Derivatives of pyrazole and pharmaceutical composition containing them

 

(57) Abstract:

Describes the new derivatives in paragraph 1 of the formula, which has antagonistic activity to releasing factor, corticotropin (CRF). They are effective for treating a wide range of diseases, including diseases, induced by the stress. Also described pharmaceutical composition on the basis of the above compounds. 2 s and 5 C.p. f-crystals, 4 PL.

The invention concerns a pyrazoles, pharmaceutical compositions containing them, and methods of introducing their patients in their antagonistic activity towards releasing factor, corticotropin (CRF).

CRF antagonists are referred to in U.S. patents NN 4605642 and 5063245 and are peptides and pyrazolinone respectively. The importance of CRF antagonists noted in the literature, for example in U.S. patent N 5063245, which is included by reference in the description for details. A description of the various activity shown CRF antagonists, discovered recently in the publication of M. I. Owens et al., Pharm. Rev. vol.43, p.425-473 (1991) are also included for information. According to research described in these two and other references, CRF antagonists are considered as an effective treatment for a wide range of diseases, including indolinyl bowel syndrome; inflammation, immune suppression, infection of human immunodeficiency virus (HIV); senile sclerosis of the brain (Alzheimer's disease), gastrointestinal disease; loss of appetite for nervous system; hemorrhagic stress; symptoms of non-acceptance or rejection of drugs and alcohol, drug addiction and problems of fertilization.

The compound of formula I below, in which A is C=O, R1means methylthio, R3represents 2-chlorophenyl and R4- 2,4,6-trichlorphenol is a commercial connection unknown practical suitability.

The present invention relates to compounds of the formula

(I)

and its salts with acids,

where A is C=O or SO2or A and R1together with the carbon to which they are attached, form pyrimidinyl or 5 - pyridyl which may be substituted, R5that represents hydrogen, (C1-C6)alkyl, fluorine, chlorine, bromine, hydroxy, amino O-(C1-C6alkyl), NH-(C1-C6alkyl), N-(C1-C6alkyl) (C1-C6alkyl), SH, S(O)n(C1-C6alkyl), where n equals 0, 1 or 2, and the above C1-C6the alkyl may be substituted by 1-3 substituents R6, Katariina, NH-(C=O)CH3, fluorine, chlorine, bromine or C1-C3thioalkyl;

R1means hydrogen, C1-C6alkyl, amino, O-(C1-C6alkyl), NH-(C1-C6alkyl), N-(C1-C6alkyl) (C1-C6alkyl), and the above C1-C6the alkyl may be substituted by 1-3 substituents R6defined above;

R2describes hydrogen, C1-C6alkyl, hydroxy, amino, O-(C1-C6alkyl), NH-(C1-C6alkyl), N-(C1-C6alkyl) (C1-C6alkyl), SH, S(O)n(C1-C6alkyl), where n is 0, 1 or 2, cyano, hydroxy, carboxy, or amido, and the above-mentioned alkali can be substituted by 1-3 substituents, such as hydroxy, amino, carboxy, amido, NH(C=O) (C1-C6alkyl), N-(C1-C6alkyl) (C1-C6alkyl), (C= O)-0-(C1-C6alkyl), C1-C3alkoxy, C1-C3thioalkyl, fluorine, bromine, chlorine, iodine, cyano or nitro;

R3represents phenyl, naphthyl, thienyl, benzothiazyl, pyridyl, hinely, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolin, benzisothiazole, thiazolyl, isoxazolyl, benzisoxazole, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indole the 12-membered bicycloalkyl, optionally containing one to three O, S or N-Z, where Z is hydrogen, C1-C4the alkyl, C1-C4alkanoyl, phenyl or vinylmation, where each one of the above groups may be substituted independently from each other by one to three substituents, such as fluorine, chlorine, bromine, C1-C6alkyl, C1-C6alkoxy or trifluoromethyl, or one Deputy, such as cyano, nitro, amino, NH-(C1-C6alkyl), N-(C1-C4alkyl) (C1-C2alkyl), COO-(C1-C4alkyl), CO-(C1-C4alkyl), SO2NH(C1-C4alkyl), SO2N(C1-C4alkyl) (C1-C2alkyl), SO2NH2, NHSO2(C1-C4alkyl),

S(C1-C6alkyl), SO2(C1-C6alkyl), and the above C1-C4alkyl and C1-C6the alkyl can be substituted by one or two substituents, such as fluorine, chlorine, hydroxy, amino, methylamino, dimethylamino or acetyl;

R4means phenyl, naphthyl, thienyl, benzothiazyl, pyridyl, hinely, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolin, benzisothiazole, thiazolyl, isoxazolyl, benzisoxazole, benzimidazolyl, triazolyl, pyrazolyl, parasail or 3 - 8-membered cycloalkyl, or 9 - to 12-membered bicycloalkyl, optionally containing one to three O, S or N-Z, where Z is hydrogen, C1-C4the alkyl, C1-C4alkanoyl, phenyl or vinylmation, each of the above groups may be substituted independently from each other by one to three substituents, such as fluorine, chlorine, bromine, trifluoromethyl, C1-C6alkyl or C1-C6alkoxy, or one Deputy, such as cyano, nitro, amino, NH(C1-C6alkyl), N(C1-C4alkyl) (C1-C2alkyl), COO(C1-C4alkyl), CO(C1-C4alkyl), SO2NH(C1-C4alkyl), SO2N(C1-C4alkyl)(C1-C2alkyl), SO2NH2, NH2SO2(C1-C2alkyl),

S(C1-C6alkyl), SO2(C1-C6alkyl), and the above C1-C4alkyl and C1-C6the alkyl can be substituted by one or two substituents, such as fluorine, chlorine, hydroxy, amino, methylamino, dimethylamino or acetyl, provided that:

(1) R4is not unsubstituted phenyl, i.e., is different from unsubstituted phenyl;

(2) when R1is amino, R2- methylamino, R4- 2,4,6-trichloro the hydrogens.

More specifically, the compounds of formula I include compounds where R3means phenyl, substituted independently one or two substituents, such as fluorine, chlorine, bromine, methyl, trifluoromethyl, nitro, C1-C6alkoxy, SO2NH2, SO2NH(C1-C6alkyl), SO2N(C1-C6alkyl)2or R3is a primary, secondary or tertiary alkyl with 4 to 9 carbon atoms, and the above C4-C9the alkyl may contain one or two double or triple bond and may be substituted by 1-3 substituents R6that represents a hydroxy, amino, C1-C3alkoxy, dimethylamino, diethylamino, methylamino, ethylamino, NH(C= O)CH3, fluorine, chlorine, bromine or C1-C3thioalkyl.

More specific compounds of formula I are compounds in which A represents C=O, compounds in which R1represents amino, methylamino or dimethylamino; compounds in which R2represents ethyl or methylthio, and compounds in which R4means 2,4,6-trichlorophenyl, 2,4,6-trimetilfenil, 2,6-dichloro-4-triptoreline or 4-bromo-2,6-dimetilfenil.

