Quinazoline derivative and pharmaceutical preparation

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

 

The technical field

The present invention relates to a derivative of hintline applicable as a pharmaceutical preparation, in particular antipruritic funds, and its pharmaceutically acceptable salts, and pharmaceutical compositions containing any of these compounds as an active ingredient.

The level of technology

Itching sensation, ie, the itchy sensation that occurs in the surface layer of the skin and mucous membranes. The sensation of itching is a sensation due to the perception of the parasite or irritation in the surface layer of the skin and the desires of the removal of the penetrating substance or stimulus scratching or otherwise. Itching can easily imagine how the feeling that causes the urge to itch, but its mechanism is still not fully understood.

Diseases accompanied by itching, conventionally divided into pruritic dermatoses accompanied by damage to the skin (for example, atopic dermatitis, urticaria, psoriasis, xeroderma and tinea), and itching, which is not accompanied by damage to the skin, but is caused due to kidney and visceral diseases [for example, diabetes, blood diseases, cholestatic liver injury (primary billiary cirrhosis of the liver) and kidney disease], gipertireoidizmom, multiple sclerosis or similar diseases. In addition, as the reamers diseases, accompanied by severe itching, can be called a disease of the cornea and conjunctiva, such as allergic conjunctivitis. Recently, any of these diseases quickly grew into a big problem from the point of view of QOL (quality of life). Common to most diseases accompanied by itching is the fact that the pathological cycle is triggered by scratching the skin. Histamine is known as typical causes itching substance, and it causes itching when added externally, and is released in the body from mastocytes.

Antihistamines, antiallergic drug, steroid external preparations, etc. is used to treat itchy skin. However, there is a medicinal product which is satisfactory for the treatment of itching due to itchy skin. Also recently it was reported that factors other than histamine, are involved in the feeling of itching in atopic dermatitis. Indeed, many clinical cases antihistamine or antiallergic drug has no significant action on pruritus in atopic dermatitis. In the treatment of pruritus in some cases prescribe antihistamines or steroid outdoor product. However, the effect is almost not noticeable, and, thus, the currently effective treatment does not exist. the AK described above, there is no satisfactory drug for diseases accompanied by itching, and drug, which effectively suppresses itching regardless of etiology, is acutely necessary from a clinical point of view.

In order to solve this problem, as the connection is applicable for antipruritic funds, the literature describes the derived hintline (see, for example, patent document 1), an inhibitor of neural synthase nitric oxide (see, for example, patent document 2), cannabinoid receptor (see, for example, patent document 3), an inhibitor of glutamate receptor (see, for example, patent document 4), a derivative of piperidine (see, for example, patent document 5), derived prostaglandin (see, for example, patent document 6), etc. Among these funds derived hintline described in patent document 1, strongly inhibited the scratching behavior, spontaneously arising in the mouse model with the destruction of the barrier of the stratum corneum, and is applicable as a drug for the effective suppression of itching regardless of etiology.

In skin diseases accompanied by itching, especially in atopic dermatitis and similar diseases, followed by skin damage, develops the destruction of the barrier of the stratum corneum or hypersensitivity h is Stateline nerves compared with healthy skin, and the skin is recognized as sensitive to irritation. When such diseases accompanied by itching, apply outside medicine, it is necessary that this drug has had a particularly weak skin irritation. However, when the external drug for a patient with atopic dermatitis use derivatives hintline described in patent document 1, which contain guanidinium in the side chain in position 4 chineselanguage skeleton, there is the likelihood of skin irritation.

Patent document 1: WO 03/091224.

Patent document 2: JP-A-2002-138052.

Patent document 3: JP-A-2003-201250.

Patent document 4: JP-A-2004-107209.

Patent document 5: JP-A-2005-047909.

Patent document 6: JP-A-2005-139194.

Non-patent document 1: J. Am. Chem. Soc., 1975, 97, 2512.

Non-patent document 2: J. Am. Chem. Soc., 1942, 64, 1827.

Non-patent document 3: J. Org. Chem., 1942, 432.

Non-patent document 4: J. Chem. Soc. Perkin Trans 2, 2000, 1435.

Non-patent document 5: J. Med. Chem., 1997, 40, 2363.

DISCLOSURE of INVENTION

Objectives of the invention

The aim of the present invention is, primarily, a new derived hintline less irritating to the skin and excellent strong suppression behavior of scratching and anti-itching agent containing such a derivative hintline as active in the of radiant.

Ways to solve these problems,

The inventors have conducted intensive studies and found that described the derived hintline, which is a new compound and its pharmaceutically acceptable salt can meet the above objectives, and thus was accomplished the present invention.

The present invention relates to a derivative of hintline represented by the following General formula [1]or its pharmaceutically acceptable salts (hereinafter referred to as “compound of the invention”).

Chemical part 2

R1represents hydrogen or alkyl;

R2represents hydrogen, alkoxy, tetrahydropyranyl, phenyl, cycloalkyl, (cycloalkyl)alkyl or alkyl. Alkoxy, tetrahydropyranyl, phenyl, cycloalkyl, (cycloalkyl)alkyl and the alkyl can be substituted one to three groups selected from the group consisting of (1) alkoxy, (2) halogen, (3) alkoxyalkyl, (4) hydroxy, (5) alkylthio, (6) 5-10-membered aromatic heterocyclic group containing one to three heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, (7) 5-7-membered saturated aliphatic heterocyclic group which may be substituted by acyl and contains one to three nitrogen atom, and (8) phenyl, which can be zames the n halogen or alkoxy;

R3and R4are the same or different and each represents hydrogen, alkyl, alkoxy or halogen.

R5combine with R6that is alkylene, or R5represents hydrogen, hydroxy, alkyl, phenyl or alkoxy. Alkylene may be substituted by hydroxy or oxo, and may be condensed with a benzene cycle. Alkyl, phenyl and alkoxy represented by R5can be substituted by one to three groups selected from the group consisting of alkoxy, alkylthio and halogen;

R6represents (1) alkyl, (2) cycloalkyl, (3) phenyl, (4) 5-10-membered aromatic heterocyclic group containing one to three heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, or (5) -N(R61)(R62). Alkyl, cycloalkyl, phenyl and aromatic heterocyclic group may be substituted by one to three groups selected from the group consisting of (1) alkoxy, (2) hydroxy, (3) phenyl, (4) pyridyl, (5) furil, (6) halogen, and (7) N,N-dialkylamino. R61combine with R62that represents-O-(CH2)n-, or R61represents hydrogen or alkyl. R62represents hydrogen or alkoxy which may be substituted by one to three groups selected from the group consisting of alkoxy, alkylthio and halogen. In this case, n is equal to a is a number from 3 to 5.

The exception is the compound in which R5represents hydrogen, and R6represents-NH2.

Preferred compounds in the present invention can be, as examples, the following derivatives of hintline (1)to(29) and their pharmaceutically acceptable salts.

(1) 4-{[(1S,2R)-2-(Econimically)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamid,

(2) N-(2,2-Dimethylpropyl)-4-({(1S,2R)-2-[(2-methoxy-2-methylpropanoyl)amino]cyclohexyl]amino}-6-methylpyrazole-2-carboxamid,

(3) 4-({(1S,2R)-2-[(3-Methoxypropanol)amino]cyclohexyl}amino)-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamid,

(4) 4-({(1S,2R)-2-[(3-Hydroxypropylamino)amino]cyclohexyl}amino)-N-isopropyl-6-methylpyrazole-2-carboxamid,

(5) 4-({(1S,2R)-2-[(3-Hydroxypropylamino)amino]cyclohexyl}amino)-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamid,

(6) 4-({(1S,2R)-2-[(2-Hydroxy-2-methylpropanamide)amino]cyclohexyl}amino)-N-isobutyl-6-methylpyrazole-2-carboxamid,

(7) N-(2-Ethoxyethyl)-4-({(1S,2R)-2-[(3-hydroxypropylamino)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamid,

(8) 4-({(1S,2R)-2-[(2-Hydroxy-2-methylpropanamide)amino]cyclohexyl}amino)-N-isopropyl-6-methylpyrazole-2-carboxamid,

(9) 4-({(1S,2R)-2-[(2-Hydroxy-2-methylpropanamide)amino]cyclohexyl}amino)-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamid,

(10) 4-({(1S,2R)-2-[(2-Methoxyethoxymethyl)amino]cyclohexyl}amino)-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamid,

(11) 4-{[(1S,2R)-2-(Econimically)cyclohexyl]amino}-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamid,

(12) 4-({(1S,2R)-2-[(2-Methoxyethoxymethyl)amino]cyclohexyl}amino)-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamid,

(13) 4-{[(1S,2R)-2-(Econimically)cyclohexyl]amino}-N-(2-ethoxyethyl)-6-methylpyrazole-2-carboxamid,

(14) N-(2-Ethoxyethyl)-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamid,

(15) 4-{[(1S,2R)-2-(Econimically)cyclohexyl]amino}-N-isopropyl-6-methylpyrazole-2-carboxamid,

(16) 4-[((1S,2R)-2-{[Amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamid,

(17) 4-[((1S,2R)-2-{[Amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamid,

(18) 4-[((1S,2R)-2-{[Amino(hydroxyimino)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamid,

(19) 4-[((1S,2R)-2-{[Amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(cyclopropylmethyl)-6-methylpyrazole-2-carboxamid,

(20) 4-[((1S,2R)-2-{[Amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-isopropyl-6-methylpyrazole-2-carboxamid,

(21) 4-{[(1S,2R)-2-({Imino[methoxy(methyl)amino]methyl}amino)cyclohexyl]amino}-N-isobutyl-6-methylpyrazole-2-carboxamid,

(22) 4-[((1S,2R)-2-{[the Mino(methoxyimino)methyl]amino}cyclohexyl)amino)-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamid,

(23) 4-[((1S,2R)-2-{[Amino(hydroxyimino)methyl]amino}cyclohexyl)amino]-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamid,

(24) 4-[((1S,2R)-2-{[Amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-ethoxyethyl)-6-methylpyrazole-2-carboxamid,

(25) 4-[((1S,2R)-2-{[Amino(amoxiillin)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamid,

(26) 4-{[(1S,2R)-2-({Amino[(2-methoxyethoxy)imino]methyl}amino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamid,

(27) 4-{[(1S,2R)-2-({Amino[(2-floratone)imino]methyl}amino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamid,

(28) 4-({(1S,2R)-2-[(Amino{[2-(methylthio)ethoxy]imino}methyl)amino)cyclohexyl}amino)-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamid,

(29) 4-[((1S,2R)-2-{[Amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide.

In addition, the present invention also relates to pharmaceutical compositions containing the compound according to the invention as an active ingredient, for example a pharmaceutical composition for suppressing itching containing compound according to the invention as an active ingredient.

Hereinafter the present invention will be described in more detail.

Examples of “alkyl” include linear or branched alkyl with 1-10 carbon atoms, and specific examples may include m is Teal, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, n-nonyl and n-decyl. Preferred alkyl with 1-8 carbon atoms, and more preferred alkyl with 1-6 carbon atoms.

Examples of alkyl groups in the alkoxy”, “(cycloalkyl)alkyl”, “alkoxyalkyl”, “alkylthio” and “N,N-dialkylamino” may include the same alkyl, examples of which are described above.

Examples of “tetrahydropyranyl” may include 2-tetrahydropyranyl, 3-tetrahydropyranyl and 4-tetrahydropyranyl.

Examples of “cycloalkyl” may include cyclic alkyl with 3 to 10 carbon atoms, which is monocyclic-tricyclic, and specific examples may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecane, substituted (1-substituted, 2-substituted, and the like), 2-bicyclo[3.1.1]heptyl and 2-bicyclo[2.2.1]heptyl. It is preferable cyclic alkyl with 4 to 9 carbon atoms, and more preferred is a cyclic alkyl with 5 to 8 carbon atoms.

Examples cycloalkyl group “(cycloalkyl)alkyl” may include the same cycloalkyl, examples of which are described above.

Examples of “halogen” may include fluorine, chlorine, bromine and iodine.

Examples of the “aromatic heterocyclic group” may include a 5-10 is certain aromatic heterocyclic group, containing one to three heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, and specific examples may include pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (2-pyrazinyl etc.), pyridazinyl (3-pyridazinyl, 4-pyridazinyl), pyrrolyl (2-pyrrolyl etc.), furyl (2-furyl, 3-furyl), thienyl (2-thienyl, 3-thienyl), imidazolyl (1-imidazolyl, 4-imidazolyl etc.), pyrazolyl (3-pyrazolyl, 5-pyrazolyl etc), oxazolyl (4-oxazolyl, 5-oxazolyl etc.), thiazolyl (1,3-thiazol-2-yl, 1,3-thiazol-5-yl and the like), isoxazolyl (isoxazol-4-yl, isoxazol-5-yl and the like) and 1,3,4-thiadiazole-2-yl.

Examples of “acyl” may include acyl with 1 to 11 carbon atoms, and specific examples may include formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl, 1-naphtol and 2-naphtol.

Examples of saturated aliphatic heterocyclic group” may include a 5-7 membered saturated aliphatic heterocyclic group, containing one to three nitrogen atom, and specific examples may include pyrrolidinyl (1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidinyl (1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), piperazinil (1-piperazinil, 2-piperazinil), homopiperazine (1-homopiperazine, 2-homopiperazin, 3-homopiperazine, 6-homopiperazine), morpholinyl (2-Mor) - Rev. oliner, 3-morpholinyl, 4-morpholinyl) and thiomorpholine (2-thiomorpholine, 3-thiomorpholine, 4-thiomorpholine).

Examples of “pyridyl” may include 2-pyridyl, 3-pyridyl and 4-pyridyl.

Examples of Shrila” may include 2-furyl and 3-furyl.

Examples of “alkylene” can include linear or branched alkylene with 1-6 carbon atoms, and specific examples may include methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene. Among them, preferred is alkylene with 2-5 carbon atoms, and more preferred is alkylene with 3-5 carbon atoms.

Examples of “itch” can include itching that accompanies atopic dermatitis, urticaria, psoriasis, xeroderma, tinea, vitiligo, local skin itching caused by excretion or secretion of an insect, nodular prurigo, hemodialysis, diabetes, blood diseases, cholestatic liver injury (primary billiary cirrhosis of the liver), liver disease, kidney disease, endocrine disorders and metabolic disorders, visceral malignancy, gipertireoidizmom, autoimmune diseases, multiple sclerosis, neurological diseases, psychoneurosis, allergic conjunctivitis, spring catarrh, atopic keratoconjunctivitis, or excessive use of certain medicinal products or with whom edst.

The best way of carrying out the invention

Chemical part 3

The connection according to the invention [1] can be obtained according to, for example, described the way from known compounds or intermediate compounds, which can be easily synthesized. When the connection according to the invention [1] when the starting material contains a Deputy, which affects the interaction, the General position is that the interaction is carried out after the original substance will enter an appropriate protective group by a method known in the art. It is clear that after the interaction the protective group is removed in a known manner.

The method of obtaining 1

The connection according to the invention [1] can be obtained according to, for example, the following pattern of interaction.

The chemical part 4

In the above formulas, R1-R6have the values specified above. L represents a group to delete (for example, alkoxy, halogen, pyrazole-1-yl or methylthio).

The connection according to the invention [1] can be obtained by the interaction of the compound [2] with one equivalent or an excess amount of compound [3] in a solvent, such as solvent-based alcohol such as methanol or ethanol, the solvent-based hydrocarbon such as benzene is whether toluene, the solvent on the basis of simple ether, such as dioxane or tetrahydrofuran, halogenated solvents such as chloroform or 1,2-dichloroethane, dimethylformamide or similar solvent, in the presence of a base such as triethylamine or N,N-diisopropylethylamine, or without, at a temperature from 0 ° C to the boiling point of the used solvent for from a few hours to several days. Preferably, the interaction was carried out in the presence of triethylamine using ethoxypropan as the deleted group L of the compound [3] and ethanol as solvent at 80 ° C for 1-48 hours.

Connection [2], which is the starting compound, can be obtained in a known manner (see, for example, patent document 1).

Connection [3], which is the starting compound, commercially available, but it can also be obtained in a known manner (see, for example, non-patent documents 1 and 2).

The method of obtaining 2

The connection according to the invention [1A], in which R5represents alkoxy, R6represents-N(R61)(R62), and R61and R62both represent hydrogen, can also be obtained according to the scheme of interaction below.

The chemical part 5

In the above formulas, R1- R4who have values, above. R51represents alkoxy which may be substituted by one to three groups selected from the group consisting of alkoxy, alkylthio and halogen.

The method of obtaining 3

The connection according to the invention [1b]in which R5represents hydrogen, and R6represents-N(R61)(R62), can also be obtained according to the scheme of interaction below.

The chemical part 6

In the above formulas, R1- R4, R61and R62have the values specified above.

The connection according to the invention [1A] or [1b] can be obtained by the interaction of the compound [4] with one equivalent or an excessive number of connections [5] or [6] in a solvent, such as solvent-based alcohol such as methanol or ethanol, the solvent-based hydrocarbon such as benzene or toluene, the solvent on the basis of simple ether, such as dioxane or tetrahydrofuran, halogenated solvents such as chloroform or 1,2-dichloroethane, dimethylformamide or similar solvent, in the presence of inorganic bases such as sodium carbonate or potassium carbonate, or organic base, such as triethylamine or N,N-diisopropylethylamine, or without, at a temperature from 0 ° C to the boiling point of the solvent used is within a few hours to several days. Preferably, the interaction was carried out in the presence of sodium carbonate with ethanol or dioxane as solvent at 50 º C-80 ° C for 1-24 hours.

Connection [4], which is the starting compound, can be obtained according to the scheme of interaction below.

Chemical part 7

In the above formulas, R1- R4have the values specified above.

Compound [4] can be obtained by the interaction of the compound [2] with one equivalent or an excessive amount of Enrichment in a solvent, such as solvent-based hydrocarbon such as benzene or toluene, the solvent on the basis of simple ether, such as dioxane or tetrahydrofuran, halogenated solvents such as chloroform or 1,2-dichloroethane, dimethylformamide or similar solvent, in the presence of inorganic bases such as sodium carbonate or potassium carbonate, or organic bases such as triethylamine or N,N-diisopropylethylamine, at temperatures from-78º to the boiling point of the used solvent for from several minutes to several days. Preferably, the interaction was carried out in the presence of triethylamine using tetrahydrofuran as solvent at 50 º C-0 ° C for 10 mine is - 1 hour.

In addition, compound [4], which is the starting compound, can also be obtained according to the scheme of interaction below.

Chemical part 8

The compound [7] can be obtained by the interaction of the compound [2] with one equivalent or an excess amount of potassium cyanate in a solvent, such as water, solvent-based alcohol such as methanol or ethanol or similar solvent, in the presence of acid, such as chloromethane acid or sulfuric acid, or without it, or bases, such as triethylamine, N,N-diisopropylethylamine, sodium hydroxide or potassium hydroxide, at temperatures from 0 ° C to the boiling point of the used solvent for from a few hours to several days. Preferably, the interaction was carried out in the presence of triethylamine using aqueous ethanol as solvent at 50 º C-100ºC for 1 hour - 5 hours. Compound [4] can be obtained by the interaction of the compounds [7] methanesulfonanilide in pyridine at-10ºC-50ºC for 30 minutes to 5 hours.

Compounds [5] and [6], which are the starting compounds are commercially available, but they can also be obtained in a known manner (see, for example, non-patent documents 3-5).

Derived hintline this izobreteny which can be used as pharmaceutical agents in the form of the free base or you can use turning to the form of pharmaceutically acceptable salts in a known manner. Examples of such salts include salts with inorganic acids such as chloromethane acid, Hydrobromic acid, sulfuric acid or phosphoric acid, and salts with organic acids such as acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluensulfonate acid, benzolsulfonat acid or methansulfonate acid, etc.

For example, the hydrochloride salt of the derivative hintline of the present invention can be obtained by dissolving the derivative hintline of the present invention in a suitable solvent and adding thereto an alcohol solution, a solution in ethyl acetate or ether chloride, followed by concentration to dryness.

Some compounds among the compounds according to the invention [1] may contain an asymmetric carbon atom, and all optical isomers and their mixtures of such compounds are also included in the scope of the present invention. Such optical isomers can be obtained, for example, based on the racemate obtained as described above using its basicity, and using optically active acids (tartaric acid, dibenzoyltartaric acid, almond acid, 10-camphorsulfonic acid or similar acid), known SPO is obom optical splitting, or using a pre-obtained optically active compounds as source materials. In addition, the optical isomers can also be obtained by the optical splitting or asymmetric synthesis using chiral columns.

In addition, among the compounds according to the invention [1] there are also compounds that may exist in the CIS-form, TRANS-form, Z-form or S-form, and each of these isomers and their mixtures are also included in the scope of the present invention.

When the connection according to the invention is administered as a pharmaceutical drug, the connection according to the invention is administered to mammals, including people, in the form in which it is, or pharmaceutically acceptable non-toxic inert carrier, for example, in the form of a pharmaceutical composition containing the compound according to the invention in amounts of 0.001%-99,5%, preferably of 0.1%-90%.

As a carrier you can use one or several types of assistive devices for compositions, such as solid, semi-solid or liquid diluents, fillers and other auxiliary tools for drug. Preferably, the pharmaceutical composition of the present invention was administered in a standard dosage form. Introduction the pharmaceutical composition can be accomplished by introducing into tissue, oral introduction the m intravenous injection, local administration (transdermal introduction, instillation, or similar), or rectal administration. It is clear that use dosage form, suitable for the respective paths of these routes of administration. For example, preferably oral administration or local administration (transdermal introduction or instillation).

Although it is preferable that the dose in the form of antipruritic tools were selected depending on the condition of the patient, such as age, body weight, the nature and extent of the disease, as well as the method of administration, the daily dose of the compounds according to the invention as an active ingredient for an adult, as a rule, is in the range of 0.1 mg to 5 g per adult, preferably from 1 mg to 500 mg per adult in the case of oral administration. In the case of transdermal dose is in the range of 0.001%-5%, preferably from 0.01% to 0.1%. In the case of instillation dose is in the range from 0.0001% to 0.5%, preferably from 0.001% to 0.01%. In some cases, sufficient can be a smaller dose, or you may need a higher dose. Typically, the dose given once a day, or it can be given intravenously and periodically within 1-24 hours.

Oral administration can be made in solid or liquid dosage form, such as bulk powder, the powder, ablate, a drug with a sugar coating, capsule, granule, suspension, liquid, syrup, drops, sublingual tablet, suppository, or other dosage forms. Bulk powder is obtained by grinding the active ingredient to a suitable size. The powder obtained by grinding the active ingredient to the appropriate size, followed by mixing with a pharmaceutical carrier such as an edible carbohydrate, including, starch or mannitol, which is crushed in a similar manner to a suitable size. If necessary, the powder can be mixed with corrigent, preservative, dispersing agent, a dye, a fragrance or other additives.

Capsule get, volumetric filling powder or powder, which is previously obtained as described above, or granules obtained as described in the section “the Pill”, for example, a capsule shell, such as a gelatin capsule. It is also possible to carry out this operation of filling after mixing lubricants, fluidizing agent, such as colloidal silicon dioxide, talc, magnesium stearate, calcium stearate or solid polyethylene glycol, with material in powder form. If you add a substance that promotes dispersal, or a solubilizer, such as carboxymethylcellulose, calcixerollic, hydroxypropylcellulose with a low from what epent replacement nitrocresols, natrocarbonatite, calcium carbonate or sodium carbonate, the effectiveness of a pharmaceutical product enclosed within the capsule may increase.

