which the compound (a-2) are given the opportunity to interact with methylamine in an inert solvent, to obtain compound (a-3).

The above methylamine can be used in an amount of 1-200 times and preferably 1 to 40 times the molar equivalent of the compound (a-2).

The type of the used solvent is not specifically og anywayt, if it dissolves the original substance to a certain extent and does not inhibit the reaction in this stage. Examples of the solvent may include aromatic hydrocarbons such as toluene, benzene or xylene; ethers, such as diethyl simple ether, tetrahydrofuran, dimethoxyethane or dioxane; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or diethylene glycol; water and mixtures of these solvents. Preferred examples include isopropanol and tetrahydrofuran.

Method add applicable methylamine is not specifically limited if it can be obtained of interest connection and are not formed detachable part of the by-products. For example, methylamine can be added in the form of a gas, a solution, such as solution in methanol, ethanol, tetrahydrofuran or water, or salt, such as hydrochloride. Methylamine preferably used in the form of a solution in methanol.

The reaction temperature is not specifically limited. It is usually between -30°C and 180°C and preferably between 0°C. and 150°C.

The reaction time is not specifically limited. It is usually between 0.5 and 200 hours and preferably between 1 and 100 hours.

In this stage usually use a sealed pressure reactor, such as reactor made of stainless steel.

Crystals soy is inane (I) of the present invention can stably be obtained on an industrial scale by obtaining the compound (I), by dissolving the above compounds by heating in a solvent and then cooling the resulting solution under stirring for crystallization or recrystallization of the obtained compound.

Examples

The compound of the present invention can be obtained by methods described in the following examples. However, these examples are presented only for illustration purposes. In any case, it is not expected that described below with specific examples limit the scope of the invention. In addition, the scope of the present invention can be made of various modifications.

Connection with which are associated the names of publications or the like, obtained according to such publications or other

Example obtain 1

Synthesis of 3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenylamine

Twenty-five grams of 2,4-dichloro-6,7-dimethoxyquinazoline suspended in 2.25 liters of a mixed solution consisting of a mixture of toluene:tetrahydrofuran:2n. a solution of sodium carbonate = 1:1:1. To the reaction mixture of 21.5 g 1/2 sulfate 3-aminophenylarsonic acid and the mixture Tegaserod, the atmosphere in the reaction vessel is replaced by nitrogen. To the reaction mixture of 2.23 g of tetrakis(triphenylphosphine)palladium(0), followed by stirring at 60°C. in a nitrogen atmosphere. Eighteen hours is after start of the reaction to the reaction mixture of 1.2 g of tetrakis(triphenylphosphine)palladium(0) and stirring is continued. After thirty hours to the reaction mixture additionally added to 1.2 g of tetrakis(triphenylphosphine)palladium(0) and stirring is further continued. Forty-eight hours after start of the reaction, the reaction mixture is cooled and then transferred into a separating funnel to separate an organic layer. The obtained organic layer was washed with 300 ml of saturated salt solution and then dried over anhydrous magnesium sulfate. The desiccant is removed by passing the organic layer through 250 g of silica gel. The silica gel was washed with 1.5 l of ethyl acetate and the organic layers are combined and concentrated to dryness. The residue is triturated with 200 ml of ethyl acetate and the resulting solid is then separated by filtration. The solid is washed with 100 ml of diethyl ether and 200 ml of a mixed solvent consisting of a mixture of n-heptane:ethyl acetate = 1:1, and dried under aeration, while receiving of 28.2 g of interest product. Output: 92,5%.

1H NMR (DMSO-d6) δ (ppm): 3,86 (3H, s)to 4.01 (3H, s), of 5.40 (2H, usher.), 6,79 (1H, DD, J=1,6, 8.0 Hz), 6,93 (1H, user. d, J=8.0 Hz), 7,02 (1H, t, J=1.6 Hz), 7,24 (1H, t, J=8.0 Hz), 7,41 (1H, s), the 7.43 (1H, s).

Example of getting 2

Synthesis of [4-(3-AMINOPHENYL)-6,7-dimethoxyquinazolin-2-yl]methylamine

Fourteen grams of 3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenylamine suspended in 135 ml of a mixed solvent consisting of a mixture of tetrahydrofuran:isopropanol = 2:1. To the reaction mixture 89 ml of a solution of methylamine in methanol and the reaction mixture was stirred in a sealed pressure tube reactor at 130°C for 24 hours. After submitting the reaction mixture opportunities to cool to room temperature it was diluted with 300 ml of ethyl acetate and then washed with 300 ml of water. The aqueous layer was extracted with 100 ml ethyl acetate and the combined organic layer was washed with 100 ml of saturated salt solution. The organic layer is separated and then dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, the organic layer is concentrated to dryness and the resulting residue triturated with a mixed solvent consisting of a mixture of ethyl acetate:tetrahydrofuran = 3:1. The obtained solid substance was separated by filtration and the filtrate is then washed with ethyl acetate and dried under aeration, while receiving 10 g of interest product. The filtrate adsorb on the column with 50 g of silica gel and then elute mixed solvent consisting of a mixture of ethyl acetate:methanol = 9:1, and the eluate concentrated to dryness. The residue is triturated with ethyl acetate and the resulting solid is then separated by filtration. The solid is washed with diethyl ether and dried under aeration, while receiving 1.4 g of interest product. Total yield: 82.9 per cent.

1H NMR (CDCl3) δ (ppm) of 3.12 (3H, d, J=5,2 Hz), 3,80 (2H, user. C), 3,82 (3H, s), a 4.03 (3H, s), and 5.30 (1H, usher.), 6,83 (1H, DD, J=1,6, 8.0 Hz), of 6.99 (1H, t, J=1.6 Hz),? 7.04 baby mortality (1H, user. d, J=8.0 Hz), 7,07 (1H, s), to 7.15 (1H, s), 7,30 (1H, t, J=8.0 Hz).

Example of getting 3

An alternative method of synthesis of 3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenylamine (example obtain 1)

To 634 g of sodium carbonate (5,98 mol) is added 2.91 kg of water in a nitrogen atmosphere, followed by stirring for dissolution. To the solution was added 3.0 l of tetrahydrofuran, 431 g of the monohydrate of 3-aminophenylarsonic acid (2,78 mol), a 30.4 g of triphenylphosphine (0,116 mol) and 26,0 g dichloropalladium (0,116 mol) in that order. To the mixture is added dropwise a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (600 g, 2.32 mol) in tetrahydrofuran (12.0 l) for 2 hours under stirring at 60°C, followed by stirring at the same temperature for 16 hours. To a mixture of 3.0 kg of 5% solution of sodium chloride and 12.0 l of tetrahydrofuran in that order and the mixture is stirred at 50°C for 1 hour and give her the opportunity to cool to 25°C. the Mixture is filtered through celite to remove insoluble materials, the filtrate is transferred into a separating funnel and the organic layer separated. To separate the organic layer, add 150 g of anhydrous magnesium sulfate and 60.0 g of activated charcoal, the mixture is stirred at 50°C for 1 hour and give her the opportunity quench the change to 25°C. The mixture is filtered through celite to remove insoluble materials and the filtrate concentrated under reduced pressure. To the residue add 6.0 liters of water and the mixture is stirred at room temperature for 1 hour, the precipitated crystals are collected by filtration. The collected crystals are dried at 50°C and under reduced pressure, thus obtaining 730 g of interest product. Output: 62,1%.

Example 4

An alternative method of synthesis of [4-(3-AMINOPHENYL)-6,7-dimethoxyquinazolin-2-yl]methylamine (example obtaining 2)

Two hundred grams of crude 3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenylamine (contents 124 g; 0,394 mol) are suspended in a mixed solvent consisting of 1.2 l of tetrahydrofuran and 0.6 l of isopropanol. To the mixture is added to 1.2 l of a solution of methylamine in methanol and the mixture is stirred in a SUS autoclave at 90°C for 15 hours. The reaction mixture allow to cool to 25°C. and concentrated under reduced pressure. To the residue add 1.0 l of water and 4.0 l of chloroform, the mixture is stirred at 50°C for 0.5 hour and give her the opportunity to cool to 25°C. the Mixture is filtered through celite to remove insoluble materials, the filtrate is transferred into a separating funnel and the organic layer separated. To separate the organic layer added to 50.0 g of anhydrous magnesium sulfate and 20.0 g of activated carbon, with the ect stirred at 50°C for 1 hour and give her the opportunity to cool to 25°C. The mixture is filtered through celite to remove insoluble materials and the filtrate concentrated under reduced pressure. To the residue add 904 ml of chloroform, the mixture is stirred at 50°C for 1 hour and stirred over night after turning off the heater. Then the mixture is stirred in an ice bath for 2 hours and the precipitated crystals are collected by filtration. The collected crystals are dried at 50°C and under reduced pressure, thus obtaining of 76.3 g of interest product. Output: 38.7 per cent.