More specific compounds of formula I also include compounds, the s, such as methyl, C2-C6straight or branched alkyl, trifluoromethyl, fluorine, chlorine, bromine or nitro, compounds in which A and R1together form a pyrimidine ring so that the bicyclic structure is a pyrazolo[3,4-d]pyrimidine, and R5substituted in 6-position, and compounds in which R3means phenyl, substituted independently one or two substituents, such as fluorine, chlorine, bromine, methyl, trifluoromethyl, nitro, C1-C6alkyl, C1-C6alkoxy, SO2NH2, SO2NH(C1-C6alkyl), or SO2N(C1-C6alkyl)2,

R4is 2,4,6-trichlorophenyl, 2,4,6-trimetilfenil, 2,6-dichloro-4-triptoreline or 4-bromo-2,6-dimetilfenil and R2represents methylthio, methyl or ethyl.

More specific compounds of formula I also include compounds in which R3means phenyl, substituted independently one or two substituents, such as fluorine, chlorine, bromine, methyl, trifluoromethyl, nitro, C1-C6alkyl, C1-C6alkoxy, SO2NH2, SO2NH(C1-C6alkyl), SO2N(C1-C6alkyl)2or R3represents a primary, secondary or tertiary alkyl with 4-9 s connection and may be substituted by 1-3 substituents R6that describes hydroxy, amino, C1-C3alkoxy, dimethylamino, diethylamino, ethylamino, methylamino, NH(C=O)CH3, fluorine, chlorine, bromine or C1-C3thioalkyl; R4means 2,4,6-trichlorophenyl, 2,4,6-trimetilfenil, 2,6-dichloro-4-triptoreline or 4-bromo-2,6-dimetilfenil, R1represents amino, methylamino or dimethylamino and R2is methylthio or ethyl.

The most preferred compounds of the invention are:

[5-amino-1-(2,6-dichloro-4-triptoreline)-3-methylsulfanyl-1H-pyrazole-4-yl]-(2,5-dimetilfenil)methanon,

[5-amino-1-(2,6-dichloro-4-triptoreline)-3-methylsulfanyl-1H-pyrazole-4-yl]-(2,5-bis-triptoreline)methanon,

[5-amino-1-(2,6-dichloro-4-triptoreline)-3-methylsulfanyl-1H-pyrazole-4-yl]-(5-isopropyl-2-were)methanon,

[5-amino-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H - pyrazole-4-yl]-(5-isopropyl-2-were)methanon and

[5-amino-1-(4-bromo-2,6-dimetilfenil)-3-methylsulfanyl-1H-pyrazole-4-yl] -(2,5-dibromophenyl)methanon.

The invention also concerns compositions for treating diseases induced or reinforced releasing factor corticotropin, which include a compound of formula I, as defined previously, or known connection Faure is 4,6-trichlorophenyl, in amounts effective for the treatment of the aforementioned diseases, and a pharmaceutically acceptable carrier; the invention also relates to compositions for treatment of inflammatory processes, diseases associated with stress and fear, including induced by the stress, depression and headaches, inflammation of the intestine, immune suppression, HIV infection, senile sclerosis of the brain, diseases of the gastrointestinal tract, loss of appetite for nervous, hemorrhagic stress, rejection symptoms of drug and alcohol addiction and problems of fertilization, which include a compound of formula I, as well as known compounds that are identified above in number, effective for the treatment of the aforementioned diseases, and a pharmaceutically acceptable carrier. More specific and preferred compositions for the treatment of such diseases and disorders include more specific and the most preferred compounds of formula I, as defined previously.

The invention also includes a method of treatment of diseases induced or reinforced releasing factor corticotropin, consisting in the introduction to the patient in need of such treatment, the compounds of formula I or known aerovane stress depression and headaches, abdominally inflammation of the intestine, inflammation, immune suppression, HIV infections, senile sclerosis of the brain, diseases of the gastrointestinal tract, loss of appetite for nervous, hemorrhagic stress, rejection symptoms of drug and alcohol addiction and problems of fertilization, especially depression, by administering to a patient requiring such treatment, the compounds of formula I, as well as known compounds that are described previously. More specific and preferred methods of treating such diseases include the introduction of more specific and most preferred compounds of formula I described earlier.

When it is mentioned C1-C6alkyl means a straight or branched chain alkyl of one to six carbon atoms, such as methyl, ethyl, isopropyl or hexyl.

When it is mentioned C1-C6alkyl in the definition of R5and R1it includes unsaturated C2-C6alkyl, such as C2-C6alkyl with one double or triple bond, C3-C6alkyl containing two double bonds, and C4-C6alkyl having two triple bond.

When it is mentioned with is a heterocyclic group, then join A, defined above, takes place through one of the carbons of the heterocyclic group. Similarly, when R4is a heterocyclic group, joining the nitrogen in the pyrazol ring occurs through one of the carbon atoms of the heterocyclic group.

When we speak about 3 - to 8-membered cycloalkyl or 9 - to 12-membered bicycloalkyl containing one to three O, S or N-Z, it is assumed that the atoms of oxygen and sulfur in the ring are not adjacent to each other.

The compounds of formula I in which R1is amino or C1-C6the alkyl and R2- methylthio can be obtained from compounds of formula

< / BR>
where R10means cyano or C(O)(C1-C6alkyl), and A and R3have the meanings previously defined for formula I, by reaction with the compound of the formula

R4-NHNH2(IV)

where R4has the values defined previously for formula I.

The reaction is usually carried out in a polar solvent, such as C1-C6the alcohols. The reaction temperature usually varies from about 20oC to 160oC and often is conveniently at the boiling temperature of the reaction mixture.

The compounds of formula III Mogul as sodium hydride, in the presence of carbon disulfide, followed by reaction of the resulting intermediate product with iodine stands in a solvent such as dimethyl sulfoxide.

The compounds of formula IV are readily available or can be obtained by known methods.

The compounds of formula V can be obtained by known methods.

The compounds of formula I in which R2means alkoxy, amino or mono - or disubstituted amino, can be obtained using the above methods with R4NHNH2from the corresponding compounds of the formula

< / BR>
or

< / BR>
where A and R3have the meanings previously defined for formula I, R10matter previously defined for formula III, and R, R' and R" each means hydrogen or C1-C6alkyl according to the definition of R2above.

The compounds of formula I in which R1is C1-C6alkoxy or C1-C6alkylthio and R2means C1-C6alkyl, can be obtained from compounds of formula

< / BR>
where Rxmeans chlorine or bromine,

R2represents C1-C6alkyl and

R3, R4and A have the meanings previously defined for formula I,

interaction is designed in a polar solvent, such as ethanol or tert-butanol, at temperatures from about 20oC to 160oC and often at room temperature.

The compounds of formula IX can be obtained by treating compounds of formula

< / BR>
palodiruyut agent such as thionyl chloride or thienylboronic, chlorosis or pentachloride phosphorus, or Brookes or pentabromide phosphorus. The reaction can be carried out without solvent or in an aprotic solvent such as methylene chloride or dichloroethane, at a temperature of from about 0oC to 100oC.

