Aminosilane pyrazoles and intermediate aminosilane pyrazoles

 

(57) Abstract:

Describes the new aminosilane pyrazoles of General formula I

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where the values of R1- R3And, Z, Y, specified in paragraph 1 of the claims, have antagonistic activity against releasing factor corticotropin. They are effective for the treatment of a wide range of diseases, including induced by the stress of the disease. Describes intermediate aminosilane pyrazine. 2 C. and 10 C.p. f-crystals, 4 PL.

The invention relates to substituted pyrazoles containing pharmaceutical compositions and their application for the treatment of stress-related and other diseases. The compounds possess antagonistic activity relative to releasing factor (factor release) corticotropin (CRF).

CRF antagonists are referred to in U.S. patent 4605642 and 5063245 and related peptides and pyrazolones, respectively. The value of CRF antagonists noted in the literature, for example in U.S. patent 5063245, which is incorporated herein by reference. Recently described a variety of activity, which have CRF antagonists, M. J. Owens et al., Pharm. Rev., Vol. 43, p. 425-473 (1991), also incorporated herein by reference. Based on these and other references CRF antagonists systems is donirovannye stress depression fear and headaches; abdominal bowel syndrome; inflammation; immune suppression; infection of human immunodeficiency virus (HIV); senile sclerosis of the brain, diseases of the gastrointestinal tract; loss of appetite for nervous system; hemorrhagic stress; drug and alcohol dependence; drug addiction and problems of fertilization.

The present invention relates to compounds of the formula

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and its pharmaceutically acceptable salts with acids, where A is CH2; X1is a covalent bond, CH2, O, S or NR, where R is hydrogen, linear C1-C6alkyl or branched C3-C8alkyl;

R1, R2and R3each independently from each other describe linear C1-C6alkyl, branched C3-C8alkyl, C3-C8alkenyl, and the double bond is not adjacent to the N or X1when X1means oxygen or sulfur, or C3-C7cycloalkyl-(CH2)nwhere n equals 0, 1, 2, 3 or 4; or R1and R2can together with the nitrogen atom to form a saturated four-, five - or six-membered ring, optionally condensed with anthropoi; and RN(C1-C6alkyl), or a covalent bond when X1not a covalent bond, and R19specifies hydrogen, linear C1-C6alkyl, branched C3-C8alkyl, C3-C8alkenyl or C3-C6cycloalkyl-(CH2)nwhere n is 0 to 4;

Y describes phenyl, thienyl, benzothiazyl, pyridyl, hinely, pyrazinyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isothiazolin, benzothiazolyl, isoxazolyl, benzisoxazole, triazolyl, pyrazolyl, pyrrolyl, indolyl, isoindolyl, oxazolyl, benzoxazolyl, pyrrolidinyl, diazolidinyl, morpholinyl, piperidinyl, each of which may be substituted by one to three substituents, such as fluorine, chlorine, bromine or methyl, or by one trifluoromethyl; provided that Y is a substituted phenyl;

and

Z means

(a)

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where ring B describes phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thienyl or indolyl, each of which can be replaced by stands, methoxy, fluorine, chlorine, bromine or iodine; a saturated 5 - or 6-membered carbocyclic ring or a partially unsaturated ring containing>
alkoxy, hydroxy, fluorine, chlorine, bromine, iodine or trifluoromethyl;

R5means hydrogen, linear C1-C6alkyl, branched C3-C8alkyl, C3-C8alkenyl, or (CH2)o-X -(CH2)r-Q2-R6;

R6describes hydrogen, linear C1-C6alkyl, branched C3-C8alkyl or C3-C8alkenyl;

X2and Q2each independently from each other is O, S, NH, N(C1-C6alkyl), or one of X2and Q2can be a covalent bond;

m equals 0 or 1;

o is 1 or 2;

p is 1 or 2; and

r is 0, 1 or 2;

(b)

< / BR>
where R4and R5have the meanings previously defined and t and n are each independently from each other are equal to 1 or 2;

(c) -NR7R8where R7and R8independently of one another represent hydrogen, C1-C6linear alkyl, branched C3-C8alkyl, C3-C8alkenyl, (CH2)vCH2OH, (CH2)vNR9R10where v is 0 to 3 and R9and R10each independently from each other describe hydrogen or linear C1-C6alkyl, C1-C12cycloalkyl; (C3-C6cycloalkyl, C1-C6hydroxyalkyl, phenyl, phenyl (C1-C3alkylen), each of which may be substituted by one or two substituents, such as hydroxy, fluorine, chlorine, bromine, C1-C5alkyl or C1-C5alkoxy; or R7and R8can be together with the nitrogen atom a saturated or partially saturated 5 - to 7-membered ring that may contain one O, S, NH or N(C1-C6alkyl) and which may be substituted C1-C6by alkyl, hydroxy or phenyl, and any double bond (connection) are not adjacent with any heteroatom;

(d)

< / BR>
where B, R4and R5have the meanings defined above, w, x, y and z each independently from each other equal to 1 or 2 and w describes (CH2)qand q has the values defined above, N(C1-C6alkyl), or oxygen;

(e)

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where B, R4m and p have the values described previously;

(f)

< / BR>
where and R4have the meanings previously defined;

(g) O(CH2)vR11< / BR>
where v equals 0-3, and R11means linear C1-C6alkyl, branched C3-C8alkyl, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, thienyl, who was Salil, benzothiazolyl, isothiazolin, benzothiazolyl, isoxazolyl, benzisoxazole, triazolyl, pyrazolyl, pyrrolyl, indolyl, isoindolyl, oxazolyl, benzoxazolyl, pyrrolidinyl, diazolidinyl, morpholinyl, piperidinyl or thienyl, each of which may be substituted by one or two substituents, such as fluorine, chlorine, bromine, methyl or trifluoromethyl;

(h)

VII

where A has the values defined above and is linked to position 1 or 2, while R14attached to position 2 or 1, respectively; F, G, H, I, J and K are independently of each other C or N, provided that not more than three of H, I, J and K are astami with no more than two adjacent astami; R12and R13each independently of one another denotes hydrogen, a linear C1-C6alkyl, branched C3-C8alkyl, C3-C8alkenyl, fluorine, chlorine, bromine, trifluoromethyl, hydroxy, thiol, C1-C12alkoxy, C1-C12thioalkyl, C3-C12alkenone or C3-C12thioalkyl, and the double bond is not adjacent to the oxygen or sulfur, and R14describes hydroxy, C1-C12alkoxy, C3-C12alkenone, and the double bond is not adjacent to the oxygen, or-X2- (the exception, that Q is sulfur, or R14is NR15R16where R15and R16each independently of one another denotes hydrogen, a linear C1-C6alkyl, branched C3-C8alkyl, C3-C8alkenyl, where the double bond is not adjacent to the nitrogen, or C3-C7cycloalkyl-(CH2)n, where n has the values defined above, or R15and R16together with the nitrogen atom form a saturated five - or six-membered ring, optionally condensed with anthropoi; or

(i)

< / BR>
where D, E, F and G are independently of each other C or N, provided that the nitrogen atoms are not more than two of D, E, F and G, and R12and R14have the meanings defined in paragraph (h), A, defined earlier, is associated with the carbon in formula XV, and R14is associated with carbon, located adjacent to the carbon attached to A.

More specific compounds of formula I of the invention include compounds where Y is phenyl, substituted with three substituents, which are in positions 2, 4 and 6, for example, 2,4,6-trichlorophenyl, 2,6-dichloro-4-triptoreline or 2,6-dichloro-4-forfinal.

Other more specific compounds forms the th represents methyl, and compounds where Z equals NR7R8and R7is phenyl or phenyl substituted by one of the substituents, such as fluorine, chlorine, nitro, methyl or methoxy, and R8has the values defined above, preferably (CH2)3OH, CH2CH2OH or methyl.

Preferred compounds of formula I are compounds where Z means 1,2,3,4-tetrahydroisoquinoline-2-yl, substituted R5that is -(CH2)o-X2-(CH2)-Q2-R6more specifically R5means -(CH2)kOH, where k equals an integer from 1 to 4, or-CH2OCH2CH2OR6. Other preferred compounds of formula I are compounds where Z is 1,2,3,4-tetrahydroquinolin-2-yl, where R5is substituted in the 3 position, and the absolute configuration at 3-position is a or S, or R, or R, s

Preferred compounds of formula I are compounds where Z has the meanings given above in paragraph (h); and compounds where Z have the meanings defined in (h), A is linked to position 1, F, G, H, I, J and K are each carbon, and R14defines methoxy, ethoxy, isopropoxy or cyclopropylmethoxy in position 2.

is it in clause (h), A connected c position 1, K is nitrogen, F, G, H, I, J and K each means carbon, and R14represents-X2-(CH2)Q2R62 position; compounds where Z has the values defined in (h), A connected c position 1, K is nitrogen, F, G, H, I and J each is a carbon, and R14is methoxy, ethoxy, isopropoxy or cyclopropylmethoxy in the second position; and compounds where Z has the values defined in (h), A is in position 1 and R14is ethoxy, isopropoxy or cyclopropylmethoxy in the second position. These preferred compounds of formula I, where Z has the values defined in (h), R12and R13are preferably the hydrogens.

Other preferred compounds of the formula are compounds where Z have the meanings previously defined in paragraph (a), B is phenyl, p and m are each equal to I and R5means CH2OCH3.

Preferred compounds of formula I include compounds where Z is

< / BR>
where B is phenyl, m is 0 and p - 1.

Specific preferred compounds of the invention include:

2-{ 1-[1-(2,6-dichloro-4-triptoreline)-5-dimethylamino-3-ethyl-1H - pyrazole-4-trisulfonic-2-(2,4,6-trichlorophenyl)-2H-pyrazole-3-yl] dimethylamine, derivative (+) -3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline;

enantiomeric [2-(2,6-dichloro-4-triptoreline)-4-(3-ethoxymethyl-3,4-dihydro-1H - isoquinoline-2-ylmethyl)-5-ethyl-2H-pyrazole-3-yl] -dimethylamine derivative (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline;

[2-(2,6-dichloro-4-triptoreline)-5-ethyl-4-(7-methoxyquinoline-8-ylmethyl) -2H-pyrazole-3-yl]-dimethylamine;

[2-(2,6-dichloro-4-triptoreline)-4-(2-ethoxy-naphthalen-1-ylmethyl)-5 - ethyl-2H-pyrazole-3-yl]-dimethylamine;

[4-(2-ethoxynaphthalene-1-Ismail)-5-ethyl-2-(2,4,6-trichlorophenyl)-2H-pyrazole-3-yl]-dimethylamine;

[4-(7-methoxyquinoline-8-ylmethyl)-5-methylsulfanyl-2-(2,4,6-trichlorophenyl) -2H-pyrazole-3-yl]-dimethylamine;

2-{ 1-[5-dimethylamino-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H - pyrazole-4-ylmethyl]-naphthalen-2-yloxy}-ethanol;

enantiomeric [2-(2,6-dichloro-4-triptoreline)-5-ethyl-4- (3-methoxymethyl-3,4-dihydro-1H-isoquinoline-2-ylmethyl)-2H-pyrazole-3-yl] - dimethylamine derivative (+)-3-hydroxymethyl-1,2,3,4-tetrahydroquinoline;

[4-(2-cyclopropylmethoxy-1-ylmethyl)-5-methylsulfanyl-2- (2,4,6-trichlorophenyl)-2H-pyrazole-3-yl]-dimethylamine;

2-{[5-dimethylamino-3-ethyl-1-(2,4,6-trimetilfenil)-1H-pyrazole-4-ylmethyl]- naphthalen-2-yloxy}-ethanol;

2-{ 1-[5-dimethylamino-3-methylsulfanyl-1-(2,4,6-trim is(2-methoxy-naphthalen-1 - ylmethyl)-2H-pyrazole-3-yl]-dimethylamine;

2-{ 1-[5-dimethylamino-3-ethyl-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4 - ylmethyl]-naphthalen-2-yloxy}-ethanol;

[5-ethyl-4-(2-methoxy-naphthalen-1-ylmethyl)-2-(2,4,6-trimetilfenil)-2H - pyrazole-3-yl]-dimethylamine;

2-{2-[1-(2,6-dichloro-4-triptoreline)-5-dimethylamino-3-ethyl-1H - pyrazole-4-ylmethyl]-1,2,3,4-tetrahydroisoquinoline-3-ylethoxy}-ethanol;

[4-(3-methoxymethyl-3,4-dihydro-1H-isoquinoline-2-ylmethyl)-5-methylsulfanyl-2- (2,4,6-trimetilfenil)-2H-pyrazole-3-yl]-dimethylamine; and

2-{2-[5-dimethylamino-3-ethyl-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-ylmethyl] - 1,2,3,4-tetrahydroisoquinoline-3-ylethoxy}-ethanol.