Example 1

Synthesis of methyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid

To a solution of 16.8 g of [4-(3-AMINOPHENYL)-6,7-dimethoxyquinazolin-2-yl]methylamine and 8.6 g of pyridine dissolved in 300 ml of tetrahydrofuran, add to 11.8 g of methyl ester 4-chlororesorcinol acid at room temperature, followed by stirring for 24 hours. To the reaction mixture was added 100 ml of dimethylsulfoxide, and the mixture partitioned between mixed solvent consisting of 2000 ml of ethyl acetate and 1000 ml of tetrahydrofuran, and 1000 ml of a saturated solution of sodium bicarbonate, the organic layer separated. The aqueous layer was further extracted with a mixed solvent consisting of 500 ml of ethyl acetate and 500 ml of tetrahydrofuran. The combined organic layer is then washed the Ute 1000 ml of saturated sodium hydrogen carbonate solution and 1000 ml of saturated salt solution in order and dried over anhydrous magnesium sulfate. The desiccant is removed by filtration with the use of pillows 100 g basic silica gel followed by thorough washing 2000 ml of ethyl acetate. The combined eluate concentrated under reduced pressure and the crude product is suspended and pound in a mixed solvent consisting of 100 ml of tetrahydrofuran and 500 ml of diethyl ether. The precipitated crystals are collected by filtration, washed with twice 100 ml of diethyl ether and dried under aeration at 50°C for 5 hours, thus obtaining 13.8 g of the crystals indicated in the title compound (yield: 53.2 per cent).

1H NMR (DMSO-d6) δ (ppm): is 2.88 (3H, d, J=4.4 Hz), 3,74 (3H, s)to 3.89 (3H, s)to 3.92 (3H, s), of 6.99 (1H, c), of 7.00 (1H, user. c), 7,17 (1H, s), 7,46 (1H, d, J=8.0 Hz), 7,55 (1H, t, J=8.0 Hz), 7,87 (1H, user. d, J=8.0 Hz), 8,08 (4H, s), to 8.20 (1H, user. C)10,61 (1H, s).

Example 2

Synthesis of hydrochloride of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid

To a solution of 2.5 g of methyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid in a mixed solvent consisting of 50 ml of tetrahydrofuran and 25 ml of methanol, add to 11.3 ml of 5N. the sodium hydroxide solution, followed by stirring at room temperature for 12 hours. The reaction mixture is acidified by the addition of 5N. hydrochloric acid and the resulting solid is then about what really filtering washed with 10 ml of water and 20 ml simple ether and dried under aeration, while receiving 2.5 g of interest product. Yield: 95.3 per cent.

1H NMR (DMSO-d6) δ (ppm): 3,05 (3H, user. C), 3,82 (3H, s), 3,98 (3H, s), 7,32 (1H, c), 7,54 (1H, user. d, J=8.0 Hz), 7,55 (1H, user. C)to 7.61 (1H, t, J=8.0 Hz), to $ 7.91 (1H, d, J=8.0 Hz), of 8.06 (4H, s), 8,35 (1H, user. C)10,71 (1H, s).

Example 3

Synthesis of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]-N',N'-dimethylterephthalate

To a solution of 100 mg of the hydrochloride of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid in 2 ml of dimethylformamide added 60 mg of WSC, 41 mg of 1-hydroxybenzotriazole, 42 μl of triethylamine and 10 mg of 4-dimethylaminopyridine, followed by stirring the mixture for 30 minutes. To the reaction mixture is added 200 μl of the solution of dimethylamine in tetrahydrofuran, followed by stirring at room temperature for 15 hours. To the reaction mixture add 2 ml of tetrahydrofuran and the reaction mixture is distributed after adding a saturated solution of sodium bicarbonate. The organic layer is extracted with 10 ml ethyl acetate, washed with saturated salt solution and dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate is removed by filtration and the organic layer concentrated to dryness, the residue triturated with a mixed solvent consisting of a mixture of tracecut:n-heptane = 1:1. The obtained solid substance was separated by filtration, washed with diethyl ether and dried under aeration, while receiving 85 mg interest of the product. Yield: 87%.

1H NMR (CD3OD) δ (ppm): a 3.01 (3H, s), 3,05 (3H, s), of 3.13 (3H, s), 3,83 (3H, c)to 3.99 (3H, c), 7,11 (1H, s), 7,27 (1H, s), 7,52 (1H, DDD, J=1,6, of 1.6, 8.0 Hz), EUR 7.57 (2H, d, J=8,4 Hz), 7,58 (1H, t, J=8,4 Hz), 7,81 (1H, DDD, J=1,6, of 2.0, 8.0 Hz), of 8.04 (2H, d, J=8,4 Hz), 8,19 (1H, t, J=2.0 Hz).

The following compounds of examples 4-10 were synthesized by methods similar to the method of example 3, using the compound of example 2 as starting compound and using the appropriate alcohol or amine.

Example 4

Synthesis of ethyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid

1H NMR (DMSO-d6) δ (ppm): of 1.33 (3H, t, J=7.2 Hz), 2,84 (3H, d, J=4,8 Hz), 3,74 (3H, c), 3,91 (3H, c), 4,34 (2H, q, J=7.2 Hz), of 6.99 (1H, s), 7,00 (1H, user. C), 7,17 (1H, s), 7,47 (1H, d, J=8.0 Hz), 7,55 (1H, t, J=8.0 Hz), 7,88 (1H, user. d, J=8.0 Hz), 8,08 (4H, s), to 8.20 (1H, user. C)10,61 (1H, s).

Example 5

Synthesis of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]-N'-methyltryptamine

1H NMR (DMSO-d6) δ (ppm): of 2.81 (3H, d, J=4.4 Hz), 2,90 (3H, d, J=5,2 Hz in), 3.75 (3H, c), 3,93 (3H, c), of 6.99 (1H, s), 7,01 (1H, user. C), 7,18 (1H, s), 7,46 (1H, d, J=8.0 Hz), 7,55 (1H, t, J=8.0 Hz), 7,89 (1H, user. d, J=8.0 Hz), of 7.96 (2H, d, J=8,8 Hz), of 8.04 (2H, d, J=8,8 Hz), 8,21 (1H, t, J=1.6 Hz), and 8.5 (1H, user.), 10,53 (1H, s).

Example 6

Synthesis of propyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid

1H NMR (DMSO-d6) δ (ppm): 0,99 (3H, t, J=7,6 Hz)of 1.76 (2H, m), 2,90 (3H, d, J=5,2 Hz), 3,76 (3H, c), 3,93 (3H, c), 4,28 (2H, t, J=6.8 Hz), 7,01 (1H, s), 7,03 (1H, user. C)7,19 (1H, s), 7,49 (1H, d, J=8.0 Hz), EUR 7.57 (1H, t, J=8.0 Hz), of 7.90 (1H, user. d, J=8.0 Hz), 8,11 (4H, s), by 8.22 (1H, user. C), 10,65 (1H, s).

Example 7

Synthesis of isopropyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid

1H NMR (DMSO-d6) δ (ppm): 1,35 (6N, d, J=6.4 Hz), 2,90 (3H, d, J=5,2 Hz), 3,76 (3H, c), 3,93 (3H, c), is 5.18 (1H, m), 7,01 (1H, s), 7,03 (1H, user. C)7,19 (1H, s), 7,49 (1H, d, J=8.0 Hz), EUR 7.57 (1H, t, J=8.0 Hz), to $ 7.91 (1H, user. d, J=8.0 Hz), of 8.09 (4H, s), by 8.22 (1H, user. C), 10,65 (1H, s).

Example 8

Synthesis of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]-N'-ethyltryptamine

1H NMR (DMSO-d6) δ (ppm): to 1.15 (3H, t, J=7.2 Hz), 2.91 in (3H, d, J=4,8 Hz), 3,32 (2H, m), 3,76 (3H, c), of 3.94 (3H, c), 7,01 (1H, s), 7,03 (1H, user. C)7,19 (1H, s)of 7.48 (1H, d, J=8.0 Hz), EUR 7.57 (1H, t, J=8.0 Hz), to $ 7.91 (1H, user. d, J=8.0 Hz), 7,98 (2H, d, J=8,4 Hz), of 8.06 (2H, d, J=8,4 Hz), by 8.22 (1H, user. C)8,64 (1H, t, J=5.6 Hz), 10,55 (1H, s).

Example 9

Synthesis of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]-N'-propertyrelated

1H NMR (DMSO-d6) δ (ppm): of 0.91 (3H,t, J=7,6 Hz), and 1.56 (2H, m), 2.91 in (3H, d, J=4,8 Hz)at 3.25 (2H, q, J=6.0 Hz), 3,76 (3H, c), of 3.94 (3H, c), 7,01 (1H, s), 7,02 (1H, user. C)7,19 (1H, s)of 7.48 (1H, d, J=8.0 Hz), EUR 7.57 (1H, t, J=8.0 Hz), to $ 7.91 (1H, user. d, J=8.0 Hz), 7,98 (2H, d, J=8,4 Hz), of 8.06 (2H, d, J=8,4 Hz), by 8.22 (1H, user. C)to 8.62 (1H, t, J=6.0 Hz), 10,55 (1H, s).

Example 10

Synthesis of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]-N'-isopropylacetanilide

1H NMR (DMSO-d6) δ (ppm): 1,19 (6N, d, J=6.8 Hz), 2.91 in (3H, d, J=4,8 Hz), 3,76 (3H, c), of 3.94 (3H, c), of 4.12 (1H, m), 7,01 (1H, s), 7,02 (1H, user. C)7,19 (1H, s)of 7.48 (1H, d, J=8.0 Hz), EUR 7.57 (1H, t, J=8.0 Hz), 7,92 (1H, user. d, J=8.0 Hz), 7,98 (2H, d, J=8,4 Hz), with 8.05 (2H, d, J=8,4 Hz), by 8.22 (1H, user. C)to 8.34 (1H, d, J=7,6 Hz), 10,55 (1H, s).