The compounds of formula X can be obtained by treating compounds of the formula

< / BR>
activated derivatives of carboxylic or sulfonic acids of the formula R3AOH, such as the acid chloride of the acid of formula R3ACl, where R3and A have the meanings previously defined for formula I, in the presence of calcium hydroxide in an aprotic solvent such as dioxane, as described in Jensen, Acta Chem. Scond, 13, 1668-1670 (1959), at temperatures from about 20oC to 100oC. the compounds of formula XI are known in the technique.

The compounds of formula I, where R1has a value of C1-C6alkoxy or C1-C6alkylthio and R2- C1-C6alkylthio, can be p is A matter, above for formula I, when interacting with C1-C6alcohol or C1-C6the mercaptan in the presence of a base. The reaction is usually carried out in a polar organic solvent such as ethanol or tert-butanol, at temperatures from about 20oC to about 160oC, often at room temperature.

The compounds of formula XII can be obtained from compounds of formula

< / BR>
reaction with a halogenation agent such as thionyl chloride or thienylboronic, chlorosis or pentachloride phosphorus, or Brookes or pentabromide phosphorus. The reaction can be carried out without solvent or in an aprotic solvent such as methylene chloride or dichloroethane, at a temperature of from about 0oC to 100oC.

The compounds of formula XIII can be obtained by treating compounds of formula

< / BR>
activated derivatives of benzoic acid or sulfonic acids, often use the acid chloride of the acid, in the presence of calcium hydroxide in an aprotic solvent such as dioxane, as described in the link above.

The compounds of formula XIV can be obtained by treating compounds of formula

< / BR>
where Rzis chlorine or b is solvent, such as tert - butanol, at temperatures from about 20oC to 160oC, most often at the boiling temperature of the reaction mixture.

The compounds of formula XV can be obtained from compounds of the formula

< / BR>
interaction with palodiruyut agent such as thionyl chloride or thienylboronic, or chlorosis or pentachloride phosphorus, or Brookes or pentabromide phosphorus. The reaction can be carried out without solvent or in an aprotic solvent such as methylene chloride or dichloromethane, at temperatures from about 0oC to 100oC.

The compounds of formula I, where R1is C1-C6alkoxy or C1-C6alkylthio and R2- C1-C6alkoxy, can be obtained from compounds of formula

< / BR>
where Rxxis chlorine or bromine,

R2- C1-C6alkoxy and

R3, R4and A have the meanings given previously for formula I,

through interaction with C1-C6alcohol or C1-C6the mercaptan in the presence of a base. The reaction is usually carried out in a polar organic solvent such as ethanol or tert-butanol, at temperatures from about 20oC to 160oC, most often when the pace is s

< / BR>
by the reaction with palodiruyut agent such as thionyl chloride or thienylboronic, or chlorosis or pentachloride phosphorus, or Brookes or pentabromide phosphorus. The reaction can be carried out without solvent or in an aprotic solvent such as methylene chloride or dichloroethane, at temperatures from about 0oC to 100oC.

The compounds of formula XVIII can be obtained by treating compounds of formula

< / BR>
activated derivatives of carboxylic or sulfonic acids of the formula R3AOH, often the acid chloride of the acid of formula R3ACl, where R3and A have the meanings previously defined for formula I, in the presence of calcium hydroxide in an aprotic solvent such as dioxane, as described in the link above Jensen.

The compounds of formula XIX can be obtained by treating compound of the above formula XV with an alcohol in the presence of a base. The reaction is usually carried out in a polar organic solvent, such as ethanol, at temperatures from about 20oC to about 160oC, most often at the boiling temperature of the reaction mixture.

The compounds of formula I, where R1is amino and R2- O(C1-C6alkyl), can be floor is La formula I,

with hydrazine in a solvent such as C1-C6alcohol, often at the boiling temperature of the solvent.

The compounds of formula XX can be obtained by treating compounds of formula

< / BR>
where R3, R4and A have the meanings previously defined for formula I,

alkylating agent such as di(C1-C6alkyl) sulfate, and a base such as sodium hydride, in a solvent such as dimethyl sulfoxide.

The compounds of formula XXI can be obtained by treating compounds of formula

< / BR>
activated derivatives of carboxylic or sulfoxylate formula R3AOH, such as the acid chloride of the acid of formula R3ACl, where R3and A have the meanings previously defined for formula I, in the presence of a Lewis acid such as aluminium chloride, in an aprotic solvent such as methylene chloride, dichloroethane or tetrachlorethane, at temperatures from about 0oC to approximately 150oC.

The compounds of formula XXII can be obtained by treating compounds of formula

< / BR>
phthalic anhydride in acetic acid at the boiling temperature of the solvent.

The compounds of formula XXIII can be obtained by the interaction cyanoacetic the emission alcohol solution in the presence of a base.

The compounds of formula I, where A and R1together form pyrimidinyl, have the formula

< / BR>
where R2, R3, R4and R5have the meanings previously defined for formula I.

These compounds can be obtained by cyclization of the compounds of formula I where A is C=O and R1means amino, with the compound of the formula

< / BR>
where R5has the values defined previously for formula I.

This reaction is usually performed at 100-250oC, often at boiling point (reflux distilled) compounds XXV.

The compounds of formula I, where A and R1form together a 5 - pyridyl, have the formula

< / BR>
where R2, R3, R4and R5have the meanings previously defined for formula I.

These compounds can be obtained as shown at the end of the reaction scheme.

The compounds of formula XXIX is obtained by reaction of a ketone of formula XVII with a compound of formula XXVIII in a suitable solvent, such as tetrahydrofuran, in the presence of a base such as sodium hydride. The reaction is usually performed at the boiling temperature of the reaction mixture.

Compound XXIX is subjected to reaction with the compound of the formula R2C(OCH3)3with OBRAZOVATEL boiling point of the reaction mixture. A wavy line in formula XXX indicates that the compound includes any isomer of this compound in accordance with generally accepted symbol to represent stereo-isomers.

Compound XXXI obtained by reaction of compound XXX with a hydrazine of the formula H2N-OTHER4where R4has the values defined previously for formula I. the Reaction is carried out in a suitable solvent, such as ethanol, usually at the boiling temperature of the reaction mixture.

The compounds of formula XXVI where R5linked to position 6, first formed from the reactions of compound XXXI with hydrazine hydrate in a suitable solvent, such as ethanol, often at the boiling temperature of the reaction mixture. Compound XXXII separated from precipitated in the sediment phthalhydrazide and placed in an organic solvent, such as toluene. Compound XXVI is formed by dehydration of compound XXXII using palladium-on-charcoal grill.

The reaction scheme 1 shows the connection XXVI, in which R5located in the 6-position. A similar sequence of reactions can be used to obtain compounds XXVI, where R5is 7-position, when the connection replacement XXVIII compound of the formula

, can be obtained by reaction of a ketone of the formula

< / BR>
with a hydrazine of formula IV, as defined previously, with the formation of the pyrazole nucleus of the compounds of formula

< / BR>
The reaction is carried out at reflux distilled in an appropriate solvent, such as ethanol. After the synthesized pyrazol compounds, for example, bromine in acetic acid to the formation of the corresponding 4-bromo-derived and conventional metallation, for example, tributyltin at -78oC in tetrahydrofuran add the activated R3carboxylic acid such as the acid chloride R3C(O)Cl, and receive the desired compound I.

