Derivatives arylpyrimidines and pharmaceutical composition containing these compounds

 

(57) Abstract:

Describes the new derivatives arylpyrimidines General formula I or their pharmaceutically acceptable salts, where AG denotes unsubstituted or one to fivefold substituted phenyl or unsubstituted or one to two times substituted naphthyl, the substituents of phenyl and afternova fragments independently from each other are represented by halogen atoms (fluorine, chlorine, bromine, iodine), a hydroxyl group, an alkyl with a number of carbon atoms one to four, alkoxyl with the number of carbon atoms one to four, triptorelin, triptoreline the group or the group-NR9R10in which R9and R10independently from each other mean a hydrogen atom, methyl, Ar may also mean phenyl, substituted-O(CH2)O - or-O(CH2)2O-group; R1and R2together with the nitrogen atom to which they are bound, form a loop

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in which R means the number 2 or 3, X is a group N(CH2)nR6or CR7R8where n means the number 0,1 or 2, R6means cycloalkyl with the number of carbon atoms from three to seven, phenyl or naphthyl, and phenyl can have from one to three times substituted atoms glogau a hydrogen atom, if R3means phenyl, b) R7means phenyl, piperidinyl, 1-methyl-piperidinyl or groups of the following formulas: (a) in those cases where R8means a hydrogen atom, carbarnoyl, acetylamino, acetyl-N-methyl-amine or a nitrile, C) R7and R8together form a residue (b), R3means a hydrogen atom or phenyl, R4means phenylalkyl or nafcillin with the number of carbon atoms in the alkyl fragments from one to four, and phenyl can have from one to three times substituted by halogen atoms (fluorine, chlorine, bromine, iodine), alkyl with the number of carbon atoms one to four, CNS group with the number of carbon atoms one to four or trifluoromethyl, R5means a hydrogen atom, alkyl with the number of carbon atoms one to four, cycloalkyl with the number of carbon atoms from three to six, carboxymethyl or carbamoylmethyl. The compounds exhibit activity antagonist neirokinina. Also describes a pharmaceutical composition containing these compounds. 2 C. and 16 h.p. f-crystals.

The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as antagoni the tee connection.

Known derivatives of 4-carboxamidine, which can be an active ingredient of pharmaceutical compositions, active as an antagonist neirokinina (see application WO 94/10 146, CL C 07 D 211/58, A 61 K 31/445, 11.05.1994 year).

The objective of the invention is the development of new nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina.

The problem is solved proposed derivatives arylpyrimidines General formula (I)

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and their pharmaceutically acceptable salts, where Ar denotes unsubstituted or one to fivefold substituted phenyl or unsubstituted or one to two times substituted naphthyl (where the substituents are phenyl and afternova fragments independently from each other are represented by halogen atoms (fluorine, chlorine, bromine, iodine), a hydroxyl group, an alkyl with a number of carbon atoms one to four, alkoxyl with the number of carbon atoms one to four, triptorelin, triptoreline the group or the group-NR9R10in which R9and R10independently from each other mean a hydrogen atom, or m2together with the nitrogen atom to which they are bound, form a loop

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where p is the number 2 or 3

X represents a group N(CH2)nR6or CR7R8where n means the number 0, 1 or 2,

R6means cycloalkyl with the number of carbon atoms from three to seven, phenyl or naphthyl, and phenyl can have from one to three times substituted by halogen atoms (fluorine, chlorine, bromine, iodine),

R7and R8have one of the following values:

a) R7and R8denote a hydrogen atom if R3means phenyl,

b) R7means phenyl, piperidinyl, 1-methyl-piperidinyl group or groups of the following formulas:

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in those cases where R8means a hydrogen atom, carbarnoyl, acetylamino, acetyl-N-methyl-amine or a nitrile,

in R7and R8together form a residue of

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R3means a hydrogen atom, or phenyl,

R4means phenylalkyl or nafcillin with the number of carbon atoms in the alkyl fragments from one to four, and phenyl can have from one to three times substituted by halogen atoms (fluorine, chlorine, bromine, iodine), alkyl with the number of carbon atoms one to four, alkoxylated, alkyl with the number of carbon atoms one to four, cycloalkyl with the number of carbon atoms from three to six, carboxymethyl or carbamoylmethyl.

Compounds of General formula I can include acid functional groups, mainly carboxyl groups, and/or basic groups, for example, amine function. Therefore, compounds of General formula I can be obtained in the form of internal salts, salts with used in pharmacy practice inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid, or with organic acids, such as maleic, fumaric, citric, tartaric or acetic acid, or they can be obtained in the form of salts used in pharmaceutical practice, a base such as hydroxides of alkali or alkaline earth metals, carbonates, hydroxides, zinc or ammonium or organic amines, for example with diethylamino, the triethylamine, triethanolamine and other amines.

Corresponding to the invention compound may be a racemate, but they can be obtained in the form of pure enantiomers, that is (R)- or (S)-form.