Fine powder of the compounds according to the invention can be suspended and dispersing in vegetable oil, polyethylene glycol, glycerin or a surface-active substance and then be encapsulated in a gelatin shell, and through that get a soft capsule. Tablets get treating powdery mixture, turning it into granules or lumps, adding thereto a substance that promotes dispersal, or grease and then extruding the mixture into tablets. A powder mixture is produced by mixing appropriately crushed material with a diluent or base as described above, and, if necessary, the mixture can also be mixed with a binder (for example, sodium carboxymethyl cellulose, hydroxypropylcellulose, methylcellulose, hypromellose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, or a similar substance), moderator of dissolution (for example, paraffin, wax, gidrirovanny castor oil or similar substance), the promoter of suction (e.g., Quaternary salt) or adsorbent (for example, bentonite, kaolin, calcium diphosphate, or like what execcom). Powdery mixture can be pelletized, moistening her binder such as syrup, starch glue, Arabian gum, a solution of cellulose or polymer solution, and then forcibly flowing the mixture through a sieve. Instead of granulating the powder described above can be subjected to the first pelletizing for tablet press machine and not get completely decorated ball, which is then crushed and receive granules. It is possible to prevent the sticking of the thus obtained granules by adding a lubricating substance such as stearic acid, stearate, talc or mineral oil or similar. The mixture is then greased thus pressed into tablets. On a flat tablet, thus obtained, can be applied film coating or sugar coating.

In addition, the connection according to the invention can also be pressed into tablets directly after mixing it with fluidized inert carrier, without granulation process or clumping described above. You can also use transparent or semi-transparent protective film obtained from shellac, a film obtained from sugar or polymeric material, and glossy film obtained from the wax.

Other oral dosage forms such as solution, syrup and elixir, also available in standard Lekarstvo the th form so to a certain amount of the drug contained a certain number of compounds according to the invention. The syrup obtained by dissolution of the compounds according to the invention in a suitable aqueous solution with the addition of corrigenda, while the elixir receive, using non-toxic alcoholic media. Suspension get dispersive compounds according to the invention in a non-toxic carrier. If necessary, you can also add a solubilizer, emulsifier (for example, ethoxylated isostearoyl alcohol or ester of polyoxyethylenesorbitan), preservative, corrigent (for example, peppermint oil or saccharin) or any other Supplement.

Standard dosage form for oral administration, if necessary, can also provide a microcapsule. This form may be coated or encapsulated in a polymer, wax or similar material, to achieve prolonged action or delayed release.

Rectal administration can be accomplished with the use of suppositories, which is obtained by mixing the compounds according to the invention with water-soluble or water-insoluble, solid substance with a low melting point such as polyethylene glycol, cacao butter, esters of higher acids (for example, ministervalletta) and their mixture.

Introduction to tissue can be performed using idlestate dosage forms, for example in the form of a solution or suspension, as preparation for subcutaneous, intramuscular, injection into the bladder or by intravenous injection. Any of these drugs can be obtained by suspendirovanie or dissolution of a certain number of compounds according to the invention in a non-toxic liquid carrier suitable for the purposes of injection, such as water or an oil medium, followed by sterilization of the resulting suspension or solution. On the other hand, a certain number of compounds according to the invention can be placed into the vial, which is then sterilized together with its contents and then hermetically closed. Auxiliary bottle and carrier can be provided in combination with a powdered or liofilizovane the active ingredient for the purpose of dissolving or mixing just before the introduction. You can add non-toxic salt or salt solution for the purpose of giving isotonicity of the solution for injection. You can also use stabilizer, preservative, emulsifier, or similar substances in combination.

Transdermal introduction you can make solid or liquid standard dosage form, such as aerosol, liquid, suspension, emulsion, adhesive preparation, ointment, poultice, liniment, lotion, or other dosage form.

Ointment get, for example, mixing is rubbing a certain number of compounds according to the invention with a pharmaceutically acceptable solid Foundation suitable for ointment, for example a water-soluble base or lipitorhistory the basis described in the Pharmacopoeia of Japan. You can also use additives such as a stabilizer, a preservative, an emulsifier or suspendisse substance.

The instillation is possible to carry out standard liquid dosage form, for example the form of a solution or suspension. Any of these drugs can be obtained by suspending or dissolving a certain amount of compounds according to the invention in a non-toxic liquid carrier suitable for instillation, such as water or an oil medium, followed by sterilization of the resulting suspension or solution. On the other hand, a certain number of compounds according to the invention can be placed into the vial, which is then sterilized together with its contents and then hermetically closed. Auxiliary bottle and carrier can be provided in combination with a powdered or liofilizovane the active ingredient for the purpose of dissolving or mixing just before the introduction. You can add pharmaceutically acceptable salt or a salt solution for the purpose of giving isotonicity of eye drops. You can also use stabilizer, preservative, emulsifier, or similar substances in combination.

EXAMPLES

Hereinafter the present invention will be described in podrobnee reference to reference examples, examples, examples, test examples and preparations. However, the invention is not limited to the given examples.

Reference example 1

4-{[(1S,2R)-2-Aminocyclohexanol]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Stage 1. tert-Butyl{(1S,2R)-2-[(2-{[(2-methoxyethyl)amino]carbonyl}-6-methylpyrazole-4-yl)amino]cyclohexyl}carbamate

To a suspension of 15.0 g of ethyl-4-({(1S,2R)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxylate in 15 ml of methanol add 7,89 g of 2-methoxyethylamine and the mixture was stirred at 50 º C for 15 hours. After cooling the reaction solution to room temperature, added 45 ml of diisopropyl ether and the mixture was stirred at 0OC for 30 minutes. Precipitated precipitated crystalline substance is collected by filtration, washed with diisopropyl ether and dried under reduced pressure, whereby obtain 12.2 g of the desired compound as a white powder.

Stage 2. 4-{[(1S,2R)-2-Aminocyclohexanol]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

To a suspension of 2.24 g of tert-butyl{(1S,2R)-2-[(2-{[(2-methoxyethyl)amino]carbonyl}-6-methylpyrazole-4-yl)amino]cyclohexyl}carbamate in 10 ml of ethyl acetate, add 10 ml of 4 n solution of hydrogen chloride in ethyl acetate and the mixture is stirred at room temperature for 48 hours. To the reaction solution to relax the Ute 20 ml diethyl ether and the mixture is stirred for 30 minutes. Then precipitated precipitated substance is collected by filtration, washed with diethyl ether and dried under reduced pressure. The resulting powder was purified column chromatography on silica gel Fuji Silysia NH (chloroform: methanol = 20:1), whereby gain of 1.61 g of the desired compound as a colorless powder.

EXAMPLE 1

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Stage 1. 4-{[(1S,2R)-2-(Econimically)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

To a solution of 450 mg of 4-{[(1S,2R)-2-aminocyclohexanol]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide and 467 mg of the hydrochloride of ethylacetoacetate in 10 ml ethanol add 764 mg of triethylamine and the mixture is stirred at 80 ° C for 8 hours. Then the reaction solution is concentrated and the residue purified column chromatography on silica gel (chloroform: methanol = 20:1) and thereby receive 391 mg of the desired compound as pale yellow powder.

Stage 2. The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

To a solution of 391 mg of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide in 5 ml of ethyl acetate add 3 ml of 4 n solution of hydrogen chloride in ethyl acetate and the mixture paramashiva the t for 10 minutes. Then to the reaction solution was added 10 ml of diethyl ether and precipitated precipitated substance is collected by filtration, washed with diethyl ether and dried under reduced pressure, whereby obtain 405 mg of the desired compound as a white powder.

Elemental analysis data (for C21H30N6O2/2 HCl/2,5 H2O)

Calculated (%): 48,84; N - 7,22; N - 16,27.

Found (%): 48,69; N - 6,83; N - 16,04.

FAB-MC, positive ions, m/z: 399 [M+H]+.

Constant optical rotation [α]20D= +EUR 110.79 (c = 0,500, methanol).

In the same manner as in example 1, to obtain the following compound 2 - 207.

EXAMPLE 2

The dihydrochloride 6-chloro-N-cycloheptyl-4-[((1S,2R)-2-{[2-(2-furyl)ethanamide]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C28H35N6O2Cl/2 HCl/1,3 H2O)

Calculated (%): 54,29; N - 6,44; N - 13,57.

Found (%): 54,22; N - 6,37; N - 13,55.

FAB-MC, positive ions, m/z: 523 [M+H]+.

Constant optical rotation [α]20D= +108,73 (c = 0,504, methanol).

Appearance: pale pink powder.

EXAMPLE 3

Trihydrochloride 6-chloro-N-cycloheptyl-4-({(1S,2R)-2-[(2-pyridin-2-latanision)amino]cyclohexyl}amino)hinzelin-2-carboxamide

Elemental analysis data (for C29H36N7OCl/3 HCl/3,1 H2O)

In chileno (%): - 49,81; N - 6,52; N - 14,02.

Found (%): 49,81; N - 6,46; N - 13,80.

FAB-MC, positive ions, m/z: 534 [M+H]+.

Constant optical rotation [α]20D= +58,40 (c = of 0.565, methanol).

Appearance: pale brown powder.

EXAMPLE 4

The dihydrochloride of 4-{[(1S,2R)-2-(n-butanilicaine)cyclohexyl]amino}-6-chloro-N-cycloheptylmethyl-2-carboxamide

Elemental analysis data (for C26H37N6OCl/2 HCl/1,8 H2O)

Calculated (%): 52,89; N - 7,27; N - 14,23.

Found (Percent): C - 52,90; N - 7,22; N - 13,98.

FAB-MC, positive ions, m/z: 485 [M+H]+.

Constant optical rotation [α]20D= +93,61 (c = 0,517, methanol).

Appearance: white powder.

EXAMPLE 5

The dihydrochloride of N-(2-ethylbutyl)-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H38N6O2/2 HCl/0,9 H2O)

Calculated (%): 55,22; N To 7.75; N - 15,46.

Found (%): 55,21; H - 7,62; N - 15,44.

FAB-MC, positive ions, m/z: 387 [M+H]+.

Constant optical rotation [α]20D= +96,52 (c = 0,518, methanol).

Appearance: white powder.

EXAMPLE 6

The dihydrochloride of N-(2-ethylbutyl)-4-({(1S,2R)-2-[(3-methoxypropanol)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H40N 6O2/2 HCl/0,8 H2O)

Calculated (%): 56,17; N - Of 7.90; N - 15,12.

Found (%): 56,22; N - 7,84; N - 14,96.

FAB-MC, positive ions, m/z: 469 [M+H]+.

Constant optical rotation [α]20D= +94,93 (c = of 0.533, methanol).

Appearance: white powder.

EXAMPLE 7

The dihydrochloride of N-(3-methoxy-2,2-dimethylpropyl)-4-({(1S,2R)-2-[(3-methoxypropanol)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H40N6O3/2 HCl/0,8 H2O)

Calculated (%): 54,60; N - Of 7.68; N - 14,69.

Found (%): 54,63; N - To 7.59; N - 14,59.

FAB-MC, positive ions, m/z: 485 [M+H]+.

Constant optical rotation [α]20D= +84,57 (c = 0,525, methanol).

Appearance: white powder.

EXAMPLE 8

The dihydrochloride of N-(2,2-dimethylpropyl)-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 441 [M+H]+.

Constant optical rotation [α]20D= +98,12 (c = 0,534, methanol).

Appearance: white powder.

EXAMPLE 9

The dihydrochloride of N-(2,2-dimethylpropyl)-4-[((1S,2R)-2-{[2-(2-furyl)ethanamide]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 477 [M+H]+.

Constant optical rotation [α]20D= +89,57 (c = 0,547, methanol).

External the appearance: red-brown powder.

EXAMPLE 10

The dihydrochloride of N-(2,2-dimethylpropyl)-4-({(1S,2R)-2-[(3-methoxypropanol)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H38N6O2/2 HCl/0,9 H2O)

Calculated (%): 55,22; N To 7.75; N - 15,46.

Found (%): 55,28; N - 7,52; N - Br15.15.

FAB-MC, positive ions, m/z: 455 [M+H]+.

Constant optical rotation [α]20D= +87,07 (c = 0,526, methanol).

Appearance: white powder.

EXAMPLE 11

Trihydrochloride 4-[((1S,2R)-2-{[3-(dimethylamino)propanamide]amino}cyclohexyl)amino]-N-(2,2-dimethylpropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H41N7O/3 HCl/1,8 H2O)

Calculated (%): 51,24; N - 7,87; N - 16,09.

Found (%): 51,48; N - 7,49; N - 15,68.

FAB-MC, positive ions, m/z: 468 [M+H]+.

Constant optical rotation [α]20D= +57,14 (c = 0,469, methanol).

Appearance: white powder.

EXAMPLE 12

The dihydrochloride of 4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methyl-N-(2,2,2-triptorelin)hinzelin-2-carboxamide

FAB-MC, positive ions, m/z: 453 [M+H]+.

Constant optical rotation [α]20D= +116,73 (c = 0,514, methanol).

Appearance: pale brownish-white powder.

EXAMPLE 13

The dihydrochloride of N-(TRANS-4-methoxycyclohexyl the l)-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H38N6O3/2 HCl/1,8 H2O)

Calculated (%): 53,11; N - 7,47; N - 14,29.

Found (%): 53,24; N - 7,41; N - 13,92.

FAB-MC, positive ions, m/z: 483 [M+H]+.

Constant optical rotation [α]20D= +105,05 (c = 0,495, methanol).

Appearance: white powder.

EXAMPLE 14

The dihydrochloride of N-(2,2-dimethylpropyl)-6-fluoro-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)hinzelin-2-carboxamide

FAB-MC, positive ions, m/z: 445 [M+H]+.

Constant optical rotation [α]20D= +63,03 (c = 0,514, methanol).

Appearance: white powder.

EXAMPLE 15

The dihydrochloride of N-(2,2-dimethylpropyl)-4-({(1S,2R)-2-[(2-ethoxyethanol)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 455 [M+H]+.

Constant optical rotation [α]20D= +92,51 (c = 0,521, methanol).

Appearance: white powder.

EXAMPLE 16

The dihydrochloride of N-(2,2-dimethylpropyl)-4-({(1S,2R)-2-[(2-ethoxyethanol)amino]cyclohexyl}amino)-6-florinopolis-2-carboxamide

Elemental analysis data (for C24H35N6O2F/2 HCl/0,9 H2O)

Calculated (%): 52,63; N - 7,14; N - 15,34.

Found (%): 52,76; N - 7,15; N - 15,25.

FAB-MC, positive ions, m/z: 459 [M+H]+.

Constant optical rotation [α]20 D= +55,25 (c = 0,514, methanol).

Appearance: white powder.

EXAMPLE 17

The dihydrochloride of N-(2-ethylbutyl)-6-fluoro-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)hinzelin-2-carboxamide

Elemental analysis data (for C24H35N6O2F/2 HCl/ H2O)

Calculated (%): 52,46; N - 7,15; N - 15,29.

Found (Percent): C - 52,65; N - 7,10; N - 15,21.

FAB-MC, positive ions, m/z: 459 [M+H]+.

Constant optical rotation [α]20D= +59,34 (c = 0,492, methanol).

Appearance: white powder.

EXAMPLE 18

The dihydrochloride 6-fluoro-N-(3-methoxy-2,2-dimethylpropyl)-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)hinzelin-2-carboxamide

FAB-MC, positive ions, m/z: 475 [M+H]+.

Constant optical rotation [α]20D= +54,82 (c = 0,518, methanol).

Appearance: white powder.

EXAMPLE 19

The dihydrochloride of N-(2,2-dimethylpropyl)-4-({(1S,2R)-2-[(2-methoxy-2-methylpropanoyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H40N6O2/2 HCl/0,9 H2O)

Calculated (%): 55,99; N - A 7.92; N - 15,07.

Found (%): 55,94; N - 7,81; N - 15,07.

FAB-MC, positive ions, m/z: 469 [M+H]+.

Constant optical rotation [α]20D= +5,49 (c = 0,510, methanol).

Appearance: white powder.

EXAMPLE 20

The dihydrochloride 6-fluoro-N-isobutyl-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)hinzelin-2-carboxamide

Elemental analysis data (for C22H31N6O2F/2 HCl/1,1 H2O)

Calculated (%): 50,50; N Is 6.78; N - 16,06.

Found (%): 50,48; N - 6,69; N - 16,03.

FAB-MC, positive ions, m/z: 431 [M+H]+.

Constant optical rotation [α]20D= +66,42 (c = 0,557, methanol).

Appearance: white powder.

EXAMPLE 21

The dihydrochloride of N-[(1-hydroxycyclohexyl)methyl]-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H38N6O3/2 HCl/2,1 H2O)

Calculated (%): 52,63; N - 7,51; N - 14,16.

Found (Percent): C - 52,57; N - 7,12; N - 14,15.

FAB-MC, positive ions, m/z: 483 [M+H]+.

Constant optical rotation [α]20D= +98,10 (c = 0,581, methanol).

Appearance: white powder.

EXAMPLE 22

The dihydrochloride of 4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-N-[2-methoxy-1-(methoxymethyl)-1-methylethyl]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H38N6O4/2 HCl/1,8 H2O)

Calculated (%): 50,73; N - 7,42; N - 14,20.

Found (%): 50,84; N - 7,17; N - Of 14.46.

FAB-MC, positive ions, m/z: 487 [M+H]+.

Constant optical rotation is [α] 20D= +99,62 (c = 0,532, methanol).

Appearance: white powder.

EXAMPLE 23

The dihydrochloride of 4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-N-(2-methoxy-2-methylpropyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 457 [M+H]+.

Constant optical rotation [α]20D= +99,99 (c = 0,542, methanol).

Appearance: white powder.

EXAMPLE 24

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(2-methoxy-2-methylpropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H34N6O2/2 HCl/3 H2O)

Calculated (%): 49,91; N - The 7.65; N - 15,18.

Found (%): 49,94; N - 7,49; N - 15,09.

FAB-MC, positive ions, m/z: 427 [M+H]+.

Constant optical rotation [α]20D= +94,18 (c = 0,516, methanol).

Appearance: white powder.

EXAMPLE 25

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(2-hydroxy-2-methylpropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C22H32N6O2/2 HCl/3,4 H2O)

Calculated (%): 48,33; N - 7,52; N - Shed 15.37.

Found (%): 48,27; N - 7,22; N - 15,26.

FAB-MC, positive ions, m/z: 413 [M+H]+.

Constant optical rotation [α]20D= +92,24 (c = 0,529, methanol).

Appearance: white powder.

EXAMPLE 26

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-[(1-hydroxycyclohexyl)methyl]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H36N6O2/2 HCl/2 H2O)

Calculated (%): 52,63; N - 7,60; N - 14,73.

Found (%): 52,45; N - 7,41; N - 14,83.

FAB-MC, positive ions, m/z: 453 [M+H]+.

Constant optical rotation [α]20D= +84,35 (c = 0,569, methanol).

Appearance: white powder.

EXAMPLE 27

The dihydrochloride of 4-({(1S,2R)-2-[(2-methoxy-2-methylpropanoyl)amino]cyclohexyl}amino)-N-(2-methoxy-2-methylpropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H40N6O3/2 HCl/ H2O)

Calculated (%): 54,26; N - 7,71; N - 14,60.

Found (%): 54,38; N - 7,46; N - 14.24 From.

FAB-MC, positive ions, m/z: 485 [M+H]+.

Constant optical rotation [α]20D= +5,61 (c = 0,534, methanol).

Appearance: white powder.

EXAMPLE 28

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-[2-methoxy-1-(methoxymethyl)ethyl]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H34N6O3/2 HCl/2,1 H2O)

Calculated (%): 49,93; N - 7,32; N - 15,19.

Found (Percent): C - 49,95; N - 7,19; N - 14,96.

FAB-MC, positive ions, m/z: 443 [M+H]+.

Constant optical rotation [α]20the D= +106,37 (c = 0,549, methanol).

Appearance: white powder.

EXAMPLE 29

The dihydrochloride of 4-[((1S,2R)-2-{[3-(dimethylamino)propanamide]amino}cyclohexyl)amino]-N-(2-methoxy-2-methylpropyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 484 [M+H]+.

Constant optical rotation [α]20D= +61,43 (c = 0,599, methanol).

Appearance: white powder.

EXAMPLE 30

The dihydrochloride of 4-({(1S,2R)-2-[(2-methoxy-2-methylpropanoyl)amino]cyclohexyl}amino)-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H38N6O3/2 HCl/ H2O)

Calculated (%): 53.47 USD; N - Rate Of 7.54; N - 14,97.

Found (Percent): C - 53,52; N - 7,24; N - 14,92.

FAB-MC, positive ions, m/z: 471 [M+H]+.

Constant optical rotation [α]20D= +9,52 (c = 0,588, methanol).

Appearance: white powder.

EXAMPLE 31

The dihydrochloride of N-(2-methoxy-2-methylpropyl)-4-({(1S,2R)-2-[(3-methoxypropanol)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H38N6O3/2 HCl/3,3 H2O)

Calculated (Percent): C - 49, 80mm; N - 7,79; N - 13,94.

Found (%): 49,48; N - 7,37; N - Of 13.75.

FAB-MC, positive ions, m/z: 471 [M+H]+.

Constant optical rotation [α]20D= +97,21 (c = 0,574, methanol).

Appearance: white powder.

EXAMPLE 32

The dihydrochloride of N-(2-methoxyethyl)-4-({(1S,2R)-2-[(2-methoxy-2-methylpropanoyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H36N6O3/2 HCl/2,3 H2O)

Calculated (%): 50,49; N - 7,52; N - 14,72.

Found (Percent): C - 50,59; N - Of 7.23; N - 14,78.

FAB-MC, positive ions, m/z: 457 [M+H]+.

Constant optical rotation [α]20D= +21,54 (c = 0,557, methanol).

Appearance: white powder.

EXAMPLE 33

The dihydrochloride of N-isobutyl-4-({(1S,2R)-2-[(2-methoxy-2-methylpropanoyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H38N6O2/2 HCl/2,3 H2O)

Calculated (%): 52,77; N - Of 7.90; N - 14,77.

Found (%): 52,74; N - 7,53; N - 14,79.

FAB-MC, positive ions, m/z: 455 [M+H]+.

Constant optical rotation [α]20D= +of 5.92 (c = 0,540, methanol).

Appearance: white powder.

EXAMPLE 34

The dihydrochloride of N-(2-methoxyethyl)-4-({(1S,2R)-2-[(3-methoxypropanol)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 443 [M+H]+.

Constant optical rotation [α]20D= +113,09 (c = 0,527, methanol).

Appearance: white powder.

EXAMPLE 35

The dihydrochloride of 4-({(1S,2R)-2-[(3-methoxypropanol)amino]Ziklag the KSIL}amino)-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 457 [M+H]+.

Constant optical rotation [α]20D= +107,53 (c = 0,571, methanol).

Appearance: white powder.

EXAMPLE 36

The dihydrochloride of N-ethyl-4-({(1S,2R)-2-[(3-methoxypropanol)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 413 [M+H]+.

Constant optical rotation [α]20D= +122,56 (c = 0,545, methanol).

Appearance: white powder.

EXAMPLE 37

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H30N6O2/2 HCl/1,5 H2O)

Calculated (%): 54,95; N - 6,46; N - 15,38.

Found (%): 54,26; N - 6,11; N - 15,31.

FAB-MC, positive ions, m/z: 447 [M+H]+.

Constant optical rotation [α]20D= +28,47 (c = 0,576, methanol).

Appearance: pale yellow powder.

EXAMPLE 38

The dihydrochloride of N-n-butyl-4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C22H32N6O/2 HCl/1,2 H2O)

Calculated (%): 53,81; N - 7,47; N - 17.11 Per Bbl.

Found (%): 53,80; N - 7,31; N - 17,22.

