Pyrazolopyrimidine and their pharmaceutically acceptable salts

 

(57) Abstract:

The invention relates to pyrazolopyrimidines General formula I and their pharmaceutically acceptable salts, where A is the group NR1R2or CR'1R'2R11, R1- H or C1-C6-alkyl, unsubstituted or substituted certain substituents, such as HE, F, CL and others, or C2-C6alkenyl; or C2-C6-quinil; R2-C1-C6-alkyl, unsubstituted or substituted certain substituents, such as HE, C1-C6-alkoxy and others; or C2-C6alkenyl or2-C6-quinil, or furanyl; and (C1-C4-alkylene)phenyl which may be substituted by 1 to 3 substituents: CL, F, C1-C4-alkyl, and one Deputy:1-C6-alkoxy, CF3, NO2, NH2; or (C1-C4-alkylen) hetaryl where hetaryl - thienyl, possibly substituted by CL, benzothiazyl, pyridyl, chinoline, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrrolidinyl, 1-benzylpiperidine, tetrahydropyranyl; or (C1-C4-alkylen)cyclopropyl; or NR1R2form hetaryl selected from the group consisting of pyrrolidyl may be replaced by the R'1is hydrogen, C1-C6-alkyl; R'2-C1-C6-alkyl; R3is hydrogen, C1-C6-alkyl, O-(C1-C6alkyl), S(C1-C4- alkyl); R4- C1-C6- alkyl, or S(O)n(C1-C6)-alkyl, where n= 0-2, R5- 2,4,6-substituted phenyl CL, C1-C6-alkyl, CF3; R11-N., HE, or COO- (C1-C2alkyl), provided that the group CR'1R'2R11not an alkyl straight chain; and when R3is N, then R4isn't C1-C6-alkyl. The compounds possess antagonistic activity relative to factor in the release of corticotropin (CRF) and can be used to treat diseases associated with stress and other diseases. 6 C.p. f-crystals, 5 PL.

Formula (I)

K

This invention relates to pyrazolopyrimidines, pharmaceutical compositions containing them and their use in the treatment of diseases associated with stress, and other illnesses. The compounds possess antagonistic activity relative to factor in the release of corticotropin (CRF).

The CRF antagonists are referred to in U.S. Pat. USA 4605642 and 5063245 and are peptides and pyrazolinone respectively. Testing the temporal description of the different activity shown CRF antagonists, see M. Y. Owens et al., Pharm. Rev. Vol. 43, RV 425-473 (1991), also incorporated herein by reference. According to research described in these two and other references, CRF antagonists are considered an effective treatment for a wide range of diseases, including diseases associated with stress, such as stress-induced depression, anxiety, and headaches; abdominal bowel syndrome; inflammation; immune suppression; 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.

Some substituted pyrazolopyrimidine described in the past. For example, European patent 496617 relates to inhibitors adenosines, among which 1-ribofuranosylthiazole and 1-substituted ribofuranosyl)pyrazolopyrimidine. Pat. USA N 4904666 reflects pyrazolopyrimidine containing 1-tetrahydrofuranyl or 1-tetrahydropyranyl deputies. Senga et al. , J. Heterocyclic Chem. 19, 1565 (1982) describes some of pyrazolopyrimidine with inhibiting the xanthine oxidase activity. A number of other pyrazolopyrimidine mentioned in U.S. Pat. USA N 2965643 and 3600389.


where

A represents NR1R2, CR1R2R11C(= CR2R12R1, NHCR1R2R11OCR1R2R11SCR1R2R11, OTHER1R2, CR2R11HR1, CR2R11OR1, CR2R11SR1or C(O)R2;

R1is hydrogen or C1-C6the alkyl, which may contain one or two double or triple bond or which may be substituted by one or two substituents R6independently from each other selected from the group consisting of hydroxy, fluorine, chlorine, bromine, iodine, C1-C6alkoxy, NH(C1-C4alkyl), amino, N(C1-C2alkyl) (C1-C4alkyl), S(C1-C6alkyl), COOH, SO2(C1-C4alkyl), SH, CN, NO2, SO(C1-C4alkyl), SO2NH(C1-C4alkyl), SO2N(C1-C4alkyl)(C1-C2alkyl), where the above-mentioned (C1-C6)alkyl may have one or two double or triple bond;