The invention also concerns the compounds of formula IA (not shown) and its pharmaceutically acceptable salts with acids. The compounds of formula IA are identical to the compounds of formula I, except that A is CH(C1-C6alkyl), C(C1-C6alkyl)2C(C1-C6alkyl) (C3-C8alkenyl), CH(CH2)n(C3-C8alkenyl), where n equals 0 to 4, or C(C3-C8alkenyl)2.

The invention includes a pharmaceutical composition for treating diseases induced or reinforced releasing factor corticotropin, which includes a compound of formula I or IA as defined above, in kolichestvo composition for the treatment of inflammatory processes, diseases caused by stress and fear, including induced by the stress, depression and headaches, abdominales bowel syndrome, immune suppression, HIV infections, senile sclerosis of the brain, gastro-intestinal diseases, loss of appetite for nervous, hemorrhagic stress, drug and alcohol dependency, drug abuse and problems with fertilization, which includes a compound of formula I or IA, as described above, in an amount effective for the treatment of the aforementioned diseases, and the pharmaceutical acceptable carrier. The preferred and more specific compositions of the invention are compositions that contain the preferred and more specific compounds of formula I described earlier.

The invention concerns also a method of treatment of diseases induced or reinforced releasing factor corticotropin, by administering to a patient in need of such treatment, the compounds of formula I or IA, as described above, and a method of treatment of diseases caused by stress and fear, including induced by the stress, depression and headache, abdominal bowel syndrome, inflammatory processes, suppression of them is ocve, hemorrhagic stress, drug and alcohol dependency, substance abuse, and problems of fertilization, especially depression, by administering to patients in need of such treatment, the compounds of formula I or IA, which is defined above. The preferred and more specific methods of the invention are methods involving the introduction of a preferred and more specific compounds of formula I, described above.

The invention also relates to intermediate compounds of the formula

< / BR>
where R is CH2OH, or C(O)O(C1-C3alkyl), R1, R2and R3denote each, independently of one another linear C1-C6alkyl, branched C3-C8alkyl, C3-C8alkenyl, where the double bond is not adjacent to the N or X1when X1is oxygen or sulfur, C3-C7cycloalkyl(CH2)nwhere n equals 0, 1, 2, 3 or 4; or R1and R2together on the nitrogen atom can form a saturated four-, five - or six-membered ring, optionally condensed with anthropoi;

X1is a covalent bond, CH2NR, where R is hydrogen or linear C1-C6alkyl, O or S; and

Y SN is l, benzofuranyl, thiazolyl, benzothiazolyl, isothiazolin, benzisothiazole, isoxazolyl, benzisoxazole, triazolyl, pyrazolyl, pyrrolyl, indolyl, isoindolyl, oxazolyl, benzoxazolyl, pyrrolidinyl, diazolidinyl, morpholinyl, or piperidinyl, each of which may be substituted by one to three substituents, such as fluorine, chlorine, bromine, or methyl, or by one trifluoromethyl; provided that Y is a substituted phenyl.

When the referred group (CH2)qQ1R19and (CH2)o-X2-(CH2)r-O2-R6then X1and Q1and X2and Q2, respectively, are not both heteroatoms, when q or r, respectively, are equal to 1.

When Y or R11are heterocyclic groups, then join the group via the carbon atom.

The compounds of formula I can be obtained by reaction of compounds of formula

< / BR>
c sulphonylchloride, such as methylsulfonylamino, in an inert solvent such as methylene chloride or toluene, at a temperature of from about -10 to about 30oC, followed by reaction with the compound of the formula ZH or Z, where Z has the meanings given above, and Mtwii solvent, such as methylene chloride or toluene, at a temperature of from about 50 to about 100oC in the presence of a strong base such as an alkali metal hydride, e.g. sodium hydride, lithium hydride or potassium hydride, except when ZH is a strong enough reason in itself, in which case can be used in stoichiometric excess ZH or stoichiometric amount of ZH in the presence of a suitable strong base, such as trialkylamine, for example, triethylamine. Reaction with Z is carried out in a solvent such as N,N-dimethylformamide, at a temperature in the range of from about 50 to about 100oC.

The compounds of formula VIII can be obtained by reaction of compounds of formula

< / BR>
where X1, Y, R1, R2and R3have the meanings given above for formula I, except that R1and R2are not hydrogens, with a reducing agent, which is compatible with the chemical substituents on aminopyrazole ring, such as diisobutylaluminium, in an inert reaction solvent such as tetrahydrofuran or ether, at temperatures from about -5 to about 30oC.

The compounds of formula IX can the Ana) by reaction first with a hydride of an alkali metal, such as sodium hydride, then with alkylating agents R1Hal and R2Hal, where Hal is chlorine or bromine and R1and R2have the meanings previously defined for formula I except hydrogen, in a solvent such as tetrahydrofuran, at temperatures from about 5 to 80oC.

The compounds of formula X can be obtained by reaction of the ester 2-cyanoacrylate acid formula

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to obtain the compounds of formula I, where X1is grey, formulas

< / BR>
to obtain the compounds of formula I, where X1is a covalent bond, the formula

< / BR>
to obtain the compounds of formula I, where X1is oxygen, or formulas

< / BR>
to obtain the compounds of formula I, where X1is NR and mean hydrogen, where R17represents a C1-C3alkyl, and R18- C1-C2alkyl,

with a hydrazine of the formula NH2NHY, where Y has the meanings given previously for formula I. the Reaction is performed in a solvent such as C1-C8alcohol, at about 50 - 150oC, most conveniently at the boiling temperature of the reaction mixture, the wavy line in some formulas here means that another isomer of this compound includes the s IX, obtained by the above reaction of the compounds of formula XIV are formula

< / BR>
They can trialkylamines when using at least three equivalents of hydride of an alkali metal and R2Hal, where Hal is chlorine or bromine, by the method described above for converting compounds of formula X in the compounds of formula IX in obtaining compounds of formula I, where R1, R2and R3have the meanings given above for formula I, except hydrogens.

The above intermediates of formula IXA can react with the connection involving the N-protective group, for replacement of hydrogen with other3the group followed by alkylation of R2Hal or R3Hal and the removal of the N-protective group to obtain the compounds of formula I, where X1is NRR3where R is hydrogen and R2and R3have the meanings given above for formula I except hydrogen.

The reaction of compounds of the formula

< / BR>
where M is X1, S, and R3is R18C1-C6the alkyl, with amines, such as RNH2or RR3NH, in an appropriate solvent, such as ethanol, at temperatures from about 0oC to about 100oC provides rezultatele, defined above for formula I, and R3means of linear alkyl, branched C3-C8alkyl or C3-C8alkenyl, where the double bond is not adjacent to c in nitrogen.

The compounds of formula I, where Z has the meanings given above in paragraphs (a), (h) or (i), where R5or R14mean X2(CH2)rQ2R6where Q2means oxygen and X2r and R6have the meanings given above, except that R6is not hydrogen, can be obtained by alkylation of the corresponding compounds where R5or R14are (CH2)o-X-(CH2)2-Q2-R6and-X2-(CH2)rQ2R6respectively, and R6means hydrogen and Q2- oxygen. In such cases, where R5and R14have terminal hydroxyl groups, the hydroxy-group at the beginning reacts with a strong base such as an alkali metal hydride, such as lithium hydride, sodium or potassium hydroxide, in a solvent such as dimethylformamide, at about 50 - 100oC.

The resulting alcoholate of an alkali metal then reacts with alkyl or arylsulfonyl ether of the formula HO(CH2)rQ2R6where is outstay solvent, such as methylene chloride or toluene, at about 50 - 100oC. Above sulfanilamide esters can be obtained in the same manner as described above to activate the compounds of formula IX.

The above alkali metal hydride may be replaced by another strong base, including ORGANOMETALLIC base such as n-utility, or base anion amine, such as diisopropylamide lithium. In such cases, the reaction of formation of metal alcoholate can be performed in tetrahydrofuran at temperatures from about -5oC to about 65oC.

The above alkylation can also be used to obtain the compounds of formula I, where X1is oxygen and R3-(CH2)qQ1R19and q, Q1and R19have the meanings previously defined for formula I, except that R19cannot be hydroxy, the corresponding compounds where X1R3means hydroxy.

The compounds of formula IA, where A is CH(C1-C6alkyl) or CH(CH2)n(C3-C8alkenyl), where n equals 0 to 4 (has the formula IB, not shown), can be obtained from compounds of formula IX by reaction with re is B>3-C8alkenyl), where n equals 0 to 4, in the usual way, for example, diethyl ether or tetrahydrofuran as solvent at about -78oC - 50oC with the formation of the ketone of the formula

< / BR>
Ketone XVI can be transformed into the corresponding enamine by reaction with the compound of the formula ZH, where Z is (a) to (d), as described previously, under standard conditions dehydrogenation catalyzed by acid. The enamine can be transformed into compounds of formula IA, where A denotes the CHR19using hydrogenation with hydrogen under pressure in the presence of a catalyst of a noble metal or recovery hydride, such as cyanoborohydride sodium or lithium in diethyl ether or tetrahydrofuran (THF).

Or the compounds of formula IB can be obtained from compounds IX by reaction with ZH, where Z has the values described previously in paragraphs (a) to (d), in the presence of a hydride reducing agent, such as cyanoborohydride sodium or lithium.

The compounds of formula IA, where A is C(C1-C6alkyl)2C(C1-C6alkyl) (C3-C8alkenyl) or C(C3-C8alkenyl)2can be obtained from compounds of formula IX by reaction with concentrated hydrochloric acid at capacitive in THF with formation of the corresponding 4-bromide of formula XVIII (not shown), which can be 4-metallicafan in situ, as well as with tert-butyllithium in diethyl ether at -78oC, followed by treatment in situ with iminium compound of the formula

< / BR>
where R19has the values defined above, R20is R19Z has the meanings given above in paragraphs (a) to (d), and X is halogen.

The compounds of formula IA, where A denotes the CHR19where R19has the values defined above, Z has the meanings given above in paragraphs (h) or (i), and R14no acidic hydrogens such as hydroxyl, can be obtained from compounds of the formula I, where Z is (h) or (i) and the other substituents have the meanings given above for formula I, by treatment with a strong base such as tert-utility in ether or THF and subsequent alkylation in the same solvent with a halide of formula R19X, where R19and X have the meanings previously defined.

When the compounds of the invention contain a chiral center, it is assumed that the invention includes the racemic mixture and the individual enantiomers of such compounds. For example, the compound of the invention where Z is 1,2,3,4-tetrahydroisoquinolines have the following chiral center when Z except hydrogen

< / BR>
where the chiral center marked with an asterisk.

Preferred compounds of the invention of formula I or IA include compounds derived from programalso (+) enantiomer of the intermediate product ZH formula

< / BR>
where R5is hydroxymethyl or (C1-C6alkoxy)stands.

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 kristallizatsii. Examples of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, Hydrobromic, itestosterone, sulfamic, sulfonic acids, such as metasolv, baselslt-, p-toluensulfonate, and other related acids.

The compound of the invention may be single or in combination with pharmaceutically acceptable carriers, as single or multiple dose. Suitable pharmaceutical carriers are inert solid diluents or fillers, CTE is when combining the new compounds of the formula I or IA and pharmaceutically acceptable carriers, then it is convenient to introduce 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, potassium 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 Arabic gum. Additionally, the process of tabletting often use lubricating agents such as magnesium stearate, 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 required active the 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 easily accessible using standard techniques known from previous works.