FAB-MC, positive ions, m/z: 397 [M+H]+.

Constant optical rotation [α]20D= +96,42 (c = 0,728, methanol).

nasni appearance: white powder.

EXAMPLE 39

The dihydrochloride of N-n-butyl-6-methyl-4-({(1S,2R)-2-[(2-methylpropanoyl)amino]cyclohexyl}amino)hinzelin-2-carboxamide

Elemental analysis data (for C24H36N6O/2 HCl/0,8 H2O)

Calculated (%): 56,31; N - 7,80; N - 16,42.

Found (Percent): C - 55,99; N - 7,37; N - 16,54.

FAB-MC, positive ions, m/z: 425 [M+H]+.

Constant optical rotation [α]20D= +1,20 (c = to 0.662, methanol).

Appearance: white powder.

EXAMPLE 40

The dihydrochloride of N-n-butyl-4-[((1S,2R)-2-{[cyclohexyl(imino)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C27H40N6O/2 HCl/1,2 H2O)

Calculated (%): 57,99; 8,00; N - 15,03.

Found (%): 58,02; N - 7,72; N - 15,14.

FAB-MC, positive ions, m/z: 465 [M+H]+.

Constant optical rotation [α]20D= +1,50 (c = 0,665, methanol).

Appearance: white powder.

EXAMPLE 41

The dihydrochloride of N-(4-methoxyphenyl)-6-methyl-4-({(1S,2R)-2-[(2-phenylalaninol)amino]cyclohexyl}amino)hinzelin-2-carboxamide

Elemental analysis data (for C31H34N6O2/2 HCl/0,8 H2O)

Calculated (Percent): C - 61,04; N - 6,21; N - 13,78.

Found (Percent): C - 61,07; 6,00; N - 13,89.

FAB-MC, positive ions, m/z: 523 [M+H]+.

Constant optical rotation [α]20D= +79,81 (c = 0,649, methanol).

<> Appearance: pale yellow powder.

EXAMPLE 42

The dihydrochloride of N-n-butyl-6-methyl-4-[((1S,2R)-2-{[N-phenylalaninol]amino}cyclohexyl)amino]hinzelin-2-carboxamide

FAB-MC, positive ions, m/z: 473 [M+H]+.

Appearance: white powder.

EXAMPLE 43

The dihydrochloride of N-(2,2-dimethylpropyl)-6-methyl-4-[((1S,2R)-2-{[N-methylaminomethyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C24H36N6O/2 HCl/0,8 H2O)

Calculated (%): 56,31; N - 7,80; N - 16,42.

Found (%): 56,44; N To 7.75; N - 16,21.

FAB-MC, positive ions, m/z: 425 [M+H]+.

Constant optical rotation [α]20D= +81,03 (c = 0,501, methanol).

Appearance: white powder.

EXAMPLE 44

The dihydrochloride of 4-({(1S,2R)-2-[(3-hydroxypropylamino)amino]cyclohexyl}amino)-N-isobutyl-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 427 [M+H]+.

Constant optical rotation [α]20D= +102,72 (c = 0,514, methanol).

Appearance: pale yellow powder.

EXAMPLE 45

The dihydrochloride of N-(2,2-dimethylpropyl)-4-({(1S,2R)-2-[(3-hydroxypropylamino)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 441 [M+H]+.

Constant optical rotation [α]20D= +58,24 (c = 0,546, methanol).

Appearance: pale-gettypedesc.

EXAMPLE 46

The dihydrochloride of 4-({(1S,2R)-2-[(3-hydroxypropylamino)amino]cyclohexyl}amino)-N-(TRANS-4-methoxycyclohexyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 483 [M+H]+.

Constant optical rotation [α]20D= +82,74 (c = 0,539, methanol).

Appearance: white powder.

EXAMPLE 47

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-6-fluoro-N-(TRANS-4-methoxycyclohexyl)hinzelin-2-carboxamide

Elemental analysis data (for C24H33FN6O2/2 HCl/2 H2O)

Calculated (Percent): C - 50,97; N - 6,95; N - 14,86.

Found (%): 51,07; N - 6,79; N - 15,07.

FAB-MC, positive ions, m/z: 457 [M+H]+.

Constant optical rotation [α]20D= +48,29 (c = 0,468, methanol).

Appearance: white powder.

EXAMPLE 48

The dihydrochloride 6-fluoro-N-(TRANS-4-methoxycyclohexyl)-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)hinzelin-2-carboxamide

Elemental analysis data (for C29H35FN6O3/2 HCl/1,7 H2O)

Calculated (%): 50,88; N - 6,90; N - 14.24 From.

Found (Percent): C - 50,97; N - 6,59; N - 14,20.

FAB-MC, positive ions, m/z: 487 [M+H]+.

Constant optical rotation [α]20D= +69,09 (c = 0,605, methanol).

Appearance: white powder.

EXAMPLE 49

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)C is clohessy]amino}-6-methyl-N-[2-(methylthio)ethyl]hinzelin-2-carboxamide

FAB-MC, positive ions, m/z: 415 [M+H]+.

Constant optical rotation [α]20D= +90,97 (c = of 0.565, methanol).

Appearance: white powder.

EXAMPLE 50

The dihydrochloride of 4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methyl-N-[2-(methylthio)ethyl]hinzelin-2-carboxamide

FAB-MC, positive ions, m/z: 445 [M+H]+.

Constant optical rotation [α]20D= +105,81 (c = 0,550, methanol).

Appearance: white powder.

EXAMPLE 51

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(2-methoxy-1,1-dimethylethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H34N6O2/2 HCl/2 H2O)

Calculated (%): 51,59; N - 7,53; N - 15,69.

Found (%): 51,53; N - Of 7.23; N - 15,63.

FAB-MC, positive ions, m/z: 427 [M+H]+.

Constant optical rotation [α]20D= +90,94 (c = 0,530, methanol).

Appearance: pale yellow powder.

EXAMPLE 52

The dihydrochloride of N-(2-methoxy-1,1-dimethylethyl)-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H36FN6O3/2 HCl/1,8 H2O)

Calculated (%): 51,30; N - 7,46; N - 14,96.

Found (%): 51,38; N - 7,18; N - 15,16.

FAB-MC, positive ions, m/z: 457 [M+H]+.

Constant optical in the stop [α] 20D= +107,93 (c = 0,580, methanol).

Appearance: white powder.

EXAMPLE 53

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-isobutyl-6-methoxyquinazoline-2-carboxamide

Elemental analysis data (for C22H32N6O2/2 HCl/2,8 H2O)

Calculated (%): 49,31; N Was 7.45; N - 15,68.

Found (%): 49,27; N - 7,10; N - 15,33.

FAB-MC, positive ions, m/z: 413 [M+H]+.

Constant optical rotation [α]20D= +123,21 (c = 0,560, methanol).

Appearance: pale yellow powder.

EXAMPLE 54

The dihydrochloride of N-isobutyl-6-methoxy-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)hinzelin-2-carboxamide

FAB-MC, positive ions, m/z: 443 [M+H]+.

Constant optical rotation [α]20D= +130,87 (c = 0,570, methanol).

Appearance: white powder.

EXAMPLE 55

The dihydrochloride of 4-({(1S,2R)-2-[(3-hydroxypropylamino)amino]cyclohexyl}amino)-N-(2-methoxy-1,1-dimethylethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H36N6O3/2 HCl/2,4 H2O)

Calculated (%): 50,33; N - 7,53; N - 14,67.

Found (%): 50,25; N - 7,30; N - 14,74.

FAB-MC, positive ions, m/z: 457 [M+H]+.

Constant optical rotation [α]20D= +91,69 (c = 0,530, methanol).

Appearance: pale yellow powder.

EXAMPLE 56/b>

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-6-methyl-[3-(methylthio)propyl]hinzelin-2-carboxamide

Elemental analysis data (for C22H32N6OS/2 HCl/2,2 H2O)

Calculated (%): 48,83; N - 7,15; N - 15,53.

Found (%): 48,77; N - 6,76; N - 15,23.

FAB-MC, positive ions, m/z: 429 [M+H]+.

Constant optical rotation [α]20D= +81,55 (c = to 0.645, methanol).

Appearance: pale yellow powder.

EXAMPLE 57

The dihydrochloride of 4-({(1S,2R)-2-[(3-hydroxypropylamino)amino]cyclohexyl}amino)-6-methyl-N-(2,2,2-triptorelin)hinzelin-2-carboxamide

FAB-MC, positive ions, m/z: 453 [M+H]+.

Constant optical rotation [α]20D= +109,54 (c = 0,555, methanol).

Appearance: pale yellow powder.

EXAMPLE 58

The dihydrochloride of 4-({(1S,2R)-2-[(3-hydroxypropylamino)amino]cyclohexyl}amino)-N-isopropyl-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 413 [M+H]+.

Constant optical rotation [α]20D= +108,07 (c = 0,570, methanol).

Appearance: pale yellow powder.

EXAMPLE 59

The dihydrochloride of 4-({(1S,2R)-2-[(3-hydroxypropylamino)amino]cyclohexyl}amino)-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H34N6O3/2 HCl/3,4 H2O)

Calculated (%): the - 47,90; N - OF 7.48; N - OF 14.57.

Found (%): 48,24; N - 7,34; N - 14,22.

FAB-MC, positive ions, m/z: 443 [M+H]+.

Constant optical rotation [α]20D= +89,92 (c = 0,685, methanol).

Appearance: pale yellow powder.

EXAMPLE 60

The dihydrochloride of 4-({(1S,2R)-2-[(2-hydroxy-2-methylpropanamide)amino]cyclohexyl}amino)-N-isobutyl-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 441 [M+H]+.

Constant optical rotation [α]20D= +27,49 (c = 0,560, methanol).

Appearance: white powder.

EXAMPLE 61

The dihydrochloride of N-(2-ethoxyethyl)-4-({(1S,2R)-2-[(3-hydroxypropylamino)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H34N6O3/2 HCl/3,4 H2O)

Calculated (%): 47,90; N - Of 7.48; N - Of 14.57.

Found (%): 48,07; N - 7,13; N - 14,21.

FAB-MC, positive ions, m/z: 443 [M+H]+.

Constant optical rotation [α]20D= +94,54 (c = 0,605, methanol).

Appearance: pale yellow powder.

EXAMPLE 62

The dihydrochloride of 4-{[(1S,2R)-2-(n-butanilicaine)cyclohexyl]amino}-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H36N6O2/2 HCl/3,4 H2O)

Calculated (%): 50,15; N - 7,86; N - 14,62.

Found (%): 50,17; N - Of 7.48; N - 14,60.

FAB-MC, positive ions /z: 441 [M+H] +.

Constant optical rotation [α]20D= +97,57 (c = 0,660, methanol).

Appearance: pale yellow powder.

EXAMPLE 63

The dihydrochloride of N-(3-methoxypropyl)-6-methyl-4-({(1S,2R)-2-[(2-methylpropanoyl)amino]cyclohexyl}amino)hinzelin-2-carboxamide

FAB-MC, positive ions, m/z: 441 [M+H]+.

Constant optical rotation [α]20D= +61,88 (c = 0,585, methanol).

Appearance: white powder.

EXAMPLE 64

The dihydrochloride of 4-({(1S,2R)-2-[(3-hydroxypropylamino)amino]cyclohexyl}amino)-N-isopropyl-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 413 [M+H]+.

Constant optical rotation [α]20D= -113,42 (c = 0,760, methanol).

Appearance: pale yellow powder.

EXAMPLE 65

The dihydrochloride of 4-({(1S,2R)-2-[(2-hydroxy-2-methylpropanamide)amino]cyclohexyl}amino)-N-isopropyl-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 427 [M+H]+.

Constant optical rotation [α]20D= +13,23 (c = 0,665, methanol).

Appearance: pale yellow powder.

EXAMPLE 66

The dihydrochloride of 4-({(1S,2R)-2-[(2-hydroxy-2-methylpropanamide)amino]cyclohexyl}amino)-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 457 [M+H]+.

Constant optical rotation [α]20D= 21,65 (c = 0,665, methanol).

Appearance: pale yellow powder.

EXAMPLE 67

The dihydrochloride of 4-({(1S,2R)-2-[(2-hydroxy-2-methylpropanamide)amino]cyclohexyl}amino)-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H34N6O3/2 HCl/ H2O)

Calculated (%): 51,78; N - 7,18; N - Of 15.75.

Found (%): 51,79; N - 6,86; N - 15,83.

FAB-MC, positive ions, m/z: 443 [M+H]+.

Constant optical rotation [α]20D= +of 4.44 (c = 0,495, methanol).

Appearance: white powder.

EXAMPLE 68

The dihydrochloride 6-chloro-N-cycloheptyl-4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C24H33ClN6O/2 HCl/2 H2O)

Calculated (%): 50,93; N - 6,95; N - 14,85.

Found (Percent): C - 50,58; N - 6,86; N - 14, 48mm.

FAB-MC, positive ions, m/z: 457 [M+H]+.

Constant optical rotation [α]20D= +99,35 (c = 0,465, methanol).

Appearance: white powder.

EXAMPLE 69

The dihydrochloride 6-chloro-N-cycloheptyl-4-[((1S,2R)-2-{[N-hydroxyethylamino]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C24H33N6O2Cl/2 HCl/1,5 H2O)

Calculated (%): 50,31; N. Of 6.68; N - 14,67.

Found (%): 50,71; N - 6,85; N - 14,49.

FAB-MC, positive ions, m/z: 473 [M+H]+.

Constant is pricescope rotation [α] 20D= +3,99 (c = 0,501, methanol).

Appearance: white powder.

EXAMPLE 70

The dihydrochloride of N-isobutyl-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H34N6O2/2 HCl/2,5 H2O)

Calculated (%): 50,73; N - To 7.59; N - 15,43.

Found (%): 50,81; N - Rate Of 7.54; N - 15,59.

FAB-MC, positive ions, m/z: 427 [M+H]+.

Constant optical rotation [α]20D= +106,99 (c = 0,529, methanol).

Appearance: white powder.

EXAMPLE 71

The dihydrochloride 6-chloro-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)hinzelin-2-carboxamide

Elemental analysis data (for C18H23N6O2Cl/2 HCl/3 H2O)

Calculated (%): 41,75; N - 6,03; N - 16,23.

Found (%): 41,85; N. Of 5.84; N - 16,22.

FAB-MC, positive ions, m/z: 391 [M+H]+.

Constant optical rotation [α]20D= +154,05 (c = 0,518, methanol).

Appearance: white powder.

EXAMPLE 72

The dihydrochloride 6-chloro-N-methoxy-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)hinzelin-2-carboxamide

Elemental analysis data (for C19H25N6O3Cl/2 HCl/2,5 H2O)

Calculated (%): 42,35; N. Of 5.99; N - 15,60.

Found (%) : - Of 42.46; H - 6,41; N - 15,36.

FAB-MC, positive ions, m/z: 421 [M+H]+.

Constant is th optical rotation [α] 20D= +21,20 (c = 0,547, methanol).

Appearance: white powder.

EXAMPLE 73

The dihydrochloride of N-n-butyl-6-chloro-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)hinzelin-2-carboxamide

Elemental analysis data (for C22H31N6O2Cl/2 HCl/1,5 H2O)

Calculated (%): 48,31; N - 6,63; N - Shed 15.37.

Found (Percent): C - 48,56; N - Of 6.49; N - 15,41.

FAB-MC, positive ions, m/z: 447 [M+H]+.

Constant optical rotation [α]20D= +111,52 (c = 0,538, methanol).

Appearance: white powder.

EXAMPLE 74

The dihydrochloride of N-(2,2-dimethylpropyl)-4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H34N6O/2 HCl/1,6 H2O)

Calculated (%): 53,92; N - 7,71; N - 16,40.

Found (%): 54,31; N - At 7.55; N - 15,98.

FAB-MC, positive ions, m/z: 411 [M+H]+.

Constant optical rotation [α]20D= +88,65 (c = 0,467, methanol).

Appearance: white powder.

EXAMPLE 75

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C22H32N6O/2 HCl/0,8 H2O)

Calculated (%): 54,61; N - 7,42; N - 17,37.

Found (%): 54,85; N - 7,39; N - 17,00.

FAB-MC, positive ions, m/z: 397 [M+H]+.

Constant optionschoose [α] 20D= +91,96 (c = 0,523, methanol).

Appearance: pale brown powder.

EXAMPLE 76

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-6-methyl-N-(2,2,2-triptorelin)hinzelin-2-carboxamide

Elemental analysis data (for C20H25N6OF3/2 HCl/0.5 H2O)

Calculated (%): 47,63; N - The Ceiling Of 5.60; N - 16,66.

Found (%): 47,76; N - 5,74; N - 16,56.

FAB-MC, positive ions, m/z: 423 [M+H]+.

Constant optical rotation [α]20D= +96,59 (c = 0,528, methanol).

Appearance: white powder.

EXAMPLE 77

The dihydrochloride of N-(cyclopentylmethyl)-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H36N6O2/2 HCl/0,7 H2O)

Calculated (%): 55,61; N - 7,39; N - 15,56.

Found (%): 55,72; N - 7,17; N - 15,58.

FAB-MC, positive ions, m/z: 453 [M+H]+.

Constant optical rotation [α]20D= +101,58 (c = 0,443, methanol).

Appearance: white powder.

EXAMPLE 78

The dihydrochloride of N-(cyclopentyl)-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H34N6O3/2 HCl/0,7 H2O)

Calculated (%): 55,00; N - 7,19; N - 16,04.

Found (%): 55,14; N - 7,22; N - 15,78.

FAB-MC, positive is s ions, m/z: 439 [M+H]+.

Constant optical rotation [α]20D= +110,19 (c = 0,559, methanol).

Appearance: white powder.

EXAMPLE 79

The dihydrochloride of N-(1,1-dimethylpropyl)-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 441 [M+H]+.

Constant optical rotation [α]20D= +96,57 (c = 0,497, methanol).

Appearance: white powder.

EXAMPLE 80

The dihydrochloride of N-(2,2-dimethylpropyl)-4-{[(1S,2R)-2-(2-econimically)cyclohexyl]amino}-6-florinopolis-2-carboxamide

Elemental analysis data (for C22H31N6OF/2 HCl/0,8 H2O)

Calculated (%): 52,65; N - 6,95; N - X 16.75.

Found (%): 52,85; N - 7,13; N - 16,53.

FAB-MC, positive ions, m/z: 415 [M+H]+.

Constant optical rotation [α]20D= +47,88 (c = 0,497, methanol).

Appearance: white powder.

EXAMPLE 81

The dihydrochloride of 4-{[(1S,2R)-2-(2-econimically)cyclohexyl]amino}-6-fluoro-N-(3-methoxy-2,2-dimethylpropyl)hinzelin-2-carboxamide

FAB-MC, positive ions, m/z: 445 [M+H]+.

Constant optical rotation [α]20D= +43,24 (c = 0,481, methanol).

Appearance: white powder.

EXAMPLE 82

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(2-isopropoxyphenyl)-6-methylpyrazole-2-carboxamid is and

Elemental analysis data (for C23H34N6O2/2 HCl/1,6 H2O)

Calculated (%): 52,29; N - Of 7.48; N - 15,91.

Found (%): 52,07; N And 7.36; N - 15,89.

FAB-MC, positive ions, m/z: 427 [M+H]+.

Constant optical rotation [α]20D= +92,65 (c = 0,490, methanol).

Appearance: white powder.

EXAMPLE 83

The dihydrochloride of 4-[((1S,2R)-2-{[N-hydroxyethylamino]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C22H32N6O2/2 HCl/ H2O)

Calculated (%): 52,48; N - 7,21; N - 16,69.

Found (%): 52,71; N - 7,31; N - 16,64.

FAB-MC, positive ions, m/z: 413 [M+H]+.

Constant optical rotation [α]20D= +3,23 (c = 0,556, methanol).

Appearance: white powder.

EXAMPLE 84

The dihydrochloride of N-(2-isopropoxyphenyl)-4-({(1S,2R)-2-[(2-methoxy-2-methylpropanoyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H40N6O3/2 HCl/ H2O)

Calculated (%): 54,26; N - 7,71; N - 14,60.

Found (%): 54,48; N - To 7.61; N - 14,71.

FAB-MC, positive ions, m/z: 485 [M+H]+.

Constant optical rotation [α]20D= +10,88 (c = 0,551, methanol).

Appearance: white powder.

EXAMPLE 85

The dihydrochloride of N-(2-isopropoxyphenyl)-4-({(1S,2R)-2-[(2-metakit imidoyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H36N6O3/2 HCl/1,5 H2O)

Calculated (%): 53,00; N - 7,34; N - 15,45.

Found (%): 53,05; N - 7,50; N - Shed 15.37.

FAB-MC, positive ions, m/z: 457 [M+H]+.

Constant optical rotation [α]20D= +119,91 (c = 0,487, methanol).

Appearance: white powder.

EXAMPLE 86

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(3-isopropoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H36N6O2/2 HCl/1,5 H2O)

Calculated (%): 53,33; N - The 7.65; N - 15,55.

Found (%): 53,46; N - 7,49; N - 15,50.

FAB-MC, positive ions, m/z: 441 [M+H]+.

Constant optical rotation [α]20D= +91,49 (c = 0,529, methanol).

Appearance: white powder.

EXAMPLE 87

The dihydrochloride of N-(3-isopropoxyphenyl)-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H38N6O3/2 HCl/2 H2O)

Calculated (%): 51,81; N - The 7.65; N - 14,50.

Found (%): 51,47; N - 7,30; N - 14,65.

FAB-MC, positive ions, m/z: 471 [M+H]+.

Constant optical rotation [α]20D= +100,40 (c = 0,500, methanol).

Appearance: white powder.

EXAMPLE 88

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]AMI is on}-N-methoxy-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 371 [M+H]+.

Constant optical rotation [α]20D= +116,79 (c = 0,500, methanol).

Appearance: white powder.

EXAMPLE 89

The dihydrochloride of N-methoxy-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 401 [M+H]+.

Constant optical rotation [α]20D= +105,19 (c = 0,500, methanol).

Appearance: white powder.

EXAMPLE 90

The dihydrochloride 6-chloro-N-cycloheptyl-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)hinzelin-2-carboxamide

Elemental analysis data (for C25H35N6O2Cl/2 HCl/1,4 H2O)

Calculated (%): 51,31; N - 6,86; N - 14,36.

Found (%): 51,30; N - Of 6.71; N - 14,20.

FAB-MC, positive ions, m/z: 487 [M+H]+.

Constant optical rotation [α]20D= +107,38 (c = 0,501, methanol).

Appearance: white powder.

EXAMPLE 91

The dihydrochloride of 4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 429 [M+H]+.

Constant optical rotation [α]20D= +114,85 (c = worn : 0.505, methanol).

Appearance: white powder.

EXAMPLE 92

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(3-methoxypropyl)-6-utilisaton-2-carboxamide

FAB-MC, positive ions, m/z: 413 [M+H]+.

Constant optical rotation [α]20D= +96,40 (c = 0,500, methanol).

Appearance: white powder.

EXAMPLE 93

The dihydrochloride of 4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H34N6O3/2 HCl/2,5 H2O)

Calculated (%): 49,29; N - 7,37; N - 14,99.

Found (%): 49,15; N - 7,37; N - 14,93.

FAB-MC, positive ions, m/z: 443 [M+H]+.

Constant optical rotation [α]20D= +107,57 (c = 0,515, methanol).

Appearance: white powder.

EXAMPLE 94

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(2-ethoxyethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C22H32N6O2/2 HCl/2,6 H2O)

Calculated (%): 49,64; N - 7,42; N - 15,79.

Found (%): 49,27; N - 7,03; N - 15,60.