In the first group before the place with the nitrogen atom, to which they are attached, form a six-membered ring of the formula

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where X represents a group N(CH2)nR6or CR7R8where n, R6, R7and R8have a higher value.

The second group preferred derivatives of arylpyrimidines formula (I) include compounds in which

X represents a group of formula N(CH2)nR6in which n means the number 0, 1 or 2, preferably 0,

R6means cycloalkyl with the number of carbon atoms from three to seven or phenyl.

In a third preferred group of derivatives of arylpyrimidines formula (I) include compounds in which

n represents the number 0,

R6means cycloalkyl with the number of carbon atoms from three to seven, preferably cyclobutyl or cyclohexyl.

In a fourth preferred group of derivatives of arylpyrimidines formula (I) include compounds in which

X represents CR7R8where

R7and R8have one of the following values:

a) R7and R8denote a hydrogen atom if R3submitted by phenyl,

b) R7means phenyl, piperidinyl, the group of the following formula:

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or

in R7and R8together form a residue of

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In the fifth group of preferred derivatives of arylpyrimidines formula (I) include compounds in which

R7and R8have one of the following values:

a) R7and R8denote a hydrogen atom if R3submitted by phenyl,

b) R7means phenyl or the group of the following formula:

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preferably R7means phenyl or group

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if R8means a hydrogen atom or a nitrile,

in R7and R8together form a residue of

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In particular, preferred compounds of the fifth group, in which R7means pyridyl and R8means a hydrogen atom.

In a sixth group of preferred derivatives of arylpyrimidines formula (I) include compounds in which

Ar denotes unsubstituted or one to two times substituted phenyl or unsubstituted naphthyl, the substituents at the phenyl fragment independently from each other are represented by halogen atoms (fluorine, chlorine, bromine, iodine), hydroxyl, stands, metaxylem, trifluoromethyl, cryptomaterial or dimethylaminopropoxy, or

Ar means someseni the CLASS="ptx2">

In the seventh group of preferred derivatives of arylpyrimidines formula (I) include compounds in which

Ar denotes unsubstituted or one to two times substituted phenyl or unsubstituted naphthyl, the substituents at the phenyl fragment independently from each other are represented by halogen atoms (fluorine, chlorine, bromine), metaxylem or trifluoromethyl, or

Ar denotes a substituted-OCH2O-phenyl group, and dioxymethylene group connects 2,3 - or 3,4-position of the phenyl ring.

In particular, preferred compounds of the seventh group, in which Ar denotes phenyl, 3,4-dichlorophenyl, 3,4-acid or 3,4-methylenedioxyphenyl.

In the eighth preferred group of derivatives of arylpyrimidines formula (I) include compounds in which

R3means a hydrogen atom.

In the ninth preferred group of derivatives of arylpyrimidines formula (I) include compounds in which

R3means atom phenyl.

In the tenth preferred group of derivatives of arylpyrimidines formula (I) include compounds in which

R4means phenylalkyl with the number of carbon atoms in the alkyl fragment from one to three, and where phenyl may of nes, chlorine, bromine, iodine), stands, metaxylem, trifluoromethyl or

R5means a hydrogen atom, alkyl with the total number of carbon atoms, one to three, carboxymethyl, carbamoylmethyl or phenethyl.

In particular, preferred compounds of the tenth group, whose

R4mean group

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R5means a hydrogen atom or methyl.

In the eleventh preferred group of derivatives of arylpyrimidines formula (I) include compounds represented by the following formula:

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or

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As mentioned above, the compounds according to the invention can be used as antagonist neirokinina.

The results of the research relevant to the invention of compounds:

Affinity for NK1the receptor (the receptor for substance P) determined on the cells lymphoblastoma man (IM-9) with the cloned NK1receptors, and measuring the displacement of labeled125J substance P. thus Obtained values of Kidemonstrate efficacy of compounds:

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Connection example 3: 1.4 nmol/l

Connection example 4: 1,0 nmol/l

Connection example 5: 1.3 nmol/l

Connection example 33: 1.3 nm is a measure 44: 1.1 nmol/l

Connection example 45: 2.3 nmol/l

Connection example 46: 6.4 nmol/l

Connection example 47: 4.2 nmol/l

Connection example 53: 9.2 nmol/l

Connection example 54: 1.4 nmol/l

Connection example 56: 1.5 nmol/l

Connection example 58: 2.8 nmol/l

Connection example 59: 2.1 nmol/l

Connection example 60: 6.8 nmol/l

Connection example 61: 1.7 nmol/l

Connection example 62: to 11.8 nmol/l

Connection example 63: 180 nmol/l

Connection example 64: 7.0 nmol/l

Corresponding to the invention compounds are valuable antagonists neirokinina (tachykinin), the antagonism which appears mainly on NK1-receptors, but they also exhibit properties NK2- and NK3-antagonists.