The compounds of formula I where A is C=O and R1and R2are different, and where R1or R2attached via C2H4the fragment can be obtained from piranha formula

< / BR>
where R3has the values defined previously, and

R2has the values defined previously, when R11means C3-C6alkyl which may be substituted by 1 to 3 groups of R6or

R2is R1when R11means C3-C6alkyl which may be substituted by one to three substituents, such as hydroxy, amino, carboxy, amido, NH(C= O) (C1-C1-C3thioalkyl, fluorine, bromine, chlorine, iodine, cyano or nitro.

Compound XXXIV is subjected to reaction with a hydrazine of the formula H2NNHR4where R4has the previously defined meanings, with the formation of compounds of formulas

< / BR>
< / BR>
after dehydration and hydrogenation result in compounds of formulas

< / BR>
< / BR>
The compounds of formula I where A is C=O and R2means O(C1-C6alkyl), can be obtained by the reaction of hydrazine of the formula R4NHNH2with the compound of the formula (A) in a suitable solvent,

< / BR>
< / BR>
such as THF or methylene chloride, and the cyclization of the obtained

in the hydrazide by heating with the formation of the intermediate product (B). This compound may be injected into reaction with activated carboxylic acid derivative such as acid chloride acid R3(CO)Cl in the presence of a Lewis acid such as aluminum chloride, in a suitable solvent, such as telengard, at temperatures from about -10oC to 80oC. the resulting compound of formula I, where R2is hydroxy, can interact with (C1-C6alkyl)L, where L is a removable group, such as chlorine, bromine or toilet, and C1-C1- C1-C6alkylamino or di(C1-C6alkyl)amino, can be obtained from corresponding compounds of formula I, where R1- amino. If R1is methylamine or dimethylamine, the reaction is carried out with meteorous agent such as methyl iodide. If R1- (C2-C6alkyl)amino or di(C2-C6alkyl)amino, the reaction is carried out with an alkylating agent such as C2-C6alkyl-L, where L represents a removable group, such as chlorine, bromine, toilet or mesilate. As methylation and C2-C6the alkylation takes place in the presence of a base such as sodium hydride and a solvent such as tetrahydrofuran, dimethylformamide or dimethylsulfoxide.

Salts with acids get in the normal way during the processing of a solution or suspension of the free base of formula I with one chemical equivalent of a pharmaceutically acceptable acid. To highlight the salts used conventional methods of concentration or crystallization. Examples of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, chloritoid is sulfo-, p-toluensulfonate, and other related acids.

The compound of the invention may be single or in combination with pharmaceutically acceptable carriers in the form of single or multiple doses. Suitable pharmaceutical carriers are inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the new compounds of formula I and pharmaceutically acceptable carriers, which are then conveniently introduced in the form of various dosage forms such as tablets, powders, cakes, syrups, injectable solutions and the like. These pharmaceutical compositions can, if necessary, contain additional ingredients such as fragrances, binders, excipients and the like. Thus, for oral administration may be tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate, along with a variety of loosening additives, such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and stearat magnesium, sodium lauryl sulfate and talc. Solid compositions of this type can also be used as fillers in obtaining soft and hard gelatin capsules. The preferred materials for this purpose are lactose or milk sugar and glycols of high molecular weight. If oral administration is required aqueous suspensions or elixirs, the essential active ingredient may be combined with various sweetening or flavouring additives, coloring additives or dyes and, if desired, emulsifying or suspendresume agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.

For parenteral administration can be used solutions of the new compounds of formula I in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution. Such aqueous solutions are, if necessary, to contain the buffer; the liquid diluent first make isotonic with the help of a suitable salt or glucose. These separate aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. Used sterile water environment are all readily available with the label of the compounds of the present invention in the treatment of inflammatory processes of the skin and then it can be creams, jellies, gels, pastes and ointments in accordance with conventional pharmaceutical practice.

An effective dose of a compound of the formula I depends on the route of administration and other factors, such as age and weight of the patient, which are usually well-known doctor. The dose also depends on the condition being treated, although usually, the daily dose varies from about 0.1 to 50 mg/kg body weight of the patient. More specifically, the daily dose for treatment-induced stress diseases is usually from about 0.1 to 50 mg/kg body weight of the patient, in the treatment of inflammatory processes require from about 0.1 to 100 mg/kg, for senile sclerosis brain is from about 0.1 to 50 mg/kg, as well as to treat diseases of the gastrointestinal tract, loss of appetite for nervous, hemorrhagic stress and symptoms of rejection of drugs and alcohol.

Test methods of the compounds of formula I, their antagonistic activity towards releasing factor, corticotropin (CRF) described in methods of Endocrinology, 116, 1653-1959 (1985) and Peptide, 10, 179-188 (1985), which determine the binding activity of the test compounds with the CRF receptor. Binding activity of compounds of the formula I usually varies from about 0.2 nanomolar to 10 micromol.

In primerka permission.

Example 1.

A. 2-Bromo-2,5-dimethylacetophenone

The mixture or 10.60 g (of 0.10 mole) of p-xylene and 16,53 g (0,105 mol) -bromoacetanilide in 300 ml of 1,2-dichloroethane in the cooling bath of ice in the atmosphere of dry N2handle portions 14,15 g (0,106 mole) aluminum chloride, stirred for 30 minutes at 0-5oC, then for 2.5 hours at room temperature. The mixture was poured on ice, the aqueous layer was acidified with concentrated HCl.

The organic layer is separated, the aqueous layer was extracted twice methylene chloride. The organic layers are combined, dried brine and magnesium sulfate, the solvent evaporated and get 23,87 g amber oil, which is used in the next reaction without further purification.

Century 2-Cyano-2,5-dimethylacetophenone

The product of the previous reaction (approximately 0,10 mol) dissolved in 300 ml of ethanol, treated with a solution 16,25 g (0.25 mole) of potassium cyanide in 30 ml of water, boil for 90 minutes, cooled, the ethanol evaporated on a rotary evaporator, the residue is acidified with concentrated hydrochloric acid to slightly acid reaction. The product is extracted with ethyl acetate, taking care to avoid contact with hydrogen cyanide. The organic extracts are dried solely with hot hexane, after cooling, separating the precipitated crystals in the form of needles and get the desired product of 8.50 g (48% for the two reactions), so pl. 75 -76oC.