FAB-MC, positive ions, m/z: 413 [M+H]+.

Constant optical rotation [α]20D= +105,74 (c = worn : 0.505, methanol).

Appearance: white powder.

EXAMPLE 95

The dihydrochloride of N-(2-ethoxyethyl)-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H34N6O3/2 HCl/1,3 H2O)

Calculated (%): 51,26; N - 7,22; N - 15,59.

Found (Percent): C - 51,20; N - 7,06; N - 15,55.

FAB-MC, positive ions, m/z: 443 [M+H]+.

Constant optical rotation [α]20D= +101,38 (c = worn : 0.505, methanol).

Appearance: white powder.

EXAMPLE 96

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(3-methoxy-2,2-dimethylpropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H36N6O2/2 HCl/1,9 H2O)

Calculated (%): 52,63; N - Of 7.69; N - 15,34.

Found (%): 52,46; N - 7,39; N - 14,98.

FAB-MC, positive ions, m/z: 441 [M+H]+.

Constant optical rotation [α]20D= +83,07 (c = 0,520, methanol).

Appearance: white powder.

EXAMPLE 97

The dihydrochloride of N-(3-methoxy-2,2-dimethylpropyl)-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H38N6O3/2 HCl/2,5 H2O)

Calculated (%): 51,02; N - 7,71; N - Of 14.28.

Found (%): 51,84; N - 7,32; N - 14,18.

FAB-MC, positive ions, m/z: 471 [M+H]+.

Constant optical rotation [α]20D= +95,68 (c = 0,510, methanol).

Appearance: white powder.

EXAMPLE 98

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(2-furylmethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23Hsub> 28N6O2/2 HCl/3 H2O)

Calculated (%): 50,46; N - 6,63; N - 15,35.

Found (Percent): C - 50,61; N - 6,24; N - 15,36.

FAB-MC, positive ions, m/z: 421 [M+H]+.

Constant optical rotation [α]20D= +100,00 (c = 0,510, methanol).

Appearance: white powder.

EXAMPLE 99

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(TRANS-4-hydroxycyclohexyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H34N6O2/2 HCl/3,6 H2O)

Calculated (%): 50,02; N - At 7.55; N - 14,58.

Found (%): 50,35; N - 7,22; N - 14,21.

FAB-MC, positive ions, m/z: 439 [M+H]+.

Constant optical rotation [α]20D= +70,58 (c = 0,510, methanol).

Appearance: white powder.

EXAMPLE 100

The dihydrochloride of N-(TRANS-4-hydroxycyclohexyl)-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 469 [M+H]+.

Constant optical rotation [α]20D= +103,59 (c = 0,500, methanol).

Appearance: white powder.

EXAMPLE 101

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-isopropyl-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 383 [M+H]+.

Constant optical rotation [α]20D= +107,32 (c = worn : 0.505, methanol).

External VI is: white powder.

EXAMPLE 102

The dihydrochloride of N-isopropyl-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C22H32N6O2/2 HCl/2 H2O)

Calculated (%): 50,67; N - 7,34; N - 16,12.

Found (%): 50,94; N - 7,15; N - 16,38.

FAB-MC, positive ions, m/z: 413 [M+H]+.

Constant optical rotation [α]20D= +127,05 (c = 0,510, methanol).

Appearance: white powder.

EXAMPLE 103

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(2-foradil)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C20H27N6OF/2 HCl/2,5 H2O)

Calculated (%): 47,62; N - 6,79; N - 16,66.

Found (Percent): C - 47,59; N - 6,56; N - 16,44.

FAB-MC, positive ions, m/z: 387 [M+H]+.

Constant optical rotation [α]20D= +114,79 (c = 0,500, methanol).

Appearance: pale brown powder.

EXAMPLE 104

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2-methoxypropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H34N6O2/2 HCl/1,1 H2O)

Calculated (%): 54,26; N - 7,25; N - 15,82.

Found (%): 54,27; H - EUR 7.57; N - 15,58.

FAB-MC, positive ions, m/z: 439 [M+H]+.

Constant optical rotation [α]20D= +8,61 (c = 0,476, methanol).

Appearance: white powder.

EXAMPLE 105

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 425 [M+H]+.

Constant optical rotation [α]20D= +79,21 (c = 0,510, methanol).

Appearance: white powder.

EXAMPLE 106

The dihydrochloride of N-(cyclopropylmethyl)-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H32N6O/2 HCl/1,4 H2O)

Calculated (Percent): C - 55,57; N - 7,15; N - 16,20.

Found (%): 55,53; 7,00; N - 16,13.

FAB-MC, positive ions, m/z: 421 [M+H]+.

Constant optical rotation [α]20D= +90,67 (c = 0,536, methanol).

Appearance: white powder.

EXAMPLE 107

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2-ethylbutyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H38N6O/2 HCl/0,9 H2O)

Calculated (%): 57,86; N - 7,81; N - 15,57.

Found (%): 57,81; N - Of 7.90; N - 15,34.

FAB-MC, positive ions, m/z: 451 [M+H]+.

Constant optical rotation [α]20D= +81,48 (c = 0,540, methanol).

Appearance: white powder.

EXAMPLE 108

The dihydrochloride of N-(cyclohexylmethyl)-4-{[(1S,R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C27H38N6O/2 HCl/1,4 H2O)

Calculated (%): 57,83; N - Of 7.69; N - 14,99.

Found (%): 58,09; N - 7,74; N - 14,70.

FAB-MC, positive ions, m/z: 463 [M+H]+.

Constant optical rotation [α]20D= +78,36 (c = 0,513, methanol).

Appearance: white powder.

EXAMPLE 109

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2,2-dimethylpropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H36N6O/2 HCl/1,8 H2O)

Calculated (%): 55,41; N - 7,74; N - 15,51.

Found (%): 55,41; N - 7,78; N - 15,51.

FAB-MC, positive ions, m/z: 437 [M+H]+.

Constant optical rotation [α]20D= +75,72 (c = 0,486, methanol).

Appearance: white powder.

EXAMPLE 110

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-[(1R,2R)-2-methoxycyclohexyl]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C27H38N6O2/2 HCl/2,1 H2O)

Calculated (%): 55,02; N - 7,56; N - 14,26.

Found (%): 55,08; N - Of 7.48; N - 14,23.

FAB-MC, positive ions, m/z: 479 [M+H]+.

Constant optical rotation [α]20D= +61,50 (c = 0,517, methanol).

Appearance: white powder.

EXAMPLE 111

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cycle is hexyl]amino}-N-ethyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C22H30N6O/2 HCl/2 H2O)

Calculated (%): 50,32; N - 7,37; N - 16,00.

Found (%): 50,40; N - 7,14; N - 15,65.

FAB-MC, positive ions, m/z: 395 [M+H]+.

Constant optical rotation [α]20D= +95,73 (c = 0,539, methanol).

Appearance: white powder.

EXAMPLE 112

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-[1-(methoxymethyl)cyclohexyl]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C28H40N6O2/2 HCl/1,7 H2O)

Calculated (%): 56,41; N - Of 7.68; N - 14,10.

Found (%): 56,45; N - The 7.65; N - At 13.84.

FAB-MC, positive ions, m/z: 493 [M+H]+.

Constant optical rotation [α]20D= +57,51 (c = 0,532, methanol).

Appearance: white powder.

EXAMPLE 113

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2-ethylbutyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H38N6O2/2 HCl/1,6 H2O)

Calculated (%): 54,94; N - 7,66; N - 14,79.

Found (%): 55,02; N - 7,30; N - 14,58.

FAB-MC, positive ions, m/z: 467 [M+H]+.

Constant optical rotation [α]20D= +114,98 (c = 0,534, methanol).

Appearance: white powder.

EXAMPLE 114

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)C is clohessy]amino}-N-[(1R)-1-(methoxymethyl)-2-methylpropyl]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H38N6O2/2 HCl/2,3 H2O)

Calculated (%): 53,75; N - 7,74; N - 14,47.

Found (%): 53,65; N - Of 7.48; N - 14,52.

FAB-MC, positive ions, m/z: 467 [M+H]+.

Constant optical rotation [α]20D= +75,61 (c = 0,529, methanol).

Appearance: white powder.

EXAMPLE 115

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2-ethylpropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H36N6O/2 HCl/1,2 H2O)

Calculated (%): 56,53; N - To 7.67; N - 15,82.

Found (Percent): C - 56,55; H - 7,62; N - 15,55.

FAB-MC, positive ions, m/z: 437 [M+H]+.

Constant optical rotation [α]20D= +91,09 (c = 0,494, methanol).

Appearance: white powder.

EXAMPLE 116

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2,2-dimethylpropyl)-6-florinopolis-2-carboxamide

Elemental analysis data (for C24H33N6OF/2 HCl/ H2O)

Calculated (%): 54,24; N - 7,02; N - 15,81.

Found (%): 54,47; N - Of 6.71; N - 15,56.

FAB-MC, positive ions, m/z: 441 [M+H]+.

Constant optical rotation [α]20D= +41,26 (c = 0,504, methanol).

Appearance: white powder.

EXAMPLE 117

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-the top-N-isobutylthiazole-2-carboxamide

Elemental analysis data (for C23H31N6OF/2 HCl/1,3 H2O)

Calculated (%): 52,83; N - 6,86; N - 16,07.

Found (%): 52,88; N - 6,76; N - 15,74.

FAB-MC, positive ions, m/z: 427 [M+H]+.

Constant optical rotation [α]20D= +48,82 (c = 0,512, methanol).

Appearance: white powder.

EXAMPLE 118

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-fluoro-N-(3-methoxy-2,2-dimethylpropyl)hinzelin-2-carboxamide

Elemental analysis data (for C25H35N6O2F/2 HCl/ H2O)

Calculated (%): 53,48; 7,00; N - 14,97.

Found (Percent): C - 53,59; N - 6,98; N - 14,69.

FAB-MC, positive ions, m/z: 471 [M+H]+.

Constant optical rotation [α]20D= +33,88 (c = 0,543, methanol).

Appearance: white powder.

EXAMPLE 119

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-[2-methoxy-1-(methoxymethyl)-1-methylethyl]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H38N6O3/2 HCl/1,9 H2O)

Calculated (%): 52,95; N - 7,49; N - 14,25.

Found (%): 52,91; N And 7.36; N - 14,02.

FAB-MC, positive ions, m/z: 483 [M+H]+.

Constant optical rotation [α]20D= +69,64 (c = 0,560, methanol).

Appearance: white powder.

EXAMPLE 120

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihyd the on-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C27H32N6O2/2 HCl/2,7 H2O)

Calculated (%): 54,58; N. Of 6.68; N - 14,14.

Found (%): 54,47; N - 7,02; N - 14,25.

FAB-MC, positive ions, m/z: 473 [M+H]+.

Constant optical rotation [α]20D= +34,84 (c = 0,683, methanol).

Appearance: yellow powder.

EXAMPLE 121

The dihydrochloride of N-n-butyl-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H34N6O/2 HCl/2 H2O)

Calculated (%): 54,23; N - To 7.59; N - 15,81.

Found (%): 54,36; N And 7.36; N 15.62 Wide.

FAB-MC, positive ions, m/z: 423 [M+H]+.

Constant optical rotation [α]20D= +86,93 (c = 0,773, methanol).

Appearance: white powder.

EXAMPLE 122

The dihydrochloride of N-n-butyl-6-methyl-4-{[(1S,2R)-2-(3,4,5,6-tetrahydropyridine-2-ylamino)cyclohexyl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C25H36N6O/2 HCl/0,9 H2O)

Calculated (%): 57,12; N - 7,63; N - 15,99.

Found (%): 57,25; N - Of 7.64; N - 15,79.

FAB-MC, positive ions, m/z: 437 [M+H]+.

Constant optical rotation [α]20D= +100,57 (c = 0,696, methanol).

Appearance: white powder.

EXAMPLE 123

The dihydrochloride of N-n-butyl-6-methyl-4-{[(1S,2R)-2-(3,4,5,6-tetrahydro-2H-azepin-2-ylamino)cyclohex the yl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C26H38N6O/2 HCl/1,6 H2O)

Calculated (%): 56,54; N - 7,88; N - 15,21.

Found (%): 56,53; N - 7,60; N - 15,28.

FAB-MC, positive ions, m/z: 451 [M+H]+.

Constant optical rotation [α]20D= +85,02 (c = of 0.741, methanol).

Appearance: white powder.

EXAMPLE 124

The dihydrochloride 6-chloro-N-cycloheptyl-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C26H35ClN6O/2 HCl/2 H2O)

Calculated (%): 52,75; N - 6,98; N - 14,20.

Found (%): 52,97; N - 6,86; N - 14,37.

FAB-MC, positive ions, m/z: 483 [M+H]+.

Constant optical rotation [α]20D= +67,28 (c = 0,535, methanol).

Appearance: white powder.

EXAMPLE 125

The dihydrochloride of N-n-butyl-6-chloro-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C23H31ClN6O/2 HCl/ H2O)

Calculated (%): 51,84; N Is 6.61; N - 15,74.

Found (Percent): C - 51,82; N - 6,74; N - 15,71.

FAB-MC, positive ions, m/z: 443 [M+H]+.

Constant optical rotation [α]20D= +88,64 (c = 0,546, methanol).

Appearance: white powder.

EXAMPLE 126

The dihydrochloride of N-cycloheptyl-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methyl shall insulin-2-carboxamide

Elemental analysis data (for C27H38N6O/2 HCl/1,5 H2O)

Calculated (Percent): C - 57,64; N - Of 7.70; N - 14,94.

Found (%): 57,52; N - 7,78; N - Of 14.90.

FAB-MC, positive ions, m/z: 463 [M+H]+.

Constant optical rotation [α]20D= +67,56 (c = 0,447, methanol).

Appearance: white powder.

EXAMPLE 127

The dihydrochloride 6-chloro-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C19H23ClN6O/2 HCl/1,3 H2O)

Calculated (%): 47,23; N - 5,76; N - 17,39.

Found (%): 47,21; N. Of 5.99; N - 17,20.

FAB-MC, positive ions, m/z: 387 [M+H]+.

Constant optical rotation [α]20D= +104,23 (c = 0,520, methanol).

Appearance: white powder.

EXAMPLE 128

The dihydrochloride 6-chloro-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-methoxyindole-2-carboxamide

Elemental analysis data (for C20H25ClN6O2/2 HCl/1,3 H2O)

Calculated (%): 46,80; N - Of 5.81; N - 16,37.

Found (%): 46,87; N - Of 5.55; N - 16,30.

FAB-MC, positive ions, m/z: 417 [M+H]+.

Constant optical rotation [α]20D= +53,81 (c = 0,524, methanol).

Appearance: white powder.

EXAMPLE 129

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(3-methoxy-2,2-dimetyl who drank)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H38N6O2/2 HCl/ H2O)

Calculated (%): 56,01; N - To 7.59; N - 15,07.

Found (Percent): C - 55,96; N Is 7.85; N - 14,85.

FAB-MC, positive ions, m/z: 467 [M+H]+.

Constant optical rotation [α]20D= +71,08 (c = 0,543, methanol).

Appearance: white powder.

EXAMPLE 130

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H34N6O/2 HCl/1,2 H2O)

Calculated (%): 55,94; N - 7,47; N - To 16.31.

Found (Percent): C - 55,89; N - Of 7.64; N - 16,24.

FAB-MC, positive ions, m/z: 423 [M+H]+.

Constant optical rotation [α]20D= +93,53 (c = 0,464, methanol).

Appearance: white powder.

EXAMPLE 131

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2-isopropoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H36N6O2/2 HCl/1,6 H2O)

Calculated (%): 54,17; N - 7,49; N - 15,16.

Found (%): 54,27; N - 7,39; N - 15,21.

FAB-MC, positive ions, m/z: 453 [M+H]+.

Constant optical rotation [α]20D= +95,25 (c = 0,527, methanol).

Appearance: white powder.

EXAMPLE 132

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]am is but}-6-methyl-N-[2-(methylthio)ethyl]hinzelin-2-carboxamide

Elemental analysis data (for C23H32N6OS/2 HCl/1,3 H2O)

Calculated (%): 51,45; N - 6,87; N - 15,65.

Found (%): 51,52; N - Of 6.96; N - 15,47.

FAB-MC, positive ions, m/z: 441 [M+H]+.

Constant optical rotation [α]20D= +88,30 (c = 0,530, methanol).

Appearance: white powder.

EXAMPLE 133

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2-methoxy-1,1-dimethylethyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 453 [M+H]+.

Constant optical rotation [α]20D= +64,62 (c = 0,489, methanol).

Appearance: white powder.

EXAMPLE 134

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-{[1-(methoxymethyl)cyclohexyl]methyl}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C29H42N6O2/2 HCl/1,4 H2O)

Calculated (Percent): C - 57,59; N - 7,80; N - 13,89.

Found (Percent): C - 57,64; N - 7,79; N - 13,67.

FAB-MC, positive ions, m/z: 507 [M+H]+.

Constant optical rotation [α]20D= +54,23 (c = mean HDI of 0.531, methanol).

Appearance: white powder.

EXAMPLE 135

Trihydrochloride 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methyl-N-(2-piperidine-1-retil)hinzelin-2-carboxamide

Elemental analysis data (for C27H39N7 O/3 HCl/2,1 H2O)

Calculated (%): Better Than Anticipated At 51.90; H Was 7.45; N - 15,69.

Found (%): 52,10; N - To 7.77; N - 15,40.

FAB-MC, positive ions, m/z: 478 [M+H]+.

Constant optical rotation [α]20D= +111,91 (c = 0,470, methanol).

Appearance: white powder.

EXAMPLE 136

The dihydrochloride of N-cyclopentyl-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H34N6O/2 HCl/2,4 H2O)

Calculated (%): 54,52; N - 7,47; N - 15,26.

Found (%): 54,64; N - 7,12; N - 15,07.

FAB-MC, positive ions, m/z: 435 [M+H]+.

Constant optical rotation [α]20D= +86,87 (c = 0,541, methanol).

Appearance: white powder.

EXAMPLE 137

The dihydrochloride N tert-butyl 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H34N6O/2 HCl/1,2 H2O)

Calculated (%) : - Is 55.74; H - Of 7.48; N - 16,25.

Found (%): 55,81; N - Of 7.68; N - 16,00.

FAB-MC, positive ions, m/z: 423 [M+H]+.

Constant optical rotation [α]20D= +79,42 (c = 0,491, methanol).

Appearance: white powder.

EXAMPLE 138

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(TRANS-4-methoxycyclohexyl)-6-methylpyrazole-2-carboxamide

Data e is cementnogo analysis (for C 27H38N6O2/2 HCl/1,5 H2O)

Calculated (%): 56,05; N - 7,49; N - 14,53.

Found (%): 56,15; N - 7,56; N - 14, 48mm.

FAB-MC, positive ions, m/z: 479 [M+H]+.

Constant optical rotation [α]20D= +77,12 (c = 0,542, methanol).

Appearance: white powder.

EXAMPLE 139

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methyl-N-(tetrahydro-2H-Piran-4-yl)hinzelin-2-carboxamide

Elemental analysis data (for C25H34N6O2/2 HCl/1,4 H2O)

Calculated (%): 54,72; N - 7,13; N - 15,32.

Found (%): 55,01; N - 7,10; N - 14,93.

FAB-MC, positive ions, m/z: 451 [M+H]+.

Constant optical rotation [α]20D= +80,15 (c = 0,519, methanol).

Appearance: white powder.

EXAMPLE 140

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-isopropyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H32N6O/2 HCl/1,3 H2O)

Calculated (%): 54,72; N - 7,31; N - 16,65.

Found (%): 54,94; N Was 7.45; N - 16,29.

FAB-MC, positive ions, m/z: 409 [M+H]+.

Constant optical rotation [α]20D= +96,16 (c = 0,547, methanol).

Appearance: white powder.

EXAMPLE 141

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(CIS-4-methoxycyclohexyl)-6-utilisaton-2-carboxamide

Elemental analysis data (for C27H38N6O2/2 HCl/2,5 H2O)

Calculated (%): 54,36; N - 7,60; N - 14,09.

Found (%): 54,39; N - 7,31; N - 13,99.

FAB-MC, positive ions, m/z: 479 [M+H]+.

Constant optical rotation [α]20D= +68,99 (c = 0,516, methanol).

Appearance: white powder.

EXAMPLE 142

The dihydrochloride of N-[(1-acetylpiperidine-4-yl)methyl]-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C28H39N7O2/2 HCl/2,2 H2O)

Calculated (%): 54,40; N - 7,40; N - 15,86.

Found (%): 54,73; N - Of 7.48; N - 15,48.

FAB-MC, positive ions, m/z: 506 [M+H]+.

Constant optical rotation [α]20D= +74,33 (c = 0,487, methanol).

Appearance: white powder.

EXAMPLE 143

The dihydrochloride of 4-[((1S,2R)-2-{[(3R)-3-hydroxy-3,4-dihydro-2H-pyrrol-5-yl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H34N6O2/2 HCl/0,4 H2O)

Calculated (Percent): C - 55,57; N - 7,15; N - 16,20.

Found (Percent): C - 55,66; N - 7,39; N - 16,07.

FAB-MC, positive ions, m/z: 439 [M+H]+.

Constant optical rotation [α]20D= +109,62 (c = 0,478, methanol).

Appearance: pale brown powder.

EXAMPLE 144

The dihydrochloride of 4-[((1S,2R-2-{[(3S)-3-hydroxy-3,4-dihydro-2H-pyrrol-5-yl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H34N6O2/2 HCl/0,9 H2O)

Calculated (%): 54,63; N - 7,22; N - 15,93.

Found (%): 54,90; N - 7,15; N - 15,61.

FAB-MC, positive ions, m/z: 439 [M+H]+.

Constant optical rotation [α]20D= +51,83 (c = 0,710, methanol).

Appearance: pale brown powder.

EXAMPLE 145

The dihydrochloride 6-chloro-N-cycloheptyl-4-({(1S,2R)-2-[(2-oxo-3,4-dihydro-2H-pyrrol-5-yl)amino]cyclohexyl}amino)hinzelin-2-carboxamide

Elemental analysis data (for C26H33N6O2Cl/2 HCl/1,5 H2O)

Calculated (%): 52,31; N - 6.42 Per; N - 14,08.

Found (%): 52,38; N - 6,51; N - 14,11.

FAB-MC, positive ions, m/z: 497 [M+H]+.

Constant optical rotation [α]20D= +133,62 (c = 0,464, methanol).

Appearance: white powder.

EXAMPLE 146

The dihydrochloride of N-(tert-butoxy)-6-chloro-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C23H31N6O2Cl/2 HCl/ H2O)

Calculated (%): 50,23; N - 6.42 Per; N - 15,28.

Found (%): 49,97; H - 6,35; N - 14,99.

FAB-MC, positive ions, m/z: 459 [M+H]+.

Constant optical rotation [α]20D= +74,84 (c = 0,473, methanol).

Appearance: white powder.

EXAMPLE 147

The dihydrochloride of N-(cyclopentylmethyl)-4-{[(1S,2R)2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H36N6O/2 HCl/ H2O)

Calculated (%): 55,65; H - 7,62; N - 14,98.

Found (Percent): C - 55,58; N - 7,24; N - 14,84.

FAB-MC, positive ions, m/z: 449 [M+H]+.

Constant optical rotation [α]20D= +51,66 (c = 0,542, methanol).

Appearance: white powder.

EXAMPLE 148

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methyl-N-[3-(methylthio)propyl]hinzelin-2-carboxamide

Elemental analysis data (for C24H34N6OS/2 HCl/ H2O)

Calculated (%) : - Of 52.84; H - 7,02; N - 15,40.