Example 11

Synthesis of methyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]isophthalic acid

A mixture of 2.00 g (6,44 mmol) 3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenylamine, 1,75 g (9,71 mmol) nanometrology ester of isophthalic acid, 2,7 ml of triethylamine, and 1.00 g of the hydrate of 1-hydroxybenzotriazole and 2.00 g of WSC hydrochloride are suspended in 15 ml of dimethylformamide, followed by stirring at room temperature over night. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over magnesium sulfate. After filtration, the residue obtained by distillation of the solvent under reduced pressure, the eat subjected to column chromatography (ethyl acetate-heptane). Then the solid substance precipitated with a mixture of ethyl acetate-hexane, collected by filtration and dried under aeration, while receiving 2.65 g specified in the title compound (yield: 87%).

1H NMR (DMSO-d6) δ (ppm): 2.91 in (3H, d, J=4,8 Hz), 3,76 (3H, c)to 3.92 (3H, c), 3,93 (3H, s), 7,01 (1H, s), 7,02 (1H, user. C)7,19 (1H, s)of 7.48 (1H, user. d, J=8.0 Hz), EUR 7.57 (1H, t, J=8.0 Hz), 7,72 (1H, t, J=8.0 Hz), 7,92 (1H, user. d, J=8.0 Hz), 8,17 (1H, user. d, J=8.0 Hz), by 8.22 (1H, t, J=1.6 Hz), compared to 8.26 (1H, user. d, J=8.0 Hz), 8,56 (1H, t, J=1.6 Hz), 10,67 (1H, s).

Example 12

Synthesis of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]isophthalic acid

To a solution 2,49 g (5,27 mmol) of the compound of example 11 obtained above in a mixed solvent consisting of 40 ml of tetrahydrofuran and 40 ml of ethanol, add 15 ml of 1N. an aqueous solution of sodium hydroxide, followed by stirring at room temperature over night. The reaction mixture to neutralize 15 ml of 1N. hydrochloric acid and to it was added 60 ml of water. The precipitated solid is collected by filtration and dried under hot air, while receiving and 3.31 g specified in the connection header.

1H NMR (DMSO-d6) δ (ppm): 2.91 in (3H, d, J=4,8 Hz), 3,76 (3H, c), of 3.94 (3H, c), 7,01 (1H, s), 7,02 (1H, user. C), 7,20 (1H, s)of 7.48 (1H, user. d, J=8.0 Hz), EUR 7.57 (1H, t, J=8.0 Hz), 7,69 (1H, t, J=8.0 Hz), 7,92 (1H, user. d, J=8.0 Hz), 8,15 (1H, user. d, J=8.0 Hz), by 8.22 (1H, user. d, J=8.0 Hz), 8,23 (1H,t, J=1,6 Hz), 8,56 (1H, t, J=1.6 Hz), 10,65 (1H, s).

The following compounds of examples 13-19 synthesized by methods similar to the method of example 3, using the compound of the above example 12 as a source of connection and using the appropriate alcohol or amine.

Example 13

Synthesis of ethyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]isophthalic acid

1H NMR (DMSO-d6) δ (ppm): of 1.36 (3H, t, J=7.2 Hz), 2.91 in (3H, d, J=4,8 Hz), 3,76 (3H, c), 3,93 (3H, c), to 4.38 (2H, q, J=7.2 Hz), 7,01 (1H, s), 7,02 (1H, user. C)7,19 (1H, s)of 7.48 (1H, user. d, J=8.0 Hz), EUR 7.57 (1H, t, J=8.0 Hz), 7,71 (1H, t, J=8.0 Hz), 7,92 (1H, user. d, J=8.0 Hz), 8,17 (1H, user. d, J=8.0 Hz), by 8.22 (1H, t, J=1.6 Hz), of 8.25 (1H, user. d, J=8.0 Hz), 8,54 (1H, t, J=1.6 Hz), 10,67 (1H, s).

Example 14

Synthesis of propyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]isophthalic acid

1H NMR (DMSO-d6) δ (ppm): 0,99 (3H, t, J=7.2 Hz), of 1.76 (2H, kW, J=7,2, 6,8 Hz), 2.91 in (3H, d, J=4.4 Hz), 3,76 (3H, c), 3,93 (3H, c), the 4.29 (2H, t, J=6.8 Hz), 7,01 (1H, s), 7,02 (1H, user. C)7,19 (1H, s), 7,49 (1H, user. d, J=8.0 Hz), EUR 7.57 (1H, t, J=8.0 Hz), 7,72 (1H, t, J=8.0 Hz), to $ 7.91 (1H, user. d, J=8.0 Hz), 8,18 (1H, user. d, J=8.0 Hz), by 8.22 (1H, t, J=1.6 Hz), of 8.25 (1H, user. d, J=8.0 Hz), 8,54 (1H, t, J=1.6 Hz), 10,67 (1H, s).

Example 15

Synthesis of isopropyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]isophthalic acid

1N the Mr (DMSO-d 6) δ (ppm): 1,36 (6N, d, J=6.4 Hz), 2.91 in (3H, d, J=4,8 Hz), 3,76 (3H, c), 3,93 (3H, c), 5,19 (1H, septet, J=6.4 Hz), 7,01 (1H, s), 7,02 (1H, user. C)7,19 (1H, s)of 7.48 (1H, user. d, J=8.0 Hz), EUR 7.57 (1H, t, J=8.0 Hz), 7,71 (1H, t, J=8.0 Hz), to $ 7.91 (1H, user. d, J=8.0 Hz), 8,15 (1H, user. d, J=8.0 Hz), 8,21 (1H, t, J=1.6 Hz), 8,24 (1H, user. d, J=8.0 Hz), charged 8.52 (1H, t, J=1.6 Hz), 10,67 (1H, s).

Example 16

Synthesis of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]-N'-methylisothiourea

1H NMR (DMSO-d6) δ (ppm): 2,82 (3H, d, J=4.4 Hz), 2.91 in (3H, d, J=4,8 Hz), 3,76 (3H, c), 3,93 (3H, c), 7,01 (1H, s), 7,02 (1H, user. C)7,19 (1H, s)of 7.48 (1H, user. d, J=8.0 Hz), EUR 7.57 (1H, t, J=8.0 Hz), to 7.64 (1H, t, J=8.0 Hz), to $ 7.91 (1H, user. d, J=8.0 Hz), 8,02 (1H, user. d, J=8.0 Hz), 8,10 (1H, user. d, J=8.0 Hz), by 8.22 (1H, t, J=1.6 Hz), 8,42 (1H, t, J=1.6 Hz), at 8.60 (1H, user. kV, J=4,8 Hz), of 10.58 (1H, s).

Example 17

Synthesis of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]-N'-ethylisopropylamine

1H NMR (DMSO-d6) δ (ppm): to 1.15 (3H, t, J=7.2 Hz), 2.91 in (3H, d, J=4.4 Hz), to 3.33 (2H, q, J=7.2 Hz), 3,76 (3H, c), 3,93 (3H, s), 7,01 (1H, s), 7,02 (1H, user. C)7,19 (1H, s)of 7.48 (1H, user. d, J=8.0 Hz), EUR 7.57 (1H, t, J=8.0 Hz), 7,63 (1H, t, J=8.0 Hz), 7,92 (1H, user. d, J=8.0 Hz), 8,03 (1H, user. d, J=8.0 Hz), of 8.09 (1H, user. d, J=8.0 Hz), by 8.22 (1H, t, J=1.6 Hz), 8,42 (1H, t, J=1.6 Hz), 8,63 (1H, user. t, J=5.4 Hz), of 10.58 (1H, s).

Example 18

Synthesis of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]-N'-propylacetamide

1H NMR (DMSO-d6) δ (who d): of 0.91 (3H, t, J=7,2 Hz), and 1.56 (2H, kW, J=7,2, 6.4 Hz), 2.91 in (3H, d, J=4.4 Hz)at 3.25 (2H, dt, J=6,4, 5,4 Hz), 3,76 (3H, c), 3,93 (3H, s), 7,01 (1H, s), 7,02 (1H, user. C)7,19 (1H, s)of 7.48 (1H, user. d, J=8.0 Hz), EUR 7.57 (1H, t, J=8.0 Hz), 7,63 (1H, t, J=8.0 Hz), 7,92 (1H, user. d, J=8.0 Hz), of 8.04 (1H, user. d, J=8.0 Hz), of 8.09 (1H, user. d, J=8.0 Hz), by 8.22 (1H, t, J=1.6 Hz), 8,42 (1H, t, J=1.6 Hz), to 8.62 (1H, user. t, J=5.4 Hz), 10,59 (1H, s).

Example 19

Synthesis of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]-N'-isopropylnaphthalene

1H NMR (DMSO-d6) δ (ppm): 1,19 (6N, d, J=6.4 Hz), 2.91 in (3H, d, J=4.4 Hz), 3,76 (3H, c), 3,93 (3H, s), 4,13 (1H, septet, J=6.4 Hz), 7,01 (1H, s), 7,02 (1H, user. C)7,19 (1H, s)of 7.48 (1H, user. d, J=8.0 Hz), EUR 7.57 (1H, t, J=8.0 Hz), a 7.62 (1H, t, J=8.0 Hz), to 7.93 (1H, user. d, J=8.0 Hz), of 8.04 (1H, user. d, J=8.0 Hz), 8,08 (1H, user. d, J=8.0 Hz), by 8.22 (1H, t, J=1.6 Hz), 8,40 (1H, user. d)to 8.41 (1H, t, J=1.6 Hz), 10,59 (1H, s).