Corresponding to the invention compounds are valuable antagonists neirokinina (tachykinin), which turned out to be antagonists as substance P and neirokinina A and, respectively, neirokinina B. They can be useful in the treatment and prevention of diseases associated with neurokinins. This can be the treatment and prevention of inflammatory and allergic diseases of the Airways such as asthma, Hani skin, as dermatitis contact eczema, urticaria, psoriasis, sunburn, insect stings, eczema, scabies, post herpetic pain,

such diseases of the gastrointestinal tract, such as stomach ulcers and duodenal ulcers, Colitis ulcerosa (ulcerative colitis), Morbus Crohn, Colon irritabile, M. Hirschsprung such joint disease, like rheumatoid arthritis, reactive arthritis and Reiter syndrome;

these compounds are suitable for treating diseases of the Central nervous system such as dementia (dementia), Alzheimer's disease, schizophrenia, psychosis, depression, headaches (e.g. migraine or headache hypertension), epilepsy;

they are suitable for the treatment of malignant tumors, collagenoses, dysfunction of the urinary tract, hemorrhoidal conditions, nausea and vomiting, caused for example by irradiation or by taking drugs or physical activity and pain of a different sort.

Due to the above the invention relates also to the application of the relevant invention compounds as medicaments and to containing these compounds medications. Preferably, their use for the treatment of humans. They can be entered in the human body intravenously, pikh introduction can be intensified by using iontophoresis or other well-known from the literature supporting means, perhaps oral administration.

For parenteral administration the compounds of formula I or their physiologically acceptable salts translate into solutions, suspensions or emulsions with the possible use of the ordinary in this area substances, such as solvents, emulsifiers or other auxiliaries. As solvents can, for example, be used water, physiological salt solutions or alcohols, for example ethanol, propandiol or glycerol, solutions of sugars, such as glucose or mannitol, but also mixtures of different solvents.

In addition, these compounds can be used in dosage forms for implantation, for example, polyactide, polyglycolide or polyhydroxyalkanoic acid, as well as in medicinal forms for insertion through the nose.

Oral efficacy of compounds of General formula I can be shown the following standard practices:

The inhibition caused by the action of NK1lowering blood pressure has shot Guinea pigs.

Intraperitoneally the introduction of pentobarbital dose of 50 mg/kg anaesthetize Guinea pigs weighing 300 to 500 g and is connected to an artificial respirator with directly in the cervical arteries. For intravenous substance use cannula in the jugular vein.

Intravenous agonist NK1[ Ala4Sar9, Met(O)2]11SP(4-11)

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dose of 0.2 mmol/kg cause a transient decrease in blood pressure, which support the re-introduction of agonist NK1with an interval of 10 minutes. Then through the duodenum introduce the antagonist neirokinina and cause reduction of blood pressure by re-introduction of agonist NK1with an interval of 10 minutes.

Determine the braking pressure drop of blood caused by the above agonist NK1by measuring it before and after the introduction of the antagonist neirokinina.

For connection example 5 set ID50equal to 1.4 mg/kg (ID50is the dose that relieves caused by agonist NK1the pressure drop of blood by 50%).

Corresponding to the invention compounds can be obtained by well-known methods.

These compounds can be carried out in various ways. Two of the most commonly used methods are given in the diagram shown at the end of the description.

Method A. Obtaining amide from a carboxylic acid and an amine HN(R5R4oC and +120oC, preferably between 0oC and 40oC.

You can also, using known methods, pre-translate carboxylic acid by the action of thionyl chloride, sulfurylchloride, phosphorotrithioite, phosphorochloridate or phosphoribosyl or mixtures thereof in an appropriate gelegenheid and spend then its reaction with the amine HN(R5R4in such an inert solvent, such as methylene chloride, tetrahydrofuran or dioxane at temperatures ranging from -50oC to +100oC, usually between 0oC and 20oC.

Another option involves the first stage of the transformation of the carboxylic acid by known methods in its alkilany ether (usually methyl ether), informed, dioxane or tetrahydrofuran. The temperature of reaction is in the range of 20oC to 150oC, usually in the range from 50oC to 120oC. This reaction can also be carried out in the apparatus under pressure.

Method B. In this sequence of operations is obtained by known methods derived-halogen-arylacetamide enter into reaction with the amine HN(R1R2. The result of this reaction cleaved galgenwaard, and to associate a spin-off or excess galgenwaard used inorganic bases such as, for example, potassium carbonate, sodium bicarbonate or calcium carbonate, and organic bases such as triethylamine, base Gunga, pyridine or 4-dimethylaminopyridine, or the reaction is carried out with an excess of amine HN(R1R2. Using dimethylformamide, tetrahydrofuran, dioxane or other inert solvents. The temperature of reaction is in the range from 0oC to 100oC, usually in the range from 10oC to 80oC.

Method C. Corresponding to the invention of compounds of the structural element R5which does not mean a hydrogen atom, can be obtained as follows: first, by the method a or method B, Sintesi the m alkyl, cycloalkyl or carboxymethyl group. This corresponds to the invention compound with a hydrogen atom in the R5deprotonized the action of an equivalent amount of sodium hydride, sodium amide, potassium hydroxide, sodium methylate or other strong bases. For the reaction using anhydrous inert solvents such as tetrahydrofuran, dioxane or diethyl ether. Then slowly add the appropriate alkylating agent in the form of the corresponding halide, tosilata or nelfinavir. The interaction is carried out in the temperature range from -50oC to +100oC, usually in the range of 0oC to +50oC. This method is described in detail in example 33.