Found (%): 52,83; N - 7,11; N - 15,33.

FAB-MC, positive ions, m/z: 455 [M+H]+.

Constant optical rotation [α]20D= +82,04 (c = 0,529, methanol).

Appearance: white powder.

EXAMPLE 149

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2-furylmethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H30N6O2/2 HCl/ H2O)

Calculated (%): 55,87; N - 6,38; N - 15,64.

Found (%): 56,09; N. Of 6.66; N - 15,26.

FAB-MC, positive ions, m/z: 447 [M+H]+.

Constant optical rotation [α]20D= +89,45 (c = 0,474, methanol).

Appearance: white powder.

EXAMPLE 150

The dihydrochloride of N-(tert-butoxy)-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclo is exil]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H34N6O2/2 HCl/0,7 H2O)

Calculated (%): 55,00; N - 7,19; N - 16,04.

Found (%): 55,00; N - 7,15; N - 15,96.

FAB-MC, positive ions, m/z: 439 [M+H]+.

Constant optical rotation [α]20D= +85,48 (c = 0,496, methanol).

Appearance: white powder.

EXAMPLE 151

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methyl-N-(2,2,2-triptorelin)hinzelin-2-carboxamide

Elemental analysis data (for C22H27N6OF3/2 HCl/0,7 H2O)

Calculated (%): 49,48; N - 5,74; N - 15,74.

Found (%): 49,37; N - 5,72; N - 15,48.

FAB-MC, positive ions, m/z: 449 [M+H]+.

Constant optical rotation [α]20D= +104,62 (c = 0,541, methanol).

Appearance: white powder.

EXAMPLE 152

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino-N-(TRANS-4-hydroxycyclohexyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 465 [M+H]+.

Constant optical rotation [α]20D= +72,65 (c = 0,490, methanol).

Appearance: white powder.

EXAMPLE 153

The dihydrochloride of N-(4-methoxyphenyl)-6-methyl-4-{[(1S,2R)-2-(pyridine-2-ylamino)cyclohexyl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C28H30N6O2/2 HCl/ H2O)

Calculated (%): 58,64; N Is 5.98; N - 14,65.

Found (%): 58,44; N - 5,90; N - 14,67.

FAB-MC, positive ions, m/z: 482 [M+H]+.

Appearance: pale brown powder.

EXAMPLE 154

The dihydrochloride of N-isobutyl-6-methyl-4-{[(1S,2R)-2-(pyridine-2-ylamino)cyclohexyl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C25H32N6O/2 HCl/1,5 H2O)

Calculated (%): 56,39; 7,00; N - 15,78.

Found (%): 56,46; N - 6,74; N - 15,84.

FAB-MC, positive ions, m/z: 432 [M+H]+.

Appearance: yellow powder.

EXAMPLE 155

The dihydrochloride 6-chloro-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]-N-[2-(4-methoxyethyl)ethyl]hinzelin-2-carboxamide

Elemental analysis data (for C31H33N6O2Cl/2 HCl/2,4 H2O)

Calculated (%): 55,30; N - 5,96; N - 12,48.

Found (%): 55,26; N - 5,72; N - 12,25.

FAB-MC, positive ions, m/z: 557 [M+H]+.

Constant optical rotation [α]20D= +78,95 (c = 0,537, methanol).

Appearance: pale brown powder.

EXAMPLE 156

The dihydrochloride 6-chloro-N-(cyclopentylmethyl)-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C28H33N6OCl/2 HCl/0,8 H2O)

Calculated (%): 56,77; N - 6,23; N - 14,19.

Found (%): 56,81; N - 6,14; N - 13,91.

FAB-MC, positive ions mz: 505 [M+H] +.

Constant optical rotation [α]20D= +94,71 (c = 0,549, methanol).

Appearance: white powder.

EXAMPLE 157

The dihydrochloride 6-chloro-N-(3,3-dimethylbutyl)-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C28H35N6OCl/2 HCl/0,8 H2O)

Calculated (Percent): C - 56,58; N - 6,55; N - 14,14.

Found (%): 56,47; N - 6,48; N - 14,26.

FAB-MC, positive ions, m/z: 507 [M+H]+.

Constant optical rotation [α]20D= +103,51 (c = 0,398, methanol).

Appearance: white powder.

EXAMPLE 158

The dihydrochloride 6-chloro-N-(3-terbisil)-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C29H28N6OClF/2 HCl/1,5 H2O)

Calculated (%): 55,20; N Is 5.28; N - 13,32.

Found (%): 55,22; N - To 5.21; N - 13,00.

FAB-MC, positive ions, m/z: 531 [M+H]+.

Constant optical rotation [α]20D= +91,81 (c = 0,501, methanol).

Appearance: white powder.

EXAMPLE 159

The dihydrochloride of 4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H32N6O3/2 HCl/0,9 H2O)

Calculated (%): 54,23; N - 6,52; N - 15,18.

Found (%): 54,28; N - 6,50; N - br15.15

FAB-MC, positive ions, m/z: 465 [M+H]+.

Constant optical rotation [α]20D= +76,07 (c = 0,510, methanol).

Appearance: white powder.

EXAMPLE 160

The dihydrochloride of 4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H30N6O3/2 HCl/1,2 H2O)

Calculated (%): 52,89; N - 6,36; N - 15,42.

Found (%): 52,94; N - 6,28; N - 15,29.

FAB-MC, positive ions, m/z: 451 [M+H]+.

Constant optical rotation [α]20D= +104,31 (c = of 0.533, methanol).

Appearance: white powder.

EXAMPLE 161

The dihydrochloride of N-(cyclohexylmethyl)-4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 476 [M+H]+.

Constant optical rotation [α]20D= +53,58 (c = 0,530, methanol).

Appearance: white powder.

EXAMPLE 162

The dihydrochloride of 4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-N-isopropyl-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 446 [M+H]+.

Constant optical rotation [α]20D= +93,55 (c = 0,543, methanol).

Appearance: white powder.

EXAMPLE 163

The dihydrochloride of N-(2-ethylbutyl)-4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}Ziklag the KSIL)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C27H36N6O2/2 HCl/1,5 H2O)

Calculated (%): 56,25; N - 7,17; N - 14,58.

Found (%): 56,21; N - Of 6.96; N - 14,43.

FAB-MC, positive ions, m/z: 477 [M+H]+.

Constant optical rotation [α]20D= +58,41 (c = 0,517, methanol).

Appearance: white powder.

EXAMPLE 164

The dihydrochloride of N-(2-ethylbutyl)-4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C28H37N7O/2 HCl/1,2 H2O)

Calculated (%): 57,77; N - 7,17; N - Of 16.84.

Found (%): 57,88; N - 7,16; N - 16,54.

FAB-MC, positive ions, m/z: 488 [M+H]+.

Constant optical rotation [α]20D= +57,76 (c = 0,554, methanol).

Appearance: white powder.

EXAMPLE 165

The dihydrochloride of N-(cyclopropylmethyl)-4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H30N6O2/2 HCl/1,2 H2O)

Calculated (%): 55,49; N - 6,41; N - 15,53.

Found (%): 55,44; N - 6,34; N - 15,42.

FAB-MC, positive ions, m/z: 447 [M+H]+.

Constant optical rotation [α]20D= +72,26 (c = 0,476, methanol).

Appearance: white powder.

EXAMPLE 166

The dihydrochloride of 4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohex the l)amino]-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 476 [M+H]+.

Constant optical rotation [α]20D= +72,40 (c = 0,511, methanol).

Appearance: white powder.

EXAMPLE 167

The dihydrochloride of N-(2,2-dimethylpropyl)-4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H34N6O2/2 HCl/0,9 H2O)

Calculated (%): 56,60; N - 6,91; N - 15,23.

Found (%): 56,57; N - 6,74; N - 15,18.

FAB-MC, positive ions, m/z: 463 [M+H]+.

Constant optical rotation [α]20D= +67,63 (c = 0,482, methanol).

Appearance: white powder.

EXAMPLE 168

The dihydrochloride of 4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-N-(3-methoxy-2,2-dimethylpropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C27H36N6O3/2 HCl/1,4 H2O)

Calculated (%): 54,90; N - Of 6.96; N - 14,23.

Found (%): 55,04; N - 6,90; N - 13,92.

FAB-MC, positive ions, m/z: 493 [M+H]+.

Constant optical rotation [α]20D= +58,92 (c = 0,482, methanol).

Appearance: white powder.

EXAMPLE 169

The dihydrochloride of 4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-N-[1-(methoxymethyl)cyclohexyl]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C29H38N6O3/2HCl/2 H 2O)

Calculated (%): 55,50; N - 7,07; N - 13,39.

Found (%): 55,53; N - For 6.81; N - 13,14.

FAB-MC, positive ions, m/z: 519 [M+H]+.

Constant optical rotation [α]20D= +77,88 (c = 0,416, methanol).

Appearance: white powder.

EXAMPLE 170

The dihydrochloride of N-ethyl-4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H28N6O2/2 HCl/2,7 H2O)

Calculated (%): 50,96; N - To 6.58; N - 15,50.

Found (%): 50,98; N - 6,18; N - Br15.15.

FAB-MC, positive ions, m/z: 421 [M+H]+.

Constant optical rotation [α]20D= +86,40 (c = 0,537, methanol).

Appearance: white powder.

EXAMPLE 171

The dihydrochloride of 4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C30H32N6O2/2 HCl/2,6 H2O)

Calculated (%): 57,34; N - 6,29; N - 13,37.

Found (%): 57,34; N - 6,15; N - 13,47.

FAB-MC, positive ions, m/z: 509 [M+H]+.

Constant optical rotation [α]20D= +12,54 (c = 0,606, methanol).

Appearance: pale yellow powder.

EXAMPLE 172

The dihydrochloride of N-n-butyl-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (C 27H34N6O/2 HCl/1,6 H2O)

Calculated (%): 57,87; N - 7,05; N - 15,00.

Found (%): 57,80; N - 7,02; N - 14,82.

FAB-MC, positive ions, m/z: 459 [M+H]+.

Constant optical rotation [α]20D= +75,63 (c = 0,788, methanol).

Appearance: white powder.

EXAMPLE 173

The dihydrochloride of N-n-butyl-6-methyl-4-[((1S,2R)-2-{[(methylimino)(phenyl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C28H36N6O/2 HCl/1,2 H2O)

Calculated (%): 59,30; N - 7,18; N - 14,82.

Found (%): 59,22; N - Of 6.96; N - 14,94.

FAB-MC, positive ions, m/z: 473 [M+H]+.

Constant optical rotation [α]20D= +29,53 (c = 0,684, methanol).

Appearance: white powder.

EXAMPLE 174

The dihydrochloride of N-n-butyl-4-{[(1S,2R)-2-(1H-isoindole-3-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C28H34N6O/2 HCl/1,2 H2O)

Calculated (%) : - To 59.51; H - 6,85; N - 14,87.

Found (Percent): C - 59,70; N - 6,76; N - 14,81.

FAB-MC, positive ions, m/z: 471 [M+H]+.

Constant optical rotation [α]20D= +46,63 (c = 0,609, methanol).

Appearance: pale yellow powder.

EXAMPLE 175

The dihydrochloride of N-n-butyl-4-[((1S,2R)-2-{[(hydroxyimino)(phenyl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Data e is cementnogo analysis (for C 27H34N6O2/2 HCl/0,8 H2O)

Calculated (%): 57,71; N - 6,74; N - 14,96.

Found (%): 57,77; N - 6,63; N - 15,03.

FAB-MC, positive ions, m/z: 475 [M+H]+.

Constant optical rotation [α]20D= +3,13 (c = 0,511, methanol).

Appearance: white powder.

EXAMPLE 176

Trihydrochloride 4-[((1S,2R)-2-{[[2-(dimethylamino)phenyl](imino)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C32H37N7O2/3 HCl/ H2O)

Calculated (%): 56,60; N - 6,23; N - 14,44.

Found (%): 56.78 Has; N - 6,24; N - 14,35.

FAB-MC, positive ions, m/z: 552 [M+H]+.

Constant optical rotation [α]20D= +21,93 (c = 0,547, methanol).

Appearance: pale yellow powder.

EXAMPLE 177

The dihydrochloride of 4-[((1S,2R)-2-{[(3-forfinal)(imino)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C30H31FN6O2/2 HCl/0,8 H2O)

Calculated (%): 58,69; N - Of 5.68; N - 13,69.

Found (%): 58,83; N - Of 5.55; N - 13,42.

FAB-MC, positive ions, m/z: 527 [M+H]+.

Constant optical rotation [α]20D= +12,78 (c = 0,735, methanol).

Appearance: pale yellow powder.

EXAMPLE 178

The dihydrochloride of 4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amine is]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C28H30N6O3/2 HCl/1,5 H2O)

Calculated (%): 56,20; N - Of 5.89; N - 14,04.

Found (%): 56,22; N - Of 5.83; N - 13,82.

FAB-MC, positive ions, m/z: 499 [M+H]+.

Constant optical rotation [α]20D= +1,86 (c = 0,642, methanol).

Appearance: pale yellow powder.

EXAMPLE 179

The dihydrochloride of N-n-butyl-6-chloro-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C26H31ClN6O/2 HCl/0.5 H2O)

Calculated (%): 55,67; N - 6,11; N - 14,98.

Found (%): 55,68; N - 6,17; N - 14,86.

FAB-MC, positive ions, m/z: 479 [M+H]+.

Constant optical rotation [α]20D= +89,76 (c = 0,684, methanol).

Appearance: white powder.

EXAMPLE 180

The dihydrochloride of N-n-butyl-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]-6-methoxyquinazoline-2-carboxamide

Elemental analysis data (for C27H34N6O2/2 HCl/1,25 H2O)

Calculated (%): 56,89; N - For 6.81; N - 14,74.

Found (%): 56,82; N - 6,65; N - 14,64.

FAB-MC, positive ions, m/z: 475 [M+H]+.

Constant optical rotation [α]20D= +108,39 (c = 0,679, methanol).

Appearance: white powder.

EXAMPLE 181

The dihydrochloride of 4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]-N-(4-methox is phenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C30H32N6O2/2 HCl/1,2 H2O)

Calculated (%): 59,74; N Is Between 6.08; N - 13,93.

Found (%): 59,73; N. Of 5.99; N - 13,94.

FAB-MC, positive ions, m/z: 509 [M+H]+.

Constant optical rotation [α]20D= +40,36 (c = 0,654, methanol).

Appearance: pale yellow powder.

EXAMPLE 182

The dihydrochloride 6-chloro-N-cycloheptyl-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C29H35ClN6O/2 HCl/1,2 H2O)

Calculated (%): 56,76; N - 6,47; N - 13,70.

Found (%): 56,84; N. Of 6.31; N - 13,66.

FAB-MC, positive ions, m/z: 519 [M+H]+.

Constant optical rotation [α]20D= +100,55 (c = 0,537, methanol).

Appearance: white powder.

EXAMPLE 183

The dihydrochloride of N-cycloheptyl-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]-6-methoxyquinazoline-2-carboxamide

Elemental analysis data (for C30H38N6O2/2 HCl/1,3 H2O)

Calculated (%): 58,97; N - 7,03; N - Of 13.75.

Found (%): 58,95; N - 6,85; N - 13,76.

FAB-MC, positive ions, m/z: 515 [M+H]+.

Constant optical rotation [α]20D= +109,66 (c = 0,538, methanol).

Appearance: white powder.

EXAMPLE 184

The dihydrochloride of N-cycloheptyl-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cycle is hexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C30H38N6O/2 HCl/2 H2O)

Calculated (%): 59,30; N - 7,30; N - 13,83.

Found (%): 59,12; N - 7,03; N - 13,99.

FAB-MC, positive ions, m/z: 499 [M+H]+.

Constant optical rotation [α]20D= +85,09 (c = 0,463, methanol).

Appearance: white powder.

EXAMPLE 185

The dihydrochloride 6-chloro-N-cycloheptyl-4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C27H33ClN6O2/2 HCl/2,2 H2O)

Calculated (%): 52,17; N - 6,39; N - 13,52.

Found (%): 52,17; N - 6,15; N - 13,70.

FAB-MC, positive ions, m/z: 509 [M+H]+.

Constant optical rotation [α]20D= +109,94 (c = 0,573, methanol).

Appearance: white powder.

EXAMPLE 186

The dihydrochloride of N-isobutyl-4-{[(1S,2R)-2-(1H-isoindole-3-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C28H34N6O/2 HCl/1,5 H2O)

Calculated (%): 58,94; N - 6,90; N - 14,73.

Found (%): 59,14; N - 6,88; N - 14,60.

FAB-MC, positive ions, m/z: 471 [M+H]+.

Constant optical rotation [α]20D= +68,82 (c = 0,555, methanol).

Appearance: white powder.

EXAMPLE 187

The dihydrochloride of N-cycloheptyl-4-{[(1S,2R)-2-(1H-isoindole-3-ylamino)cyclohexyl]amino}-6-methylpyrazolo the-2-carboxamide

Elemental analysis data (for C31H38N6O/2 HCl/2 H2O)

Calculated (Percent): C - 60,09; N - 7,16; N - 13.56MHz.

Found (%): 59,88; N - 7,13; N - Of 13.58.

FAB-MC, positive ions, m/z: 511 [M+H]+.

Constant optical rotation [α]20D= +29,96 (c = 0,534, methanol).

Appearance: pale yellow powder.

EXAMPLE 188

The dihydrochloride 6-chloro-N-cycloheptyl-4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C28H34ClN7O/2 HCl/2,2 H2O)

Calculated (%): 53,16; N - 6,44; N - 15,50.

Found (%): 53,20; N - 6,59; N - 15,32.

FAB-MC, positive ions, m/z: 520 [M+H]+.

Constant optical rotation [α]20D= +93,92 (c = 0,477, methanol).

Appearance: white powder.

EXAMPLE 189

The dihydrochloride of N-n-butyl-4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H33N7O/2 HCl/2,5 H2O)

Calculated (%): 54,07; N - 6,98; N - 16,98.

Found (%): 53,87; N And 7.36; N - 16,73.

FAB-MC, positive ions, m/z: 460 [M+H]+.

Constant optical rotation [α]20D= +75,62 (c = 0,521, methanol).

Appearance: white powder.

EXAMPLE 190

The dihydrochloride of 4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-N-(3-meth is XI-2,2-dimethylpropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C28H37N7O2/2 HCl/1,6 H2O)

Calculated (%): 55,55; N - 7,03; N - 16,20.

Found (%): 55,76; N - 6,77; N - 15,95.

FAB-MC, positive ions, m/z: 504 [M+H]+.

Constant optical rotation [α]20D= +49,33 (c = 0,454, methanol).

Appearance: white powder.

EXAMPLE 191

The dihydrochloride of N-ethyl-4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H29N7O/2 HCl/1,5 H2O)

Calculated (%): 54,24; N - 6,45; N - Of 18.45.

Found (%): 54,14; N - Of 6.49; N - 18,28.

FAB-MC, positive ions, m/z: 432 [M+H]+.

Constant optical rotation [α]20D= +93,78 (c = 0,499, methanol).

Appearance: white powder.

EXAMPLE 192

Trihydrochloride 4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-N-(2-methoxy-1,1-dimethylethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C27H35N7O2/3 HCl/1,4 H2O)

Calculated (%): 51,95; N - 6,59; N - 15,71.

Found (%): 52,10; N - 6,62; N - 15,42.

FAB-MC, positive ions, m/z: 490 [M+H]+.

Constant optical rotation [α]20D= +88,29 (c = 0,564, methanol).

Appearance: white powder.

EXAMPLE 193

The dihydrochloride of 4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl is)amino]-N-(TRANS-4-methoxycyclohexyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C28H36N6O3/2 HCl/ H2O)

Calculated (%): 56,47; N - 6,77; N - 14,11.

Found (%): 56,46; N - 6,88; N - 14,11.

FAB-MC, positive ions, m/z: 505 [M+H]+.

Constant optical rotation [α]20D= +78,74 (c = 0,508, methanol).

Appearance: white powder.

EXAMPLE 194

The dihydrochloride of N-(2,2-dimethylpropyl)-4-[((1S,2R)-2-{[imino(1H-pyrrol-2-yl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H35N7O/2 HCl/0,75 H2O)

Calculated (%): 56,98; N - 7,08; N - 17,89.

Found (%): 57,19; N - 6,85; N - 17,70.

FAB-MC, positive ions, m/z: 462 [M+H]+.

Constant optical rotation [α]20D= -25,62 (c = 0,484, methanol).

Appearance: white powder.

EXAMPLE 195

The dihydrochloride 6-fluoro-4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-N-(TRANS-4-methoxycyclohexyl)hinzelin-2-carboxamide

Elemental analysis data (for C27H33FN6O3/2 HCl/1,8 H2O)

Calculated (%): 52,82; N - 6,34; N - 13,69.

Found (%): 52,94; N - 6,23; N - 13,72.

FAB-MC, positive ions, m/z: 509 [M+H]+.

Constant optical rotation [α]20D= +36,36 (c = 0,495, methanol).

Appearance: white powder.

EXAMPLE 196

The dihydrochloride of 4-[((1S,2R)-2-{[3-furyl(imino)methyl]amino}C is clohessy)amino]-N-(TRANS-4-methoxycyclohexyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C28H36N6O3/2 HCl/1,4 H2O)

Calculated (%): 55,79; N - 6,82; N - 13,94.

Found (%): 55,94; N - Of 6.73; N - 13,69.

FAB-MC, positive ions, m/z: 505 [M+H]+.

Constant optical rotation [α]20D= +88,09 (c = 0,563, methanol).

Appearance: white powder.

EXAMPLE 197

The dihydrochloride of N-(4,4-diverticulosis)-4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 511 [M+H]+.

Constant optical rotation [α]20D= +79,24 (c = 0,530, methanol).

Appearance: white powder.

EXAMPLE 198

Trihydrochloride 4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 509 [M+H]+.

Constant optical rotation [α]20D= -4,42 (c = 0,995, methanol).

Appearance: Golden yellow powder.

EXAMPLE 199

Trihydrochloride 4-[((1S,2R)-2-{[imino(pyridin-3-yl)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C29H31N7O2/3 HCl/1,5 H2O)

Calculated (%): 53,92; N Is 5.77; N - 15,18.

Found (%): 53,89; N - 5,80; N - 15,14.

FAB-MC, positive ions, m/z: 509 [M+H]+.

Constant optical the CSOs rotation [α] 20D= -23,50 (c = 0,570, methanol).

Appearance: yellow powder.

EXAMPLE 200

Trihydrochloride 4-[((1S,2R)-2-{[imino(pyridin-4-yl)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C29H31N7O2/3 HCl/0,3 H2O)

Calculated (%): 55,78; N - 5,59; N - 15,70.

Found (%): 55,76; N Is 5.77; N - 15,74.

FAB-MC, positive ions, m/z: 509 [M+H]+.

Constant optical rotation [α]20D= -9,04 (c = 1,105, methanol).

Appearance: yellow powder.

EXAMPLE 201

The dihydrochloride 6-chloro-N-cycloheptyl-4-{[(1S,2R)-2-(hinzelin-4-ylamino)cyclohexyl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C30H34N7OCl/2 HCl/0,8 H2O)

Calculated (%): 57,07; 6,00; N - 15,53.

Found (%): 57,06; N - 5,94; N - 15,32.

FAB-MC, positive ions, m/z: 544 [M+H]+.

Constant optical rotation [α]20D= +7,06 (c = 0,764, methanol).

Appearance: white powder.

EXAMPLE 202

The dihydrochloride of 4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C27H34N6O/2 HCl/2,2 H2O)

Calculated (%): 56.78 Has; N - 7,13; N - 14,71.

Found (%): 56,71; N - 6,82; N - 14,62.