In addition, it is possible topical application 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 obese from about 0.1 to about 50 mg/kg body weight of the patient. More specifically for the treatment of inflammatory processes require from about 0.1 to about 50 mg/kg, for senile sclerosis of the brain, from about 0.1 to about 50 mg/kg, as well as for treatment-induced stress diseases, gastrointestinal diseases, loss of appetite for nervous, hemorrhagic stress, drug and alcohol addictions, and problems of fertilization.

Methods of testing compounds of the formula I or IA in their CRF antagonistic activity described in methods of Enolocrinology, 116, 1653-1659 (1985) and Peptioles, 10, 179-188 (1985), which determine the binding activity of the test compounds with the CRF receptor. Binding activity of compounds of formulas I and IA usually varies from about 0.2 nanomoles to about 10 micromol.

The following examples illustrate the invention.

Example 1.

A. Methyl ester of 5-amino-3-methylsulfanyl-1- (2,4,6-trichlorophenyl)-1H-pyrazole-4-carboxylic acid

A solution of methyl ester of 2-cyano-3,3 - bis-methylsulfanyl-acrylic acid (of 454.3 g of 2.23 mol) and 2,4,6-trichlorophenylhydrazine (472,7 g of 2.23 moles) in ethanol (3.5 l) vigorously boiled for 1.5 hours, left overnight at room temperature, add water (850 ml), the resulting mixture is ill dried in the air, then under vacuum (45oC) for 2 days and get the named compound as a yellow crystalline substance, so pl. 160-162oC.

B. Methyl ester 5-dimethylamino-3-methylsulfanyl-1- (2,4,6-trichlorophenyl)-1H-pyrazole-4-carboxylic acid

To a suspension of sodium hydride (232,4 g of 60% dispersion of sodium hydride in mineral oil, 139,4 g, 5,81 of moles of sodium hydride), cooled in a bath with ice, in anhydrous tetrahydrofuran (4 l) was added dropwise with good stirring 711,6 g of compound of stage A (1.94 moles) dissolved in anhydrous tetrahydrofuran, then make dropwise modesty methyl (1376 g, 9.7 moles). The reaction mixture was then stirred for 18 hours at room temperature in a nitrogen atmosphere, the solvent is evaporated in vacuo, to the residue to dissolve add ethyl acetate (2 l) and water (3 l). The separated aqueous phase is twice extracted with portions in 2 l of ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate, evaporated in vacuum and get a named connection in the form of an amorphous solid in quantitative yield.

13C NMR (CDCl3): 163,0, 156,9, 152,7, 136,0, 135,8, 134,2, 128,8, 51,1, 42,2, 13,4.

C. (5-Dimethylamino-3-methylsulfanyl-1-(2,4,6 which the furan (4.5 l) under cooling in a bath of ice with good stirring, added dropwise over 2 hours a solution of diisobutylaluminium (2,863 l, 1.0 M solution in tetrahydrofuran, of 2.86 moles), the reaction mixture was then stirred for an additional 40 minutes at 0 to 5oSince then processed (when cooled in a bath with ice) with methanol (400 ml), make a saturated aqueous solution of Rochelle salt in water (1 : 1 by volume) (4 l) and ethyl acetate (3 l) under vigorous stirring. The organic phase is separated, extracted sequentially with equal volumes of water and brine, dried over anhydrous magnesium sulfate, evaporated in vacuo, the solid residue is crystallized from cyclohexane (3 l) and receive 132 g of the named compound as colourless crystals, so pl. 108 - 110oC.

Example 2

A. Methyl ester of 5-amino-1-(2,6-dichloro-4-triptoreline)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid

A mixture of methyl ester of 2-cyano-3,3-bis-methylsulfonylamino acid (49,8 g, 0,245 mol) and 2,6-dichloro-4-triftormetilfullerenov (60,0, 0,245 moles) in anhydrous ethanol (390 ml) vigorously boiled for 1.5 hours, then at quiet heating and good stirring continuously add (dropwise, fast flow) for 10 minutes, water (480 ml), stirred overnight at room temperature, filtered precipitated colorless solid precipitate these compounds, which dried the fir 1-(2,6-dichloro-4-triptoreline)- 5-dimethylamino-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid

To a solution of compound of stage A (35.4 g, 88,45 mmol) and iodotope bromide (55,08 ml, 0,884 moles) in anhydrous tetrahydrofuran (255 ml) with vigorous stirring at 5oC is added in portions within 10 minutes sodium hydride (to 10.62 g, 60% dispersion of sodium hydride in mineral oil; 6,37 g 0,266 of moles of sodium hydride), the mixture is vigorously boiled for 5 hours. Control reactions TLC (thin layer chromatography) shows the end of the reaction. The mixture is evaporated in vacuo, the solid residue dissolved in a mixture of ethyl acetate/water (150 ml each), bring the pH to 9 by adding sodium carbonate. The organic extract was separated, dried over anhydrous sodium sulfate, evaporated in vacuum and get the named compound as a colourless amorphous solid, 41,16,

1H NMR (CDCl3): of 2.44 (3H, c), of 2.72 (6H, c), 3,86 (3H, c), 7,71 (2H, s).

C. 1-(2,6-Dichloro-4-triptoreline)-5-dimethylamino-3-methylsulfanyl-1H - pyrazole-4-yl-methanol

To a solution of compound stage B (6.4 g, 14.9 mmol) in anhydrous tetrahydrofuran (175 ml) at a temperature of -78oC with good stirring, slowly add dropwise within 10 minutes diisobutylaluminium in toluene (49,3 ml, 1.0 M solution, 49.3 mmol). After 20 minutes peremeshivaniem to room temperature, stand for 20 minutes at this temperature and watch the end of the reaction (in addition to the desired product identified less polar soprodukta as the corresponding C-4 methylpropane). The mixture is treated with methanol (162 ml), gently at first, in order to suppress the reaction. The mixture is heated at 35oC for 15 minutes and observed precipitation. The reaction is evaporated in vacuo to a solid residue, which was extracted with ethyl acetate (150 ml). The solid product is separated from the organic extract by filtration, the filtrate evaporated in vacuo to an oil, which chromatographic (silica gel, 40 micron, while elution with ethyl acetate/hexane, 1: 3 by volume), and gain of 1.93 g of the named compound as a colorless amorphous foamy substance.

1H NMR (CDCl3): 2,50 (3H, s), 2,70 (6H, s), 4,50 (2H, s), of 7.70 (2H, s).

Example 3.

A. Methyl ester of 5-amino-1-(4-bromo-2,6-dimetilfenil)-3 - methylsulfanyl-1H-pyrazole-4-carboxylic acid

According to the method of Example 2A 4-bromo-2,6-dimethylpiperidin (11,17 g, 55 mmol) is reacted with methyl ester of 2-cyano-3,3-bis-methylsulfonylamino acid (13.8 g, 55 mmol) in 90 ml of ethanol. A named connection get as light yellow amorphous solid,1-(4-bromo-2,6-dimetilfenil)-5 - dimethylamino-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid

According to the method of Example 1B using the connection phase A (13,0 g, 35 mmol) of sodium hydride (4,2 g of 60% dispersion of sodium hydride in mineral oil, 105 mmol of sodium hydride), iodotope bromide (10.9 ml, 175 mmol) and tetrahydrofuran (90 ml) as solvent, get a named connection (14,15 g) as a yellow amorphous solid.

13C NMR (CDCl3): 163,1, 155,5, 151,2, 138,5, 136,8, 131,3, 122,8, 100,8, 51,0, 42,0, 17,6, 13,4.

C. 1-(4-Bromo-2,6-dimetilfenil)-5-dimethylamino-3 - methyl-effect-free remedy 1H-pyrazole-4-yl-methanol

According to the method of Example 2C using the connection phase B (12.0 g, 30 mmol), diisobutylaluminium (100 ml, 1.0 M solution in toluene, 100 ml) and anhydrous tetrahydrofuran (170 ml) get the named compound (3.6 g) as a colourless oil.

13C NMR (CDCl3): 151,8, 148,1, 138,7, 137,2, 131,1, 122,3, 106,7, 61,7, 42,6, 17,8, 15,7.

Example 4

A. Methyl ester of 5-amino-3-methyl-1-(2,4,6-trichlorophenyl)- 1H-pyrazole-4-carboxylic acid

To a solution of methyl ester of 2-cyano-8 - methyl-3-ethoxy-acrylic acid (3.5 g, 0,021 moles) in glacial acetic acid (20 ml) was added under stirring 2,4,6-trichlorophenylhydrazine (of 4.38 g, 0,021 moles), followed by triethylamine (2.0 ml, of 1.46 g of 0.014 moles), boiled for 13 hours, the solvent UI layer is separated, extracted with equal volumes of water, dried over anhydrous sodium sulfate, evaporated in vacuum and get orange oil (5.8 g), which is completely chromatographic (silica gel, 40 micron; elution with ethyl acetate/hexane = 1:3 by volume) and get a named connection (3,20 g) as a pale orange amorphous solid. Thin layer chromatography (TLC) shows Rf(silikagelya plate, UV-irradiation, ethyl acetate/hexane = 1:8 by volume) : 0,43.

Century Methyl ester 5-dimethylamino-3-methyl-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carboxylic acid

To a solution of compound of stage A (3.2 g, 9.6 mmol) and iodotope bromide (3.0 ml, at 6.84 g, 48 mmol) in anhydrous tetrahydrofuran (20 ml) under cooling in a bath with ice under stirring was added in portions sodium hydride (1,15 g, 60% dispersion of sodium hydride in mineral oil, 690 mg, 29 mmol of sodium hydride), the reaction mixture is stirred for 15 minutes with 5oC, left for 20 hours at room temperature, evaporated in vacuum and get a light yellow solid, which was dissolved in ethyl acetate/water (100 ml each), pH adjusted to 12 by the introduction of sodium carbonate. The aqueous layer was separated, extracted twice with 50 ml portions of ethyl acetate, the extracts of the volume of the E. orange amorphous solid. TLC Rf(silicagel plate, UV-irradiation, ethyl acetate/hexane = 1:3 by volume) : 0,73.

C. [5-Dimethylamino-3-methyl-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-yl]-methanol

To a solution of compound stage B (350 mg, 0.96 mmol) in anhydrous tetrahydrofuran (3 ml) under stirring at a temperature of -78oC added dropwise diisobutylaluminium (2,90 ml of 1.0 M diisobutylaluminium in tetrahydrofuran; 2.9 mmol of diisobutylaluminium), stirred for 1 hour at -78oC, optionally allowed to stand for 1 hour in 5oC, stirred for 2 hours at room temperature, the reaction is quenched by adding (at the 5oC) dropwise methanol (7 ml), the mixture is stirred for 15 minutes at room temperature, then 10 minutes at 35-40oC, evaporated in vacuum, receives a yellow solid, which was extracted with ethyl acetate (7 ml). The remaining solid nerastvorimaya substance is removed by filtration, the filtrate is extracted with an equal amount of water, dried (anhydrous sodium sulfate), evaporated in vacuum and get the named compound as a pale orange oil (0.32 g). The product is used in the next stage without additional purification.

D. Enantiomeric { 2-[5-dimethylamino-3-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-yl-who amine (0,08 ml, 0.60 mmol) in anhydrous methylene chloride (3 ml) under stirring and cooling in a bath with ice add unexpectedly methanesulfonanilide (0.04 ml, a 59.2 mg, 0.52 mmol), stirred for 15 minutes with 5oC until complete formation in situ nelfinavir connection stage C add programalso enantiomer of 3-hydroxymethyl-1,2,3,4 - tetrahydroisoquinoline (310 mg, 1.9 mmol), anhydrous N, N-dimethylformamide (0.51 ml) and acetonitrile (1.2 ml), stirred for 1/2 hour at room temperature, heated 19 hours at 55oC, evaporated in vacuum. The orange residue was dissolved in ethyl acetate/water (100 ml each), pH adjusted to 10 with sodium carbonate. The aqueous phase is separated, extracted twice with 50 ml portions of ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate, evaporated in vacuo, get orange semi-crystalline compound (0.7 g), which is completely chromatographic (silica gel, 40 MK; elution with ethyl acetate/hexane = 1:3 by volume) and get titled compound (170 mg) as a pale orange oil.