Example 20

2-Methoxyethoxy ester of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid

A mixture of 55 mg (0.11 mmol) of the hydrochloride of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid, 40 μl (0.51 mmol) 2-methoxyethanol, 47 μl of triethylamine, 17 mg hydrate of 1-hydroxybenzotriazole and 35 mg of WSC hydrochloride are suspended in 2 ml of dimethylformamide, followed by stirring at room temperature over night. The reaction mixture was poured into water and extracted with ethyl acetate. Organic is the cue layer was washed with saturated salt solution and then dried over magnesium sulfate. The residue obtained by filtration and distillation of the solvent under reduced pressure, subjected to column chromatography on silica gel (ethyl acetate-heptane). Then the solid substance precipitated with a mixture of ethyl acetate-hexane, collected by filtration and dried under aeration, while receiving 40 mg indicated in the title compound (yield: 70%).

1H NMR (DMSO-d6) δ (ppm): 2.91 in (3H, d, J=4,8 Hz), 3,32 (3H, s), of 3.69 (2H, m), 3,76 (3H, s), 3,93 (3H, s), of 4.45 (2H, m), 7,01 (1H, s), 7,03 (1H, user. C)7,19 (1H, s), 7,49 (1H, user. d, J=7,6 Hz), EUR 7.57 (1H, t, J=7,6 Hz), of 7.90 (1H, user. d, J=7,6 Hz), 8,11 (4H, s)to 8.12 (1H, t, J=1,8 Hz), 10,65 (1H, s).

Example 21

2-Methoxyethoxy ester of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]isophthalamide acid

Specified in the header of the connection get method, which is equivalent to the method of example 3, using the compound of example 12 as a source of connection and using 2-methoxyethanol.

1H NMR (DMSO-d6) δ (ppm): 2.91 in (3H, d, J=4,8 Hz), 3,32 (3H, s), of 3.69 (2H, m), 3,76 (3H, s), 3,93 (3H, s), 4,46 (2H, m), 7,01 (1H, s), 7,03 (1H, user. C)7,19 (1H, s), 7,49 (1H, user. d, J=8.0 Hz), EUR 7.57 (1H, t, J=8.0 Hz), 7,73 (1H, t, J=8.0 Hz), 7,92 (1H, user. d, J=8.0 Hz), 8,17 (1H, dt, J=8.0 a, 1,6 Hz), by 8.22 (1H, t, J=1.6 Hz), compared to 8.26 (1H, dt, J=8.0 a, 1,6 Hz), 8,54 (1H, t, J=1.6 Hz), is 10.68 (1H, s).

Example 22

Anhydrous crystals of 1 methyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]t is Retalhuleu acid (example 1)

To to 75.28 mg of the compound obtained in example 1, add 9 ml of acetonitrile and the mixture is heated on an oil bath for dissolution, and the solution allow to cool to room temperature. The precipitate is collected by filtration and dried at 50°C during the night, while receiving specified in the header of the crystals.

Example 23

Anhydrous crystals of methyl 2-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid (example 1)

To 52,93 mg of the compound obtained in example 1, add 12 ml of 2-propanol, the mixture is heated on an oil bath to dissolve and the solution allow to cool to room temperature. The precipitate is collected by filtration and dried at 50°C during the night, while receiving specified in the header of the crystals.

Example 24

Crystals 1 hydrate methyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid (example 1)

To 75,71 mg of the compound obtained in example 1 was added 15 ml of acetone, the mixture is heated on an oil bath to dissolve and the solution allow to cool to room temperature. The precipitate is collected by filtration and dried at 50°C during the night, while receiving specified in the header of the crystals.

Example 25

Crystals 2 hydrate methyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide sour is you (example 1)

To 75,88 mg of the compound obtained in example 1, add 16 ml of methanol, the mixture is heated on an oil bath to dissolve and the solution allow to cool to room temperature. The precipitate is collected by filtration and dried at 50°C during the night, while receiving specified in the header of the crystals.

Example 26

Crystals 3 hydrate methyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid (example 1)

To 49,90 mg of the compound obtained in example 1, add 2 ml of tetrahydrofuran, the mixture is heated on an oil bath to dissolve and the solution allow to cool to room temperature. Then to the mixture is added 10 ml of water and leave it standing. The precipitate is collected by filtration and dried at 50°C during the night, while receiving specified in the header of the crystals.

Example 27

Amorphous methyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid (example 1)

To 36,49 mg of the compound obtained in example 1, add 0.2 ml of dimethyl sulfoxide to dissolve the connection. Then to the mixture additionally add 10 ml of water and the mixture was kept when standing. The precipitate is collected by filtration and dried at 50°C during the night, while receiving specified in the header of the amorphous substance.

Example 28

Alternative SPO is about obtaining anhydrous crystals of 1 methyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid (example 1)

A suspension consisting of 10,00 g (55,51 mmol) monomethylaniline and 90 ml of 1,2-dimethoxyethane, stirred while cooling it at a cooling bath at 10°C. To the suspension is added 2.0 ml of N,N-dimethylformamide and 6.61 g (52,75 mmol) of thionyl chloride, in that order. The suspension is stirred under heating at 60°C-65°C for 1 hour and give her a chance to cool off. Then, the suspension is additionally stirred while cooling in an ice bath. Then to the mixture are added dropwise 6,83 g (52,82 mmol) diisopropylethylamine. Then the reaction mixture was stirred at room temperature. Thirty minutes after reaching an internal temperature of 20°With stirring finish. The reaction mixture was placed in a 200-ml flask in the form of eggplant, followed by measurement of its content and receiving 109,49 g of mixed solution consisting of [a mixture of the acid chloride of monomethylaniline/diisopropylethylamine] (the content of the acid chloride of monomethylaniline: 8,89 g), in the form of a light reddish-brown solution.

Then, the suspension comprising of 9.50 g (30,00 mmol) [4-(3-AMINOPHENYL)-6,7-dimethoxyquinazolin-2-yl]methylamine and 380 ml of tetrahydrofuran, stirred under cooling at 0°C. To the suspension is added dropwise over 1 hour 80,71 g of the above mixed solution consisting of [a mixture of the acid chloride of monomethylaniline/diisopropyl is Ilumina] (the content of the acid chloride of monomethylaniline: 6,55 g; 33,00 mmol). The mixture was then stirred at 0°C for 11 hours. Then to the reaction mixture while cooling at 0°C add 190 ml of ethyl acetate and then added dropwise to the mixture of 380 g of 5% sodium hydrogen carbonate solution. The reaction mixture was transferred into a separating funnel and add 190 ml of ethyl acetate. After extraction the organic layer is separated and washed with 190 g of 5% solution of sodium chloride and 190 ml of water (twice) in this order. The organic layer is concentrated under reduced pressure and at 40°C. To the residue add 143 ml of methanol and the mixture is stirred while heating to 40°C. thirty-three minutes after the start of mixing the oil bath temperature set at 75°C. Then 30 minutes after the internal temperature reaches 60°C, the temperature of the oil bath set at 50°C. When the internal temperature falls to 55°C. to the mixture are added dropwise 143 ml of 2-propanol. Then, the inner temperature is gradually reduced to 27.3°C and the mixture is then stirred at 20°C for 17 hours. The precipitated crystals are subjected to vacuum filtration and the resulting product is washed with a mixed solvent composed of 14.3 ml of methanol and 14.3 ml of 2-propanol. The resulting product is subjected to suction in the vacuum line for 10 minutes to remove the liquid, while receiving 15,72 g crude, before the other commercial interest in the product (wet mass; contents interest of product: 13,31 g) as light-yellow crystals (yield: 93.9 per cent).

A suspension consisting of 15,48 g of the crude interest of product (wet weight) (contents interest of product: 13,11 g; 27,00 mmol) and 40 ml of dimethyl sulfoxide is stirred under heating at 60°C and the crystals dissolve. The resulting solution is subjected to clarifying filtration and washed with 10 ml of dimethylsulfoxide. The filtrate is transferred into a 1000-ml chetyrehpolnye glass vessel, which was pre-heated jacket with hot water at 60°C, and the residue washed with 10 ml of dimethylsulfoxide. The mixture was then stirred under heating at 60°C. thereafter, to the specified solution are added dropwise 119 ml of 2-propanol and the mixture is placed to 49.3 mg of seed crystals of interest product. Then to the mixture dropwise addition add 60 ml of 2-propanol. This suspension is stirred at 60°C for 2 hours, the temperature of the shirt set to 80°C. and the suspension is continuously stirred while heating for 16.5 hours. Then the suspension is added dropwise to 120 ml of 2-propanol and 3 hours to a suspension optional add 362 ml of 2-propanol. After that, the mixture is gradually cooled to 20°C (10°C/hour) and then stirred at the same temperature. Five hours later besieged Krista the crystals are collected by filtration, and the crystals are washed with a mixed solvent consisting of 2,6 ml of dimethyl sulfoxide and 24 ml of 2-propanol. The crystals are optionally washed with 40 ml of 2-propanol and then sucked into the vacuum line to remove the liquid. The obtained crystals are dried under reduced pressure, thus obtaining 9,84 g representing the interest of product as yellow crystals (yield: 73,7%).