FAB-MC, positive ions, m/z: 459 [M+H]+.

Kee is Naya optical rotation [α] 20D= +72,00 (c = 0,500, methanol).

Appearance: white powder.

EXAMPLE 203

The dihydrochloride 6-chloro-N-cycloheptyl-4-[((1S,2R)-2-{[(3-forfinal)(imino)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C29H34N6OClF/2 HCl/2,5 H2O)

Calculated (%): 53,18; N. Of 6.31; N - 12,83.

Found (%): 53,40; N - 6,14; N - 12,70.

FAB-MC, positive ions, m/z: 537 [M+H]+.

Constant optical rotation [α]20D= +82,28 (c = 0,559, methanol).

Appearance: white powder.

EXAMPLE 204

The dihydrochloride of 4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-N-(2-isopropoxyphenyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 490 [M+H]+.

Constant optical rotation [α]20D= +107,86 (c = 0,534, methanol).

Appearance: white powder.

EXAMPLE 205

The dihydrochloride of 4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-6-methyl-N-[2-(methylthio)ethyl]hinzelin-2-carboxamide

FAB-MC, positive ions, m/z: 478 [M+H]+.

Constant optical rotation [α]20D= +74,85 (c = 0,521, methanol).

Appearance: white powder.

EXAMPLE 206

The dihydrochloride of 4-[((1S,2R)-2-{[imino(4-methoxyphenyl)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (the La C 28H36N6O2/2 HCl/ H2O)

Calculated (%): 58,03; N - Of 6.96; N - 14,50.

Found (%): 58,05; N - 6,91; N - 14,59.

FAB-MC, positive ions, m/z: 489 [M+H]+.

Constant optical rotation [α]20D= +55,88 (c = 0,476, methanol).

Appearance: white powder.

EXAMPLE 207

The dihydrochloride of 4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C27H34N6O2/2 HCl/2,5 H2O)

Calculated (%): 54,73; N - 6,97; N - 14,18.

Found (%): 54,71; N - 6,60; N - 14,21.

FAB-MC, positive ions, m/z: 475 [M+H]+.

Constant optical rotation [α]20D= +73,66 (c = worn : 0.505, methanol).

Appearance: pale brown powder.

EXAMPLE 208

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Stage 1. 4-{[(1S,2R)-2-(Cyanoimino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

In an argon atmosphere to a solution 3,30 g of 4-{[(1S,2R)-2-aminocyclohexanol]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide in 80 ml of tetrahydrofuran at -20 ° C and successively added and 1.54 ml of triethylamine and 978 mg CYANOGEN bromide and the mixture is stirred at the same temperature for 0.5 hours. To the reaction solution was added to the DN and the mixture is subjected to extraction with ethyl acetate. The organic layer is washed with water and saturated brine and dried over magnesium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel (chloroform: methanol = 50:1), whereby receive a 1.96 g of the desired compound as a pale yellow crystalline substance.

Stage 2. 4-[((1S,2R)-2-{[Amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

To a solution of a 1.96 g of 4-{[(1S,2R)-2-(cyanoimino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide and 8,56 g of the hydrochloride methoxyamine in 80 ml ethanol add 10,96 g of sodium carbonate and the mixture is refluxed for 1 hour. The reaction solution is added to 400 ml of a mixture of ice water and the precipitated precipitated substance is collected by filtration. After washing the collected settled the matter by water it is dried under reduced pressure. The resulting powder was washed with a mixture of solvents (chloroform: isopropyl alcohol = 1:1) and get 1,71 g of the desired compound as a white powder.

Elemental analysis data (for C21H31N7O3)

Calculated (%): 58,72; N - 7,27; N - To 22.83.

Found (%): 58,48; N - 7,17; N - 22,76.

FAB-MC, positive ions, m/z: 430 [M+H]+.

Appearance: white powder.

Stage 3. The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohex the l)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Suspended 1,71 g of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide in 20 ml of ethyl acetate, is added to a suspension of 5 ml of 4 n solution of hydrogen chloride in ethyl acetate and the mixture is stirred for 15 minutes. To the reaction solution was added 40 ml of diethyl ether and the resulting precipitated precipitated substance is collected by filtration, washed with diethyl ether, dried under reduced pressure and get a 2.01 g of the desired compound as a white powder.

FAB-MC, positive ions, m/z: 430 [M+H]+.

Constant optical rotation [α]20D= +56,80 (c = 0,500, methanol).

In the same manner as in example 208, receive the following compounds 209-247, 249 and 250.

EXAMPLE 209

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H31N7O3/2 HCl/0,6 H2O)

Calculated (%): 53,50; N - 6,14; N - 17,48.

Found (%): 53,81; N - 6,11; N - 17,14.

FAB-MC, positive ions, m/z: 478 [M+H]+.

Constant optical rotation [α]20D= -20,23 (c = 0,771, methanol).

Appearance: yellow powder.

EXAMPLE 210

The dihydrochloride of 4-[((1S,2R)-2-{[amino(hydroxyimino)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazolo the-2-carboxamide

Elemental analysis data (for C24H29N7O3/2 HCl/ H2O)

Calculated (%): 51,99; 6,00; N - 17,68.

Found (%): 52,23; N - 6,07; N - 17,55.

FAB-MC, positive ions, m/z: 464 [M+H]+.

Constant optical rotation [α]20D= -34,15 (c = 0,650, methanol).

Appearance: pale yellow powder.

EXAMPLE 211

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C22H33N7O2/2 HCl/2,5 H2O)

Calculated (%): 48,44; N - 7,39; N - 17,97.

Found (Percent): C - 48,59; N - 7,05; N - 17,88.

FAB-MC, positive ions, m/z: 428 [M+H]+.

Constant optical rotation [α]20D= +45,71 (c = 0,525, methanol).

Appearance: white powder.

EXAMPLE 212

The dihydrochloride of 4-[((1S,2R)-2-{[amino(hydroxyimino)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 414 [M+H]+.

Constant optical rotation [α]20D= +33,55 (c = 0,590, methanol).

Appearance: white powder.

EXAMPLE 213

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-6-methyl-N-(n-propyl)hinzelin-2-carboxamide

Elemental analysis data (for C21H31N7O2/2 HCl/1,8 H2O)

Calculated (%): - 48,61; N - 7,11; N - 18,90.

Found (%): 48,32; N - Of 6.71; N - 18,60.

FAB-MC, positive ions, m/z: 414 [M+H]+.

Constant optical rotation [α]20D= +48,84 (c = 0,520, methanol).

Appearance: white powder.

EXAMPLE 214

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(cyclopropylmethyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 426 [M+H]+.

Constant optical rotation [α]20D= +46,72 (c = 0,535, methanol).

Appearance: white powder.

EXAMPLE 215

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-hydroxyethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C20H29N7O3/2 HCl/3 H2O)

Calculated (%): 44,28; N - 6,87; N - 18,07.

Found (%): 44,59; N - 6,48; N - 18,14.

FAB-MC, positive ions, m/z: 416 [M+H]+.

Constant optical rotation [α]20D= +56,32 (c = of 0.625, methanol).

Appearance: white powder.

EXAMPLE 216

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-isopropyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C21H31N7O2/2 HCl/2 H2O)

Calculated (%): 48,28; N - 7,14; N - 18,77.

Found (%): 48,52; N - 6,79; N - 18,72.

FAB-MC, positive ions, m/z: 414 M+H] +.

Constant optical rotation [α]20D= +43,61 (c = determined as 0.720, methanol).

Appearance: white powder.

EXAMPLE 217

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-cyclopropyl-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 412 [M+H]+.

Constant optical rotation [α]20D= +49,39 (c = 0,575, methanol).

Appearance: white powder.

EXAMPLE 218

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-cyclobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C22H31N7O2/2 HCl/1,6 H2O)

Calculated (%): 50,11; N - 6,92; N - 18,59.

Found (%): 50,19; N - 6,69; N - 18,55.

FAB-MC, positive ions, m/z: 426 [M+H]+.

Constant optical rotation [α]20D= +35,10 (c = 0,490, methanol).

Appearance: white powder.

EXAMPLE 219

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-6-methyl-N-(2,2,2-triptorelin)hinzelin-2-carboxamide

FAB-MC, positive ions, m/z: 454 [M+H]+.

Constant optical rotation [α]20D= +56,92 (c = 0,520, methanol).

Appearance: white powder.

EXAMPLE 220

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-ethyl-N,6-dimethylthiazole-carboxamide

Elemental analysis data (for C21H31N7O2/2 HCl/2,3 H2O)

Calculated (%): 47,78; N - 7,18; N - A 18.57.

Found (Percent): C - 47,80; N - 6,74; N - 18,53.

FAB-MC, positive ions, m/z: 414 [M+H]+.

Constant optical rotation [α]20D= +37,14 (c = 0,490, methanol).

Appearance: white powder.

EXAMPLE 221

The dihydrochloride of 4-[((1S,2R)-2-{[imino(1,2-oxazine-2-yl)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C28H35N7O3/2 HCl/0,8 H2O)

Calculated (%): 55,59; N - To 6.43; N - 16,21.

Found (Percent): C - 55,89; N. Of 6.66; N $ 15.87 With.

FAB-MC, positive ions, m/z: 518 [M+H]+.

Constant optical rotation [α]20D= -14,90 (c = 0,510, methanol).

Appearance: yellow powder.

EXAMPLE 222

The dihydrochloride 6-chloro-N-cycloheptyl-4-[((1S,2R)-2-{[imino(1,2-oxazine-2-yl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C27H38N7O2Cl/2 HCl/2,2 H2O)

Calculated (%): 50,62; N - 6,99; N - 15,30.

Found (%): 50,45; N - 6,59; N - 15,19.

FAB-MC, positive ions, m/z: 528 [M+H]+.

Constant optical rotation [α]20D= +57,73 (c = 0,485, methanol).

Appearance: white powder.

EXAMPLE 223

The dihydrochloride of 4-[((1S,2R)-2-{[imino(1,2-oxazine-2-is)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C25H37N7O2/2 HCl/ H2O)

Calculated (%): 53,76; N - 7,40; N - 17,55.

Found (%): 53,51; N - 7,20; N - 17,26.

FAB-MC, positive ions, m/z: 468 [M+H]+.

Constant optical rotation [α]20D= +56,76 (c = 0,532, methanol).

Appearance: white powder.

EXAMPLE 224

The dihydrochloride of N-cycloheptyl-4-[((1S,2R)-2-{[imino(1,2-oxazine-2-yl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C28H41N7O2/2 HCl/1,5 H2O)

Calculated (%): 55,35; N - 7,63; N - 16,14.

Found (Percent): C - 55,67; N - 7,73; N - 15,92.

FAB-MC, positive ions, m/z: 508 [M+H]+.

Constant optical rotation [α]20D= +52,47 (c = 0,404, methanol).

Appearance: white powder.

EXAMPLE 225

The dihydrochloride 6-chloro-N-cycloheptyl-4-[((1S,2R)-2-{[imino(isoxazolidine-2-yl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C26H36N7O2Cl/2 HCl/2,5 H2O)

Calculated (%): 49,41; N - 6,86; N - 15,51.

Found (%): 49,18; N - 6,86; N - 15,41.

FAB-MC, positive ions, m/z: 514 [M+H]+.

Constant optical rotation [α]20D= +76,82 (c = 0,492, methanol).

Appearance: white powder.

EXAMPLE 226

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methylamino}cyclohexyl)amino]-6-chloro-N-cycloheptylmethyl-2-carboxamide

Elemental analysis data (for C24H34N7O2Cl/2 HCl/ H2O)

Calculated (%) : - Of 49.79; H - 6,62; N - 16,93.

Found (%): 49,66; N Is 6.54; N - 17,12.

FAB-MC, positive ions, m/z: 488 [M+H]+.

Constant optical rotation [α]20D= +54,20 (c = 0,424, methanol).

Appearance: white powder.

EXAMPLE 227

The dihydrochloride 6-chloro-N-cycloheptyl-4-{[(1S,2R)-2-({imino[methoxy(methyl)amino]methyl}amino)cyclohexyl]amino}-hinzelin-2-carboxamide

Elemental analysis data (for C25H36N7O2Cl/2 HCl/2,5 H2O)

Calculated (%): 48,43; N - 6,99; N - 15,81.

Found (%): 48,28; N - 6,60; N - 15,97.

FAB-MC, positive ions, m/z: 502 [M+H]+.

Constant optical rotation [α]20D= +78,83 (c = 0,515, methanol).

Appearance: white powder.

EXAMPLE 228

The dihydrochloride of N-(2,2-dimethylpropyl)-4-[((1S,2R)-2-{[imino(isoxazolidine-2-yl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 468 [M+H]+.

Constant optical rotation [α]20D= +50,28 (c = of 0.533, methanol).

Appearance: white powder.

EXAMPLE 229

The dihydrochloride of 4-[((1S,2R)-2-{[imino(isoxazolidine-2-yl)methyl]amino}cyclohexyl)amino]-6-methyl-N-[3-(methylthio)propyl]hinzelin-2-carboxamide

Elemental analysis data (for C24H35N7 O2S/2 HCl/ H2O)

Calculated (Percent): C - 49,99; N - 6,82; N - 17,00.

Found (%): 50,05; N - 6,72; N - 16,87.

FAB-MC, positive ions, m/z: 486 [M+H]+.

Constant optical rotation [α]20D= +56,42 (c = 0,514, methanol).

Appearance: white powder.

EXAMPLE 230

The dihydrochloride of 4-[((1S,2R)-2-{[imino(isoxazolidine-2-yl)methyl]amino}cyclohexyl)amino]-N-(3-methoxy-2,2-dimethylpropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H39N7O3/2 HCl/ H2O)

Calculated (%): 53,06; N And 7.36; N - 16,66.

Found (%): 53,44; N - 7,13; N - 16,52.

FAB-MC, positive ions, m/z: 498 [M+H]+.

Constant optical rotation [α]20D= +48,19 (c = 0,527, methanol).

Appearance: pale yellow powder.

EXAMPLE 231

The dihydrochloride of 4-[((1S,2R)-2-{[imino(isoxazolidine-2-yl)methyl]amino}cyclohexyl)amino]-6-methyl-N-(tetrahydro-2H-Piran-4-yl)hinzelin-2-carboxamide

Elemental analysis data (for C25H35N7O3/2 HCl/2,4 H2O)

Calculated (%): 50,23; N - 7,05; N - 16,40.

Found (%): 50,29; N - 6,88; N - 16,39.

FAB-MC, positive ions, m/z: 482 [M+H]+.

Constant optical rotation [α]20D= +62,18 (c = 0,550, methanol).

Appearance: white powder.

EXAMPLE 232

The dihydrochloride of 4-[((1S,2R)-2-{[imino(isoxazolidine-2-yl)methyl]amino}cyclohexyl)am is but]-N-(TRANS-4-methoxycyclohexyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C27H39N7O3/2 HCl/2 H2O)

Calculated (%): 52,42; N - 7,33; N - 15,85.

Found (%): 52,13; N - 7,19; N - 15,69.

FAB-MC, positive ions, m/z: 510 [M+H]+.

Constant optical rotation [α]20D= +61,67 (c = 0,548, methanol).

Appearance: white powder.

EXAMPLE 233

The dihydrochloride of N-(2-ethylbutyl)-4-[((1S,2R)-2-{[imino(isoxazolidine-2-yl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H39N7O2/2 HCl/ H2O)

Calculated (%): 54,54; H - EUR 7.57; N - 17,12.

Found (%): 54,49; N - 7,38; N - 16,91.

FAB-MC, positive ions, m/z: 482 [M+H]+.

Constant optical rotation [α]20D= +52,57 (c = 0,563, methanol).

Appearance: white powder.

EXAMPLE 234

The dihydrochloride of N-(2,2-dimethylpropyl)-4-{[(1S,2R)-2-({imino[methoxy(methyl)amino]methyl}amino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H37N7O2/2 HCl/0.5 H2O)

Calculated (%): 53,63; N - 7,50; N - 18,24.

Found (%): 53,63; N - 7,56; N - 17,89.

FAB-MC, positive ions, m/z: 456 [M+H]+.

Constant optical rotation [α]20D= +64,07 (c = 0,518, methanol).

Appearance: white powder.

EXAMPLE 235

The dihydrochloride of 4-[((1S,2R)-2-{[imino(isoxazol the Jn-2-yl)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C24H35N7O2/2 HCl/1,2 H2O)

Calculated (%): 52,59; N - 7,25; N - 17,89.

Found (Percent): C - 52,55; N - 7,13; N - 17,59.

FAB-MC, positive ions, m/z: 454 [M+H]+.

Constant optical rotation [α]20D= +59,96 (c = 0,507, methanol).

Appearance: white powder.

EXAMPLE 236

The dihydrochloride of 4-{[(1S,2R)-2-({imino[methoxy(methyl)amino]methyl}amino)cyclohexyl]amino}-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H35N7O2/2 HCl/0,7 H2O)

Calculated (%): 52,41; N - 7,34; N - 18,60.

Found (%): 52,44; N - 7,22; N - 18,26.

FAB-MC, positive ions, m/z: 442 [M+H]+.

Constant optical rotation [α]20D= +73,00 (c = 0,526, methanol).

Appearance: white powder.

EXAMPLE 237

The dihydrochloride of 4-{[(1S,2R)-2-({imino[methoxy(methyl)amino]methyl}amino)cyclohexyl]amino}-N-(TRANS-4-methoxycyclohexyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C26H39N7O3/2 HCl/ H2O)

Calculated (%): 53,06; N And 7.36; N - 16,66.

Found (%): 53,34; N - 7,17; N - 16,40.

FAB-MC, positive ions, m/z: 498 [M+H]+.

Constant optical rotation [α]20D= +70,16 (c = 0,496, methanol).

Appearance: white powder.

EXAMPLE 238

The dihydrochloride of 4-{[(1S,2R)-2-({imino[m is toxi(methyl)amino]methyl}amino)cyclohexyl]amino}-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H35N7O3/2 HCl/2 H2O)

Calculated (%): 48,76; N - 7,29; N - 17,31.

Found (%): 48.38 Per; N - 6,89; N - 17,14.

FAB-MC, positive ions, m/z: 458 [M+H]+.

Constant optical rotation [α]20D= +66,80 (c = 0,500, methanol).

Appearance: white powder.

EXAMPLE 239

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C22H33N7O3/2 HCl/2,2 H2O)

Calculated (%): 47,36; N - 7,15; N - 17,57.

Found (%): 47,19; N - 6,76; N - 17,50.

FAB-MC, positive ions, m/z: 444 [M+H]+.

Constant optical rotation [α]20D= +47,45 (c = 0,510, methanol).

Appearance: white powder.

EXAMPLE 240

The dihydrochloride of 4-[((1S,2R)-2-{[amino(hydroxyimino)methyl]amino}cyclohexyl)amino]-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 430 [M+H]+.

Constant optical rotation [α]20D= +31,28 (c = worn : 0.505, methanol).

Appearance: white powder.

EXAMPLE 241

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-ethoxyethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H33N7O3/2 HCl/2 H2 O)

Calculated (Percent): C - 47,83; N - 7,11; N - 17,75.

Found (Percent): C - 47,59; N - 6,94; N - 17,72.

FAB-MC, positive ions, m/z: 444 [M+H]+.

Constant optical rotation [α]20D= +57,20 (c = 0,500, methanol).

Appearance: white powder.

EXAMPLE 242

The dihydrochloride of 4-[((1R,2S)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 430 [M+H]+.

Constant optical rotation [α]20D= -53,09 (c = 0,550, methanol).

Appearance: white powder.

EXAMPLE 243

The dihydrochloride of 4-[((1S,2R)-2-{[amino(amoxiillin)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 444 [M+H]+.

Constant optical rotation [α]20D= +55,04 (c = worn : 0.505, methanol).

Appearance: white powder.

EXAMPLE 244

The dihydrochloride of 4-[((1S,2R)-2-{[amino(propoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H35N7O3/2 HCl/3,3 H2O)

Calculated (%): 49,23; N - 7,26; N - 17,47.

Found (Percent): C - 48, 97mm; N - 6,88; N - 17,48.

FAB-MC, positive ions, m/z: 458 [M+H]+.

Constant optical rotation [α]20D= +50,29 (c = worn : 0.505, methanol).

Appearance: white powder.

NOTE THE R 245

The dihydrochloride of 4-{[(1S,2R)-2-({amino[(2-methoxyethoxy)imino]methyl}amino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H35N7O4/2 HCl/2,4 H2O)

Calculated (%): 46,84; N - 7,14; N - 16,63.

Found (%): 46,82; N - 6,82; N - 16,50.

FAB-MC, positive ions, m/z: 474 [M+H]+.

Constant optical rotation [α]20D= +48,40 (c = 0,500, methanol).

Appearance: white powder.

EXAMPLE 246

The dihydrochloride of 4-{[(1S,2R)-2-({amino[(2-floratone)imino]methyl}amino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C22H32N7O3F/2 with HCl/2 H2O)

Calculated (%): 46,32; N - Of 6.71; N - 17,19.

Found (%): 46,32; N - 6,36; N - 17,09.

FAB-MC, positive ions, m/z: 462 [M+H]+.

Constant optical rotation [α]20D= +47,76 (c = 0,515, methanol).

Appearance: white powder.

EXAMPLE 247

The dihydrochloride of 4-({(1S,2R)-2-[(amino{[2-(methylthio)ethoxy]imino}methyl)amino]cyclohexyl}amino)-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C23H35N7O3S/2 HCl/2 H2O)

Calculated (%): 46,15; N - 6,90; N - 16,38.

Found (%): 46,05; N - Of 6.73; N - 16,26.

FAB-MC, positive ions, m/z: 490 [M+H]+.

Constant optical VR is the value of [α] 20D= +39,19 (c = 0,500, methanol).

Appearance: white powder.

EXAMPLE 248

1/2 Sulfate 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Suspended 300 mg 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide in 9 ml of methanol and the suspension add 35.4 mg of concentrated sulfuric acid. After stirring the mixture for 15 minutes there was added 75 ml of diisopropyl ether. Precipitated precipitated substance is collected by filtration, washed with diisopropyl ether, and dried under reduced pressure and get 314 mg of the desired compound as a white powder.

Elemental analysis data (for C21H31N7O3/0,5 H2SO4/1,5 H2O)

Calculated (Percent): C - 49,89; N - 6,98; N - 19,39.

Found (%): 49,78; N Is 6.61; N - MT 19 : 18.

FAB-MC, positive ions, m/z: 430 [M+H]+.

Constant optical rotation [α]20D= -27,63 (c = 0,550, methanol).

EXAMPLE 249

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 372 [M+H]+.

Constant optical rotation [α]20D= +57,20 (c = 0,465, methanol).

Appearance: white powder.

EXAMPLE 250

Dihydrochlor the d 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-methoxy-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C19H27N7O3/2 HCl/0,8 H2O)

Calculated (%): 46,69; N. Of 6.31; N - Grade Of 20.06.

Found (%): 46,95; N - 6,27; N - 19,87.

FAB-MC, positive ions, m/z: 402 [M+H]+.

Constant optical rotation [α]20D= +8,80 (c = 0,500, methanol).

Appearance: white powder.