C. 3,3-Bis-methylthio-2-(2,5-dimethylbenzoyl)Acrylonitrile

The solution 4,96 g (28.6 mmol) of 2-cyano-2,5-dimethylacetophenone in 120 ml of dry dimethyl sulfoxide and 3,43 ml systems (57.3 mmol) of carbon disulfide in a three-neck round-bottom flask in a dry nitrogen atmosphere was stirred at 15-18oC, 5 portions contribute to 1.41 g (58.7 mmol) of sodium hydride, free from oil, the resulting solution was deep red color is stirred for 1 hour at 18oC, cooled to 15oC, after which make dropwise to 3.92 ml (of 8.95 g, 63,0 mmole) of methyl iodide, adding the temperature rises to about 22oC, stirred for 2 hours at room temperature and pour the reaction mixture into cold water. The aqueous layer was extracted 3 times with ethyl acetate. The extracts are combined, washed 3 times with water, dried with brine and magnesium sulfate, evaporated and get 8,96 g of the above compound in the form of a hard orange oil, which crystallized in the refrigerator. The analytical sample is crystallized from ethanol, so pl. 74,5-75,5oC.

D. 5-Amino-1-(2,6-dichloro-4-triptoreline)-4-(2,5 - dimethylbenzoyl)-3-meth is hydrazine in 100 ml of ethanol is boiled for 2 hours, the resulting solution is heated, the ethanol is then mostly removed on a rotary evaporator and the residue partitioned between dilute aqueous solution of hydrogen chloride and ethyl acetate. The organic layer is washed with water and brine, dried over magnesium sulfate, treated with decolorizing charcoal. The filtered solution is evaporated, the residue is crystallized from 10:1 hexane/ ethyl acetate and receive 12.00 g (88%) of the named product is in two portions, so pl. 130-132oC.

Example 2. 5-Methylamino-4-(2-chlorobenzoyl)-3-methylthio-1-(2, 4,6-trichlorophenyl)pyrazole and 5-dimethylamino-4-(2-chlorobenzoyl)-3-methylthio-1-(2,4,6-trichlorophenyl)pyrazole

A mixture of 0.50 g (1.16 mmol) of 5-amino-4-(2-chlorobenzoyl)-3 - methylthio-1-(2,4,6-trichlorophenyl)of pyrazole in 5 ml of tetrahydrofuran is treated with 50 mg (1.16 mmol) of sodium hydride, stirred for 30 minutes at room temperature, is added dropwise 0.75 ml (1,71 g, 12.0 mmol) methyl iodide, stirred for 60 minutes at room temperature, the reaction is quenched with water, the product extracted with ethyl acetate, the extract evaporated, the residue chromatographic on silica gel with a mixture of hexane and ethyl acetate, get less polar dimethylamino-compound (300 mg, 54%) as a white foamy substance.

4, H 3.09, N 9.01

The more polar monomethylamine-allocate connection with the column in a similar way in the form of a white foamy substance (34 mg, 6%). Elementary analysis for C18H13ON3SCl4:

Calculated: C, 46.88, H 2.84, N 9.11

Found: C at 46.54, H 2.89, N 9.07

Example 3. 5-Amino-4-(2-methoxybenzoyl)-3 - methylthio-1-(2,4, 6-trichlorophenyl)pyrazole

To a solution of 2-methoxyphenylacetamide obtained from 18.7 g (of 0.10 mole) of 2-bromoanisole and 2.43 g (0,10 mol) of magnesium shavings in the air in a dry nitrogen, add 1.6 g (5.0 mmol) of 5-amino-4-cyano - 3-methylthio-1-(2,4,6-trichlorophenyl)pyrazole, boiled with stirring for 16 hours, cooled, treated with 50 ml of a saturated aqueous solution of ammonium chloride. The organic layer is extracted with aqueous hydrogen chloride, the acid extract was treated with 10 ml of concentrated hydrogen chloride, heated 10 minutes at 80-90oC, then the mixture is cooled, alkalinized, extracted with methylene chloride, the extract chromatographic with a mixture of hexane and ethyl acetate and get 313 mg (14%) of these connections, so pl. 200-202oC.

Elementary analysis for C18H14O2N3SCl3:

Calculated: C, 48.82, H 3.18, N 9.49

Found: C, 48.54, H 3.32, N 9.09

Example 4.

< is (20.0 mmol) of 5-methylisoxazole, boil for 8 hours, stirred overnight at room temperature, add to 4.23 g (20.0 mmol) of 2,4,6-trichlorophenylhydrazine, the reaction mixture is again boiled for 4 hours, add the second portion of sodium in methanol, and then continuously boiled for 24 hours. The reaction mass is treated with ether, diluted hydrogen chloride. The organic extracts washed with diluted hydrogen chloride and brine, dried over magnesium sulfate, evaporated and get the crystals, so pl. 132-134oC. Analysis for this substance, especially two of the CN band in the IR spectrum at 2190 cm-1and 2250 cm-1shows that it is a mixture of CIS - and TRANS-isomers of 1-cyanoacetic - 2,4,6-trichlorophenylhydrazine. This material is suspended in methanol, treated 10,0-mmol of sodium methylate in 5 ml of methanol, allowed to stand 5 minutes at room temperature, water is added to the crystallization of the product, then it is filtered off, washed well with water, air-dried and gain of 2.21 g (40%), so pl. 134-135,5oC. Despite the similarity in melting temperatures, the latter substance is distinctly different from the first, with Rf0,67 versus 0.78 for the intermediate product on silicagel the TLC plate when elution with 1:1 hexane-ethyl acetate, and clearly differs in spectrospin of 2.34 g (17,50 mmol) of aluminum trichloride in 20 ml of 1,1,2,2-tetrachlorethane process 2,02 ml (2,78 g, 15.9 mmol) of 2-chlorobenzylchloride, stirred for 20 minutes at room temperature, add a 2.00 g (7.23 mmol) of the product of stage A, is boiled for 16 hours, cooled, poured on ice, nerastvorimaya substance is filtered off, washed with ethyl acetate. The organic layer is separated, the aqueous layer was washed twice with ethyl acetate. The organic layers are combined, dried over magnesium sulfate, evaporated, the residue chromatographic on silica gel with elution with 4:1 hexane-ethyl acetate and get 2,05 g (51%) of the named product as an amorphous foamy substance. Elemental analysis for C24H14O2N3Cl5:

Calculated: C, 52.06, H 2.55, N 7.59

Found: C, 52.11, H 2.57, N 7.27

C. 5-Amino-4-(2-chlorobenzoyl)-3-methyl-1-(2,4,6-trichlorophenyl)pyrazole

A solution of 1.94 g (3.50 mmol) of the product stage In 20 ml of glacial acetic acid is treated with 20 ml of 48% HBR, boiled with stirring for 8 hours, cooled, treated with water for crystallization of the product, which is filtered off, washed with water, dried in air and get a product named 1.45 g (100%), so pl. is softened at about 210oC and melted at 222oC.