Examples

Example 1.

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The first stage. In 150 ml of anhydrous dimethylformamide was dissolved 2.2 g of 1-cyclohexylpiperazine, add 2 g of potassium carbonate, stirred for 20 minutes at room temperature and cooled to a temperature of 5oC. Then added 2.7 g of methyl ester of (R,S)- -bromoferrocene acid and leave the resulting suspension overnight under stirring at room temperature. The precipitate is filtered off and the filtrate evaporated, the residue is dissolved in ethyl acetate and extravert the tub sodium sulfate, filtered and evaporated. Obtain 3.7 g of methyl ester of (R,S)-1-cyclohexyl-4-piperazine derivatives-phenylacetic acid as a yellow oil.

A yield of about 100%.

The second phase. In 10 ml of methanol was dissolved 2.3 g obtained in the first stage of the product, add 14 ml of 1N. the sodium hydroxide solution and leave the resulting emulsion under stirring at room temperature overnight. Then the clear solution is neutralized by adding 14 ml of 1N. hydrochloric acid, evaporated to dryness, the residue is extracted with isopropanol, filtered off the solid and the filtrate evaporated. The residue is again triturated with isopropanol, solid is sucked off and combine with the previously obtained precipitate. Thus obtained 1.6 g (R,S)-1-cyclohexyl-4 - piperazine derivatives-phenylacetic acid in the form of a solid substance.

A yield of 75%.

The third stage. In 60 ml of a mixture of tetrahydrofuran and methylene chloride (1:1) suspended 0.6 g obtained in the second stage of the product of 0.48 g of 3,5-bis(trifluoromethyl)-benzylamine and 0.32 g of 1-hydroxybenzotriazole add 0.7 ml of base Gunga until a pH value of 8.5, then 0,77 g tetrafluoroborate O-benzotriazolyl - tetramethylurea and left under stirring overnight at room temperatue with 10% solution of potassium bisulfate, once with saturated sodium chloride solution, twice with 10% solution of potassium bicarbonate and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated to obtain a crystalline product. Get 0,685 g of N-(3,5-bis-trifloromethyl)amide (R, S)-1-cyclohexyl-4-piperazine derivatives-phenylacetic acid as a yellowish solid.

Yield 64%, so pl. 124-129oC, mass spectrum bombarded by fast atoms: (M+N)+= 528,2.

Example 2.

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The first stage. In 30 ml of anhydrous methylene chloride was dissolved 0,49 g of 3,5-bis(trifluoromethyl)-benzylamine, add 0.3 ml of triethylamine, cooled the mixture in a bath of ice and within 20 minutes was added dropwise a solution and 0.46 g of the acid chloride (R,S)- -bromoferrocene acid in 10 ml of methylene chloride. The reaction mass is left for two days at room temperature, the solvent is distilled off, the solid residue triturated with ethyl ether, sucked off and the filtrate evaporated. The result is N(bis - trifloromethyl)-amide-bromoferrocene acid in the form of a light beige solid.

The output of 43.5%.

The second phase. In 30 ml of anhydrous dimethylformamide of restore anatoy temperature. To the resulting mixture for 20 minutes, added dropwise a solution of 0.68 g obtained in the first stage product in 10 ml of dimethylformamide and left under stirring overnight at room temperature. The suspension is filtered, the filtrate evaporated, obtained in the form of oil residue is dissolved in ethyl acetate and extracted with twice 10% solution of potassium bicarbonate and once with a saturated solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered, the filtrate evaporated, and the resulting partially solid residue triturated with diethyl ether and sucked off. The result is 0.33 g of N-(3,5-bis-trifluoromethyl-benzyl)-amide (R, S)-4-propionamido-1-piperidino-phenylacetic acid as a white solid.

Yield 64%, so pl. 189-191oC, mass spectrum bombarded by fast atoms: (M+N)+= 516,4.

Can be similarly obtained other relevant invention compounds, for example, the following:

Example 3.

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So pl. 235-238oC, mass spectrum bombarded by fast atoms: (M+N)+= 542,2.

Example 4.

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So pl. > 240oC (decomp.), mass spectrum bombarded by fast atoms: (M+N)+= USD 542.3.

,4.

Example 6.

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So pl. 97-99oC, mass spectrum bombarded by fast atoms: (M+N)+= 556,3.

Example 7.

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So pl. > 240oC (decomp.), mass spectrum bombarded by fast atoms: (M+N)+= 528,4.

Example 8.

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So pl. 102-105oC, mass spectrum bombarded by fast atoms: (M+N)+= 640,3.

Example 9.

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So pl. 141-149oC, mass spectrum bombarded by fast atoms: (M+N)+= 579,2.

Example 10.