To confirm the validity of the compounds of the present invention as an antipruritic agent, the authors of the present invention conducted the following test.

The test example 1

To estimate the effects of compounds on the model behavior with scratching (carpagnano), induced oxazolone

<test Method>

As the test animals used commercially available 5-week-old female mice (Japan SLC, Inc. and CRJ, Inc.). For acclimatization, the mice were kept for 7 days pre-breeding period. After this test was applied only animals that have not been detected changes in the General condition and body weight is favorably increased.

(1) Sensitization and induction

Sensitization was performed by applying 20 µl of a solution in acetone (Wako Pure Chemical Industries, Ltd.), which contained 0.5% of 4-ethoxymethylene-2-phenyl-2-oxazoline-5-it (hereinafter referred to as "oxazolone", Sigma) for each of the left and right auricles 6-week-old mice that PR is passed acclimatization period.

Induction was performed by applying 10 μl of 0.3% oxazolone on the left ear of each mouse, a total of 3 times, at intervals of 2-3 days from the fifth day after sensitization.

(2) Measurement of the number of pokusyvanii (Carpani)

For an objective evaluation of the action of compounds number of pokusyvanii (Carpani) of each mouse were automatically measured using Micro devices Act device (NeuroScience, Inc.). A piece of magnet (diameter: 1 mm; length: 3 mm; NeuroScience) was injected into the skin of the left hind paws of each mouse, shot diethyl simple ether (Wako Pure Chemical Industries, Ltd.) not later than the day before the measurement. As soon as it was induced behavior carpagnano applying oxazolone, the mouse was transferred into the chamber (diameter: 11 cm height: 18 cm) spiral. After that, the electric current induced by the movement of the magnet entered in the paw of the mouse was measured over a certain period of time. The characteristic waveform that reflects this behavior with carepages, were detected by Micro device Act and the frequency of occurrence of wave detektirovanii forms was calculated as the number Carpani.

(3) to estimate the effects of the tested compounds

Preparation of test compounds: the compounds of examples 1, 4, 5, 7, 14, 20 and 21 prepared so as to have a concentration of 0.1-0.3% (based on the concentration of the mixed solvent (acetone:ethanol = 1:1).

As for the groups of the tested compounds was performed determine actions for the following 5 groups: (1) normal group - use of a mixed solvent (acetone:ethanol = 1:1); (2) control group - the group the use of a mixed solvent (acetone:ethanol = 1:1); (3) the application group of the compound of example 1; (4) the application group of the compound of example 4 and (5) application group of the compound of example 5. In addition, spent determining steps for the following 5 groups: (1) normal group - use of a mixed solvent (acetone:ethanol = 1:1); (2) control group - the group the use of a mixed solvent (acetone:ethanol = 1:1); (3) the application group of the compound of example 7; (4) the application group of the compound of example 14 and (5) application group of the compound of example 21. In addition, conducted determine the effect of 3 of the following groups: (1) normal group - use of a mixed solvent (acetone:ethanol = 1:1); (2) control group - the group the use of a mixed solvent (acetone:ethanol = 1:1); (3) the application group of the compound of example 20. The mice were divided into groups so that the number Carpani becomes a constant based on the number Carpani received during the 2nd induction.

To estimate the effects of the test compounds: ten microlitres of the test compounds (only mixed solvent (atzet the n:ethanol = 1:1) was used for the normal group and the control group) was administered 1 hour before the 3rd application oxazolone. Assessment of the validity of the test compounds was carried out using as an indicator the number Carpani obtained within 2 hours after induction due to 3rd applying oxazolone (mixed solvent (acetone:ethanol = 1:1) was used for the normal group). In addition, another evaluation of the actions carried out on the basis of skin symptom. That is, when the detection Carpani received before the 3rd drawing oxazolone and after 1 day or 4 days after application, namely for each of paragraphs (1) scratch and (2) bleeding/erosion was determined 4 degrees of intensity from 0 to 3 (0: no symptoms; 1: mild symptoms; 2: moderate symptoms, and 3: severe symptoms). Thus, using the difference in the estimates in the scores obtained before and after induction by oxazolone as an indicator, evaluated the behavior tarpanam. Such a degree of intensity was determined for each item and total score in points was defined as the score assigned to each of the individuals.

<test>

(1) the measurement Results for the number Carpani shown in figures 1, 9 and 12 (normal group: n=11; other groups: n=17 figure 1; each group: n=10 in figures 9 and 12).

(2) the measurement Results in the case of skin symptoms shown in figures 2, 10, 11, 13, and 14.

Figures 2, 10 and 13 are graphs constructed on the basis of value, is received by subtracting the score, obtained before the introduction of the score obtained 1 day after injection, and figures 11 and 14 are graphs constructed on the basis of values obtained by subtracting the score obtained before the introduction of the score obtained 4 days after injection (normal group: n=11; other groups: n=17 figure 2; normal group: n=8; other groups: n=9 in figures 10 and 11; each group: n=8 in figures 13 and 14).

From these results, it was found that the compounds of the present invention inhibit the behavior tarpanam and suppress damage in the form of skin symptoms caused by such behavior with carepages, thereby exhibiting excellent antipruritic effect.

The test example 2

The experiment to evaluate the induction of enzyme activity, metabolizing the drug (CYP), with the use of frozen human hepatocytes

<Operation tests"

Frozen human hepatocytes (XenoTeck) were rapidly thawed at 37°C, and viable cells were obtained with a set allocation of hepatocytes (Nosan Corporation). After the obtained cells were diluted with ice environment E William s (10% FBS, +PSG) with a concentration of 5×105viable cells/ml, cells were seeded on 48-hole, covered with collagen tablet (BD Biosciences) at a concentration of 1×105/sup> cells/cm2, and were cultured at 37°C in an atmosphere with 5% CO2within 24 hours. Then the medium was replaced Hepato-STIM (registered trademark: BD Biosciences) (+EGF, PSG, -FBS) and the cells were additionally cultured at 37°C in an atmosphere with 5% CO2within 24 hours. Hepato-STIM (+EGF, PSG, -FBS) was used as a culture medium and cells were incubated with culture medium containing the test compound, β-naphthoflavone (hereinafter briefly referred to as β-NF, SIGMA), used as positive control CYPIA person, or rifampicin (hereinafter briefly referred to as Rif, Wako Pure Chemical Industries, Ltd.), used as a positive control, human CYP3A4, at 37°C in an atmosphere with 5% CO2within approximately 48 hours. The culture medium containing the test compound, β-NF or Rif, was replaced every 24 hours. Each of the test compounds, β-NF and Rif, was dissolved in dimethyl sulfoxide (DMSO: Wako Pure Chemical Industries, Ltd.) and the culture medium containing the test compound (final concentration: 1, 3 and 10 μm), β-NF (final concentration 10 μm) or Rif (final concentration 10 μm), was obtained by adding them to the Hepato-STIM (+EGF, PSG, -FBS), respectively. It was found that the final concentration of DMSO was 0.1%, and the culture medium containing 0.1% DMSO was used for control. After treatment cells were washed one PBS and total RNA was purified using the kit for purification of total RNA (Applied Biosystems). Purified total RNA was subjected to reverse transcription reaction using reagents TaqMan Reverse reduced Reagents (Applied Biosystems) for cDNA synthesis, where oligo dT was used as a primer. The reaction was carried out using the system PCR Gene Amp 9700 at 25°C for 10 minutes, then at 48°C for 60 minutes. Then reverse transcriptase deactivated at 95°C for 10 minutes. Levels of mRNA for CYP1A1 and GAPDH were quantitatively determined using a set of reagents SYBR Green PCR Core Reagents Kit (Applied Biosystems) and the levels of mRNA for CYP1A2 and levels of mRNA for CYP3A4 was measured using a set of reagents Taqman PCR Core Reagents Kit (Applied Biosystems) and of a detection system ABI Prism 7900 Sequence Detection System (Applied Biosystems). Sequence of primers and PCR conditions used for the quantitative determination of each mRNA are shown in tables 1 and 2 respectively.

Sequence primer

[Table 1]

The PCR conditions

[Table 2]
TemperatureTime
95 10 min
9415 secDenaturation
5820 secResaturate
7230 secThe reaction elongation
* Cycle consisting of denaturation, renaturation and elongation reaction was repeated 50 times.

<Calculating ability to induce CYP>

The ability of test compounds to induce CYP1A1 was calculated as follows.

The ability of test compounds to induce CYP1A1 (%) = {[(number of CYP1A1 mRNA in the treated test connection cells)/(the amount of GAPDH mRNA in the treated test connection cells)/[(number of CYP1A1 mRNA in control cells)/(the amount of GAPDH mRNA in control cells)]-1}/{[(number of CYP1A1 mRNA in the treated positive control cells)/(the amount of GAPDH mRNA in the treated positive control cells)]/[(number of CYP1A1 mRNA in control cells)/(the amount of GAPDH mRNA in control cells)]-1}×100.

The ability to induce CYP1A2 or CYP3A4 was calculated in the same way as described above.