Example test 1. Test for skin sensitization in Guinea pigs (method adjuvant and skin samples)

The back area of male Hartley Guinea pigs (n = 5) aged 7 weeks shaved with an electric razor and the next day initiate primary sensitization. During primary sensitization emulsified full beta-blockers administered intradermal dose of 0.1 ml only at the initial moment of time and in the place where entered adjuvant, causing the plaster to the skin sample in a closed condition with 0.1 g of an ointment containing 1% of tested compounds. As the basis for ointments use vaseline containing 1% sesquioleate sorbitan (surfactant). 24 hours after you have applied the adhesive tape for skin samples, the adhesive tape is removed and the application site is cleaned by wiping. The procedure of such primary sensitization is carried out every day and continue on the whole 3 days. On day 7 after the initial application of the primary sensitization work in secondary sensibili is the situation. The area subjected to primary sensitization, shaved and open put the ointment containing 10% lauryl sodium. After 24 hours the application site clean, wiping it, and in the closed state impose a cotton bandage, which is applied to 0.2 g of an ointment containing 1% of tested compounds. 48 hours after applying the bandage is removed and the application site is cleaned by wiping. The provocation carried out on day 13 after the second sensitization. Region of the back and side area is shaved and the place provocations put 0.01 g of an ointment containing 1% of the test compounds, and leave for about 24 hours. Approximately 24 hours and 48 hours after the provocation carried out the inspection of the surface of the skin to determine the presence or absence of sensibilizirovannoy. Determination carry out the evaluation according to the evaluation criteria (see table 1) according to the method of Draize (1959).

In this regard, as a positive control, using 1-chloro-2,4-dinitrobenzene (DNCB) (sensitization: 1%, provocation: 0,1%). As the test compounds are used compounds of example 58 and example 248. As a control for comparison use the dihydrochloride of 4-[((1S,2R)-2-{[amino(imino)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide described in example 383 in patent document 1 (sensitization: 1%induction: 0,1%)./p>

Table 1
ErythemaSwelling
0No erythema0There is swelling
1Very faint erythema (barely perceptible)1Very weak edema (barely perceptible)
2Distinct erythema2Weak edema (edges of area well distinguishable by a visible bulge)
3Erythema moderate to strong3Moderate edema (bulge approximately 1 mm)
4Strong erythema prior to the formation of a small scab (deep injury)4Edema (issue shall clost 1 mm or more and spread over the area of effect)

As a result of sensitization with the test compounds do not see. But see strong erythema in positive control with DNCB (score 3 in 3/5 cases, grade 2 in 1/5 of the cases and a score of 1 in 1/5 of the cases) and mild edema (score 1 in 3/5 cases and a score of 0 in 2/5 cases). In addition, in the group with connection control for comparison of swelling is not observed in all cases, while in 2/5 cases see clearly perceptible erythema (score 2).

Therefore, it is apparent that the compounds according to the invention, which do not show sensibilizirovannoy, very applicable not only to external agents, but also for drugs in other dosage forms.

Example of test 2. Test for primary skin irritation in rabbits

The back region in female rabbits Kbs: JW (n=3-32) at the age of 20 weeks shaved with an electric razor and the next day the skin of the back put a band-aid for skin samples with 0.1 g of an ointment containing the test compound (introduction). As the basis for ointments use vaseline containing 5% sesquioleate sorbitan (surfactant). 24 hours after the introduction of the adhesive tape for skin samples were removed and the application site is cleaned by wiping. Then observe the formation of erythema and swelling at the site of application. The definition of irritation carry out the evaluation according to the evaluation criteria (table 1) according to the method of Draize (1959), used in the example test 1.

As a simple primary indicator of skin irritation using the average of the sum of the assessments of erythema and edema. As control compounds for comparison, which is structurally similar to the compounds according to the invention, use of the dihydrochloride of 4-[((1S,2R)-2-{[amino(imino)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide (hereinafter referred to as the control for comparison (A)described in example 383 in patent document 1; the dihydrochloride of 4-[((1S,2R)-2-{[amino(imino)methyl]amino}cyclohexyl)amino]-6-methyl-N-neopentylglycol-2-carboxamide (hereinafter referred to as the control for comparison), described in example 29 in patent document 1; the dihydrochloride of 4-[((1S,2R)-2-{[amino(imino)methyl]amino}cyclohexyl)amino]-N-(2-ethoxyethyl)-6-methylpyrazole-2-carboxamide (hereinafter referred to as the control to compare With), described in example 372 in patent document 1; the dihydrochloride of 4-[((1S,2R)-2-{[amino(imino)methyl]amino}cyclohexyl)amino]-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide (hereinafter referred to as the control for comparison (D)described in example 346 in patent document 1; the dihydrochloride of 4-[((1S,2R)-2-{[amino(imino)methyl]amino}cyclohexyl)amino]-N-isopropyl-6-methylpyrazole-2-carboxamide (hereinafter referred to as the control for comparison (E), described in example 388 in patent document 1; and the dihydrochloride of 4-[((1S,R)-2-{[amino(imino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide (hereinafter referred to as the control for comparison (F), described in example 48 in patent document 1.

More specifically, the connection control for comparison And is different from the compounds of examples 211, 212, 236 and 60 according to the present invention only by the substituent in position 4; the connection to control for comparison differs from the compound of example 19 of the present invention only by the substituent in position 4; the connection to control for comparison With differs from the compounds of examples 94, 95 and 61 according to the present invention only by the substituent in position 4; the connection to control for comparison D differs from the compounds of examples 239, 240, 92, 59, 35 and 93 according to the present invention only by the substituent in position 4; the connection to control for comparison E differs from the compounds of examples 101 and 58 of the present invention only by the substituent in position 4; the connection to control for comparison F differs from the compounds of examples 208, 1 and 91 according to the present invention only by the substituent in position 4; and all other groups have the same structure. The results are given in table 2.

Example 91
Table 2
The test compound or a control compound to compareConcentration (%)Simple primary indicator of rasdr the supply of the skin
The control for comparison And3,01,8
Example 2113,01,5
Example 2123,00,8
Example 2363,01,6
Example 603,01,0
The control for comparison In3,02,4
Example 193,00,4
Control to compare With3,02,3
Example 943,01,0
Example 953,00,7
Example 613,00,4
The control for comparison D3,02,0
the example 239 3,01,0
Example 2403,01,0
Example 923,00,0
Example 593,00,2
Example 353,01,5
Example 933,00,2
The control for comparison E3,03,6
Example 1013,02,6
Example 583,00,4
The control for comparison F3,02,2
Example 2083,00,2
Example 2483,00,8
Example 13,00,3
3,00,5

As can be seen from table 2, the substitution of guanidinium in the side chain in position 4 derived hintline such substituents, which are the compounds according to the invention, significantly reduces primary skin irritation. Therefore, it is apparent that the compounds according to the invention is highly applicable as external agents with less skin irritation.

Example of test 3. Impact on scratching behavior in mice, caused by the use of serotonin

On the neck and the backs of ICR male mice (n=3-6) aged 4-6 weeks put 100 μl of a solution obtained by dissolving the hydrochloride serotonin in ethanol, in a concentration of 0.1% (hereinafter referred to as serotonin), and count the count of the number of episodes of scratching at the application hind legs, taking place immediately after the application within 15 minutes after injection. The introduction of the test compounds carry the application to the skin, intravenous injection or by oral administration. In the case of application to the skin of the test compound, which is dissolved in ethanol, put in the amount of 100 μl simultaneously with serotonin. In the case of intravenous administration of the test compound dissolved in physiological solution, injected at a dose of 10 ml/kg 5 minutes before the skin is of serotonin. In the case of oral administration of the test compound, dissolved in water, injected at a dose of 10 ml/kg over 20 minutes before application of serotonin. The control group for each method of administration give the appropriate solvent and compare the magnitude of the scratching behavior between the control group and the group treated with the test compound.

The results obtained when applied to the skin of the tested compounds are given in table 3; the results obtained by intravenous injection of the test compounds are given in table 4; and the results obtained by oral administration of the tested compounds are given in table 5.

Table 3
Test connectionConcentration (%)The average number of episodes of scratching-
of
Standard errorThe average number of episodes of scratching in the control group
Example 2110,173,0the 9.7134,8
Example 2120,149,8 7,8180,3
Example 190,169,29,8164,6
Example 2390,155,813,9134,8
Example 2400,165,37,1111,3
Example 920,176,311,7138,3
Example 590,157,89,3131,0
Example 350,169,05,3168, 8mm
Example 1010,156,87,5137,0
Example 580,155,56,8131,0
Example 2080,181,015,2211,2
Example 10,157,86,6101,8
Example 910,170,5the 11.6KZT 166.5

Table 4
Test connectionDose (mg/kg)The average number of episodes combingStandard errorThe average number of episodes of scratching in the control group
Example 60364,08,5156, 3mm
Example 208353,814,3158,8

Table 5
Test connectionDose (mg/kg)The average number of episodes combingStandard errorThe average number of episodes of scratching in the control group
Example 2393088,69,6148, 8 persons
Example 24030for 95.26,2229,2
Example 9230141,012,4229,2

As can be seen from tables 3-5, the compounds according to the invention significantly inhibit the behavior of scratching in the neck and back caused by application of serotonin. From the obtained results it is obvious that the use of the compounds according to the invention as an external drug, intravenous drugs or drug for oral administration useful in case of itching caused by various diseases accompanied by itching.

Example of test 4. Effect on spontaneous scratching behavior in mice, caused by the destruction of the barrier of the stratum corneum

p> Neck and back in male ICR mice aged 5 weeks shave under ether anesthesia and destroy the barrier of the stratum corneum, causing solvent mixture of acetone and ether in the ratio 1:1 on the shaved area, and then applying twice a day with distilled water during the following days (within 10 days). Spontaneous scratching behavior near the shaved area, caused by the destruction of the barrier of the stratum corneum, see before and after application of the tested drugs within 30 minutes using a video system that works automatically, and the measured change (%) number of episodes tangle free. As drug use ointment containing the test compound, and the area around the clipping is applied 50 mg ointment. In this regard, in the control group as the basis for ointments use vaseline containing sesquioleate sorbitan (surfactant) in an amount of 1%. The results are given in table 6.

Table 6
Test connectionConcentration (%)The rate of change (%)Standard error
The control group -100,916,9
Example 600,155,2the 5.7
Example 940,143,910,2
Example 610,151,714,8
Example 2390,147,911,3
Example 2400,154,411,7
Example 921,055,912,4
Example 350,160,48,0
Example 580,167,715,5
Example 2080,141,610,7

As can be seen from table 6, the compounds according to the invention is substantially the basement who have spontaneous scratching behavior, caused by destruction of the barrier of the stratum corneum. From the obtained results it is obvious that the use of the compounds according to the invention as an external drug ointment is also effective in the treatment of itching caused by xerodermia or atopic dermatitis, itching accompanying hemodialysis, and other itching.

Example of test 5. Test for acute toxicity in mice

Using male ICR mice aged 4-6 weeks. The connection according to the invention is administered intravenously at a dose of 10 ml/kg into the tail vein and then observe the behavior of the mice within 2 hours. The results are given in table 7.

Table 7
Test connectionConcentration (mg/kg)The change in behavior
Example 21110No noticeable changes
Example 21210No noticeable changes
Example 605No noticeable changes
Example 23910No C is a noticeable change
Example 24010No noticeable changes
Example 9210No noticeable changes
Example 10110No noticeable changes
Example 5810No noticeable changes
Example 20820No noticeable changes
Example 110No noticeable changes

As can be seen from table 7, changes in symptoms, such as sedative effect, not observed in all mice that were administered the test compound. Accordingly, the toxicity of the compounds according to the invention is extremely low, and connections can be safely used as a pharmaceutical preparation.

Sample preparation 1

Put 100 g of compound according to the invention of example 1, 292 g of D-mannitol, 120 g of corn starch and 28 g hydroxypropylcellulose with a low degree of substitution in the granulator-dryer fluidized bed (STREA; manufacturer PAUREC) and granular is to spray a quantity of aqueous 5% solution of hydroxypropylcellulose. After drying and subsequent grinding in a crusher/mill (COMIL; manufacturer PAULEC) in the mixture is mixed with a certain amount of stearate in the mixer (container mixer BOHRE, model MS; manufacturer KOTOBUKI-GIKEN), the mixture is formed into tablets with a diameter of 7 mm and a weight of 140 mg per tablet with a rotary swaging tablet press machine (CORRECT 12HUK; manufacturer KIKUSUI) and receive a tablet containing 25 mg of the compounds according to the invention.

Example product 2

Placed 75 g of compound according to the invention of example 1, 180 g of lactose, 75 g of corn starch and 18 g calcixerollic in with stirring granulator (vertical granulator, model VG-01), add a quantity of aqueous 5% solution of hydroxypropylcellulose, the mixture granularit and dried in the granulator-dryer fluidized bed (STREA; manufacturer PAUREC) and then crushed in the crusher/mill (COMIL; manufacturer PAULEC). Fill in 120 g of crushed material capsule No. 3 using capsulearava machine (filler capsules; SHIONOGI QUALICAPS) and receive capsules containing 25 mg of the compounds according to the invention.

The example of the drug 3

Weigh 2.5 g of the compounds according to the invention of example 1 and 4.5 g of sodium chloride, add 450 ml of water for injection, the mixture is stirred until dissolved and then bring the pH to 6.5 with 0.1 mol/l hydrochloric acid or 0.1 mol/l sodium hydroxide solution. Then add the keys water for injection to obtain a total volume of 500 ml Then the thus obtained solution is filtered under pressure through a membrane filter (pore size 0.22 μm). Then 5,3 ml of the filtrate is aseptically fill a 5-ml brown vial and receive a preparation for injection containing 25 mg of the compounds according to the invention. The procedure from receipt of the filling is carried out in aseptic conditions.

Sample preparation 4

At 45 º C dissolve of 99.75 g of Vihterpalu N-15 (manufactured by HIRTH), add 0.25 g of the compounds according to the invention of example 1 and dispersed by stirring. The resulting dispersion is poured into a 1-d form of suppository at high temperatures, paying attention to the prevention of the deposition, utverjdayut and removed from the form, get the suppository contains 25 mg of the compounds according to the invention.

Sample preparation 5

Weigh 0.5 g of the compounds according to the invention of example 1, and 5.2 g of sodium dihydrophosphate, 11.9 g of monohydratefast sodium, 2.5 g of sodium chloride and 0.3 g of benzalkonium chloride, add 950 ml of distilled water and the mixture is stirred until dissolution. Then add distilled water to obtain a total volume of 1000 ml of Solution, thus obtained, was filtered under pressure through a membrane filter (pore size 0.2 µm). Then 5 ml of the filtrate is filled aseptically sterilized 5-ml vial for eye drops and get eye drops (5 ml)containing 0.5 mg/ml preprogram the ia according to the invention. The procedure from receipt of the filling is carried out in aseptic conditions.

Sample preparation 6

Weigh 80 g olive oil 15 g of cetyl alcohol and 15 g of stearyl alcohol, the mixture is stirred and dissolved by heating at 70 º C in a water bath (oil phase). Separately, weigh 1 g of compound according to the invention of example 1, 10 g Polysorbate 80, 5 g of lauryl sodium, 0.25 g of methyl para-hydroxybenzoate, 0.15 g propyl-para-hydroxybenzoate and 880 g of distilled water, the mixture is stirred and dissolved by heating at 70 º C in a water bath (aqueous phase). The oil phase and the aqueous phase is placed in a vacuum emulsifier and the mixture is then emuleret under stirring with a high speed mixer-homogenizer at 70 º C in vacuum. Then, the resulting emulsion is cooled with water to 35 º C while mixing with a low speed. Then 50 ml of the resulting emulsion fill a 50-ml container of lotion and get lotion (50 ml)containing 1.0 mg/ml of the compounds according to the invention.

Example of preparation 7

Weighed 250 g white vaseline, 250 g of stearyl alcohol and 40 g polyoxyethylene hydrogenated castor oil 60, the mixture is stirred and dissolved by heating at 70 º C in a water bath (oil phase). Separately, weigh 1 g of compound according to the invention of example 1, 120 g of propylene glycol, 0.25 g of methyl para-hydroxybenzoate, ,15 g of propyl-para-hydroxybenzoate and 340 g of distilled water, the mixture is stirred and dissolved by heating at 70 º C in a water bath (aqueous phase). The oil phase and the aqueous phase is placed in a vacuum mixer and then the mixture emuleret under stirring at 70 º C in vacuum. The ointment obtained by cooling the resulting emulsion and a light mixing up until the emulsion not hardened, fill the 10-g containers for ointments or 10-g tubes for ointments and get an ointment containing 1.0 mg/g of compound according to the invention.

Example of preparation 8

Weighed 110 g of gelatin, 25 g of polyvinyl alcohol and 10 g of methyl cellulose, mix and get the powder mixture. Then it was added 13 g of glycerin and the powder was dispersed therein using a small mixer. Then to the mixture was added 100 g of distilled water and the mixture is dissolved in water when heated to 60OC. Then added to the mixture of 85 g of kaolin and dispersed therein at 60 ° C. To the resulting dispersion added to the dispersion obtained separately by mixing 20 g of glycerol and 5 g of sodium polyacrylate, and all dissolved and stirred at 60'C. Then to the mixture is added 15 g of polybutene and dispersed therein at 60 ° C. To the dispersion is added 0.5 g of compound according to the invention of example 1 and dispersed at 50 º C, getting through this pasta. Then the paste is spread on the basis of (non-woven product) (100 g/700 cm2and then covered the base cover protective Proclus is coy, made from polyethylene film (50 μm), cut and get through this sticky product. The connection according to the invention is contained in an amount of 1 mg to 7 cm2sticky drug.

Industrial applicability

As described above, the compounds according to the invention have a strong inhibitory effect on the behavior of scratching, slight irritations of the skin and not sensibiliser the skin and therefore highly applicable as external agents. Moreover, the compounds according to the invention have a overwhelming effect on the behavior of brushing not only by application to the skin, but also intravenous, subcutaneous and oral administration, and therefore highly applicable as a drug in different dosage form.

1. Derived hintline represented by the following General formula [1]or its pharmaceutically acceptable salt

where R1represents hydrogen or alkyl;
R2represents hydrogen, alkoxy, cycloalkyl, (cycloalkyl)alkyl or alkyl where the alkoxy, cycloalkyl, (cycloalkyl)alkyl and the alkyl can be substituted one to three groups selected from the group consisting of (1) alkoxy, (2) halogen, (3) alkoxyalkyl, (4) hydroxy, (5) alkylthio, (6) furil, (7) piperidine which may be substituted and the sludge;
R3and R4are the same or different and each represents hydrogen, alkyl, alkoxy or halogen;
R5and R6imagine the following:
(i) R5combine with R6that is alkylen where alkylene may condense with benzene loop;
(ii) R5represents hydrogen, hydroxy, alkyl or alkoxy, where alkyl and alkoxy may be substituted by one to three groups selected from the group consisting of alkoxy, alkylthio and halogen; and R6is (1) alkyl, (2) cycloalkyl, (3) phenyl, or (4) a 5-6-membered aromatic heterocyclic group containing one to three heteroatoms selected from the group consisting of nitrogen atom and oxygen atom, where the alkyl, cycloalkyl, phenyl and aromatic heterocyclic group may be substituted by one to three groups selected from the group consisting of (1) alkoxy, (2) hydroxy, (3) phenyl, (4) pyridyl, (5) furil, (6) halogen, and (7) N,N-dialkylamino;
(iii) R5represents hydrogen, hydroxy or alkoxy, where the alkoxy may be substituted by one to three groups selected from the group consisting of alkoxy, alkylthio and halogen; and R6represents-N(R61)(R62), where R61is hydrogen and R62represents hydrogen or alkoxy;
with the exception of compounds in which R5represents hydrogen, and R6predstavljaet a-NH 2.

2. Derived hintline or its pharmaceutically acceptable salt according to claim 1, where
(i) R5combine with R6that is alkylen where alkylene may be condensed with a benzene cycle; or
(ii) R5represents hydrogen, alkyl or alkoxy; and R6represents (1) alkyl, (2) cycloalkyl, (3) phenyl or (4) a 5-6-membered aromatic heterocyclic group containing one to three heteroatoms selected from the group consisting of nitrogen atom and oxygen atom, where the alkyl, cycloalkyl, phenyl and aromatic heterocyclic group may be substituted by one to three groups selected from the group consisting of (1) alkoxy, (2) hydroxy, (3) phenyl, (4) pyridyl, (5) furil, (6) halogen, and (7) N,N-dialkylamino.

3. Derived hintline or its pharmaceutically acceptable salt according to claim 1, where
R2represents hydrogen, cycloalkyl, (cycloalkyl)alkyl, or alkyl, where cycloalkyl, (cycloalkyl)alkyl and the alkyl can be substituted one to three groups selected from the group consisting of (1) alkoxy, (2) halogen, (3) hydroxy, and (4) alkylthio;
R3and R4are the same or different and each represents hydrogen, alkyl or halogen;
(iii) R5represents hydrogen, hydroxy or alkoxy, where the alkoxy may be substituted by one to three groups selected from the group consisting of Sarcoxie, alkylthio and halogen; and
R6represents-N(R61)(R62);
R61represents hydrogen;
R62represents hydrogen or alkoxy;
with the exception of compounds in which R5represents hydrogen, and R6represents-NH2.

4. Derived hintline or its pharmaceutically acceptable salt according to claim 2, where
R2represents (1) hydrogen, (2) alkoxy, (3) cycloalkyl, which can be substituted one to three groups selected from the group consisting of halogen, alkoxy, alkoxyalkyl and hydroxy, (4) (cycloalkyl)alkyl which may be substituted by one to three groups selected from the group consisting of alkoxyalkyl and hydroxy, or (5) alkyl;
(i) R5combine with R6that is alkylen where alkylene may condense with benzene loop;
(ii) R5represents hydrogen, alkyl or hydroxy, and R6is (1) alkyl which may be substituted by one to three groups selected from the group consisting of alkoxy, hydroxy, N,N-dialkylamino, phenyl, pyridyl and Furie, (2) cycloalkyl, (3) phenyl which may be substituted by one to three groups selected from the group consisting of alkoxy, halogen and N,N-dialkylamino, or (4) a 5-6-membered aromatic heterocyclic group containing one to three heteroatoms selected and the group, consisting of nitrogen atom and oxygen atom.

5. Derived hintline or its pharmaceutically acceptable salt according to claim 3, where
R2represents (1) hydrogen, (2) cycloalkyl, which may be substituted by alkoxy, (3) (cycloalkyl)alkyl or (4) alkyl which may be substituted by one to three groups selected from the group consisting of halogen, alkoxy, and alkylthio;
R3and R4are the same or different and each represents hydrogen, alkyl or halogen;
(iii) R5represents (1) hydrogen, (2) hydroxy, or (3) alkoxy which may be substituted by one to three groups selected from the group consisting of alkoxy, alkylthio and halogen; and
R6represents-N(R61)(R62), where R61represents hydrogen, R62represents hydrogen or alkoxy;
with the exception of compounds in which R5represents hydrogen, and R6represents-NH2.

6. Derived hintline or its pharmaceutically acceptable salt according to claim 1, where the compound is chosen from the group comprising compounds (1)to(15):
(1) 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide;
(2) N-(2,2-dimethylpropyl)-4-({(1S,2R)-2-[(2-methoxy-2-methylpropanoyl)amino]cyclohexyl]amino}-6-methylpyrazole-2-carboxamide;
(3) 4-({(1S,2R)-2-[(3-methoxyp animator)amino]cyclohexyl}amino)-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide;
(4) 4-({(1S,2R)-2-[(3-hydroxypropylamino)amino]cyclohexyl} amino)-N-isopropyl-6-methylpyrazole-2-carboxamide;
(5) 4-({(1S,2R)-2-[(3-hydroxypropylamino)amino]cyclohexyl}amino)-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide;
(6) 4-({(1S,2R)-2-[(2-hydroxy-2-methylpropanamide)amino]cyclohexyl}amino)-N-isobutyl-6-methylpyrazole-2-carboxamide;
(7) N-(2-ethoxyethyl)-4-({(1S,2R)-2-[(3-hydroxypropylamino)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide;
(8) 4-({(1S,2R)-2-[(2-hydroxy-2-methylpropanamide)amino]cyclohexyl}amino)-N-isopropyl-6-methylpyrazole-2-carboxamide;
(9) 4-({(1S,2R)-2-[(2-hydroxy-2-methylpropanamide)amino]cyclohexyl}amino)-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide;
(10) 4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide;
(11) 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide;
(12) 4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide;
(13) 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(2-ethoxyethyl)-6-methylpyrazole-2-carboxamide;
(14) N-(2-ethoxyethyl)-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide and
(15) 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-isopropyl-6-methylpyrazole-2-carboxamide.