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So pl. 218-223oC, mass spectrum bombarded by fast atoms: (M+N)+= 579,3.

Example 11.

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So pl. > 220oC (decomp.), mass spectrum bombarded by fast atoms: (M+N)+= 571,3.

Example 12.

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So pl. 205-210oC, mass spectrum bombarded by fast atoms: (M+N)+= 591,3.

Example 13.

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So pl. 87-95oC, mass spectrum bombarded by fast atoms: (M+N)+= 571,2.

Example 14.

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So pl. 164-166oC, mass spectrum bombarded by fast atoms: (M+N)+= 537,3.

Example 15.

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So pl. 208-210oC, mass spectrum when bombardirovsciki fast atoms: (M+N)+= USD 542.3.

Example 17

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So pl. 118-123oC, mass spectrum bombarded by fast atoms: (M+H)+= 556,3.

Example 18

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So pl. 134-136oC. mass spectrum bombarded by fast atoms: (M+N)+= 514,3.

Example 19

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So pl. > 240oC (decomp.), mass spectrum bombarded by fast atoms: (M+N)+= 564.

Example 20.

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So pl. 180-185oC, mass spectrum bombarded by fast atoms: (M+N)+= made 564.3.

Example 21.

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So pl. 228-232oC, mass spectrum bombarded by fast atoms: (M+N)+= 606/608.

Example 22.

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So pl. 70-73oC, mass spectrum bombarded by fast atoms: (M+N)+= 586.

Example 23.

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So pl. 248-254oC, mass spectrum bombarded by fast atoms: (M+N)+= 596/598/600.

Example 24.

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So pl. 210oC, mass spectrum bombarded by fast atoms: (M+N)+= 664,1.

Example 25.

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So pl. 192-199oC, mass spectrum bombarded by fast atoms: (M+N)+= USD 542.3.

Example 26.

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So pl. 112-118oC, mass spectrum bombarded by fast is tirovke fast atoms: (M+N)+= 606/608.

Example 28.

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So pl. 118-120oC, mass spectrum bombarded by fast atoms: (M+N)+= 606/608.

Example 29.

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So pl. 120-122oC, mass spectrum bombarded by fast atoms: (M+N)+= 562/564.

Example 30.

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So pl. > 240oC, mass spectrum bombarded by fast atoms: (M+N)+= 562/564.

Example 31.

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So pl. > 240oC, mass spectrum bombarded by fast atoms: (M+N)+= 546,3.

Example 32.

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So pl. 125-130oC (decomp.), mass spectrum bombarded by fast atoms: (M+N)+= 610,4.

Example 33.

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Using potassium bicarbonate and transferred into the corresponding free base 0.3 g obtained in example 25 compound, dried and dissolved in 5 ml of anhydrous tetrahydrofuran. To the solution was added 34 mg of 60% sodium hydride in suspension in oil, stirred for 1.5 hours at room temperature, then add 0.1 g under the conditions and left overnight under stirring. To the reaction mass was added 2 ml of a mixture (1:1) of tetrahydrofuran and water, then add 25 ml water and three times extracted with ethyl ether. Objetivo connection in the form of free base (oil). The addition of a solution of an excess of hydrogen chloride in ether is transferred to the dihydrochloride, drop down in the form of yellow crystals.

Yield 113 mg (36%).

So pl. > 240oC, mass spectrum bombarded by fast atoms: (M+N)+= 556,4.

Example 34.

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So pl. 145-151oC, mass spectrum bombarded by fast atoms: (M+N)+= 641,3.

Example 35.

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So pl. 175-176,5oC

Example 36.

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So pl. 157-158oC

Example 37.

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So pl. 155-172oC, mass spectrum bombarded by fast atoms: (M+N)+= 592,2.

Example 38.

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So pl. 142-150oC, mass spectrum bombarded by fast atoms: (M+N)+= 558,2.

Example 39.

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So pl. 107-111oC, mass spectrum bombarded by fast atoms: (M+N)+= 575,6.

Example 40.

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So pl. > 230oC

Example 41.

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So pl. > 230oC

Example 42.

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So pl. 127-137oC, mass spectrum bombarded by fast atoms: (M+N)+= 592.

Example 43.

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So pl. 106-110oC, mass spectrum bombarded by fast atoms: (M+N)+= 549,4.

Example 45.

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So pl. 110-120oC, mass spectrum bombarded by fast atoms: (M+H)+= 570,4.

Example 46.

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So pl. 212-216oC (decomp.), mass spectrum bombarded by fast atoms: (M+N)+= 624,3/626,3/628,3.

Example 47

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So pl. 244-246oC (decomp), mass spectrum bombarded by fast atoms: (M+H)+= 624,1/626,2/628.

Example 48

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So pl. 113-123oC (decomp), mass spectrum bombarded by fast atoms: (M+H)+= 550,3.

Example 49

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So pl. 195-205oC (decomp).

Example 50

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So pl. 210-218oC, mass spectrum bombarded by fast atoms: (M+H)+= 620/622.

Example 51.