13C NMR (CDCl3): 151,6, 151,0, 136,2, 135,3, 135,0, 133,6, 129,0, 128,6, 127,0, 126,5, 126,1, 107,5, 62,0, 58,0, 47,6, 45,6, 42,6, 26,2, 13,1.

Example 5

A. Methyl ester 2-cyano-3,3-diethoxyaniline acid

Somalia) is heated 5 hours at 130oC, then 18 hours at 110oC, cooled, extracted twice 125 ml portions of hexane, there's an orange oil, insoluble in hexane, containing about 40% by weight of the desired compound (as determined by NMR spectroscopy). This crude product is used in the next stage without additional purification. TLC Rf(silikagelya plate, UV-irradiation, ethyl acetate/hexane = 15:85 by volume) : 0,13.

B. Methyl ester of 5-amino-3-ethoxy-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carboxylic acid

The crude product obtained in stage A (4,76 g, containing approximately 1.9 g, 9.6 mmol methyl ester 2-cyano-3,3-diethoxyaniline acid) was added to 2,4,6-trichlorophenylhydrazine (2,02 g, 9.6 mmol) in ethanol (15 ml), boiled for 18 hours. The solvent is evaporated in vacuum, the residue is extracted with methylene chloride and water of 100 ml each, pH adjusted to 10 with sodium carbonate. The separated aqueous extract is washed with two 50 ml portions of methylene chloride. Three volume organic extracts are combined, dried over anhydrous sodium sulfate, evaporated in vacuum and get oil (5,98 g). The purity of this crude product significantly improves chromatography (silica gel, 40 MK; elution with ethyl acetate/hexane = 15:85 to object/hexane = 15:85 by volume) : 0,26. The product is used in the next stage without additional purification.

C. Methyl ester 5-dimethylamino-3-ethoxy-1- (2,4,6-trichlorophenyl)-1H-pyrazole-4-carboxylic acid

To a solution of compound stage B (910 mg, 2.5 mmol) and iodotope bromide (778 μl, 12.5 mmol) in anhydrous tetrahydrofuran (10 ml) under cooling in a bath with ice added in portions over 5 minutes sodium hydride (300 mg, 60% dispersion of sodium hydride in mineral oil; 180 mg, 7.5 mmol of sodium hydride), stirred for 18 hours at room temperature, the solvent is evaporated in vacuum, the residue is extracted with methylene chloride/water (60 ml each). The aqueous layer was separated, extracted twice with 30 ml portions of methylene chloride. The organic extracts are combined, dried over anhydrous sodium sulfate, evaporated in vacuo to an amber oil (980 mg), chromatographic it completely (silica gel, 40 MK; ethyl acetate/hexane = 5:95 by volume) and get the named compound as a colourless oil (353 mg).

TLC Rf(plate of silica gel, UV light, ethyl acetate/hexane = 5:95 by volume) : 0,26.

D. [5-Dimethylamino-3-ethoxy-1-(2,4,6-trichlorophenyl)-1H - pyrazole-4-yl]-methanol

According to the method of Example 2C connection stage 5C (340 mg, 0.87 mmol) privredna the next stage without additional purification.

TLC Rf(plates of silica gel, UV light, ethyl acetate/hexane = 15:85 by volume) : 0,20.

That is, the Enantiomeric {2-[5-dimethylamine-3-ethoxy-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-ylmethyl-]-1,2,3,4-tetrahydroisoquinoline-3-yl}-methanol

To a solution of compound stage 5D (estimated 69 mg, 0,19 mmol) and triethylamine (32 μl, 0.23 mmol) in methylene chloride (1 ml) with good stirring and cooling in a bath with ice add methansulfonate (16 μl, 0.21 mmol), stirred for 15 minutes, make programalso isomer 3-hydroxymethyl-1,2,3,4 - tetrahydroisoquinoline (124 mg, to 0.72 mmol) and anhydrous N, N-dimethylformamide (0.1 ml), heated for 4 hours at 50oC, stirred at room temperature for another 48 hours, the solvent is evaporated in vacuum, the residue is extracted with methylene chloride/water (60 ml each) when bringing the pH to 10 with sodium carbonate. The aqueous layer was separated, extracted twice with 30 ml portions of methylene chloride. The organic extracts are combined, dried (anhydrous sodium sulfate), evaporated in vacuo to an oil (410 mg), which chromatographic completely (silica gel, 40 MK; elution with ethyl acetate/hexane = 1:4 by volume) and get titled compound (7 mg) as a colorless foamy substance.

Example 6

Enantiomeric { 2-[1-(4-bromo-2,6-dimetilfenil)-5-dimethylamino-3 - methylsulfanyl-1H-pyrazole-4-ylmethyl]-1,2,3,4-tetrahydroisoquinoline-3-yl}- methanol

When using programalso isomer of 3-hydroxymethyl - 1,2,3,4-tetrahydroisoquinoline (528 mg, 3.24 mmol) in acetonitrile/anhydrous N,N-dimethylformamide (15 ml and 0.5 ml, respectively), obtained in situ nelfinavir from Example 3C (300 mg, 0.81 mmol), triethylamine (169 μl, 1.20 mmol) and methanesulfonamide (81,5 μl, 1.05 mmol) in anhydrous methylene chloride (6 ml) get the named compound (21 mg, 5% yield) in the form of a colorless amorphous solid by the method of Example 4D in combination with the method/extraction and chromatography (silica gel, 40 MK; elution with ethyl acetate/hexane = 1:9 by volume).

TLC Rf(silikagelevye plate under UV light, ethyl acetate/hexane = 1:4 by volume): 0,30. HRMS m/z 514,1402 (M, C25H30BrN4OS).

Example 7

The racemic mixture of {2-[5-dimethylamino-3-methylsulfanyl-1- (2,4,6-trichlorophenyl)-1H-pyrazole-4-ylmethyl]-1,2,3,4-tetrahydroisoquinoline 3-yl}-methanol

To a solution of compound of Example 1C (700 mg, 1.9 mmol) and triethylamine (0,304 ml, 2.2 mmole (0,164 ml, 2.1 mmol) before the formation of the corresponding nelfinavir in situ, stirred for 25 minutes with 5oC, add a solution of ()-3-hydroxymethyl-1,2,3,4 - tetrahydroisoquinoline (1.24 g, 7.6 mmol) in acetonitrile/anhydrous N,N-dimethylformamide (5 ml and 1.5 ml, respectively), the reaction mixture is heated at 55 - 60oC in an oil bath for 18 hours, the solvent is evaporated in vacuum, the residue is dissolved in ethyl acetate/water (100 ml each) when bringing the pH to 9.5 with sodium carbonate. The organic extract was separated, dried over anhydrous sodium sulfate, evaporated in vacuo to an amber glassy mass, chromatographic fully on silica gel; (elution with ethyl acetate/hexane = 1:10) and get the named compound (800 mg) as a colorless amorphous solid.

13C NMR (CDCl3): 151,8, 149,6, 136,2, 135,5, 134,7, 133,6, 133,4, 129,0, 128,7, 127,1, 126,4, 126,0, 108,6, 62,6, 57,7, 48,3, 45,3, 42,8, 25,9, 14,7.

Example 8

Enantiomeric { 2-[5-dimethylamino-3-methylsulfanyl-1- (2,4,6-trichlorophenyl)-1H-pyrazole-4-ylmethyl]-1,2,3,4-tetrahydroisoquinoline - 3-yl}-methanol

To a solution of compound of Example 1C (258 mg, 0,704 mmol) and triethylamine (0,112 ml, 0.80 mmol) in anhydrous methylene chloride at +5oC add methansulfonate to education with oximeter-1,2,3,4-tetrahydroisoquinoline (230 mg, 1.4 mmol) in acetonitrile/anhydrous N,N-dimethylformamide (2.5 ml and 1 ml, respectively), heated 18 hours at 60oC in the oil bath, the solvent is evaporated in vacuo, the resulting solid residue is dissolved in methylene chloride/water (25 ml each) when bringing the pH to 9.5 with sodium carbonate. The organic layer is separated, washed with an equal volume of water, dried (anhydrous sodium sulfate), evaporated in vacuo to a solid residue, which is treated with isopropyl alcohol (3 ml), stirred for 1 hour at room temperature, the solid product is filtered off. The filtrate is evaporated in vacuo to an oil (0,41 g), the sample is fully chromatographic (silica gel, 40 MK; elution with ethyl acetate/hexane = 1:5 by volume) and get titled compound (60 mg) as a colorless amorphous solid.

13C NMR (CDCl3): identical to the spectrum of the racemate obtained in Example 7.

Example 9

Enantiomeric { 2-[dimethylamino-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4 - ylmethyl]-1,2,3,4-tetrahydro-isoquinoline-3-yl}-methanol

According to the method of Example 4D using levogyrate enantiomers of 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline as a nucleophile get called joint spectrum for the racemate of the compound of Example 7.

Example 10

Enantiomeric { 2-[1-(2,6-dichloro-4-triptoreline)-5 - dimethylamino-3-methylsulfanyl-1H-pyrazole-4-ylmethyl] - 1,2,3,4-tetrahydroisoquinoline-3-yl} -methanol

According to the method of Example 4D and thin-layer chromatography (silica gel, 40 micron; methanol/methylene chloride = 1:4 by volume) obtained using programalso enantiomers of 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (376 mg, 2.3 mmol) in acetonitrile/anhydrous N,N-dimethylformamide (1.5 ml and 0.5 ml, respectively) and obtained in situ nelfinavir compound of Example 2C above compound (56 mg) as a colorless oil. TLC Rf(silicagel plate under UV light, methanol/methylene chloride = 1:4 by volume): 0,4. HRMS m/z 544,1078 (M, C24H24Cl2F3N4OS).

Example 11

A. the Racemate (2,3-dihydro-1H-indol-2-yl)-methanol

The racemate 2,3-dihydro-1H-indole-2-carboxylic acid (5.0 g, 30.6 mmol) suspended in methanol (50 ml), contribute sodium methylate (1.66 g, 30.6 mmol), the resulting suspension is stirred for a few minutes, evaporated in vacuo, the residue suspended in anhydrous tetrahydrofuran (60 ml) is added within 15 minutes dropwise to alumoweld lithium (1.0 M in tetrahydrofuran; 30,6 ml, 30.6 mmol), boiled for 3 hours. The mixture is cooled in a bath with filter, the filtrate is evaporated in vacuum and receive (+)-2-hydroxymethyl-indolin (of 3.69 g) as a viscous brown oil and used in the next stage without additional purification. TLC Rf(plates of silica gel under UV light, while elution with ethyl acetate/hexane = 1:4 by volume) : 0,15.

B. the Racemate { 1-[5-dimethylamino-3-methylsulfanyl-1- (2,4,6-trichlorophenyl)-1H-pyrazole-4-ylmethyl]-2,3-dihydro-1H - indol-2-yl}-methanol

According to the method of Example 4D racemic mixture from stage A (895 mg, 6 mmol) is reacted with the obtained in situ mesilate 500 mg (1.5 mmol) of the compound of Example 1C. The crude product after separation by chromatography (silica gel, 40 MK, while elution with ethyl acetate/hexane = 1:4 by volume) as described in Accept 4D, give the named compound as a colourless oil (124 mg).

13C NMR (CDCl3): 153,0, 150,7, 148,6, 136,2, 135,7, 135,0, 129,6, 128,7, 127,2, 124,5, 119,2, 109,7, 108,9, 67,8, 63,1, 45,1, 31,7, 14,4.