R2means C1-C12alkyl, aryl or (C1-C10alkylene)aryl, where the aforementioned aryl is phenyl, naphthyl, teinila, benzothieno, pyridium, chinaillon, personalism, pirimidinom, what intimidation, triazolam, pyrazolyl, pirrallo, indolium, isoindolyl, oxazolium or benzoxazolium; 3 - to 8-membered cycloalkyl or (C1-C6alkylen)cycloalkyl, where the above-mentioned cycloalkyl can have one or two O, S or N - Z , where Z is hydrogen, C1-C4the alkyl, benzyl or C1-C4alkanoyl, where each of the above groups may be substituted independently from each other from one to three substituents, such as chlorine, fluorine, (C1-C4)alkyl, or one Deputy, such as hydroxy, bromine, iodine, C1-C6alkoxy, S(C1-C6)alkyl, NH2, NH(C1-C2alkyl), N(C1-C2alkyl)(C1-C4alkyl), N(C1-C4alkyl) COOH, (C1-C2alkyl), SH, CN, NO2, SO(C1-C4alkyl), SO2(C1-C4alkyl), SO2NH(C1-C4alkyl), SO2N(C1-C4alkyl)(C1-C2alkyl), and where the above-mentioned C1-C12alkyl or C1-C10alkylen can have from one to three double or triple links; or

NR2R2or CR1R2R11may form a saturated 4 - to 8-membered ring, optionally containing one or two O, S or N - Z, where Z is hydrogen -C6alkyl, fluorine, chlorine, bromine, iodine, hydroxy, amino, (C1-C6alkyl), NH(C1-C6alkyl), N(C1-C4alkyl), (C1-C2alkyl), SH, S(C1-C4alkyl), SO(C1-C4alkyl), or SO2(C1-C4alkyl), where the above-mentioned C1-C4alkyl and C1-C6the alkyl may have one or two double or triple links and can contain from 1 to 3 substituents R7selected independently of one another from the group consisting of hydroxy, amino, C1-C3alkoxy, dimethylamino, diethylamino, methylamino, ethylamino, fluorine , chlorine or C1-C3thioalkyl;

R4describes hydrogen, C1-C6alkyl, fluorine, chlorine, bromine, iodine, C1-C6alkoxy, amino, NH(C1-C6alkyl), N(C1-C6alkyl)(C1-C2alkyl), SOn(C1-C6alkyl), where n means 0, 1 or 2, cyano, hydroxy, carboxy, or amido, where the above-mentioned group C1-C6the alkyl may contain as substituents of one to three hydroxy, amino, carboxy, amido, , NH(C1-C4alkyl), NH(C1-C4alkyl)(C1-C2alkyl), C1-C3alkoxy, C1-C3thioalkyl, fluorine, bromine, chlorine, iodine, cyano or nitro;

R5predstavenstvem, benzothiazolyl, isothiazolin, benzothiazolyl, thiazolyl, isoxazolyl, benzisoxazole, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridine, benzoxazolyl, oxazolyl, pyrrolidinyl, diazolidinyl, piperazinil, piperidinyl, tetrazolyl, 3 - to 8-membered cycloalkyl or 9 - to 12-membered bicycloalkyl, optionally containing one or two O, S or N - Z , where Z denotes hydrogen, C1-C4alkyl, C1-C4alkanoyl, phenyl or benzyl, where each of the above groups may independently of one another can contain from one to three such substituents as fluorine, chlorine, bromine, formyl, C1-C6alkoxy or trifluoromethyl, or one Deputy, such as hydroxy, iodine, cyano, nitro, amino, cyclopropyl, NH(C1-C4alkyl), 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), where the above-mentioned C1-C4alkyl and C1-C6the alkyl may have one double or triple bond and may contain one or two Deputy, tremendum by phenyl;

R11means hydrogen, hydroxy, fluorine, chlorine, COO(C1-C2alkyl), cyano, or CO(C1-C2alkyl); and

R12is hydrogen or C1-C5by alkyl; with the following conditions;

(a) A is an indirect chain C1-C12of alkyl;

(b) R5is not a group of sugars;

(c) when R3and R4are hydrogens and R5- chlorophenyl, A is not NH-CH(CH3)-(CH2)3-N(C2H5)2;