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So pl. 215-224oC, mass spectrum bombarded by fast atoms: (M+H)+= 576/578.

Example 52.

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So pl. 85-92oC, mass spectrum bombarded by fast atoms: (M+H)+= 572,5.

Example 53.

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so pl. 148-156oC, mass spectrum bombarded by fast atoms: (M+H)+= 578,4.

Example 54.

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So pl. 113-117oC (decomp), mass spectrum bombarded by fast atoms: (M+H)+= 528,5.

Example

Example 56.

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So pl. 236-238oC (decomp.), mass spectrum bombarded by fast atoms: (M+H)+= consists 528.3.

Example 57.

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So pl. 177-187oC, mass spectrum bombarded by fast atoms: (M+H)+= 605,3.

Example 58.

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So pl. 123-133oC (decomp.), mass spectrum bombarded by fast atoms: (M+H)+= 616,3

Example 59.

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So pl. 87-97oC, mass spectrum bombarded by fast atoms: (M+H)+= 600,2

Example 60.

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So pl. > 230oC.

Example 61.

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So pl. > 230oC.

Example 62.

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So pl. > 230oC.

Example 63.

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So pl. 91-98oC, mass spectrum bombarded by fast atoms: (M+H)+= 574,4.

Example 64.

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So pl. 234-236oC.

Example 65.

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So pl. 195-198oC.

Example 66.

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So pl. 129-134oC.

Example 67.

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So pl. 138-148oC.

Example 68.

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So pl. 75-80oC.

Example 69.

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So pl. 168-173oC.

Example 70.

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So pl. 223-225oC.

Example 71.

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So pl. 160-161oC

Examples of pharmaceutical compositions

Injection

200 mg of Active substance*,

1.2 mg monogalia salt of phosphoric acid (KH2PO4),}(buffer)

0.2 mg of the disodium salt of phosphoric acid (Na2HPO42H2O)

94 mg sodium chloride or} (isotonic components),

520 mg of glucose

4 mg albumin (for protection from proteases),

q.s sodium hydroxide solution,} to pH 6

q.s. hydrochloric acid,

to 10 ml water for injections

Injection

200 mg of Active substance*,

94 mg sodium chloride or

520 mg of glucose,

4 mg albumin,

q.s. the sodium hydroxide solution,} to pH 9

q.s hydrochloric acid,

to 10 ml of water for injection.

The lyophilisate

200 mg of Active substance*,

520 mg of mannitol (isotonic and strukturoobraznyh additive),

4 mg albumin.

Solvent 1 for freeze-dried

10 ml of water for injection.

Solvent 2 for freeze-dried

20 mg of Polysorbate80 = twin80 (surfactant)

10 ml of water for injection.

*Active substance: appropriate ASS="ptx2">

1. Derivatives arylpyrimidines General formula I

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or their pharmaceutically acceptable salt,

where Ar denotes unsubstituted or one to fivefold substituted phenyl, or unsubstituted or one to two times substituted naphthyl, the substituents of the phenyl or afternova fragments independently from each other are represented by halogen atoms (fluorine, chlorine, bromine, iodine), a hydroxyl group, an alkyl with a number of carbon atoms one to four, alkoxyl with the number of carbon atoms one to four, triptorelin, triptoreline the group or the group-NR9R10in which R9and R10independently from each other mean a hydrogen atom, methyl, Ar may also mean phenyl, substituted-O(CH2)O - or-O(CH2)2O-group;

R1and R2together with the nitrogen atom to which they are bound, form a loop

< / BR>
where p is the number 2 or 3;

X means a group N(CH2)nR6or CR7R8where n means the number 0, 1 or 2;

R6means cycloalkyl with the number of carbon atoms from three to seven, phenyl or naphthyl, and phenyl can have from one to three times substituted by halogen atoms (fluorine, chlorine, bromine, iodine);

R3means phenyl,

b) R7means phenyl, piperidinyl, 1-methylpiperidine or group of the following formula:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
or

< / BR>
in those cases where R8means a hydrogen atom, carbarnoyl, acetylamino, acetyl-N-methylamine or nitrile,

in R7and R8together form a residue of

< / BR>
R3means a hydrogen atom or phenyl;

R4means phenylalkyl or nafcillin with the number of carbon atoms in the alkyl fragments from one to four, and phenyl can have from one to three times substituted by halogen atoms (fluorine, chlorine, bromine, iodine), alkyl with the number of carbon atoms one to four, CNS group with the number of carbon atoms one to four or trifluoromethyl;

R5means a hydrogen atom, alkyl with the number of carbon atoms one to four, cycloalkyl with the number of carbon atoms from three to six, carboxymethyl or carbamoylmethyl.

2. Connection on p. 1, in which R1and R2together with the nitrogen atom to which they are attached, form a six-membered ring of the formula

< / BR>
where x is the group N(CH2)nR6or CR7R8where n, R2)nR6in which n means the number 0, 1 or 2, and R6means cycloalkyl with the number of carbon atoms from three to seven or phenyl.