Example 12

A. 2-Benzyl-4H-isoquinoline-1,3-dione

A mixture containing holoptelia acid (25 g, 0,139 moles) and benzylamine (15.2 ml, 14,91 g, 0,139 moles) is heated 2 hours at 165-180oC, which is accompanied by vigorous release of water vapor, is cooled with the formation of a dark green solid, which is crushed, treated with ether, filtersusa in the next stage without additional purification.

TLC Rf(plates of silica gel; under UV light, while elution with ethyl acetate/hexane = 15:85 by volume) : 43.

13With NMR (CDCl3): 169,9, 164,8, 137,1, 134,1, 133,7, 129,3, 129,0, 128,4, 127,7, 127,5, 125,4, 43,3, 36,5.

B. the Racemate of 2-benzyl-3-hydroxy-3,4-dihydro-2H-isoquinoline-1-it

To a solution of 2-benzyl-4H-isoquinoline-1,3-dione (5.0 g, 20 mmol) in methanol (40 ml) under stirring and cooling in a bath with ice added in portions over 20 minutes of borohydride sodium (3.0 g, 80 mmol), stirred for 48 hours at room temperature. Control reactions TLC shows significant formation of the product and some starting material. TLC Rfthese compounds (plate of silica gel under UV light, while elution with ethyl acetate/hexane = 3,7 by volume) : 0,24. Upon cooling the reaction mixture in a bath with ice carefully add water (3 ml). To the dry mixture was added anhydrous sodium sulfate, then filtered, the filtrate evaporated in vacuo to a dark green oil (3.5 g), which chromatographic (silica gel, 40 MK, while elution with ethyl acetate/hexane = 3,7 by volume) and get a named connection in the form of a colorless amorphous solid (1.35 g). Unstable material and is quick to follow is lots

To a solution of the racemic mixture from stage (1.35 g, of 5.34 mmol) in anhydrous tetrahydrofuran (20 ml) with vigorous stirring under cooling in a bath of ice are added in portions over several minutes sodium hydride (307 mg, 60% dispersion of sodium hydride in mineral oil; 184 mg, 7.7 mmol of sodium hydride), then make portions within a few minutes metiltiofosfonata (1,76 ml, 2,015 g, 9.6 mmol), the resulting mixture is stirred for 24 hours at room temperature, the solvent is evaporated in vacuum, the residue is dissolved in ethyl acetate/water (50 ml each). The aqueous layer was separated, extracted twice with 20 ml portions of ethyl acetate. The organic extracts are combined, dried, dried over anhydrous sodium sulfate, evaporated in vacuo to a brown oil (2.4 g), which chromatographic completely (silica gel, 40 MK, while elution with ethyl acetate/hexane = 15:85 by volume) and get the named compound (650 mg) as a colorless viscous oil.

13With NMR (CDCl3): 171,3, 163,7, 137,8, 135,6, 132,2, 128,9, 128,3, 128,1, (2), 127,6, 127,3, 51,7, 48,7, 36,2, 32,5.

D. the Racemate of 2-(2-benzyl-1,2,3,4-tetrahydro-isoquinoline-3-yl)- ethanol

To a solution of the racemate with stage C (650 mg, 2.0 mmol) in anhydrous tetrahydrofuran (10 ml) at anidride lithium in tetrahydrofuran (6,11 ml, 1.0 M solution, 6.11 mmol of lithium aluminum hydride), stirred for 24 hours at room temperature, cooled in a bath with ice and carefully make a 15% aqueous sodium hydroxide (2 ml), add anhydrous sodium sulfate to dry the mixture, then it is filtered, the filtrate evaporated in vacuum and get a named connection in the form of a colorless oil in quantitative yield.

TLC Rf(silikagelevye plate under UV light, while elution with ethyl acetate/hexane = 1:4 by volume) : 0,21.

E. the Racemate of 2-(1,2,3,4-tetrahydro-isoquinoline-3-yl)-ethanol

()-2-(2-Benzyl-1,2,3,4-tetrahydro-isoquinoline-3-yl)-ethanol (610 mg, 2.3 mmol) hydronaut when 0,3812106PA on the Parr apparatus (305 mg of 10% palladium catalyst on carbon in the solvent methanol/concentrated hydrochloric acid (15 ml and 0.25 ml, respectively) for 5 hours. The catalyst is filtered off, the filtrate evaporated in vacuo to an oil which is dissolved in dilute aqueous (pH 9) sodium carbonate/methylene chloride (50 ml each). The aqueous phase is separated, extracted with two portions (10 ml) methylene chloride. The organic extracts are combined, dried over anhydrous sodium sulfate, evaporated in vacuum and get a named connection in the form of elm is 55,5, 47,9, 37,2, 35,5.

F. the Racemate of 2-{ 2-[5-dimethylamino-methylsulfanyl-1- (2,4,6-trichlorophenyl)-1H-pyrazole-4-ylmethyl]-1,2,3,4 - tetrahydro-isoquinoline-3-yl}-ethanol

According to the method of Example 4D racemate of 2-(1,2,3,4-tetrahydro-isoquinoline-3-yl)- ethanol (400 mg, 2.4 mmol) is reacted with in situ obtained by mesilate compound of Example 1C and get titled compound (80 mg) as a colorless viscous oil.

13C NMR (CDCl3): 151,9, 149,8, 136,2, 135,5, 134,8, 133,1, (2), 129,3, 128,7, 126,9, 126,2, 108,0, 62,3, 55,3, 48,0, 46,1, 42,3, 32,5, 29,1, 14,8.

Example 13

[4-(3-Butoxymethyl-3,4-dihydro-1H-isoquinoline-2-ylmethyl)-5 - methylsulfanyl-2-(2,4,6-trichlorophenyl)-2H-pyrazole-3-yl)] - dimethylamine

To a solution of the racemate of Example 7 (0.21 g, 0.41 mmol) in anhydrous tetrahydrofuran (2 ml) was added sodium hydride (82 mg, 60% dispersion of sodium hydride in mineral oil; 49 mg, 2.0 mmol of sodium hydride), stirred for 10 minutes, make a n-butylated (0,19 ml, 307 mg, 1.7 mmol), stirred for 24 hours. TLC shows that the reaction is not finished, so add additional sodium hydride (82 mg, 60% dispersion of sodium hydride in mineral oil; 49 mg, 2.0 mmol of sodium hydride), anhydrous tetrahydrofuran (0.5 ml) and n-butylated (0,19 ml, 307 mg, 1.7 mmol), stir the resulting mixture for 24 hours at room testate/water (50 ml each). The aqueous extract is separated, extracted with three 10 ml portions of ethyl acetate. The organic extracts are combined, dried (anhydrous sodium sulfate), evaporated in vacuo to a viscous orange oil (0.3 g), which chromatographic sequentially in a thin layer, then the method itself when elution (silica gel 40 MK; elution with ethyl acetate/hexane = 1:0 by volume) and get titled compound (150 mg) as a viscous yellow oil.

13C NMR (CDCl3): 152,0, 149,9, 136,1, 135,3, 134,9, 134,7, 134,0, 129,1, 128,6, 126,4, 126,0, 125,5, 109,4, 71,1, 69,8, 56,2, 50,4, 47,9, 42,4, 31,9, 30,8, 19,4, 15,2, 13,9.

Example 14

The racemate [4-(3-methoxymethyl-3,4-dihydro-1H-isoquinoline - 2-ylmethyl)-5-methylsulfanyl-2-(2,4,6-trichlorophenyl)-2H - pyrazole-3-yl]-amine

To a solution of the racemate from Example 7 (200 mg, 0.39 mmol) in anhydrous tetrahydrofuran (2.0 ml) was added sodium hydride (78 mg, 60% dispersion of sodium hydride in mineral oil; 46 mg, 2.0 mmol of sodium hydride), stirred for 15 minutes at room temperature, add modesty methyl (0.10 ml, 1.6 mmol), the mixture is stirred for 18 hours at room temperature, the solvent is evaporated in vacuum, the residue is dissolved in ethyl acetate/water (20 ml each), the aqueous phase is separated, extracted with three equal volumes allocat yellow oil, which chromatographic in a thin layer (silica gel, 40 MK, while elution with ethyl acetate/hexane = 1:10 by volume) and get the named compound (118 mg) as a pale yellow oil.

13C NMR (CDCl3): 152,0, 149,8, 136,1, 135,3, 134,8, 134,6, 133,9, 129,1, 128,6, 126,5, 126,1, 125,6, 109,2, 71,8, 58,9, 56,0, 50,6, 47,6, 42,4, 30,6, 15,2.

Example 15

Enantiomeric [4-(3-methoxymethyl-3,4-dihydro-1H-isoquinoline - 2-ylmethyl)-5-methylsulfanyl-2-(2,4,6-trichlorophenyl)-2H-pyrazole - 3-yl]-dimethylamine

To a solution of the compound from Example 8 (200 mg, 0.39 mmol) in anhydrous tetrahydrofuran (3 ml) under vigorous stirring was added sodium hydride (78 mg, 60% dispersion of sodium hydride in mineral oil, 46.8 mg, 2.0 mmol of sodium hydride), stirred for 5 minutes at room temperature, make modesty methyl (0,097 ml, 1.6 mmol), stirred for 16 hours at room temperature, the solvent is evaporated in vacuum, the residue is extracted with ethyl acetate/water (60 ml each). The aqueous phase is separated, extracted with three equal volumes of fresh ethyl acetate. An ethyl acetate extracts are combined, dried (anhydrous sodium sulfate), evaporated in vacuo to an orange oil (510 mg), which chromatographic in a thin layer (silica gel, 40 MK, with elution by ethyl acetate/hexane is on). Data TLC Rf,1H NMR and13From the NMR spectra are identical in all aspects to data obtained for the corresponding racemate obtained in Example 14.

Example 16

Enantiomeric [4-(3-isopropoxyphenyl-3,4-dihydro-1H-isoquinoline-2-ylmethyl) -5-methylsulfanyl-2-(2,4,6-trichlorophenyl)-2H-pyrazole-3-yl]-dimethylamine

To a solution of compound of Example 8 (310 mg, and 0.61 mmol) in anhydrous tetrahydrofuran (3 ml) under vigorous stirring was added sodium hydride (140 mg, 60 % dispersion of sodium hydride in mineral oil, 84 mg, 3.5 mmol of sodium hydride, stirred for 5 minutes at room temperature, contribute isopropylated (0,42 ml, 4.2 mmol), stirred for 23 hours at room temperature, bring an additional quantity of anhydrous tetrahydrofuran (1 ml) and sodium hydride (120 mg of a 60% dispersion of sodium hydride in mineral oil, 72 mg, 3.0 mmol), after 5 minutes, make a second portion of isopropylidene (of 0.30 ml, 3.0 mmol), stirred for additional 5 hours at room temperature, the solvent is evaporated in vacuum, the residue is extracted with ethyl acetate/water (60 ml each). The aqueous phase is separated, extracted twice with 30 ml portions of fresh ethyl acetate. The organic extracts are combined, dried over anhydrous sulfate the elution with ethyl acetate/hexane = 1:10 by volume) and get titled compound (2.0 mg) as a pale yellow oil. TLC Rfand these NMR spectrum of these compounds are identical in all aspects with the data of the racemate obtained in Example 17.

Example 17

The racemate [4-(3-isopropoxyphenyl-3,4-dihydro-1H-isoquinoline-2-ylmethyl)-5 - methylsulfanyl-2-(2,4,6-trichlorophenyl)-2H-pyrazole-3-yl]-amine

Using the methods of Example 15 compound of Example 7 (215 mg, 0.42 mmol) in anhydrous tetrahydrofuran (2 ml) is reacted first with sodium hydride (100 mg, 60% dispersion of sodium hydride in mineral oil, 60 mg, 2.5 mmol of sodium hydride), then isopropylidene (0,29 ml, 497 mg, 2.9 mmol) and get titled compound (20 mg) as a yellow oil.

13With NMR (CDCl2): 152,1, 149,7, 136,1, 135,3, 134,7(2), 134,0, 129,1, 128,6, 126,0, 125,5, 109,4, 71,9, 67,0, 56,6, 50,3, 48,0, 42,4, 30,9, 22,3, 22,1, 15,2.