7. Derived Chinas the Lin or its pharmaceutically acceptable salt according to claim 1, where the compound is chosen from the group comprising compounds (1)to(14):
(1) 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide;
(2) 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide;
(3) 4-[((1S,2R)-2-{[amino(hydroxyimino)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide;
(4) 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(cyclopropylmethyl)-6-methylpyrazole-2-carboxamide;
(5) 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-isopropyl-6-methylpyrazole-2-carboxamide;
(7) 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino)-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide;
(8) 4-[((1S,2R)-2-{[amino(hydroxyimino)methyl]amino}cyclohexyl)amino]-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide;
(9) 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-ethoxyethyl)-6-methylpyrazole-2-carboxamide;
(10) 4-[((1S,2R)-2-{[amino(amoxiillin)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide;
(11) 4-{[(1S,2R)-2-({amino[(2-methoxyethoxy)imino]methyl}amino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide;
(12) 4-{[(1S,2R)-2-({amino[(2-floratone)imino]methyl}amino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide;
(13) 4-({(1S,2R)-2[(amino{[2-(methylthio)ethoxy]imino}methyl)amino)cyclohexyl}amino)-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide and
(14) 4-[((1S,2R)-2-{[amino(2-methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide.

8. Pharmaceutical composition having activity antipruritic agent containing as an active ingredient derived hintline or its pharmaceutically acceptable salt according to any one of claims 1 to 7.

9. The pharmaceutical composition of claim 8, which is used to suppress itching caused by skin damage or skin itching.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to di(arylamino)aryl derivatives presented in the patent claim. The compounds show an inhibitory effect on protein EML4-ALK v1 and protein EGFR kinase activity. Also the invention refers to a pharmaceutical composition containing said compounds, the hybrid protein EML4-ALK and mutant protein EGFR kinase activity inhibitor, the use of said compounds for preparing the pharmaceutical composition, and to a method of preventing or treating non-small-cell lung cancer or EML4-ALK hybrid polynucleotide-positive and/or mutant EGFR polynucleotide-positive non-small-cell lung cancer.

EFFECT: use of di(arylamino)aryl as the protein EML4-ALK v1 and protein EGFR kinase activity inhibitors.

12 cl, 95 tbl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted sulphamide derivatives of formula I: , in which n, m, R1, R2a-c, R3, R4, R5 and R6 are as described in claim 1, in form of a racemate, enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a separate enantiomer or diastereomer, bases and/or salts of physiologically compatible acids. The invention also relates to a method of producing said compounds, a medicinal agent having antagonist action on bradykinin receptor 1 (B1R), containing such compounds, use of such compounds to produce medicinal agents, as well as sulphamide-substituted derivatives selected from a group of compounds given in claim 8.

EFFECT: providing novel compounds which are suitable as pharmacologically active substances in medicinal agents for treating disorders or diseases which are at least partially transmitted through B1R receptors.

13 cl, 581 ex

FIELD: chemistry.

SUBSTANCE: invention is a 6-10-member aryl selected from phenyl, naphthyl, tetrahydronaphthalenyl, indanyl or a 6-member heteroaryl containing 1-2 N atoms, selected from pyridyl or pyrimidinyl, where the aryl and heteroaryl groups can be unsubstituted or substituted with 1-3 substitutes selected from a group consisting of C3-6-cycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy, halogen atom, C1-7-alkyl, C1-7-alkoxy, oxazolyl, piperidin-1-yl, or C1-7-alkyl, substituted with a halogen atom, or represents phenyl, where at least one hydrogen atom is substituted with deuterium or tritium; R2 is a hydrogen atom, C1-7-alkyl or is benzyl, unsubstituted or substituted C1-7-alkoxy or halogen atom; or R1 and R2 together with a N atom with which they are bonded form 2,3-dihydroindol-1-yl or 3,4-dihydro-1quinolin-1-yl. The invention also relates to a method of producing compounds of formula and to a pharmaceutical composition having high affinity for the TAAR1 receptor.

EFFECT: compounds of formula (I), having high affinity for the TAAR1 receptor.

29 cl, 4 dwg, 1 tbl, 183 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are produced new diazepane substituted compounds representing various heterocyclic systems, including condensed, pharmaceutical compositions containing said compounds.

EFFECT: producing the compounds and compositions for preventing and treating neurological and mental disorders and diseases with involved orexin receptors.

13 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel cyanoisoquinoline derivatives of formula I , where R is selected from a group comprising hydrogen and C1-C10 alkyl, R1, R2, R3 and R4 are independently selected from a group comprising hydrogen, halogen, hydroxy, C1-C10 alkyl, substituted with 1-3 halogen atoms or C6-C14 acryl, C6-C14 aryl, -OR7, -SR7 and -SO2R7, where R7 is selected from a group comprising C1-C10 alkyl, C1-C10 alkyl substituted with C6-C14 aryl, C3-C10 cycloalkyl, C6-C14 aryl and C7-C8 heteroaryl containing 1-2 heteroatoms selected from a group comprising N, O and S, where C6-C14 aryl and C7-C8 heteroaryl are optionally substituted with 1-3 substitutes selected from a group comprising halogen, C1-C6 alkoxy, C1-C10 alkyl, C1-C6 dialkylamino and C4 heterocyclyl containing 2 heteroatoms selected from a group comprising nitrogen and oxygen, and R5 and R6 are independently selected from a group comprising hydrogen and C1-C3 alkyl, or pharmaceutically acceptable salts thereof. The invention also relates to novel cyanoquinoline derivatives of formula II , where R31, R32, R33 and R34 are independently selected from a group comprising hydrogen, hydroxy, halogen, C1-C10 alkyl substituted with 1-3 halogen atoms or with C6-C14 aryl, C6-C14 aryl, -OR37, -SR37 and -SO2R37, where R37 is selected from a group comprising C1-C10 alkyl, C1-C10 alkyl substituted with C6-C14aryl, C3-C10 aryl, C7-C8 heteroaryl containing 1-2 heteroatoms selected from a group comprising N, O and S, where C6-C14 aryl and C7-C8 heteroaryl are substituted with 1-3 substitutes selected from a group comprising halogen, C1-C6 alkoxy, C1-C10 alkyl, C1-C6 dialkylamino C4 heterocyclyl containing 2 heteroatoms selected from a group comprising nitrogen and oxygen, R35 denotes hydrogen or methyl, or pharmaceutically acceptable salts thereof. The invention also relates to specific cyanoisoquinoline compounds, a pharmaceutical composition based on the compound of formula I, a hypoxia-inducible factor (HIF) hydroxylase inhibiting method, a method of treating, preventing or slowing down development of a condition associated with hypoxia-inducible factor (HIF), a condition associated with erythropoietin (EPO), anaemia, based on use of the compound of formula I.

EFFECT: obtaining novel cyanoisoquinoline compounds having useful biological properties.

42 cl, 1 tbl, 54 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (I): wherein n means 1 or 2, X means an oxygen atom, a sulphur atom or NH, R1 means a side group of natural α-amino acid or its homologues or isomers specified in hydrogen, methyl, propan-2-yl, propan-1-yl, 2-methyl-propan-1-yl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxy-ethyl, carboxymethyl, 2-carboxyethyl, carbamoyl-methyl, 2-carbamoyl ethyl a, 4-aminobutan-1-yl, 3-aminopropan-1-yl, 3-guanidinopropan-1-yl, benzyl or 4-hydroxybenzyl, R2 means hydrogen or methyl, R3 means hydrogen, or R1 and R3 are coupled together by the group (CH2)3- or (CH2)4- and together with nitrogen and carbon atoms whereto attached form a five- or six-member ring, as well to their salts, solvates and salt solvates.

EFFECT: preparing compounds for treating and/or preventing the diseases, first of all thromboembolic diseases.

2 cl, 2 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing optionally substituted 4-(benzimidazo-2-yl methylamino)benzamidine of formula (I) in which R1 denotes a methyl group, R2 denotes a R21NR22 group, where R21 denotes an ethyl group which is substituted with an ethoxycarbonyl group, and R22 denotes a pyridin-2-yl group, R3 denotes an n-hexyloxycarbonyl group, where at step (a) phenyldiamine of formula (II) where R1 and R2 assume values given for formula (I), which reacts with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid, to obtain a product of formula (III) where R1 and R2 assume values given for formula (I), which is hydrogenated at temperature from 30 to 60°C at hydrogen pressure from 1 to 10 bar, over palladium on activated charcoal (Pd/C) in a mixture of tetrahydrofuran and water, and then, without any preliminary extraction of the hydrogenation product, the obtained compound of formula (I), in which R3 denotes hydrogen, in the presence of potassium carbonate reacts with a compound of formula (IV) R3-X (IV), where R3 assumes values given for formula (I), and X denotes a suitable splitting group.

EFFECT: simple method of producing optionally substituted 4-(benzimidazo-2-yl methylamino)benzamidine.

3 cl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new piperazine amide derivatives of formula wherein X represents N or CH; Y represents N or CH; R1 represents lower alkyl, phenyl, phenyl-lower alkyl wherein phenyl can be optionally substituted by 1-2 substitutes independently specified in a group consisting of halogen, lower alkyl; R2 represents lower alkyl, phenyl, naphthyl or heteroaryl specified in dimethylisoxazolyl, quinolinyl, thiophenyl or pyridinyl wherein phenyl or heteroaryl are optionally substituted by 1 substitute optionally specified in a group consisting of halogen, lower alkoxy group, fluor-lower alkyl, lower alkoxy-carbonyl and phenyl; R3 represents phenyl, pyridinyl or pyrazinyl wherein phenyl, pyridinyl or pyrazinyl are substituted by 1-2 substituted optionally specified in a group consisting of halogen, lower alkyl and fluor-lower alkyl; R4, R5, R6, R7, R8, R9, R10 and R11 independently represent hydrogen, as well as to their physiologically acceptable salts. These compounds are bound with LXR alpha and LXR beta, and are applicable as therapeutic agents for treatment and/or prevention of high lipid levels, high cholesterol levels, low HDL cholesterol, high LDL cholesterol, atherosclerotic diseases, diabetes, non insulin dependent diabetes mellitus, metabolic syndrome, dislipidemia, sepsis, inflammatory diseases, infectious diseases, skin diseases, colitis, pancreatitis, cholestasis, liver fibrosis, psoriasis, Alzheimer's disease, etc.

EFFECT: preparing new piperazine amide derivatives.

15 cl, 88 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula , where R1 denotes OH, OPO3H2 or OCOR5; R2 denotes H, OH or OPO3H2; A denotes N or CR6; R3 denotes fluorine; R4 denotes H, C1-3alkyl or C3-6cycloalkyl; R5 denotes an alanine residue; R6 denotes H, C1-6alkoxy group or halogen; and n=0 or 1; and to pharmaceutically acceptable salts of compounds of formula I. The invention also relates to a pharmaceutical composition having antibacterial activity, and to use of compounds of formula I to obtain a medicinal agent for preventing or treating bacterial infections.

EFFECT: compounds of formula I, having antibacterial activity.

14 cl, 3 dwg, 2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I):

, where: R=NO2, or and Het denotes an azolyl radical selected from nitroazolyl and tetrazolyl radicals; except 3- and nitro-4-(4-nitro-1,2,3-triazol-1-yl)furazan. The invention also describes a method of producing a compound of formula I and an energy composition based on said compounds.

EFFECT: compounds have high energy characteristics, low sensitivity and high thermal stability.

11 cl, 7 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives having PGDS inhibiting properties. In formula (I): (I), R1 denotes phenyl or a 5- or 6-member heteroaryl containing 1-3 heteroatoms selected from N, O and S, each optionally having one or more of the following independent substitutes: halogen, (C1-C6)-alkyl, or (C1-C4)-haloalkyl; R2 denotes hydrogen or (C1-C6)-alkyl, which is optionally substituted with one or more halogens; R3 denotes hydrogen, (C1-C6)-alkyl or phenyl; R4 denotes C6-cycloalkyl, phenyl, a 6-member heterocyclyl containing one N heteroatom, a 6-member heteroaryl containing one N heteroatom, -C(=O)-NY1Y2, -C(=S)-NY1Y2, or -C(=O)-R5, where the phenyl, 6-member heteroaryl or 6-member heterocyclyl group optionally has one or more independent substitutes R6, or R3 and R4 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclyl containing one or two heteroatoms selected from N, O and S, a 6-member heterocyclenyl containing two or three N heteroatoms, a 5-member monocyclic or 9-member bicyclic heteroaryl containing one to three N heteroatoms, phenylheterocyclyl, where the heterocyclyl is 5- or 6-membered and contains one or two heteroatoms selected from N and O, each optionally having one or more independent substitutes R6. Values of R5, R6, Y1, Y2 are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds.

EFFECT: improved method.

15 cl, 227 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to di(arylamino)aryl derivatives presented in the patent claim. The compounds show an inhibitory effect on protein EML4-ALK v1 and protein EGFR kinase activity. Also the invention refers to a pharmaceutical composition containing said compounds, the hybrid protein EML4-ALK and mutant protein EGFR kinase activity inhibitor, the use of said compounds for preparing the pharmaceutical composition, and to a method of preventing or treating non-small-cell lung cancer or EML4-ALK hybrid polynucleotide-positive and/or mutant EGFR polynucleotide-positive non-small-cell lung cancer.

EFFECT: use of di(arylamino)aryl as the protein EML4-ALK v1 and protein EGFR kinase activity inhibitors.

12 cl, 95 tbl, 55 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: it has been confirmed that the new azolcarboxamide compound or its pharmaceutically acceptable salt wherein a thiazole ring or an oxazole ring is bound to a benzene ring, a pyridine ring, a pyridazine ring, a thiophen ring, a pyrazole ring or a pyrrol ring through carboxamide or its ring possess high activity of receptor trkA inhibition; it has been found that they may be used as a therapeutic and/or preventive agent which is different in the fact concerning the effectiveness and safety for repeated urination, frequent micturate urge and urine incontinence associated with various urogenital diseases, including higher bladder activity, various lower bladder diseases accompanied with urogenital pain, such as interstitial cystitis, chronic prostatitis and others, and various diseases accompanied by pain; thereby the present invention has been created.

EFFECT: provided therapeutic and/or preventive agent for repeated urination, frequent micturate urge and urine incontinence associated with various urogenital diseases, including higher bladder activity, various lower bladder diseases accompanied with urogenital pain, such as interstitial cystitis, chronic prostatitis and others, and various diseases accompanied by pain on the basis of excellent inhibitory action on the receptor trkA.

24 cl, 1195 ex, 215 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (1), where R1 denotes a C1-C4 halogenalkyl group, R2 denotes a halogen atom, R3 denotes a C1-C6alkyl group, C1-C6alkoxy group or a halogen atom, m equals an integer from 0 to 5, n equals an integer from 0 to 4, M denotes an oxygen or sulphur atom, R4 is as defined in the claim. The invention also relates to a insect control method, use of compounds of formula (1) and a composition containing compounds of formula (1) for insect control.

EFFECT: obtaining compounds of formula (1) for insect control.

20 cl, 119 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel xinafoate salt of N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-on)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonyl methyleneoxy)phenyl]-2,4-pyrimidine diamine, having the structural formula given below. The invention also relates to a method of producing a salt, use of the latter, a pharmaceutical composition and a treatment method. The method of producing a xinafoate salt involves dissolving N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-on)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonyl methyleneoxy)phenyl]-2,4-pyrimidine diamine and 1-1.1 molar equivalents of 1-hydroxy-2-naphthoic acid in a minimum amount of a suitable organic solvent such as acetone, acetonitrile or methyl ethyl ketone, each optionally containing a small amount of water, and subsequent slow cooling of the solution with optional stirring until precipitation of the salt from the solution.

EFFECT: obtained salt has Syk-kinase inhibiting properties and can be used in treating an inflammatory condition such as asthma (I).

12 cl, 6 tbl, 1 ex

New compounds // 2458920

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or to its pharmaceutically acceptable salts wherein -A-(R1)a means a group; -B-(R2)b means a group specified in the patent claim 1, R3 means hydrogen; X means CH2 or O; and Y means CH2. Also, the invention refers to a pharmaceutical composition exhibiting FGFR inhibitor activity on the basis of the declared compound.

EFFECT: there are produced new compounds and based pharmaceutical composition which can find application in medicine for preparing a cancer drug.

8 cl, 1 tbl, 180 ex

New compounds // 2456273

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula: wherein B is specified in a group consisting of pyridine, pyridazine, pyrimidine and oxazole which can be optionally substituted by halogen, C1-7-alkyl or a C1-7-alkoxy group; L1 is specified in a group consisting of -NH-, -C(O)NH- and -NHC(O)-, A means C3-C12-cycloalkyl, C6-C12-aryl, a 4-7-member monocyclic heterocyclic group consisting of 1-3 heteroatoms optionally specified in O N and S, or a bicyclic heterocyclyl specified in a group consisting of benzimidazolyl, benzoxazolyl, benzothiazolyl, wherein cycloalkyl, aryl, mono- or bicyclic heterocyclyl can be optionally substituted by one or more substitutes optionally specified in a group consisting of a cyano group, halogen, an oxo group, C1-7-alkyl, C1-7-halogenalkyl, a C1-7-alkoxy group, C1-7-halogenalkoxy group, an amino group, a di-C1-7-alkylamino group, a C1-7-alkylthio group and C3-8-cycloalkyl, 1-2- means a bivalent residue specified in a group consisting of: - a bivalent alkyl group consisting of 1 to 4 carbon atoms, a bivalent alkenyl group consisting of 2 to 3 carbon atoms, - -C(O)-, - -C(O)-[R4]c-R5- wherein c is equal to 0, and R5 is specified in a group consisting of a bivalent C1-C4-alkyl group optionally substituted by another C1-4-alkyl, a C4-C8-cycloalkyl group, a phenyl group and a 5- or 6-member heterocyclyl group consisting of N heteroatoms, - -C(O)-NH-, - -(CH2)1-3-C(O)-NH-(CH2)1-3-, - -C(O)-NH-R4- wherein R4 is specified in a group consisting of a bivalent C1-C7-alkyl group optionally substituted by another C1-4-alkyl, a cyclohexyl group and a cyclopentyl group, and E is specified in a group consisting of: - COOH, - a ester group of carboxylic acid, or to its pharmaceutically acceptable salts. What is also described is a pharmaceutical composition exhibiting DGAT1 modulatory activity, on the basis of the presented compounds, and also a method of treating pathological conditions or disorders associated with DGAT1 activity.

EFFECT: there are prepared and described new compounds applicable for treating or preventing the pathological conditions or disorders associated with DGAT1 activity.

22 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (1): R1 means haloalkyl containing 1-6 fluorine atoms; R2 means C1-C6alkyl or halogen; R3 means -L-NR4R5, -X-NR-C(O)R8 or -X-NR-C(O)NR4R5 wherein L means -X-C(O), -(CR2)j, -O(CR2)1-4 or and X means (CR2)j or [C(R)(CR2OR)]; R4 and R5 independently mean H, C1-C6alkyl, halogen-substituted C1-C6alkyl, hydroxy group-substituted C1-C6alkyl, or (CR2)k-R6; R8 independently means (CR2)k-R6 or C1-C6alkyl, or halogen-substituted C1-C6alkyl; R7 means H; alternatively, R4 and R5 together with N atom in each NR4 R5 form a 4-7-member heterocyclic ring containing 1 -2 heteroatoms independently specified in N and O substituted by 0-3 groups R11; R11 means R8, (CR2)k-OR7, CO2R7, (CR2)k-C(O)-(CR2)k-R8, (CR2)kC(O)NR7R7 or (CR2)kS(O)1-2R8; each R means H or C1-C6alkyl; each k is equal to 0-6; and j and m are independently equal to 0-4; provided R1 does not mean trifluoromethoxygroup, provided R3 means C(O)NH2, C(O)NR12R13; wherein R12 and R13 together form piperazinyl; the values of the radical R6 are presented in the patent claim. The invention also refers to the pharmaceutical composition containing said compounds.

EFFECT: producing new 5-(4-(halogenalkoxy)phenyl)pyrimidin-2-amine derivatives showing c-kit, PDGFRα, PDGFRβ kinase inhibitory activity, optionally in the form of isomers or pharmaceutically acceptable salts.

12 cl, 77 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes poly(ADP-riboso)polymerase inhibitors of formula (Ik) its pharmaceutically acceptable salt wherein R101, R104 and R105 represent H; R102 represents R11 wherein R11 is specified from pyrrolidinyl, oxazolyl, imidazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl and azepanyl with R102 being substituted by one or two (O) substitutes; R103 represents fluorine, besides, a pharmaceutical composition on the basis of said compounds showing poly(ADP-riboso)polymerase (PARP) inhibitory activity, a method of treating cancer and a method of reducing tumour volume in a mammal.

EFFECT: there are produced and described new compounds which show poly(ADP-riboso)polymerase (PARP) inhibitory activity.

9 cl, 491 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to quinoline derivatives of formula I

, or to its pharmaceutically acceptable salts, wherein X1 represents O; p represents 0, 1 or 2; each group R1 which can be identical or different and which can be located only in positions of 6- and/or 7-quinoline ring, specified in halogen, cyano, carboxy, (1-6C)alkoxycarbonyl, carbamoyl, (1-6C)alkoxy, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, or in a group of formula: Q1-X2-, wherein X2 represents CO and Q1 represents pyrrolidine, q represents 0 or 1; R2 represents (1-6C)alkoxy; R3 represents hydrogen or (1-6C)alkyl; R4 represents hydrogen; R5 represents hydrogen, methyl, ethyl, propyl, allyl, 2-propynyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-cyanoethyl or 3-cyanopropyl; the ring A represents a 5-membor monocyclic heteroaryl ring with up to three ring heteroatoms specified in oxygen, nitrogen and sulphur; r represents 0, 1 or 2; and each group R6 which can be identical or different is specified in amino, (1-6C)alkyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, or in a group of formula: -X6-R15 wherein X6 represents a single link and R15 represents (1-6C)alkoxy-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl or in a group of formula: -X7-Q3 wherein X7 represents C(R17)2N(R17) wherein each R17 represents hydrogen and Q3 represents (3-8C)cycloalkyl, and wherein any CH2 group within the R6 group optionally carries a hydroxy group on each said group. Also, the invention refers to methods for making the compound of formula I, to a pharmaceutical composition on the basis of the compound of formula I, to applying the compound of formula I and the combinations on the basis of the compound of formula I and additional anticancer drugs.

EFFECT: there are produced new quinoline derivatives effective in treating diabetic retinopathy and disturbed cell proliferation.

15 cl, 6 tbl, 32 ex

FIELD: medicine.

SUBSTANCE: invention refers to a new compound of formula or to its pharmaceutically acceptable salt. What is prepared and described is the new compound applicable as a modulator of ATP-binding cartridge (ABC) transporter or their fragments including a cystic fibrosis transmembrane regulator (CFTR).

EFFECT: higher efficacy.

1 cl, 422 ex, 7 tbl

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