4. Connection on p. 3, in which n represents the number 0 and R6means cycloalkyl with the number of carbon atoms from three to seven.

5. Connection on p. 4, in which R6means cyclobutyl or cyclohexyl.

6. Connection on p. 2, in which X is CR7R8where R7and R8have one of the following values:

a) R7and R8denote a hydrogen atom if R3submitted by phenyl,

b) R7means phenyl, piperidinyl, groups of the following formulas

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
or

< / BR>
if R8means a hydrogen atom, carbarnoyl, acetylamino, acetyl-N-methylamine or nitrile or

in R7and R8together form a residue of

< / BR>
7. Connection on p. 6, in which R7and R8have one of the following values:

a) R7and R8denote a hydrogen atom if R3submitted by phenyl,

b) R7means phenyl or the group of the following formula:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>8together form a residue of

< / BR>
8. Connection on p. 7, in which R7means phenyl group

< / BR>
or

< / BR>
if R8means a hydrogen atom or a nitrile.

9. Connection on p. 8, in which R7means pyridyl and R8means a hydrogen atom.

10. Connection PP.1 to 9, in which Ar denotes unsubstituted or one to two times substituted phenyl or unsubstituted naphthyl, the substituents at the phenyl fragment independently from each other are represented by halogen atoms (fluorine, chlorine, bromine, iodine), hydroxyl, stands, metaxylem, trifluoromethyl, cryptomaterial or dimethylaminopropoxy, or Ar denotes a substituted-OCH2O-phenyl group, and dioxymethylene group connects 2,3 - or 3,4-position of the phenyl ring.

11. Connection on p. 10, in which Ar denotes unsubstituted or one to two times substituted phenyl or unsubstituted naphthyl, the substituents at the phenyl fragment independently from each other are represented by halogen atoms (fluorine, chlorine, bromine), metaxylem or trifluoromethyl, or Ar denotes a substituted-OCH2O-phenyl group, and dioxymethylene group connects 2,3 - or 3,4-position of the phenyl Kohl is dioxyphenyl.

13. Connection at one PM.1 to 12, in which R3means a hydrogen atom.

14. Connection at one PM.1 to 12, in which R3means phenyl.

15. Connection at one PM.1 through 14, in which R4means phenylalkyl with the number of carbon atoms in the alkyl fragment from one to three, and where phenyl may bear one or two substituent, and the substituents independently of one another are represented by halogen atoms (fluorine, chlorine, bromine, iodine), stands, metaxylem or trifluoromethyl, R5means a hydrogen atom, alkyl with the total number of carbon atoms, one to three, carboxymethyl, carbamoylmethyl Il phenethyl.

16. Connection on p. 15, in which R4mean group

< / BR>
R5means a hydrogen atom or methyl.

17. Connection on p. 1, represented by formula

< / BR>
< / BR>
< / BR>
< / BR>
or

< / BR>
18. The pharmaceutical composition active as an antagonist neirokinina, characterized in that it contains a compound according to one of paragraphs.1 - 17.

Priority signs:

14.04.95 - all the features of the invention except for the following: Ar is phenyl, substituted by a group-OCH2O - or-O(CH2)2O-; p = 3, R7- phenyl, pianny group-OCH2O - or-O(CH2)2O-; p = 3, R7- phenyl, piperidinyl, 1-methylpiperidine; R8is cyano; R5group-CH2C(O)NH2.

 

Same patents:

The invention relates to new derivatives of pyrrolidinone possessing biological activity, in particular derivatives of 1H-3-aryl-pyrrolidin-2,4-dione

The invention relates to new derivatives of piperidine F.-ly (I), where R1- aryl, heterocyclyl, R2is phenyl, naphthyl, acenaphthyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, oxopyridine, diazines, triazoles, thienyl, oxazolyl, oxadiazolyl, thiazolyl, pyrrolyl or furyl which may be substituted with halogen, hydroxy, cyano, CF3, alkyl, R3-H, hydroxy, alkoxy, alkenylacyl, R4-H, alkyl, alkenyl, alkoxy, benzyl, oxo, Q is ethylene or absent, X is a bond, oxygen, sulfur, W is oxygen or sulfur, Z - alkylen, albaniles, -Oh, -S; n = 1, m = 0 or 1

The invention relates to arylalkylamines formula I, where In - unsubstituted pyridyl, pyrazinyl, isoxazolyl or thienyl; Q - CH2; X - CH2or S; R1and R2each - H; and R3- OR5; R4OA; R5- Or cycloalkyl with 4-6 C atoms; And the alkyl with 1-6 C-atoms, and their physiologically acceptable salts

The invention relates to new substituted pyrimidinediamine or alkylating compounds, their pharmaceutically acceptable salts, hydrates, N-oxides and method for inhibition of reverse transcriptase of the virus