Elemental analysis for C17H11ON3Cl4:

Vechicle is metilamino-4-(2-chlorobenzoyl)-3 - methyl-1-(2,4,6-trichlorophenyl)pyrazole

The solution 0,208 g (0.5 mmol) of the compound of example 4C in 20 ml of tetrahydrofuran (THF) is stirred in a bath of ice/water, while adding 5.0 ml of 1.0 M hexamethyldisilazide sodium in THF, followed by depositing 0.5 ml (1,14 g, 8 mmol) iodotope bromide, stirred overnight at room temperature, the reaction was poured into water, the products are extracted with ethyl acetate, dried, and evaporated. The remainder chromatographic on silica gel with elution with 5:1 hexane/ethyl acetate and get less polar dimethylamino connection, 52 mg (23%), so pl. 108 - 109oC (ether/pentane).

The more polar product similarly crystallized from ether/pentane and obtain 39 mg (18%) monomethylamine connection, so pl. 174-175oC.

Example 6. 5-Amino-1-(2,6-dichloro-4-triptoreline)-4-(2,5-dimethylbenzoyl)-3-(n-propyl)pyrazole

A solution of 0.52 g (3.0 mmol) of 2,5-dimethylaminoacetonitrile, 0.45 g (3.0 mmol) of triethylorthoformate and 0,632 g (of 0.58 ml, 6.2 mmol) of acetic anhydride in 5.0 ml of ethyl acetate is boiled overnight, cooled, evaporated in vacuo, the residue is dissolved in 10 ml of ethanol. Half of this solution containing 1.5 mmol of 1-cyano-1-(2,5-dimethylbenzoyl)-3-methoxy-1-pentene, mixed with 0.7 ml (0.51 g, 5.0 mmol) of triethylamine and 0.37 g (1.50 mmol) of 2,6 - dichloro-4-tee ethyl acetate. The organic layer was washed with water, dried with brine and magnesium sulfate, the solvent evaporated and get the oil that chromatographic on silica gel in a thin layer upon elution with 4:1 hexane/ethyl acetate and get a named connection in the form of amorphous foamy substance.

Analysis for C22H20ON3Cl2F3: calculated: 469,0935; found: 469,0889

Example 7.

A. 5-Amino-3-hydroxy-1-(2,4,6-trichlorophenyl)pyrazole

Zanoxolo acid (8.5 g, of 0.10 mole) in 200 ml of dry ether is treated to 20.8 g (0,10 mol) pentachloride phosphorus, briefly boiled, allowed to cool to room temperature, and during this time the entire pentachloride phosphorus dissolved, filtered small number of nerastvorimogo material, the ether evaporated on a rotary evaporator, make 100 ml of toluene and evaporated to remove phosphorus oxychloride. The remaining pale yellow oil immediately dissolved in 50 ml of cold methylene chloride, is added to the cold suspension to 21.15 g (0,10 mol) of 2,4,6 - trichlorophenylhydrazine in of 14.0 ml of triethylamine and 100 ml of methylene chloride, keeping the temperature below 20oC through the use of baths with ice, leave to raise the temperature up to which a small amount of methylene chloride and receive the intermediate product, 2-cyano - N-(2,4,6-trichlorophenyl)acethydrazide, 14,92 g (54%), so pl. 166-168oC. Elemental analysis for C9H6ON3:

Calculated: C 38.81, H 2.17, N 15.09

Found: C 38.83, H 2.06, N 14.81

This material (14,92 g, 53 mmole) is dissolved in the solution 2,80 g (0.12 moles) of sodium in 200 ml of methanol, boiled for 4 hours, stirred overnight at room temperature, the methanol is mostly evaporated, the residue poured into water. The aqueous layer was extracted with ether, acidified with concentrated hydrochloric acid. The product is extracted with ethyl acetate. The extracts are dried with brine and magnesium sulfate, evaporated and get foamy substance which crystallized from ether, and get to 12.28 g (93%) of these connections, so pl. 221-223oC. Elemental analysis for C9H6ON3:

Calculated: C 38.81, H 2.17, N 15.09

Found: C 38.81, H 2.16, N 14.84

B. 3-Hydroxy-5-phthalimido-1-(2,4,6-trichlorophenyl) pyrazole

The mixture 4,50 g (18.0 mmol) of compound of stage A and of 2.81 g (19.0 mmol) of phthalic anhydride in 40 ml of glacial acetic acid is boiled for 4 hours, left overnight at room temperature, is added dropwise in about two volumes of water, the resulting solid precipitate is filtered off, washed with water. The crude residue is treated with a small amount of this is out of 5.11 g (69%), so pl. 295-298oC (decomposition).

Elemental analysis for C17H8O3N3Cl3:

Calculated: C 49.97, H 1,97, N 10.28

Found: C, 49.28, H 1.95, N 10.06

C. 4-(2-Chlorobenzoyl)-3-Hydroxy-5-phthalimido-1-(2,4,6 - trichlorophenyl)pyrazole

To a solution of 2-chlorobenzylchloride in 60 ml of 1,1,2,2-tetrachlorethane added aluminum trichloride (2,34 g, 17.6 mmol), stirred for 30 minutes at room temperature, add 2,87 g of compound stage unexpectedly, the reaction mass is boiled overnight, cooled, poured into water. The aqueous layer was extracted three times with ethyl acetate. The organic extracts are dried with brine and magnesium sulfate, evaporated and get a red oil, which is treated with methanol, crystallized and get a named connection of 2.97 g (77%), so pl. 245-246oC.

D. 4-(2-Chlorobenzoyl)-3-ethoxy-5-phthalimido-1-(2,4,6 - trichlorophenyl)pyrazole

A solution of 0.55 g (1.0 mmol) of the compound of stage C in 10 ml of dry dimethyl sulfoxide handle portions 36 mg (1.5 mmol) of sodium hydride, stirred for 30 minutes at room temperature, contribute to 0.21 ml (0.25 g, 1.61 mmol) diethylsulfate, stirred for 1 hour at room temperature, poured into water and the product extracted with ethyl acetate. The extracts washed with water, dried is anola and receive the product (230 mg, 40%) in the form of thin crystals, so pl. 215-216oC.

E. 5-Amino-4-(2-chlorobenzoyl)-3-ethoxy-1-(2,4,6-trichlorophenyl)pyrazole

Suspension 184 mg of the compound of stage D in 10 ml of ethanol is treated with 0.5 ml of 55% hydrazine hydrate is added, boiled for 1 hour, cooled, the solid residue is filtered off and discarded. The filtrate is evaporated to a resinous mass, triturated with ether, filtered. The filtrate is again evaporated to a foamy substance which shows 104 mg of analytically pure titled compound. Elemental analysis for C18H13O2N3Cl4:

Calculated: C, 48.57, H 2.94, N 9.44

Found: C 48.41, H 2.52, N 9.43

Example 8. 5-Dimethylamino-4-(2-chlorobenzoyl)-3-methoxy-1-(2, 4,6-trichlorophenyl)pyrazole

A solution of 60 mg (about 0.14 mmole) of 5-amino-4-(2-chlorobenzoyl)-3 - methoxy-1-(2,4,6-trichlorophenyl)pyrazole obtained by the method of example 7 in 5 ml of dry dimethyl sulfoxide is treated with 22 mg (from 0.88 mmole) free from oil of sodium hydride and get a yellow solution, which was allowed to stand for 1 hour at room temperature, add 0.2 ml (0,46 g is 3.21 mmol) of methyl iodide, stirred for 5 hours, poured into water and extracted the product with ethyl acetate. The extract is dried with brine and magnesium sulfate, the solvent evaporated and get a n is H, m), 7.48 (2H, s).