<test Results>

The results regarding the compounds of examples 1, 4, 5, 7, 14, 16, 20 and 21, shown in table 3. As a comparative example was used, the compound described as example 1 in WO 99/37622, (4-(3-benzoylamino)-6,7-dimethoxy-2-methylaminophenol.

The results showed that the compounds of the present invention do not show any activity in relation to the induction of CYPs, whereas the activity in relation to the induction of CYPs was observed in the comparative example.

/tr>
[Table 3]
The ability to induction compared
with a positive control (%)
CYP1A1CYP1A2CYP3A4
Rifampicin10 µm100,0
β-Naphtoflavone10 µm100,0100,0
Example 11 micron0,1-0,1-2,4
3 microns0,6a-0.7-3,4
10 µm4,62,5-4,0
Example 41 micron0, 1-1,1-5,6
3 microns0,40,60,1
10 µm1,56,1-6,1
Example 51 micron0,0-2,0-6,9
3 microns0,0-1,3is 6.2
10 µm0,00,5-2,0
Example 71 micron0,20,5-6,6
3 microns1,81,5-9,8
10 µmthe 5.7 3,1-11,9
Example 141 micron0,21,20,7
3 microns0,33,0-0,1
10 µm0,71,8of-1.5
Example 161 micron0,00,2a-0.7
3 microns0,3a 3.9-0,3
10 µm1,01,22,7
Example 201 micron0,1-1,7-2,0
3 microns0,1-1,6of-2.1
10 µm0,8-1,2-2,2
Example 21 1 micron0,00,6-1,2
3 microns0,0-0,3-1,6
10 µm0,10,4-2,0
Comparative example1 micron2,17,21,6
3 microns18,534,310,8
10 µm51,935,0of 17.0

Measured x-ray crystal and amorphous compounds obtained in examples 22-27. This measurement was performed according to the method of measurement of powder x-rays described in the General test in the Pharmacopoeia of Japan, under the following conditions.

(Equipment)

System x-ray differential thermal analysis (DTA) Rigaku: (manufactured by Rigaku Corporation).

(Method of operation)

The sample was crushed in an agate mortar and then sprayed on the copper plate. Then the measurement was performed under the following conditions.

Used x-ray) is the increase: CuKα rays.

The tube voltage: 40 kV.

Tube current: 200 mA.

Slit the divergence of the beam: 1/2 C.

Reception slot: 0,3 mm

Slit scattering: 1/2 C.

Scanning speed: 2°/min

Step scan of 0.02°.

The scanning range (2θ): 5° to 40°.

Powder x-ray crystal and amorphous substances obtained in examples 22-27, shown in figures 3-8. In addition, the characteristic peaks of diffraction angles (2θ) are summarized in table 4.

[Table 4]
ExampleThe diffraction angle (2θ)
228,2°, 16,5°, 24,5°
239,4°, 16,8°, 23,3°
248,6°, 9,1°, 23,2°
257,0°, 10,4°, 12,6°
265,4°, 10,9°, 11,9°

Industrial applicability

The present invention provides an agent that can be applied to eliminate the itchiness caused by atopic disease or the like.

1. The compound represented by formula (I)or its pharmacologically acceptable salt

where R is the Wallpaper With 1-6alkoxy, optionally substituted methoxy, or amino, monosubstituted With1-6the alkyl, where the group R-C(=O)-, is attached in the meta or paraprotein.

2. The compound or its pharmacologically acceptable salt according to claim 1, where R represents a C1-3alkoxy, optionally substituted methoxy, or amino, monosubstituted With1-3the alkyl.

3. The compound or its pharmacologically acceptable salt according to claim 1, where R is a methoxy, ethoxy, 1-propoxy, 2-propoxy, methoxyethoxy, methylamino or ethylamino.

4. The compound or its pharmacologically acceptable salt according to claim 1 or 2, selected from the following groups:
methyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid,
ethyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid,
N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]-N'-methyltryptamine,
isopropyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid,
isopropyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]isophthalic acid,
2-methoxyethoxy ester of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid, or
2-methoxyethoxy ester of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]isophthalamide acid.

5. The compound according to claim 4, representing methyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)filterflow acid or its pharmacologically acceptable salt.

6. The compound according to claim 4, which represents ethyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid or its pharmacologically acceptable salt.

7. The compound according to claim 4, representing N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]-N'-methyltryptamine or its pharmacologically acceptable salt.

8. The compound according to claim 4, which represents isopropyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid or its pharmacologically acceptable salt.

9. The compound according to claim 4, which represents isopropyl-N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]isophthalic acid or its pharmacologically acceptable salt.

10. The compound according to claim 4, representing a 2-methoxyethoxy ester of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]terephthalamide acid or its pharmacologically acceptable salt.

11. The compound according to claim 4, representing a 2-methoxyethoxy ester of N-[3-(6,7-dimethoxy-2-methylaminophenol-4-yl)phenyl]isophthalamide acid or its pharmacologically acceptable salt.

12. Pharmaceutical composition having anti-itching action, comprising as active ingredient an effective amount of a compound according to any one of claims 1 to 11 or its pharmacologically acceptable salt.

13. Antipruritic agent for atopic diseases, not only the abuser a compound according to any one of claims 1 to 11 or its pharmacologically acceptable salt.

14. Antipruritic agent according to item 13, where atopic disease is atopic dermatitis.

15. Antipruritic tool to eliminate itching, for which the steroid drug is ineffective, representing a compound according to any one of claims 1 to 11 or its pharmacologically acceptable salt.

16. Antipruritic agent according to any one of p-15 in the form of a medicinal product for external use.

17. A method of reducing itching for a subject, including the appointment of the subject compounds according to any one of claims 1 to 11 or its pharmacologically acceptable salt.

18. The method according to 17, wherein the subject is suffering from atopic diseases.

19. The method according to p in which atopic disease is atopic dermatitis.

20. The method according to 17, wherein the steroid drugs are ineffective against itching.

21. The method according to any of PP-20, which antipruritic tool used in the form of the preparation for external use.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, which are HSP90 (heat-shock proteins) inhibitors and can be used to prepare a medicinal agent for treating tumorous diseases affected by HSP90 inhibition. In formula I R1 denotes Hal, H, OA or A, R2, R3 each independently denotes -O-(X)s-Q, -NHCO-(X)s-Q, -CONH-(X)s-Q, -NH(CO)NH-(X)s-Q, -NH(CO)O-(X)s-Q, -NHSOr(X)s-Q, NHCOA, Hal, Het or H, where, if R2=H, then R3≠H, or if R3=H, then R2≠H, R4 denotes H, R5 denotes H, Hal, A, OA, (CH2)nCOOH, (CH2)nCOOA, O(CH2)oCONH2, NHCOOA, NHCO(CH2)nNH2, NHCONHA or O(CH2)oHet1, A denotes a straight or branched alkyl containing 1-10 carbon atoms, in which 1-5 hydrogen atoms may be substituted with F, Cl and/or Br, X denotes a straight or branched C1-C10 alkylene which is unsubstituted or substituted once, twice or thrice by A, O A, OH, Hal, CN, COOH, COOA, CONH2, NH2, NHCOA, NHCOOA, Q denotes H, Ar or Het, Ar denotes phenyl which is unsubstituted or substituted once, twice or thrice with A, OA, OH, NO2, Hal, CN, (CH2)nCOOH, (CH2)nCOOA and/or tetrazole, Het denotes a cyclic saturated or aromatic 5-6-member heterocycle containing 1-2 N and/or O atoms, optionally condensed with a benzene ring which may be substituted once, twice or thrice with A, OA, OH and/or =O (carbonyl oxygen), Het1 denotes a monocyclic saturated, unsaturated or aromatic heterocycle containing 1-2 N and/or O atoms, which may be mono- or disubstituted with A, OA, OH, Hal and/or =O (carbonyl oxygen), Hal denotes F, Cl, Br or I, n equals , 1, 2, 3 or 4, o equals 1, 2 or 3, s equals 0, 1 or 2.

EFFECT: high efficiency of using said derivatives.

4 cl, 4 dwg, 1 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein Q together with carbon and nitrogen atoms whereto attached forms a 5-6-members monocyclic heteroaromatic ring; or Q together with carbon and nitrogen atoms whereto attached forms a 9-10-members bicyclic heterocycle; R1 and R2 independently mean hydrogen, halogen, alkyl, alkyl substituted by one or more halogen, alkoxygroup, alkoxygroup substituted by alkoxygroup, alkylthiogroup, sulphonyl, free or etherified carboxygroup, carbamoyl, sulohamoyl, morpholinyl or pyridinyl; or R2 is absent; R3 means (C3-C6)cycloalkyl; R4 means hydrogen, halogen, lower alkyl or lowest alkyl substituted by one or more halogen; R5 means (C3-C6cycloalkyl, (C6-C10) aryl, (C3-C10)heterocyclyl or (C1-C6)alkyl optionally substituted by (C1-C6)alkoxygroup, (C3-C7)cycloalkyl, (C6-C10)aryl or (C3-C10)heterocyclyl; R6 means free or etherified carboxygroup; and n is an integer equal to 1-6; or to its enanthiomer, or a mixture of its enanthiomers, or its pharmaceutically acceptable salt. Besides, the invention refers to a method of glucokinase activation in mammals, to a method of treating pathological conditions associated with glucokinase activation in mammals and impaired glucose tolerance, as well as to a pharmaceutical composition based on these compounds and to application of said compositions for preparing a drug.