(d) when R3and R4are hydrogens and A-NR1R2where R1represents a C3-C7cycloalkyl and R2-C2-C6alkenyl, phenyl-(C1-C6alkylen) or hetero-(C1-C6alkylen), where heterological means furyl, thienyl or pyridinyl, and where the above-mentioned phenyl may contain as substituents of fluorine, chlorine, bromine or iodine, R5is not tetrahydrofuranyl or tetrahydropyranyl;

(e) when R3is methoxy, methylthio or methylsulfonyl, R4is hydrogen and R5- tetrahydrofuranyl or tetrahydropyranyl, then A is not NH(C1-C2alkyl), mohanram, hydrazino or NHC2H4C6H5, phenyl which can soda-C6alkyl, hydrazino, chlorine, bromine, SH or S(C1-C4alkyl), R4is hydrogen and R5-C3-C8cycloalkyl, then A is not hydrazino, NH(C1-C2alkyl) or N(C1-C6alkyl)(C1-C12alkyl);

(g) when R3and R4are hydrogens and A represents NH(CH2)mCOOH, where m means 1-12, R5is not phenyl substituted with one fluorine, chlorine, bromine or iodine;

(h) when R3is hydrogen, hydroxy, methylthio, chlorine or NH, R4is hydrogen and R5- chlorophenyl or bromperidol, then A is not NH(C1-C12alkyl), NH(allyl) or N(C1-C6alkyl)(C1-C12alkyl), where the above-mentioned C1-C12the alkyl may contain as Deputy NC2H5or NH, which may contain as substituents one or two bromine, chlorine, fluorine, NC2H5phenyl or morpholinopropan;

(i) when R3and R4are hydrogens and R5- nitrophenyl, then A is other2where R2represents a C1-C2alkyl which may be substituted by two hydroxy groups, or R2represents phenyl or benzyl;

(j) when R3independently of one another are hydrogen or C1-C6the alkyl, R5is not a chlorophenyl;

(k) when R3is hydrogen, a benzyl or venetiam and R4- fluorine, chlorine, bromine or iodine, R5is not 5'-deoxyribofuranosyl or 5'-amino-5'-deoxyribofuranosyl.

Preferred compounds of formula (I) of the invention are the compounds where R1represents a C1-C4alkyl, (C2-C4alkylene)O(C1-C4alkyl or C2-C4hydroxyalkyl; compounds, where R2means C1-C5alkyl, benzyl, phenylethyl or benzyl substituted by one or two substituents, such as chlorine, fluorine, methyl, ethyl, methoxy, ethoxy or tert-butyl, or by one trifluoromethyl; (2 thienyl)methyl; (2-thienyl)ethyl; (2 furanyl)methyl; 2-(4 - chloranil)methyl; (2-benzofuranyl)methyl; (2-benzothiazyl)methyl; (2-thiazolyl)methyl or (2-benzothiazolyl)methyl; compounds where R1represents a C1-C4alkyl, C2-C4alkyl, C2-C4hydroxyalkyl or (C2-C4alkyl)-O-(C1-C2alkyl); compounds, where R3means hydrogen, methyl, ethyl, methoxy, fluorine or chlorine; compounds, where R4describes methylthio, methylsulphonyl, methylsulfinyl, vtoroj CLASS="ptx2">

More specific compounds of formula I are compounds where A denotes the NR1R2, NHCH1R2or OCHR1R2where R1represents a C1-C6alkyl, which may contain as a substituent hydroxy, fluorine or C1-C2alkoxy and may have one double or triple bond, and R2is benzyl or C1-C5the alkyl, which may contain one double or triple bond, and the above C1-C6alkyl or phenyl in the benzyl may be substituted by fluorine, C1-C6the alkyl or C1-C6alkoxy; connections, where A describes CR1R2R11where R1represents a C1-C6alkyl which may be substituted by one C1-C6alkoxy or hydroxy, R2- benzyl or C1-C6alkyl, where the above-mentioned C1-C6alkyl or phenyl in the benzyl may be substituted by one C1-C6the alkyl, C1-C6alkoxy, fluorine, chlorine or bromine, and R11means hydrogen or fluorine.