Example 9.

A. 3,3-Bis-ethoxy-2-(3-trifloromethyl)Acrylonitrile

Sodium (0.126 g, 5.5 mmol) dissolved in 15 ml of ethanol and 20 ml of dioxane, add to 1.59 g (5.0 mmol) of 3,3-bis - methylthio-2-(3-trifloromethyl)Acrylonitrile, boiled for 4 hours, stirred overnight at room temperature. This compound is relatively unstable in aqueous conditions and as such is not allocated. Instead, fold the amount of the mixture is withdrawn and the product is identified according to the1H NMR 300 MHz NMR (DMSO - d6): 1.14 (6H, t, J=7), 3.45 (4H, q, J=7), 7.44-8.16 (4H, m).

B. 5-Amino-1-(2,6-dichloro-4-triptoreline)-3-ethoxy-4- (3-trifloromethyl)pyrazole

Multiple of the number of videolooking solution of stage A, containing about two millimole 3,3-bis-2-(3-trifloromethyl)Acrylonitrile, boiled for nights of 0.49 g (2.0 mmole) of 2,6-dichloro-4-triftormetilfullerenov in 10 ml of ethanol, cooled, poured into dilute hydrogen chloride (HCl) and extracted with ethyl acetate (EtOAc). The extract is washed with water, brine, dried over magnesium sulfate (MgSO4), chromatographic on silica gel with elution with 4:1 hexane/ EtOAc and get a named connection 320 mg (31%), so pl. 77 - 78oC, from pentane.

oC.

Example 11. 1-(2,6-Dichloro-4-triptoreline)-5-methyl-4- (3-methylbenzoyl)-3-methylthiophenol

A solution of 2.97 g (16.9 mmol) of 4-(3-were)butane-2,4-dione and 4.04 ml (5,14 g, 67.6 mmol) of carbon disulfide in dry dimethylsulfoxide is treated with portions of 0.89 g (37.1 mmol) of the free oil of sodium hydride at 15-18oC, stirred for 30 minutes, added dropwise 2,31 ml (5,27 g, 37.1 mmol) methyl iodide, leave to rise to room temperature, stirred for 1 hour at this temperature, poured the reactions g (91%) oil, which crystallized in the refrigerator, so pl. 44-46oC.1H NMR (CDCl3): 2.16 (3H, s), 2.38 (6H, s), 2.72 (3H, s), 7.26-7.38 (2H, m), 7.58-7.74 (2H, m).

A mixture of 1.95 g (of 6.96 mmol) of 3,3-bis-methylthio-2- (3-methylbenzoyl)-2-acetylene, 1,71 g of 2,6-dichloro-4-triftormetilfullerenov in 20 ml of ethanol is boiled for 6 hours, stirred for 48 hours at room temperature, the reaction was poured into dilute HCl solution and the product extracted with EtOAc. The solution is dried, evaporated and the residue chromatographic on silica gel with elution 10: 1 hexane/EtOAc and get the named compound, which crystallized from pentane, 1,67 g (52%), so pl. 103-104oC.

Example 12. 5-Amino-1-(2,6-dichloro-4-triptoreline)-4- (5-[3-hydroxypropyl]-2-methylbenzoyl)-3-methylthiophenol

To a solution of 0,530 g (1.0 mmol) 5-amino-1-(2,6-dichloro-4 - triptoreline)-4-(5-[-methoxycarbonylethyl]-2 - methylbenzoyl)-3-methylthiophenol in 10 ml of THF while cooling in a bath with ice add to 1.33 ml of a 1.5 M solution of DIBAL in THF, the reaction temperature was raised to room temperature, quench the reaction with water and the product extracted with EtOAc, dried, evaporated, the residue chromatographic on silica gel with elution by the mixture hexane/EtOAc, allocate product named in the form of amorphous foamy substance, 174 mg (34%). Cell is 1.10, H 3.96, N 7.60

Example 13. [5-Amino-1-(2,6-dichloro-4-triptoreline)-3-methylsulphonyl-1H-pyrazole-4-yl]-(2,5-dimetilfenil)-methanon

To a solution of 200 mg (0.42 mmol) [5-amino-1-(2,6-dichloro-4 - triptoreline)-3-methylsulphonyl-1H-pyrazole-4-yl]-(2,5 - dimetilfenil)methanone in 10 ml of THF added 0,176 g (2.10 mmol) of anhydrous sodium bicarbonate followed by treatment with a solution of 145 mg (0,42 mmole) 3-chlormadinone acid in 8 ml of THF, incubated 2 hours at room temperature, contribute an additional 0.5 g of sodium bicarbonate and 260 mg (from 0.84 mmole) 3-chlormadinone acid, the mixture is immediately heated to 50oC, allowed to cool, stirred overnight at room temperature, poured into water and the product extracted with ethyl acetate. The organic extracts washed with diluted sodium bicarbonate solution, dried and evaporated. The compound obtained is crystallized from ether and receive 150 mg (70% yield) of colorless crystals, so pl. of 193.5-194,5oC.

Example 14.

The following compounds in tables 1 and 2 receive according to the given examples.

Example 15.

A. 3-Triftormetilfullerenov

The sodium (and 0.62 g of 27.0 mmol), dissolved in 40 ml of ethanol, add 4,79 g (26.9 mmol) of 3-triptoreline the Ute when cooled one volume of ether, the precipitation is filtered off. The filtrate is evaporated on a rotary evaporator and receive the product in the form of oil with almost quantitative yield. This material is used for the next reaction without further purification.

B. 3-Triftormetilfullerenov

A solution of 3.00 g (13.8 mmol) of 3-triftormetilfullerenov in 130 ml of methylene chloride cooled to 5oC and in an atmosphere of dry N2process 4,89 g (28,35 mmol) m-chlormadinone acid, stirred for 48 hours at room temperature, cooled on ice, after which insoluble particles are filtered. The filtrate is washed with 10% solution of sodium sulfate until then, until you have removed all traces of peroxide, then dried over magnesium sulfate, evaporated to a light yellow oil which is used without further purification in the next stage.

C. 3,3-Bis-methylthio-1-(3-triftormetilfullerenov)- Acrylonitrile

To a solution of 13,82 mmol (crude product of 3-trifluoromethyl of forceunauthorized in 30 ml of dry dimethyl sulfoxide and 1.25 ml (1,58 g, 20.7 mmol) CS2when cooled to approximately 15oC ice in a dry nitrogen atmosphere add portions of 0.99 g (41.5 mmol) of the free oil of sodium hydride t the th temperature, the mixture is cooled to 15oC, quenched 2,58 ml (of 5.89 g, 41.5 mmol) of methyl iodide, stirred overnight at room temperature, poured into a mixture of ice/water and leave to granulomatosa for 3.5 hours. The product is filtered, air-dried and receive 3.51 g (72%) of product. The analytical sample is crystallized from EtOH/H2O, so pl. 109-110oC.