EFFECT: there are produced and described new compounds which are activators and can be used as therapeutic agents for treating the glucokinase mediated pathological conditions.

31 cl, 4 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to new compounds with formula (I), their esters, carbamates and pharmaceutically used salts, which can be used as inhibitors of p38 kinase, which means they can be used for curing diseases and conditions for which p38 is the mediator. In formula (I): Q represents -C(R1R2R3); R1 is chosen from hydrogen, C1-C8 alkyl, hydroxyC1-C8alkyl, and C1-C8alkoxy C1-C8alkyl; R2 and R3 are chosen: (i) independently from: (a) hydrogen, under the condition that, if R1 represents hydrogen, then only one of R2 and R3 can be chosen from hydrogen; (b) C1-C8alkyl; C1-C8alkyl, substituted with one or two radicals halogen, -OR8, -S(O)pR10;(c) -OR8; or (ii) R2 and R3 together with the carbon atom to which they are bonded, form optionally substituted C3-C7cycloalkyl or substituted heterocyclic ring system; R4 and R5 are independently chosen from halogen; R8 and R9 are independently chosen from hydrogen, C1-C8alkyl; R10 represents C1-C8alkyl; m equals 0, n equals 0; and p equals 2; where the term "substituted cycloalkyl" stands for a cycloalkyl group, containing one or two substitutes, which are independently chosen from a group, consisting of -Y-ORs, -Y-S(O)0-2RS, C(=O)ORs, where Y is absent; Rs is independently chosen from hydrogen, C1-C8alkyl, except when the said substitute represents -Y-S(O)1-2Rs, then RS represents hydrogen; the term "heterocyclic ring system" stands for a saturated non-aromatic monocyclic fragment, consisting of 5 to 6 atoms, which are part of the ring system, from which one atom, which is part of the ring system, is a heteroatom, chosen from N, O, and the rest of the atoms in the ring system are carbon atoms; the term "substituted heterocyclic ring system" stands for a heterocyclic fragment mentioned above, containing one substitute, chosen from the group, -Y-Rs, -Y-ORs, -Y-C(O)2Rs, -Y-S(O)0-2Rs, where Y is absent or represents a C1-C4alkylene group, Rs represents the same as was defined above for the substituted cycloalkyl group.

EFFECT: used for treating diseases and conditions.

13 cl, 2 dwg, 5 tbl, 17 ex

FIELD: medicine.

SUBSTANCE: invention refers to application of enterovirus in preparing a pharmaceutical composition for prevention or treatment of the diseases associated with IgE-mediated allergic sensitisation and related diseases with using an enteroviral vaccine in which enterovirus does not contain an exogenous nucleotide sequence integrated into a viral genome and coding an allergen causing said allergic sensitisation, and also to a method for prevention or treatment of said diseases.

EFFECT: effective products for treating said diseases.

10 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: nutritional and pharmaceutical composition in form of baby food contains fat, protein and carbohydrate components and includes milk serum and casein with weight ratio of casein to serum from 1:1 to 1:2.4. They contain, at least: 3 g of arginine per 100 g of protein, from total content of fatty acids: 10 wt % of linoleic acid, 1 wt % of alpha-linoleic acid, one long-chain polyunsaturated fatty acid, selected from group, consisting of docosahexaenic, arachidonic and eicosapentaenoic acid, to 25 wt %, at least one polyunsaturated fatty acid and 2-12 g of indigestible oligosaccharides with polymerisation degree from 2 to 100 per 100 g of dry weight of said composition, as well as neutral and acidic oligosaccharides, containing units of uronic acid. Pharmaceutical composition is applied in treatment and/or prophylaxis of inflammatory disease, diarrhea, eczema and/or atopic dermatitis. Prevention of allergy or diarrhea is performed by introduction of composition to child enterally or perorally.

EFFECT: inventions ensure stimulation of immune system maturing and development in babies of intestine and intestinal flora, similar to flora, obtained during breast feeding, optimal feeding, prevents penetration of allergens into general blood circulation and reduces risks associated with feeding with baby's formula based on milk serum.

17 cl, 4 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine and can be applied for treatment of hyperaemia and edema of mucous membrane of upper airways. For this purpose introduced is loratadine or proper quantity in form of its acceptable salt in combination with phenylephrine or as monomedication. Loratadine is introduced in regimen 2.5 mg four times per day, and phenylephrine is introduced in regimen 8-10 mg four times per day. Loradadine introduction in regimen 2.5 mg per day makes it possible to reach high efficiency of treatment in absence of side reactions.

EFFECT: treatment efficiency by loratadine in combination with phenylephrine in claimed regimen is conditioned by their synergetic effect as well as in absence of side reactions.

28 cl, 3 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to peptides inhibiting mucin hypersecretion. The peptides have an amino acid sequence containing up to 24 amino acid residues of the sequence GAQFSKTAAKGEAAAERPGEAAVA which can have at least one amino acid substitute in said sequence selected from a group consisting of the substitute of A by K, the substitute of F, K, G, Q, S, T and/or E for A; or the substitute of Q for E.

EFFECT: preparation of a pharmaceutical composition on the basis of the peptides for mucin hypersecretion inhibition.

28 cl, 9 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: claimed is application of solid peroral dosing composition of prolonged action, which includes (a) core, containing effective amount of pseudoephedrine or its salt, (b) first envelope, covering core and including swelling in water film-forming neutral or cationogenic copolymer ester, film modifier and lubricating substance, and (c) second envelope, covering first envelope and including effective amount of desloratadine, amount of pseudoephedrine or its salt is sufficient for ensuring maximaum of average geometrical values of pseudoephedrine concentration in plasma, from 345 to 365 ng/ml, for the time from 7.60 to 8.40 h, and amount of desloratadine is sufficient for ensuring maximum of its average geometrical values of concentration in plasma, from 2.10 to 2.45 ng/ml, for period from 4.0 to 4.5 h after intake of single dose of said composition, for preparation of medication for treatment of allergic and/or inflammatory states of upper and lower respiratory ways and skin, or urticaria and nasal and non-nasal symptoms of year-round and seasonal allergic rhinitis.

EFFECT: composition ensures necessary profile of active agents release and is efficient in treatment of allergic bronchospasm, couphing, seasonal allergic rhinites.

3 cl, 4 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new acid dihydrogenphosphate of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyrimidine-4-yl}phenyl)-2-methylpropionic acid of formula optionally in a crystalline form exhibiting cAMP inhibitor properties. Also, the invention refers to a pharmaceutical composition.

EFFECT: compound can find application for treating the diseases associated with cell expression of prostaglandin D2 in such diseases, as allergic rhinitis, bronchial asthma, allergic conjunctivitis, etc.

3 cl, 12 dwg, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, namely to creation of medication, which possesses anti-inflammatory and regenerating action. Medication contains the following ingredients: conifer needle extract, purified oleoresin of cedar or pine, or spruce, or fir, or larch or their mixture in equal proportions, vegetable oil.

EFFECT: medication has increased effectiveness and efficiency and also extends arsenal of medications, which have anti-inflammatory and regenerating action.

7 cl, 9 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: in formula (I) Cy1 is a 6-member heterocyclyl containing N as a heteroatom, a 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S and O, phenyl or phenyl condensed with a 5-member heterocycle containing O as a heteroatom, each optionally having 1-3 identical or different substituting Cy1 groups which are: (C1-C6)-acyl, cyano, carboxy, hydroxy, (C1-C6)alkylsulphonyl, (C3-C6)-cycloalkyl, a 6-member heterocyclyl containing 1-2 heteroatoms selected from O and N, phenyl, a 5-member heteroaryl containing 1-3 heteroatoms selected from N, S and O, Y1Y2N-, Y1Y2NC(=O)-, Y1Y2NSO2-, (C1-C6)-alkyl-SO2-N(R5)-C(=O)-, R6-C(=O)-N(R5)-, R7-NH-C(=O)-NH-; (C1-C6)-alkoxycarbonyl; (C1-C6)-alkyl, which optionally contains 1-3 identical or different substitutes which are halogen, carboxy, cyano, hydroxy, Y1Y2N-, Y1Y2N-C(=O)-, R6-C(=O)-N(R5)-, R8-SO2-N(R5)-C(=O)-, 5-member heterocyclyl, containing N as a heteroatom, 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; or (C1-C6)-alkoxycarbonyl; as well as (C1-C6)-alkoxy which optionally have 1-3 identical or different substitutes which are carboxy, (C1-C6)-alkoxycarbonyl, cyano, 3-member heterocyclyl containing O as a heteroatom, or 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; where phenyl or heteroaryl fragments in the substituting Cy1 groups optionally and independently have substitutes represented by hydroxy, (C1-C6)-alkyl, (C1-C6)-alkoxy, carboxy, (C1-C6)-alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-; and where cycloalkyl fragments in the substituting Cy1 groups which optionally and independently have substitutes represented by (C1-C6)-alkoxy, carboxy; Cy2 is a 9-member cycloalkenyl, phenyl, 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteratoms selected from N, S and O, or phenyl condensed with a 5,6-member heterocycle containing 1-2 heteroatoms selected from N and O, each independently and optionally having 1-3 identical or different substitutes represented by (C1-C6)-alkoxy, (C1-C3)-alkyl, hydroxy, halogen, halogen-(C1-C6)-alkoxy, nitro, Y1Y2N-; L1 is an alkylene with a straight or branched chain containing 1-6 carbon atoms, optionally substituted carboxy; or L1 is -CH2-(C1-C5)halogenalkylene; L2 is a bond, -O- or -CH2-O-. Other values of radicals are given in the formula of invention.