Example 18

The racemate dimethyl-{ 4-[3-(3-methyl-butoxymethyl)-3,4-dihydro - 1H-isoquinoline-1-ylmethyl]-5-methylsulfanyl-2-(2,4,6-trichlorophenyl)-2-pyrazole-3-yl}-amine

Using the methods of Example 16 compound of Example 7 (210 mg, 0.41 mmol) in anhydrous tetrahydrofuran (2 ml) is reacted first with sodium hydride (100 mg, 60% dispersion of sodium hydride in mineral oil, 60 mg, 2.5 mmol of sodium hydride), and then isopentylamine (570 mg, 2.9 mmol) with the formation's name is, 26,4, 126,0, 125,5, 109,3, 69,8, 50,3, 47,9, 42,4, 38,6, 30,9, 25,1, 22,7, 22,6, 15,2.

Example 19

The racemate {4-[3-(2-methoxyethoxymethyl) 3,4-dichloro-1H-isoquinoline-2-ylmethyl] -5-methylsulfanyl-2-(2,4,6-trichlorophenyl)-2H-pyrazole-3-yl}-amine

To a solution of compound of Example 7 (65 mg, 0.12 mmol) in anhydrous tetrahydrofuran (0.5 ml), was added sodium hydride (17.5 mg, 60% dispersion of sodium hydride in mineral oil; 10.5 mg, 0.44 mmol of sodium hydride), stirred for 15 minutes, bring 1-iodine-2-methoxyethane (0.1 ml, 0.5 mmol), stirred for 48 hours, boiled for 6 hours. Controlling the reaction time TLC shows that the reaction is not finished, so bring an additional amount of sodium hydride (33 mg, 60% dispersion in mineral oil, 20 mg, 1.0 mmol of sodium hydride), 1-iodine-2-methoxyethane (100 μl, 0.5 mmol) and anhydrous tetrahydrofuran (0.8 ml), boiled for 18 hours before the end of the reaction, the solvent is evaporated in vacuum, the residue is dissolved in ethyl acetate/water (20 ml each), the aqueous phase is separated, extracted with three equal volumes of ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate, evaporated in vacuum and get orange resinous substance that chromatographic in a thin layer (silica gel, 40 MK; elution with ethyl acetate (CDCl3): 152,1, 149,7, 136,3, 135,4, 134,7(2), 134,0, 129,1, 128,6, 126,5, 126,0, 125,5, 109,4, 72,0, 70,5, 70,3, 59,1, 56,0, 50,2, 47,9, 42,4, 30,7, 15,2.

Example 20

Enantiomeric 2-{ 2-[5-dimethylamino-3-methylsulfanyl-1- (2,4,6-trichlorophenyl)-1H-pyrazole-4-ylmethyl] -1,2,3,4-tetrahydro - isoquinoline-3-ylethoxy}-ethanol and the corresponding tert-butyl - dimethylsiloxy ether

To a solution of compound of Example 8 (100 mg, of € 0.195 mmol) in anhydrous tetrahydrofuran (0.2 ml) is added sodium hydride (18,4 mg of 60% dispersion in mineral oil; 11,04 mg, and 0.46 mmol of sodium hydride), stirred for 5 minutes at room temperature, was added 1-iodine-2-(tert-butyldimethylsilyloxy)ethane (222 mg, 0.39 mmol), heated for 2.5 hours at 85oC. Control reactions TLC shows that the alkylation is completed, therefore, the solvent is evaporated in vacuum, the residue is dissolved in ethyl acetate/water (50 ml each). The organic extract was separated, dried over anhydrous sodium sulfate, evaporated in vacuum and receives a yellow oil (285 mg) which is purified chromatographically in a thin layer (silica gel, 40 MK; elution with ethyl acetate/hexane = 2,5:a 97.5 by volume) and get Siciliano titled compound (14 mg) as a colourless oil.

13With NMR (CDCl3) per million hours 152,0, 149,9, 136,1, 135,3, 134,8, 134,6, 133,9, 1�wow compound (14 mg, 0,021 mmol) is dissolved in tetrahydrofuran, add tetrabutylammonium (42 μl, of 1.00 M solution in tetrahydrofuran, 0,042 mmol), the resulting mixture is stirred for 1 hour at room temperature. Thin layer chromatography shows the presence of a small number similarvideo connection, so bring an additional amount of 4 μl, 1.0 M of tetrabutylammonium in tetrahydrofuran to finish desirelove within 30 minutes. Then the solvent is evaporated in vacuum, the residue is dissolved in ethyl acetate/water (20 ml each), the layers separated, the aqueous portion is extracted twice with 10 ml portions of fresh ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate, evaporated in vacuo to an oil (20 mg), which chromatographic in a thin layer (silica gel, 40 MK in the elution with ethyl acetate/hexane = 1:3 by volume) and get a named connection (11,5 mg) as a colourless oil.

TLC Rf(silikagelevye plate; UV light, ethyl acetate/hexane = 1:3 by volume) : 0,20.

Example 21

1-[5-Dimethylamino-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)- 1H-pyrazole-4-ylmethyl] -naphthalen-2-ol and dimethyl-[5-methylsulfanyl-4- (naphthalen-2-intoximeter)-2-(2,4,6-trichlorophenyl)-2H-who situ in anhydrous methylene chloride (12 ml). Separately added in portions over several minutes to a solution of 2-naphthol (1.73 g, 12 mmol) in anhydrous N,N-dimethylformamide (4 ml), sodium hydride (480 mg, 60% dispersion in mineral oil, 288 mg, 12 mmol of sodium hydride), stirred for 20 minutes at room temperature, add the mixture of sodium salts of 2-naphthol and N, N-dimethylformamide to the above obtained solution nelfinavir/methylene chloride. The resulting mixture is stirred for 18 hours at 50oC, the solvent was evaporated in vacuum, the residue is extracted with ethyl acetate/water (60 ml each) when bringing the pH to 6 (1 N aqueous hydrochloric acid). The aqueous phase is separated, extracted with 60 ml of fresh ethyl acetate. The organic extracts are combined extracted with an equal volume of water, dried over anhydrous sodium sulfate, evaporated in vacuum and get amber oil (2.9 g), which chromatographic in a thin layer (silica gel, 40 MK; elution with ethyl acetate/hexane = 1:9 by volume) and receive the first named connection (product C-alkylation; 388 mg) as a colorless foamy substance, and then the second named connection (product O-alkylation; 46 mg) as a colourless oil.

The first named connection (product C-alkylation):

13C is the group (O-alkylation):

13C NMR (CDCl3): 156,5, 153,4, 149,7, 136,1, 135,6, 134,6, 129,4, 128,7, 127,7, 126,8, 126,4, 123,8, 119,3, 107,3, 107,0, 60,5, 42,6, 15,7.

Example 22

Dimethyl-(5-methylsulfanyl-4-phenoxymethyl-2-(2,4,6-trichlorophenyl)-2H-pyrazole-3-yl-amine and 2-[5-dimethylamino-3-methylsulfanyl-1- (2,4,6-trichlorophenyl)-1H-pyrazole-4-ylmethyl]-phenol

To a solution of phenol (564 mg, 6.0 mmol) in anhydrous N,N-dimethylformamide (1.0 ml) was added in portions over 5 minutes sodium hydride (240 mg, 60% dispersion of sodium hydride in mineral oil; 144 mg, 6.0 mmol of sodium hydride). The mixture is stirred for 15 minutes at room temperature. Separately using the methods of Example 4D receive in situ mesilate compound of Example 1C (1.5 mmol) in anhydrous methylene chloride (6 ml), then with stirring and cooling in a bath of ice suddenly make to the above obtained solution nelfinavir and stir the mixture for 18 hours at 50oC. the Solvent is evaporated in vacuo, the resulting residue is extracted in the ethyl acetate/water (60 ml each) when bringing the pH of the aqueous phase to 6.0 by addition of 1 N hydrochloric acid. The aqueous layer was separated, extracted twice with 30 ml portions of fresh ethyl acetate. The organic extracts are combined extracted with an equal volume of water, dried over anhydrous sulphate of soda is and elution with ethyl acetate/hexane = 1:9 by volume) and get dirty sample (90 mg) C-alkylated compounds and like the purified sample (190 mg) O-alkylated these compounds. Final cleaning of both compounds is performed by chromatography in thin layer of silica gel each sample (elution with hexane/methylene chloride = 2: 3 by volume) and get 11 mg 58 mg, respectively, C-these compounds are alkylated and O-alkylated these compounds.

The second named connection (product C-alkylation):

13With NMR (CDCl3): 154,5, 149,4, 149,0, 136,4, 135,0, 130,2, 128,8, 127,8, 126,1, 120,3, 116,1, 111,2, 42,7, 24,2, 15,2.

The first named connection (product O-alkylation):

13C NMR (CDCl3): 158,6, 153,1, 149,5, 136,1, 135,6, 134,5, 129,5, 128,7, 121,0, 115,1, 107,2, 60,4, 42,6, 15,7.

Example 23

[4-(2-Methoxy-naphthalen-1-ylmethyl)-5-methylsulfanyl-2- (2,4,6-trichlorophenyl)-2H-pyrazole-3-yl]-dimethylamine

To a solution of the first compound of Example 21 (121 mg, 0.25 mmol) in anhydrous tetrahydrofuran (1.0 ml) under vigorous stirring was added in portions over 5 minutes sodium hydride (25 mg, 60% dispersion of sodium hydride in mineral oil, 15 mg, 0.63 mmol of sodium hydride) was stirred 10 minutes at room temperature, make modesty methyl (78 μl, 1.25 mmol), stirred for 1 hour (room temperature), then make a second portion iodotope bromide (78 μl, 1.25 mmol), stirred for 18 hours at which the extract is separated, extracted twice with 30 ml portions of fresh ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate, evaporated in vacuum and receives a yellow oil (138 mg), which is completely chromatographic in a thin layer (silica gel, 40 MK, while elution with ethyl acetate/hexane = 1:9 by volume) and get the named compound (74 mg) as a colorless amorphous solid.

13C NMR (CDCl3): 154,9, 149,9, 148,4, 136,3(2), 135,3, 133,5, 129,3, 128,5, 128,4, 128,3, 125,9, 124,2, 123,3, 121,1, 113,5, 112,7, 41,7, 19,8, 15,2.

Example 24

[4-(2-Isopropoxy-naphthalen-1-ylmethyl)-5-methylsulfanyl - 2-(2,4,6-trichlorophenyl)-2H-pyrazole-3-yl]-dimethylamine

To a solution of the first named compound from Example 21 (120 mg, 0.24 mmol) in anhydrous tetrahydrofuran (1.0 ml) under vigorous stirring was added sodium hydride (29 mg, 60% dispersion of sodium hydride in mineral oil; 17,4 mg, 0.73 mmol of sodium hydride) in portions over 5 minutes, stirred for 30 minutes at room temperature, add 2-iodopropane (192 μl, of 1.92 mmol), the mixture is stirred for 18 hours at room temperature. Reaction controls TLC shows that the reaction is not finished, so make a second portion of 2-iodopropane (200 μl, 2.0 mmol), the mixture is stirred dopolnity layer is separated, extracted twice with 20 ml portions of fresh ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate, evaporated in vacuum and receives a yellow oil (161 mg), which chromatographic in a thin layer (silica gel, 40 MK; elution with ethyl acetate/hexane = 5:95 by volume) and get the named compound as a colorless foamy substance.

13With NMR (CDCl3): 153,4, 150,0, 148,4, 136,3(2), 135,2, 133,8, 129,4, 128,4, 128,2, 128,1, 125,7, 124,5, 123,3, 116,2, 112,8, 71,6, 41,6, 22,6, 20,1, 15,3.