D. 5-Amino-1-(2,6-dichloro-4-triptoreline)-4-(3 - trifloromethyl)-3-methylthiophenol

A suspension of 0.50 g (1.42 mmol) of 3,3-bis-methylthio-2-(3 - triftormetilfullerenov)Acrylonitrile, and 0.35 g (1.42 mmol) of 2,6-dichloro-4-triftormetilfullerenov in 10 ml of ethanol is boiled for 2.5 hours, the solution is left to cool to room temperature, stirred overnight at this temperature, poured into cold water. The product is extracted with ethyl acetate, the extracts dried over magnesium sulfate and evaporated. The residue is crystallized from ether, the product is filtered, air-dried and receive 314 mg (40%) of the desired product, so pl. 201-203oC. Elemental analysis for C18H11O2N3S2Cl2F6:

Calculated: C at 39.28, H 2.02, N 7.64

Found: C at 39.35, H 2.19, N 7.48

E. Dimethylamino-1-(2,6-dichloro-4-triptoreline)-4- (benzazolyl)-3-methylthiophenol

To Rast is added in dry nitrogen atmosphere at room temperature for 36 mg (1.5 mmol) of the free oil of sodium hydride, survive 30 minutes and get a clear light yellow solution, which was treated with 0.5 ml (8.0 mmol) of methyl iodide, stirred for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate. The combined extracts are dried with brine and magnesium sulfate, evaporated, the residue is crystallized from ether and receive the desired product with 81% yield, so pl. 163-164oC.

Example 16.

The compounds obtained according to the method of example 15 are shown in table. 3.

Example 17. 4-(2-Chlorophenyl)-1-(2,6-dichloro-4 - triptoreline)-3-methylthiotetrazole[3,4-d]pyrimidine

Suspension 669 mg (1.39 mmol) of 5-amino-1-(2,6-dichloro-4 - triptoreline)-4-(2-chlorobenzoyl)-3-methylthiophenol in 5 ml of formamide is heated overnight at 150oC, cooled, and the reaction mixture appears light yellow precipitate, contribute to the suspension with stirring in 50 ml of water until complete precipitation of the product, which is filtered off, washed with water. Undelimited traces of starting material is observed in the product by TLC, so the above method is repeated, getting a brown solid that does not contain traces of starting material. This substance RUB clean with methylene chloride and receive light yellow solution, S="ptx2">

The compounds obtained according to the method of example 17 are shown in table. 4.

1. Derivatives of pyrazole of the General formula I

< / BR>
in which R1represents C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)(C1-C6alkyl), NHCH2COOH or NH(CH2)3OC6H5, R2represents C1-C6alkyl, O(C1- C6alkyl) or S(O)n(C1-C6)alkyl), where n = 0, 1, or 2;

R3is phenyl, substituted by one or two substituents selected independently from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, C1- C6alkyl, C1-C6alkoxy, nitro, N(C1- C4alkyl)(C1-C2alkyl), COO(C1- C4alkyl), SO2NH2, SO2N(C1- C4alkyl) (C1-C2alkyl), cyclopropyl, 2-thienyl, phenyl, pyrrolyl, CH2CO2C2H5, (CH2)3CO2C2H5where C1- C6the alkyl may be substituted by hydroxy, provided that the phenyl R3the group is para-substituted by phenyl, or C1-C6alkylcyclopentanes, or 1-naphthyl, possibly substituted C1-C6alkoxy;

R4represents phenyl, someseni-C6alkyl, or 1,3-di(C1- C6)alkyl-4-nitropyrazole-5-yl, with the proviso that when R1is amino, R2represents methylthio, R4is 2,4,6-trichlorophenyl, R3is not 2-chlorophenyl.

2. The compounds of formula I under item 1, in which R3represents phenyl, substituted with one or two substituents selected independently from the group consisting of fluorine, chlorine, bromine, methyl, trifluoromethyl, nitro, C1-C6alkoxy, SO2NH2, SO2N(C1-C4alkyl)(C1-C2alkyl).

3. Connection PP.1 and 2, in which R4is 2,4,6-trichlorophenyl, 2,4,6-trimetilfenil, 2,6-dichloro-4-triptoreline, or 2,6-dimethyl-4-bromophenyl.

4. Connection PP.1 to 3, in which R1represents amino, methylamino or dimethylamino.

5. Connection PP.1 to 4, in which R2is methylthio or ethyl.

6. Connection on p. 1, representing 5-amino-1-(2,6-dichloro-4-triptoreline)-4-(2,5-dimethylbenzoyl)-3-methylthiophenol, 5-amino-1-(2,6-dichloro-4-triptoreline)-4-[(2,5-bistritei)benzoyl] -3-methylthiophenol, 5-amino-1-(2,6-dichloro-4-triptoreline)-4-(2-methyl-5-isopropylbenzyl)-3-methylthiophenol, 5-amino-1-(2) - Rev. oil)-3-methylthiophenol.

7. Pharmaceutical composition having antagonistic activity to releasing factor, corticotropin (CRF) containing the active ingredient and pharmaceutically acceptable additives, such as fillers or diluents, wherein as the active ingredient it contains a compound of formula I under item 1 in an effective amount.

 

Same patents:

Substituted pyrrole // 2141960

The invention relates to new imidazolidinedione intended for use in the pharmaceutical industry as active ingredients in the manufacture of medicines

The invention relates to new nitrogen-containing heterocyclic compounds possessing biological activity, and more particularly to derivatives of 1,2,4-triazolo[1,5-a]pyrimidines, their pharmaceutically acceptable salts and stereoisomers, pharmaceutical compositions containing them, and method of inhibiting seizures

The invention relates to new derivatives of arylsulfonamides having, in particular, valuable pharmacological properties, more particularly to a derivative of arylsulfonamides General formula (I)

< / BR>
where R1benzyl, thienyl, chloranil, tetramethylene pentamethylbenzyl, phenyl, unsubstituted or monosubstituted by a halogen atom, a nitro-group, stands, metaxylem or trifluoromethyl, phenyl, disubstituted by chlorine atoms or methoxypropane,

R2a hydrogen atom, methyl,

R3pyridyl,

R4and R5hydrogen atoms or together denote a carbon-uglerodnoi communication,

R6hydroxyl, methoxyl,

A group of the formula

< / BR>
where R7and R8a hydrogen atom or together denote a methylene or ethylene group

X N-methyl-aminogroup or sulfur atom, and the group-CHR7associated with the group-NR2-,

B a carbon-carbon bond or unbranched Allenova group with 2-4 carbon atoms,

their mixtures, isomers or individual isomers and physiologically tolerated additive salts with bases, if R6means hydroxyl, which

The invention relates to the derivatives of triazole, exhibiting antifungal activity

The invention relates to heterocyclic compounds having excellent pharmacological properties, and to intermediate compounds used for the synthesis of these compounds

The invention relates to heterocyclic compounds having angiotensin II antagonistic activity
Up!