More specific compounds of formula I include compounds where R2is a (C1-C4alkylene) aryl, and the above-mentioned aryl is fanilo the More specific compounds of formula I, in addition, include compounds where R2represents benzyl substituted in paraprotein-ethyl, tert-bootrom, methoxy, trifluoromethyl, nitro, fluorine, chlorine or stands.

Other more specific compounds of formula I include compounds where R2attached to Honolulu, pyrrolyl, pyrrolidinyl, pyridyl, tetrahydropyranyl, cyclopropyl, piperidinyl or benzyl-piperidinyl through a methylene or ethylene bridge.

More specific compounds (I) are compounds where R1or R2means C1-C6alkyl, which may contain as a substituent hydroxy, methoxy, ethoxy, chlorine, fluorine, OC(O)CH3, CO(O)NHCH3or C(O)NH2.

Other more specific compounds (I) include compounds where R2represents a C1-C6alkyl, substituted with two methoxy or ethoxy groups or one COOC2H5, methylthio or phenyl group.

Other more specific compounds (I) include compounds where A is NR1R2or CHR1R2in which R1and R2together with N or CH to form a 5 - or 6 - membered ring containing an additional nitrogen, sulfur and/or one oxygen azolyl, pyridyl, pyrazinyl or pyrimidyl.

Other more specific compounds (I) include compounds where A is NHCHR1R2or OCHR1R2where CHR1R2represents 5 - or 6-membered ring which may contain one oxygen or sulfur, such as tetrahydrofuranyl, tetrahydropyranyl and cyclopentenyl.

The most preferred compounds of formula (I) include:

3-{ (4-methylbenzyl)-[3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo [3,4-d]pyrimidine-4-yl]-amino}-propan-1-ol;

diethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidine-4-yl] amine;

2-{ butyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidine-4-yl]-amino}-ethanol;

dibutil-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidine-4-yl]-amine;

butyl-ethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)- 1H-pyrazolo[3,4-d]pirlimycin-4-yl]-amine;

butyl-ethyl-[6-methyl-3-methylsulphonyl-1-(2,4,6-trichlorophenyl)-1H - pyrazolo[3,4-d]pyrimidine-4-yl]-amine;

butyl-cyclopropylmethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)- 1H-pyrazolo[3,4-d]pyrimidine-4-yl]-amine;

di-1-propyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H - pyrazolo[3,4-d]pyrimidine-4-yl]-am is Teal-[6-chloro-3-methylsulfanyl-1-(2,4,6-trichlorophenyl) -1H-pyrazolo[3,4-d]pirlimycin-4-yl]-amine;

butyl-ethyl-[6-methoxy-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H - pyrazolo[3,4-d]pyrimidine-4-yl]-amine;

propyl-ethyl-[3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo[3,4-d] pyrimidine-4-yl]-amine;

4-(1-ethyl-propyl)-6-methyl-3-methylsulfanyl-1-(2,4,6-trimetilfenil)-1H - pyrazolo[3,4-d]pyrimidine;

2-[3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo[3,4-d] pyrimidine-4-ylamine] -butane-1-ol;

[3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo[3,4-d] pyrimidine-4-yl)-(1-methylpropyl)amine; and

4-(1-methoxymethylethoxy)-3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H - pyrazolo[3,4-d]pyrimidine.

The invention also concerns pharmaceutical compositions for the treatment of diseases caused or reinforced releasing factor corticotropin; compositions contain, as defined above, the compounds of formula I in an amount effective for the treatment of the aforementioned diseases, and a pharmaceutically acceptable carrier; a pharmaceutical composition for the treatment of various inflammations, such as arthritis, asthma and allergies; anxiety; depression; fatigue; headaches; pain; cancer; inflammation of the intestine, including Crohn's disease, convulsions and inflammation of the colon; immune dysfunction; infections of human immunodeficiency virus (AIDS); neurodegenerative diseases, takeit to the nervous system; hemorrhagic stress; alcohol dependence and preparative; drug abuse; induced stress psychopathic States and problems with conception, which include a compound of formula I, defined above, in an amount effective for the treatment of the aforementioned diseases, and a pharmaceutically acceptable carrier.