The invention relates to new Amida condensed terracarbon acid of General formula I, where G is Q(C)k-W-(C)m-Z, Q is phenyl, 2-, 3-, 4-pyridyl, which may be substituted; T is halogen, hydrogen, hydroxyl, amino, C1-C6alkoxy; W is-O-, -N-, -S-, CR7R8where R7and R8the same or different and represent H, C1-C6alkyl; X is hydrogen; Z is hydroxyl, C1-C6alkoxy, C3-C7cycloalkylation, NH2and other, NR9COR10where R9and R10the same or different represent H, C1-C6alkyl, etc

The invention relates to an improved method for producing a magnesium salt of substituted sulfinil-heterocyclic compounds containing imidazole group corresponding to the formula (I), where Ar represents (a) or (b); Z represents a (c) or (d), and X is an (e) or (f), where N inside the benzene ring of the benzimidazole group means that one of the carbon atoms of substituted radicals R7-R10may may be replaced by a nitrogen atom without any substituents; R1, R2and R3are the same or different and selected from hydrogen, alkyl, alkylthio, alkoxy, possibly substituted by fluorine, alkoxyalkane, dialkylamino, piperidino, morpholino, halogen, phenylalkyl, funeralcare, where alkyl and alkoxygroup can be branched or linear and may contain cyclic alkyl groups, such as cycloalkylcarbonyl; R4and R5are the same or different and selected from hydrogen, alkyl and aralkyl; R6is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy; R7-R10are the same or different and selected from hydrogen, alkyl, alkoxy, halogen, halogenoalkane, alkylcarboxylic, alkoxycarbonyl, ACS is optionally substituted; R11represents hydrogen or forms alkylenes circuit with R3and R12and R13are the same or different and selected from hydrogen, halogen, alkyl or alkoxygroup where alkoxygroup can be branched or normal C1- C9-chains, and alkyl and alkoxygroup may contain cyclic alkyl groups, such as cycloalkenyl, which replaced sulfinil-getall formula I are mixed together with a weak base selected from the group consisting of organic amines and ammonia, and a source of magnesium selected from the group consisting of magnesium acetate, magnesium nitrate, magnesium sulfate, carbonates of magnesium and magnesium chloride

The invention relates to new derivatives of piperidine F.-ly (I), where R1- aryl, heterocyclyl, R2is phenyl, naphthyl, acenaphthyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, oxopyridine, diazines, triazoles, thienyl, oxazolyl, oxadiazolyl, thiazolyl, pyrrolyl or furyl which may be substituted with halogen, hydroxy, cyano, CF3, alkyl, R3-H, hydroxy, alkoxy, alkenylacyl, R4-H, alkyl, alkenyl, alkoxy, benzyl, oxo, Q is ethylene or absent, X is a bond, oxygen, sulfur, W is oxygen or sulfur, Z - alkylen, albaniles, -Oh, -S; n = 1, m = 0 or 1

The invention relates to 2-[1',2',4'-triazole-3'-roximation] anilides formula I

< / BR>
in which the index and the substituents have the following meanings:

n means 0, 1, 2, 3 or 4, where the substituents R1may be different if n is greater than 1;

X represents a direct bond, O, or NRa;

Rameans hydrogen, alkyl, alkenyl, quinil, cycloalkyl or cycloalkenyl;

R1means nitro, cyano, halogen, optionally substituted alkyl, alkenyl, quinil, alkoxy, alkenylacyl, alkyloxy or

if n is 2, additionally represents associated with two adjacent ring atoms optionally substituted by a bridge containing three or four members from the group containing 3 or 4 carbon atoms, 1-3 carbon atoms and 1 or 2 nitrogen atom, oxygen and/or sulphur, and this bridge together with the ring to which it is linked, may form a partially unsaturated or aromatic radical;

R2means hydrogen, nitro, cyano, halogen, C1-C4alkyl, C1-C4halogenated, C1-C4alkoxy, C1-C4alkylthio or C1-C4alkoxycarbonyl; R3means optionally substituted is which, together with the carbon atoms may contain one to three heteroatoms as members of a cycle of the following: oxygen, sulfur and nitrogen, or an optionally substituted single or dual core aromatic radical, which together with the carbon atoms may contain as members of the cycle from one to four nitrogen atoms or one or two nitrogen atom and one oxygen atom or sulfur or one oxygen atom or sulfur;

R4means hydrogen, optionally substituted alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, alkylaryl or alkoxycarbonyl;

R5means alkyl, alkenyl, quinil, cycloalkyl or cycloalkenyl or if X is NRaadditionally represents a hydrogen

The invention relates to new 4-aryl-1-phenylalkyl-1,2,3,6-tetrahydropyridine F.-ly (I), where Y is CH or N; R1-H, halogen, CF3; R2-H, halogen, (C3- C4)alkyl or (C1- C4)alkoxy; R3and R4- H or (C1- C3)alkyl; X represents: (a) (C3- C6)alkyl, (C3- C6)alkoxy or (C1- C4)alkoxycarbonyl(C3- C6)alkoxy, (b), (C3- C7)cycloalkyl or c) Deputy chosen from the group comprising phenyl, phenoxybenzyl, their salts, solvate or Quaternary ammonium salts
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