Example 25

4-[5-Dimethylamino-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-ylmethyl]-4H-isoquinoline-1,3-dione

To a solution of homophthalic (467 mg, 2.9 mmol) in anhydrous N,N-dimethylformamide (1.8 ml) was added all at once a number of sodium hydride (128 mg, 60% dispersion of sodium hydride in mineral oil, with 76.8 mg, 3.2 mmol of sodium hydride), the mixture is heated for 20 minutes at 65oC. Then, by using the method of Example 4D receive in situ compound of Example 1C (1.9 mmol). Then both mixtures, homophthalic sodium/N,N-dimethylformamide and the solution nelfinavir, cooled to 5oC, unite, add acetonitrile (5 ml), heated for 18 hours at 65oC, the solvent was evaporated in vacuum and get a solid product, which exterous equal volume of a diluted aqueous solution of sodium carbonate (pH 9); then an equal volume of water, dried over anhydrous sodium sulfate, evaporated in vacuum and get foamy substance (909 mg) which crystallized from isopropyl alcohol (30 ml), and obtain 140 mg (14,4% yield) of the named compound (colorless crystals, so pl. 186-187oC).

Example 26

2-[5-Dimethylamino-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H - pyrazole-4-ylmethyl]-isoindole-1,3-dione

To a solution of phthalimide (427 mg, 2.9 mmol) in anhydrous N,N-dimethylformamide (4 ml) under vigorous stirring and cooling in a bath of ice was added sodium hydride (128 mg, 60% dispersion of sodium hydride in mineral oil, 77 mg, 3.2 mmol of sodium hydride), stirred for 20 minutes at room temperature. Separately, to a solution of compound of Example 1C (700 mg, 1.9 mmol) and triethylamine (304 μl, 2.2 mmol) in anhydrous methylene chloride (9 ml) under cooling in a bath with ice add all at once methanesulfonanilide (104 μl, 2.1 mmol); the resulting mixture is stirred (5oC) 15 minutes before the end of the formation in situ nelfinavir compound of Example 1C, then under stirring and cooling to 5oC is added all at once a solution of phthalimide sodium/N,N-dimethylformamide (also cooled to 5oC), the resulting mixture is soft is one bicarbonate (pH 8, 100 ml of each). The organic layer is separated, dried over magnesium sulfate, evaporated in vacuo to an oil (762 mg), which chromatographic in a thin layer (30 g silica gel, 40 MK; elution with ethyl acetate/hexane in a volumetric ratio 6:94, 8:92, 12:88 and 1:4, respectively for each of the four consistently collected 250 ml volumes eluant) and get titled compound (160 mg) as a colorless amorphous solid.

13With NMR (CDCl3): 167,8, 151,7, 148,6, 136,3, 135,6, 134,7, 133,9, 132,1, 128,6, 123,3, 106,4, 42,5, 31,9, 15,0.

Example 27

A. Methyl ester of 5-amino-1-(2,6-dichloro-4-triptoreline)- 3-ethyl-1H-pyrazole-4-carboxylic acid

A solution of methyl ester of 2-cyano-3-ethyl-3-ethoxyacrylate acid (20,14 g, 109 mmol) and 2,6-dichloro-4-triftormetilfullerenov (26,93 g, 109 mmol) in glacial acetic acid (42 ml) is boiled for 4 hours, then stirred for 18 hours at room temperature, the solvent is evaporated in vacuum, the residue is extracted with 150 ml of ethyl acetate. The remaining acetic acid is removed from the extract with aqueous saturated sodium bicarbonate solution. An ethyl acetate extract is separated, dried over anhydrous sodium sulfate, evaporated in vacuum and get a brown oil (47 g), which chromatogra (19.5 g) as a waxy solid. TLC Rf(silikagelevye plate under UV light; ethyl acetate/hexane = 15:85 by volume) : 0,30.

13C NMR (CDCl3): 165,2, 157,0, 151,5, 137,0, 127,5, 126,1(2), 123,8, 120,4, 116,7, 93,2, 50,8, 22,1, 12,8.

B. Methyl ester 1-(2,6-dichloro-4-triptoreline)- 5-dimethylamino-3-ethyl-1H-pyrazole-4-carboxylic acid

According to the General method of Example 4B using of 19.4 g (52 mmol) of compound of stage A get the named compound as an orange oil (22,73 g), TLC Rf(silikagelevye plate under UV light; ethyl acetate/hexane = 15:85 by volume) : 0,73.

13C NMR (CDCl3): 163,7, 158,6, 156,5, 136,3, 127,6, 125,8, 125,7, 124,0, 120,4, 116,8, 102,4, 51,0, 42,1, 22,7, 13,0.

C. [1-(2,6-Dichloro-4-triptoreline)-5-dimethylamino-3 - ethyl-1H-pyrazole-4-yl]-methanol

To a solution of compound stage B (9.0 g, 22.6 mmol) in anhydrous tetrahydrofuran (80 ml) under cooling with a mixture of dry ice with acetone are added dropwise within 5 minutes of 1.0 M solution of diisobutylaluminium (75 ml, 75 mmol of diisobutylaluminium), stirred for 30 minutes with 5oC (bath with ice), the reaction is quenched by addition of water (4.5 ml), stirred for 10 minutes before heating the mixture to 50oC, then the solvent evaporated in vacuum on a heterogeneous (gelatinases) mixture, the residue is treated e is Zetta/hexane (1:9 by volume), the resulting colorless solid product is filtered off and dried (5,1 g). Additionally the full sample purified by three successive treatments with 20 ml of hexane (product emit filtering) and get the named compound (3.6 g) as a colourless solid.

TLC Rf(silikagelevye plates in UV light; ethyl acetate/hexane = 1:4 by volume) : 0,40.

13C NMR (CDCl3): 156,5, 152,1, 136,5, 127,7, 126,7(2), 124,1, 120,5, 116,9, 106,7, 61,4, 43,1, 20,6, 13,4.

D. 8-[1-(2,6-Dichloro-4-triptoreline)-5-dimethyl-amino-3 - ethyl-1H-pyrazole-4-ylmethyl]-quinoline-7-ol

According to the method of Example 21 using 7-hydroxyquinoline solution (237 mg, 1.63 mmol) instead of 2-naphthol as a nucleophile and obtained in situ nelfinavir connection phase C as a substrate to receive a named connection (product C-alkylation, 208 mg) as a pale yellow amorphous solid. TLC Rf(silikagelevye plate under UV light; ethyl acetate/hexane = 1:4 by volume) : 0,36. HRMS m/z 509.10872 (M+1, C24H22N4OCl2F3).

Example 28

Enantiomeric { 2-[1-(2,6-dichloro-4-triptoreline)-5 - dimethylamino-3-ethyl-1H-pyrazole-4-ylmethyl]-1,2,3,4-tetrahydro-athineon-3-yl}-methanol

According to the method of Example 4D when ispolzovanlu substrate receive a named connection in the form of an amorphous solid (190 mg). TLC Rf(silikagelevye plate; UV light; ethyl acetate/hexane = 1,4 by volume) : 0,16.

13C NMR (CDCl3): 156,5, 151,4, 136,7, 136,6, 133,6, 133,3, 129,0, 127,8, 126,9, 126,5, 126,0, 125,6, 124,2, 120,5, 117,0, 107,2, 61,9, 58,2, 47,8, 45,7, 42,6, 26,6, 10,7, 13,2.

Example 29

A. Methyl ester of 5-amino-3-ethyl-1-(2,4,6-trichlorophenyl)-1 - 1H-pyrazole-4-carboxylic acid

According to the method of Example 27A methyl ester 2-cyano-3-ethyl-3 - ethoxyacrylate acid (145 g of 0.79 moles) is reacted with 2,4,6-trichlorophenylhydrazine (167 g of 0.79 moles) education (after chromatography on 40 MK silica gel; elution with ethyl acetate/hexane = 1:4 by volume) of the named compound as an orange oil (176 g). TLC Rf(silikagelevye plate under UV light; ethyl acetate/hexane = 1:4 by volume) : 0,43.

1H NMR (CDCl3): the 7.43 (2H, c), 5,14 (2H, Shir. C) of 3.78 (3H, c), is 2.74 (2H, q, J=7,6 Hz) of 1.20 (3H, t, J=7,6 Hz).

B. Methyl ester 5-dimethylamino-3-ethyl-1- (2,4,6-trichlorophenyl)-1H-pyrazole-4-carboxylic acid

According to the method of Example 4B using the connection phase A (with 4.64 g, 1.3 mmol) get the named compound (2.9 g) as an orange solid. TLC Rf(silikagelevye plate under UV light; elution with ethyl acetate/hexane = 1:10 by volume): 0,42.

1H NMR (CDCl3
According to the method of Example 27C using the connection phase B of this Example (1.50 g, 4.0 mmol) get the named compound as a colourless waxy solid (320 mg). TLC Rf(silikagelevye plate under UV light; ethyl acetate/hexane = 1:4 by volume) : 0,16.

1H NMR (CDCl3): of 7.36 (2H, c), 4,50 (2H, m), 2,65 (6H, c), 2,58 (2H, q, J=7,6 Hz) to 1.21 (3H, t, J=7,6 Hz).

D. Enantiomeric {2-[5-dimethylamino-3-ethyl-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-ylmethyl]- 1,2,3,4-tetrahydroisoquinoline-3-yl}-methanol

According to the method of Example 4D and using programalso enantiomer (+)-3-hydroxy-1,2,3,4-tetrahydroisoquinoline (240 mg, 1.4 mmol) as a nucleophile and obtained in situ nelfinavir connection phase C as a substrate to obtain the desired compound as a pale yellow oil (12 mg of pure material after chromatographic purification (silica gel 40 MK; elution with ethyl acetate/hexane = 1:6 by volume)) of crude product.

13C NMR (CDCl3): 155,5, 151,9, 135,3, 134,1, 133,5, 128,9, 128,6, 126,7, 126,2, 109,3, 86,8, 71,6, 58,2, 50,6, 43,1, 31,3, 20,5, 13,8. HRMS m/z 493.1345 (M + 1, C24H28N4OCl3).

Example 30

The dihydrochloride [2-(2,6-dichloro-4-triptoreline)-4- (3-ethoxymethyl-3,4-dihydro-1H-isoquinoline-2-ylmethyl)-5-me Example (38 mg) in a mixture of anhydrous hydrogen chloride/diethyl ether (0.5 ml) at room temperature was added 5 drops of a saturated solution of hydrogen chloride/diethyl ether, once formed white crystals of salt (called a connection) is filtered off, dried in vacuum (35 mg, so pl. 75,0-75,3oC).

Example 31

The following connections receive according to the methods of Examples in the table. 1.

Example 32

The following connections receive according to the method of Example 4D, followed by alkylation according to the method of Example 15 for those compounds of Table 2, where R ' is not hydrogen, and they are obtained from programalso enantiomer (+)-3-substituted-1,2,3,4 - tetrahydroisoquinoline obtained by the usual method from Method 2, below. Pyrazol original material produced by the method of Example noted in the table. 2.

Example 33

The following connections get on the methods of Examples listed in table. 3.

Example 34

The following connections receive according to the method of Example 23. Starting compound used in this method, produced by the method of Example 21 (see tab. 4).

Example 35

A. Tert-Butyl ether dimethylsilicone 2-{1-[1-(2,6-dichloro-4 - triptoreline)-5-dimethylamino-3-ethyl-1H-pyrazole-4-ylmethyl] - naphthalen-2-yloxy}-ethanol

To a solution of 1-[1-(2,6-dichloro-4-triptoreline)-5 - dimethylamino-3-ethyl-1H-pyrazole-4-ylmethyl]-naphthalen-2-ol (130 m is s for 5 minutes, sodium hydride (31 mg, 60% dispersion of sodium hydride in mineral oil; 19 mg, 0.78 mmol of sodium hydride), incubated for 5 minutes and make 744 mg (2.6 mmol) of 1-iodine-2-(tert-butyldimethylsilyloxy)ethane, heated 18 hours at 45 - 50oC, after which time TLC shows that the reaction is not finished, so add additional double-744 mg (2.6 mmol) of 1-iodine-2-(tert-butyldimethylsilyloxy)ethane, each time conducting subsequent heating for 18 hours at 50oC. and Then evaporated the solvent in vacuo, the residue is extracted with ethyl acetate/water (100 ml each). The organic extract was separated, dried over anhydrous sodium sulfate, evaporated in vacuo to an oil, which chromatographic (silica gel, 40 MK, while elution with ethyl acetate/hexane 5:95 by volume) and get a named connection in the form of oil (53 mg).