The invention also relates to a method of treatment of diseases caused or reinforced releasing factor corticotropin by administering to a subject in need of such treatment, the compounds of formula I, defined above, in an amount effective for such treatment, and treatment of inflammation, such as arthritis, asthma and allergies; anxiety; depression; fatigue; headaches; pain; cancer; inflammation of the intestine, including Crohn's disease, convulsions and inflammation of the colon; immune dysfunction; infections of human immunodeficiency virus (AIDS); neurodegenerative diseases, such as senile sclerosis of the brain; gastrointestinal diseases; disorders of appetite, such as loss of appetite for nervous system; hemorrhagic stress; alcohol and preparative dependence; drug abuse; induced stress psychopathic States and the problem of the treatment. The preferred method of the invention is a method of introducing preferred compounds of formula I described earlier.

Although R5includes cycloalkyl and bicycloalkyl containing oxygen atoms in the ring and hydroxyl and hydroxymethylene substituents on the ring, the compounds of formula I do not include groups of sugars CnH2n-1On-1such as C5H9O4(ribofuranosyl) and C6H11O5(ribofuranosyl), which contain more than two hydroxy groups, directly or through something attached to the sugar ring group.

When a reference is made to alkyl, it includes straight and branched chain alkyl, unless otherwise specified.

When we speak about 3 - to 8-membered cycloalkyl or 9 - to 12-membered bicycloalkyl containing from one to three O, S or N - Z, this implies that the atoms of oxygen and sulfur in the ring are not adjacent relative to each other. A ternary cycloalkyl has just one O, S or N - z Example of a six-membered rings of cycloalkyl containing O and N, is morpholinyl.

When R2or R5is a heterocyclic group, join the group via the carbon atom.

When there is which may contain one or two double or triple bond", I mean that at least two carbon atoms present in the alkyl in the formation of one double or triple bond and at least four carbon in the formation of two double or triple bonds.

When the alkoxy group is, for example, when the definition of R1and R2may have a double or triple bond, then it implies that such a double or triple bond is not attached directly to the oxygen.

The compounds of formula I, where A is NR1R2, NHCR1R2R11OCR1R2R11SCR1R2R11or other1R2and R2represents hydrogen, C1-C6alkyl or chlorine (in the future, R9), can be obtained by reaction of compounds of formula

< / BR>
where D is Cl and R4, R5and R6have the meanings given above for formula I, with a compound of the formula AH, where A is as defined above values. The reaction is carried out in a solvent in the presence of a base at a temperature from about 0oC to approximately 150oC. Suitable solvents are organic solvents, such as acetonitrile, dimethylsulfoxide, acetone, C2-C15Ukrspirt, tetrahydrofuran, chloroform, benzene,R2, NHNR1R2or NHCR1R2R11use an excess of AH. In return can be used other bases such as potassium carbonate or tri-(C1-C6)alkylamine. The reaction is carried out at a temperature of about 75-150oC. If the reaction is carried out in the presence of a base such as sodium hydride or C1-C4the potassium alcoholate is used the molar equivalent of the amine. If A is OCR1R2R11or SCR1R2R11it can be used a base which is capable of deprotonating AH, such as an alkali metal hydride such as potassium hydride or sodium, or an ORGANOMETALLIC base, for example diisopropylamide sodium bis(trimethylsilyl)amide, sodium, diisopropylamide lithium bis(trimethylsilyl)amide lithium, C1-C4the sodium alcoholate or n-utillity. As the solvent used tetrahydrofuran, dimethylsulfoxide, methylene chloride or toluene, the reaction temperature varies from about -78oC to the boiling temperature of the reaction mixture, preferably 0oC-80oC.

The compounds of formula II, where D is chlorine, can be obtained by reaction of the corresponding 4-hydroxy compounds of formula III (not pok is, the usual at the boiling temperature of the reaction mixture. If the reaction is performed in a solvent, suitable solvents are halogenated alkanes such as methylene chloride or chloroform. The reaction can be carried out in the presence of a base, such as N,N-diethylaniline, trimethylamine or potassium carbonate.

The compounds of formula II, described above, can be obtained by reaction of compounds of formula

< / BR>
where

R4and R5have the meanings previously defined for formula I, with a compound of the formula where R9has the previously described meaning. The reaction is usually carried out in the absence of solvent at temperatures between about 100oC-250oC.