EFFECT: novel compounds have prostaglandin D2 receptor antagonist properties, can be used in treating primarily allergic disorders such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy and other diseases.

39 cl, 1 tbl, 99 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to application in an effective amount and to new nicotine receptor agonists described by general formula (i) or (ii) for treating inflammatory diseases chosen from a group including asthma, chronic obstructive pulmonary disease (COPD), interstitial pulmonary tissue fibrosis (IPF), sarcoidosis, hypersensitivity pneumonitis (HP), chronic hypersensitivity pneumonitis and bronchiolitis obliterans organising pneumonia (BOOP). The compounds (i) and compounds (ii) relate to formulae (i) (ii) where in formula (i) R1 and R2 independently mean alkyl with 1-10 carbon atoms; Xa means CH or N; Ya means one or more substitutes chosen from hydrogen, halogen, cyano, hydroxyl, alkyl with 1-10 carbon atoms optionally substituted with one or more halogen atoms, and alkoxy with 1-10 carbon atoms; n means an integer 0 or 2; J means a counterion representing a compound for maintaining electric neutrality, e.g., halogen, sulphate, sulphonate; in formula (ii) R3 is chosen from or Xb means N or N+-R10; R4 means one or more substitutes chosen from hydrogen, halogen; each R10, R11 and R12 independently means alkyl with 1-10 carbon atoms; provided the presence of the counterion when Xb means N+-R10.

EFFECT: use of nicotine receptor agonists in the effective amount for treating inflammatory diseases.

26 cl, 40 dwg, 3 tbl, 38 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and concerns cat allergen fused proteins and application thereof. Substance of the invention involves a compositions containing a virus-like particle (VLP) or a viral particle and at least, one antigen, first of all at least, one cat antigen, and more specifically at least one cat antigen which is human allergen. In specific versions of the invention, said antigen represents cat antigen Fel d1 or its fragment covalently bound with the VLP.

EFFECT: invention can be applied for preparing vaccines first of all aimed at treatment and/or prevention of cat dander allergy and other cat antigens and allergens responses.

25 cl, 20 ex, 5 tbl, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to certain N-alkylcarbonylaminoacid esters of formula where R1 independently represents hydrogen or methyl; R2 independently represents alkyl C1-C2 and R3 independently represents alkyl C1-C4, offered in the present invention, as well as to compositions and therapies with using the declared compounds.

EFFECT: preparing new compounds which effect on sensory processes.

27 cl, 7 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically to a composition for treating dermatoses. The pharmaceutical composition for treating skin affections contains mometazone furoat as an active ingredient, and a hydrophobic phase, a hydrophilic phase, a mat additive, macrogol cetostearate, glyceryl monostearate and cetostearyl alcohol as adjuvants. The hydrophobic phase represents vaseline and white wax. The hydrophilic phase represents hexylene glycol, phosphoric acid and water. The mat additive represents aluminium starch octenylsuccinate and titanium dioxide. The pharmaceutical composition is presented in soft dosage form, preferentially as cream. The method for preparing the composition involves slurrying of the mat additive in fused vaseline, addition of glyceryl monostearate, cetostearyl alcohol, macrogol cetostearate and white wax to suspension, and emulsification in the prepared mixture of mometazone furoate solution in the hydrophilic phase.

EFFECT: new composition is characterised by high pharmacological activity, storage-stability, good packing extrusion, high degree of uniformity and optimum pH.

8 cl, 1 tbl

FIELD: medicine, veterinary science.

SUBSTANCE: agent for treating inflammatory and allergic skin disease in cats and dogs contains Polcortolon as a glucocorticosteroid, Levomycetin and Metronidazole as an antibiotic, excipients - lidocaine hydrochloride, dimethyl formamide, dimethyl sulphoxide, isopropyl alcohol and polyethylene glycol 400, additionally contains calendula extract and Metronidazole, in the following ratio, wt %: Polcortolon 0.01-3.0; Levomycetin 0.1-3.0; lidocaine hydrochloride 0.1-6.0; dimethyl formamide 10.0-15.0; dimethyl sulphoxide 10.0-15.0; calendula extract 0.1-4.0; Metronidazole 0.1-5.0; polyethylene glycol 400 10.0-15.0; isopropyl alcohol - the rest.

EFFECT: invention provides reduced recovery time of allergic and inflammatory functional condition of skin in an animal.

3 ex

FIELD: medicine.

SUBSTANCE: external skin preparation contains as active components a ferrous compound and a compound chosen from 5-aminolevulin acid, salt of 5-aminolevulin acid, ester of 5-aminolevulin acids, ester of salt of 5-aminolevulin acids, N-acyl-5-aminolevulin acids, salts of N-acyl-5 aminolevulin acid and ester of N-acyl-5-aminolevulin acid. The ferrous compound is chosen from iron (II) citrate, sodium-iron citrate, ammonium-iron citrate, iron acetate, iron oxalate, iron (II) succinate, sodium-iron succinate and citrate, iron (II) pyrophosphate, iron (III) pyrophosphate, heme iron, iron dextrane, iron lactate, iron (II) gluconate, sodium-iron diethylene triaminepentaacetate, ammonium-iron diethylene triaminepentaacetate, ethylenediaminetetraacetate sodium-iron ethylene aminpentaacetate, ammonium-iron ethylene aminpentaacetate, iron triethylene tetraamine, sodium-iron dicarboxymehtyl glutamate and ammonium-iron dicarboxymehtyl glutamate.

EFFECT: improved skin look, prevention or reduction of roughness, dryness, wrinkles, flabbiness, and pigment spots, efficient for atopic dermatitis.

16 cl, 2 ex, 2 dwg

FIELD: medicine.

SUBSTANCE: carboxylic acid compounds are presented by formula (I) where R1 represents (1) hydrogen atom, (2) C1-4alkyl; E represents -CO-; R2 represents (1) halogen atom, (2) C1-6 alkyl, (3) trihalogen methyl; R3 represents (1) halogen atom, (2) C1-6alkyl; R4 represents (1) hydrogen atom; R5 represents (1) C1-6alkyl; represents phenyl; G represents (1) C1-6alkylene; represents 9-12-merous bicyclic heterocycle containing heteroatoms, chosen of 1-4 nitrogen atoms, one or two oxygen atoms; m represents 0 or an integer 1 to 4, n represents 0 or an integer 1 to 4, and i represents 0 or an integer 1 to 11 where R2 can be identical or different provided m is equal to 2 or more, R3 can be identical or different provided n is equal to 2 or more, and R5 can be identical or different provided i is equal to 2 or more; both R12 and R13, independently represent (1) C1-4alkyl, (2) halogen atom, (3) hydroxyl or (4) hydrogen atom, or R12 and R13 together represent (1) oxo or (2) C2-5alkylene and where provided R12 and R13 simultaneously represent hydrogen atom, carboxylic acid compound presented by formula (I), represents a compound chosen from the group including the compounds (1) - (32), listed in cl.1 of the patent claim. Besides the invention concerns a pharmaceutical composition based in the compound of formula I and to application of the compound of formula I for making the pharmaceutical composition.

EFFECT: there are produced new carboxylic acid derivatives with antagonistic activity with respect to DP receptor.

14 cl, 74 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to an agent for treating skin allergosis. The agent for treating skin allergosis, containing talc, starch and zinc oxide as a base, and s a reactant - dissolved dry extract of herbal raw material - nettle leaves, birch leaves, cowberry leaves, knotgrass herb, violet herb, licorice root, hop collective fruits in 40% ethanol in the ratio 1:3. Herewith the total extract is made by mixing powdered dry aqueous extracts of herbal raw material taken in equal quantities, in certain relation of components.

EFFECT: mentioned agent has the evident therapeutic effect in treating skin manifestations of allergic reactions of various aetiologies.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I) or to its salts: , where R1 is ,, in which n is an integer ranging from 0 to 6; Y is aryl, where the said aryl is optionally substituted at a substitutable position with one or more substitutes selected from a group which consists of halogen or C1-6alkyl, optionally substituted with mono-, di- or trihalogen; R2 is hydrogen; R3 is hydrogen or halogen; and R4 is hydrogen. The invention also relates to derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I-i) or to its salts, to a drug, to use of compounds in paragraph 1, as well as to a drug in form of a standard single dosage.

EFFECT: obtaining new biologically active compounds, which are active towards CRTH2.

23 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to creation of medicinal composition in form of gel for external application, which has anti-inflammatory and antiallergic effect. Gel includes as active substance Xymedon, as antihistamine preparation - diphenhydramine, or clemastine, or cetirizine, gel base with thickener carbopol, polyethylene oxide with molecular weight 400-6000 Da and purified water. Gel also can contain glycerin, ethanol, menthol, preservative - nipagin or benzalkonium chloride, stabiliser and neutralising agent.

EFFECT: gel is characterised by high therapeutic activity in treatment of skin diseases, vasomotor and allergic rhinitis, inflammatory diseases of eyes with allergic manifestations.

5 cl, 2 tbl, 29 ex

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