1H NMR (CDCl3): of 0.07 (6H, c) to 0.88 (9H, s) to 0.92 (3H, t, J=7.5 Hz), 2,24 (2H, q, J= 7.5 Hz), 2,42 (6H, s), of 3.96 (2H, t), is 4.15 (2H, t), 7,16 - to 7.32 (3H, m), 7,58 (2H, s), of 7.64 to 7.75 (2H, m), 7,8 - 7,88 (1H, m)

B. 2-{1-[1-(2,6-Dichloro-4-triptoreline)-5-dimethylamino-3-ethyl - 1H-pyrazole-4-ylmethyl]-naphthalen-2-yloxy}-ethanol

Solution connect phase A (50 mg, of 0.075 mmol) and tetrabutylammonium (150 µl 1,00 M tetraphenylboron solution, 0.15 moles) in tetrahydrofuran (0.25 ml) is stirred for 2 hours at room temperature. The entire sample Mami water, dried (anhydrous sodium sulfate), evaporated in vacuo to an oil (50 mg), chromatographic the entire sample (silica gel, 40 MK; elution with ethyl acetate/hexane = 3:7 by volume). TLC Rf(silikagelevye plate, UV-irradiation, ethyl acetate/water = 3: 7 by volume) : 0,34.

1H NMR (CDCl3): and 1.00 (3H, t, J=7.5 Hz), 2,12 (1H, Shir. m) of 2.34 (2H, q, J= 7.5 Hz), 2,47 (6H, s), 3.95 to 4,08 (2H, m), 4,24 (2H, t), to 4.33 (2H, s), 7,25-7,46 (3H, m), 7,68 (2H, s), 7,75-7,94 (2H, m), 8,00 (1H, m).

Example 36

2-{ 8-[1-(2,6-Dichloro-4-triptoreline)-5-dimethyl - amino-3-ethyl-1H-pyrazole-4-ylmethyl]-quinoline-7-yloxy}-ethanol

According to the method of Example 35 compound of Example 27D (200 mg, 0.39 mmol) turns on the named compound (36 mg, in the form of amorphous solids).

1H NMR (CDCl3): to 0.96 (3H, t) 2,02 (1H, Shir.) of 2.34 (6H, c), 3,86 (2H, m), of 4.13 (2H, t), br4.61 (2H, c), 7,14-7,42 (2H, overlapped the multiplets), to 7.61 (2H, s), 7,71 (1H, d), 8,08 (1H, DD), 8,88 (1H, m).

The following methods illustrate the production of intermediate products.

Method 1

The racemate (1,2,3,4-tetrahydro-isoquinoline-3-yl)-methanol also known as ()-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline

To a suspension of the hydrochloride 1,2,3,4-tetrahydroisoquinoline-3 - carboxylic acid (75 g, 0,351 moles Afdrich Chemical Co.) in anhydrous methanol (600 ml) is within 10 minutes the sodium methylate (37,92 g, 0,702 mol), stirred for 30 minutes, the methanol is evaporated, the colorless residue is dried overnight in vacuum. The sample is completely stirred in anhydrous tetrahydrofuran, causing complete dissolution of the organic part. To the mixture with vigorous stirring for 20 minutes (moderately exothermically) was added at a rapid flow of 1.0 M solution of lithium aluminum hydride in tetrahydrofuran (351 ml, 0,351 moles). The reaction mixture was then vigorously boiled for 2 hours, after which the reaction at the 5oC quenched carefully by the addition of 15% aqueous sodium hydroxide. The mixture is filtered, the filtrate evaporated in vacuo to a yellow solid. The sample is completely dissolved in methylene chloride (400 ml), filtered to remove residual inorganic salts, the solvent is evaporated in vacuum and get the named compound as an orange solid (47,01 g, 70% yield). TLC Rf(silikagelevye plate, UV-irradiation; elution with methanol/methylene chloride = 5:95 by volume) : 0,46.

13With NMR (CDCl3): 135,4, 134,1, 129,3, 126,3, 126,1, 125,9, 65,4, 55,0, 47,8, 30,9.

Method 2

Programalso enantiomer (1,2,3,4-tetrahydro-isoquinoline-3 - yl)-methanol (also known as (+)-3-hydroxymethyl-1,2,3,4 - tetrahydroisoquinoline)

To Rast is billaut a solution of (S)-(+)-almond acid (43,81 g, in 0.288 mol) in isopropyl alcohol (159 ml), left for 48 hours at room temperature, during which observe the formation of an orange crystalline mass, crystals separated (13,06 g), dissolved in hot isopropyl alcohol (63 ml), left for 1 hour at room temperature, the newly formed crystals are filtered (8,2 g, so pl. 138oC), the recrystallization was repeated twice, using 63 ml and 60 ml volumes of isopropyl alcohol, and receive, respectively, was 7.08 g and 6.75 g of crystalline material. (In each case, the crystallization is held for 2 hours at room temperature before filtration). After the final crystallization so pl. is 138 - 139oC. the Sample is completely dissolved in methylene chloride/water (300 ml and 100 ml, respectively) with bringing the pH to 9.5 (potassium carbonate). The phases are separated, the aqueous portion is extracted with three 50 ml portions of fresh methylene chloride. The organic extracts are combined, dried (anhydrous sodium sulfate), evaporated in vacuum and receive optical isomer of the above compound as a colourless amorphous solid (2,02 g, 8.6% yield). []2D0+ 103o(C = 1,83, CH2Cl2);

13C NMR (CDCl2 the measures (1,2,3,4-tetrahydroisoquinoline - 3-yl)-methanol also known as (-)-3-hydroxymethyl - 1,2,3,4-tetrahydroisoquinoline

Substitution (S)-(+)-almond acid (R)-(-)-almond acid in the Method 2 (using 17.9 g of the alcohol-amine, obtained by the Method 1) results levogyrate titled compound (0.65 g, a 7.3% yield) as a colorless amorphous solid (2,02 g, 8.6% yield). []2D0- 100,4o(CH2Cl2c = 1,43);1H NMR and13NMR (CDCl3): the spectra are identical in all aspects spectra obtained for the racemate (Method 1) and programalso isomer (Method 2).

1. Aminosilane pyrazoles of General formula I

< / BR>
or their pharmaceutically acceptable salt additive acid,

where A is CH2;

X1means covalent bond, O, or S;

R1, R2and R3mean C1- C6alkyl;

Y - 2,4,6-triple-substituted phenyl, where the Deputy represents fluorine, chlorine, bromine, methyl or trifluoromethyl, provided that the phenyl contains not more than one trifluoromethyl group as a substituent;

Z represents a group of the formula

< / BR>
where R4is hydrogen or C1- C6alkoxy;

R5means hydrogen or a group of the formula

(CH2)oX2(CH2)rQ2R6,
- C8alkenyl;

X2and Q2independently of one another are oxygen or one can be a covalent bond;

m is 0 or 1,

p is 1 or 2,

o is 1 or 2,

r is 0, 1 or 2;

or a group of the formula NR7R8,

where R7and R8each independently from each other denote hydrogen, a linear C1- C6alkyl, branched C3- C8alkyl, C1- C6hydroxyalkyl, (C3- C12cycloalkyl) - (CH2)nwhere n is 0 to 4, 1,2,3,4-tetrahydronaphthyl, phenyl(C1- C3alkylen), possibly substituted in the phenyl ring hydroxy, fluorine, chlorine, bromine, C1- C5the alkyl, C1- C5alkoxy or nitro, or R7and R8together with the nitrogen atom to which they are attached form a 2,6-di(C1- C6alkyl)piperidino or hexahydro-1H-indolering group, both R7and R8may not mean hydrogen;

or a group of the formula

< / BR>
or a group of the formula

< / BR>
or a group of the formula

O(CH2)vR11< / BR>
where v is 0 to 3;

R11means linear C1- C6alkyl, branched C3- C8alkyl, phenyl, naphthyl, 1,2,3,4-tetrahydro the SUB> and R13independently of one another denote hydrogen or C1- C6alkoxy, R14is hydroxy, C1- C12alkoxy, C3- C12alkenylacyl, where the double bond is not adjacent to the oxygen group

O(CH2)rR9< / BR>
where R9is hydroxy or cyclopropyl;

r is 1 or 2;

or a group of the formula

< / BR>
2. Connection on p. 1, in which Y is 2,4,6-trichlorophenyl or 2,6-dichloro-4-cryptomaterial.

3. Connection on p. 1, in which the group X1R3represents ethyl or matertial.

4. Connection PP.1 to 3, in which R1and R2each are stands.

5. Connection PP. 1 to 4, in which Z stands for a group NR7R8where R7means phenyl(C1- C3alkylen), possibly substituted in the phenyl ring by chlorine, nitro, stands or methoxy, R8- 2-hydroxyethyl or 3-hydroxypropyl.

6. Connection PP.1 to 4, in which Z signifies 1,2,3,4-tetrahydroisoquinoline-2-yl, substituted at position 3 R5where R5mean group (CH2)kOH, where k is 1 to 4, or a group CH2OCH2CH2OR6where R6means C1- C4alkyl.

7. Audigy configuration S or R or R, S.

8. Connection PP.1 to 4, in which Z represents a group of the formula

< / BR>
with the absolute configuration at the 3 position specified by its derived from (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline, where R19means methyl, ethyl, isopropyl.

9. Connection PP.1 to 4, in which Z represents a group

< / BR>
where K is CH or nitrogen;

R20represents methyl, ethyl, isopropyl, cyclopropylmethyl or hydroxyethyl.

10. Connection PP.1 to 4, in which Z represents a group

< / BR>
11. Connection on p. 1, selected from the group comprising: 2-{1-[1-(2,6-dichloro-4-triptoreline)-5-dimethylamino-3-ethyl-1H-pyrazole-4-yl-methyl] naphthyl-2-oxy} -ethanol; enantiomeric [4-(3-methoxymethyl-3,4-dihydro-1H-isoquinoline-2-yl-methyl)-5-methylthio-2-(2,4,6-trichlorophenyl)-2H-pyrazole-3-yl] -dimethylamine obtained from (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline; enantiomeric [2-(2,6-dichloro-4-triptoreline)-4-(3-ethoxymethyl-3,4-dihydro-1H-isoquinoline-2-yl-methyl)-5-ethyl-2H-pyrazole-3-yl] -dimethylamine obtained from (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline; [2-(2,6-dichloro-4-triptoreline)-5-ethyl-4-(7-methoxyquinoline-8-yl-methyl)-2H-pyrazole-3-yl] -dimethylamine; [2-(2,6-dichloro-4-trifter the chlorophenyl)-2H-pyrazole-3-yl]-dimethylamine; [4-(7-methoxyquinoline-8-yl-methyl)-5-methylthio-2-(2,4,6-trichlorophenyl)-2H-pyrazole-3-yl] -dimethylamine; 2-{ 1-[5-dimethylamino-3-methylthio-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-yl-methyl] -naphthyl-2-oxy}-ethanol; enantiomeric [2-(2,6-dichloro-4-triptoreline)-5-ethyl-4-(3-methoxymethyl-3,4-dihydro-1H-isoquinoline-2-yl-methyl)-2H-pyrazole-3-yl] -dimethylamine obtained from (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline; 4-(2-cyclopropylmethoxy-1-methyl)-5-methylthio-2-(2,4,6-trichlorophenyl)-2H-pyrazole-3-yl]-dimethylamine.

12. Intermediate aminosilane pyrazoles of General formula II

< / BR>
where R' represents the group CH2OH, or a group C(O)O(C1- C3alkyl);

X1means covalent bond, O, or S;

R1, R2and R3mean C1- C6alkyl;

Y - 2,4,6-triple-substituted phenyl, where the Deputy represents fluorine, chlorine, bromine, methyl or trifluoromethyl, provided that the phenyl contains not more than one trifluoromethyl group as a substituent.

 

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