Compounds of formulas IV and V or available, or can be obtained by conventional methods.

As shown in scheme I, the compounds of formula I, where R3is the groups other than R9(in the future, R10), can be obtained by the reaction of the compounds of formula I, where R3represents chlorine, indicated in scheme I, formula VIII, with a nucleophile of the formula R10H with or without organic or inorganic bases. Suitable bases are sodium, sodium hydride and hydroxide salocrophobia use, when R10H means alkanol, C1-C6alkanethiol, amine, such as NH(C1-C6alkyl), or a fluoride of tetrahydropalmatine. Suitable solvents are dimethyl sulfoxide, acetonitrile, C1-C5Ukrspirt tetrahydrofuran, benzene, toluene or methylene chloride.

< / BR>
The compound of formula IV, as defined previously, is reacted with an excess of urea at the boiling temperature with the formation of the compounds of formula VI. Compound of formula VII is formed by the reaction of compound VI with phosphorus oxychloride or thionyl chloride at a temperature between about 70oC-140oC and conveniently at the boiling temperature of the reaction mixture when the optional presence of a base, such as N,N-diethylaniline. The compound of formula VIII is formed by the reaction of compound VII with AH in the same reaction conditions as described above for the reaction of compound II with AH.

The compounds of formula I, where II is CR1R2R11or C(=CR12R13R2can be obtained as described below in scheme 2, from corresponding compounds of formula II, where R4and R5have the meanings previously defined, and R9is R3as defined for formula I, by reaction with the compound of the formula CHR11-C2alkyl), CO(C1-C2or CN with the formation of compounds of formula IA. The reaction is carried out in the presence of a base such as sodium hydride, C1-C5the alcoholate of potassium bis(trimethylsilyl)amide lithium or sodium and diisopropylamide sodium or lithium, in an environment inert to the reaction solvent, such as dimethylsulfoxide, acetonitrile, C2-C6alkyl alcohol or N-methyl-pyrrolidone, preferably dimethyl sulfoxide. The reaction is preferably performed at elevated temperatures of about 100oC-110oC.

< / BR>
The compounds of formula IB can be obtained by the reaction of compounds of formula IA, where R14and R15everyone is COOR, where R is the stands or ethyl, with diisobutylaluminium in an inert reaction solvent at temperatures from about -78oC to 40oC, preferably about -20oC - +25oC. Suitable solvents are toluene, benzene and tetrahydrofuran, preferably toluene.

The compounds of formula IB can be transformed into the corresponding compounds of formula

< / BR>
the reaction with the compound of the formula R2L, where R2has the values defined for formula I and L is removed groppoli temperatures from about 0 to 50oC, preferably at room temperature. Suitable solvents are dimethyl sulfoxide, C2-C6alkyl alcohol, tetrahydrofuran, methylene chloride and dioxane. The compounds of formula

< / BR>
can be obtained from corresponding compounds of formula IC by reaction with lithium iodide in a solvent such as dimethylformamide, dimethylsulfoxide and dioxane, at temperatures from about 50oC to 200oC, preferably about 100-150oC. the Reaction with the formation of compound IE is in the presence of air.

If R2in the above formula IE is a group of the formula CHR2R12then the compounds of formula IE may also be transformed into the corresponding compounds of formula

< / BR>
using the same reaction conditions used for the conversion of compounds IC in ID.

The compounds of formula I, where A is CR1R2R11or C(=CR2R12R1can be obtained according to scheme 3.

< / BR>
< / BR>
The compounds of formula XIV can be obtained by the reaction of dialkoxybenzene R4C(OR)3where R is C1-C2the alkyl and R4has the meaning as defined in formula I, with a compound of formulas is objazatelnom the presence of a solvent, such as ethyl acetate, methylene chloride, chloroform or toluene. The reaction is carried out at temperatures from about 30oC to 150oC, preferably 80oC-120oC. the Compound of formula XV is obtained by reaction of the corresponding compounds of formula XIV with a hydrazine of the formula R5NHNH2where R5defined in the formula I, in a solvent such as C1-C4Ukrspirt or acetonitrile, at a temperature of from about 60oC to 120oC, preferably at the boiling point.

The compounds of formula I, where A is CR1R2R11can be obtained by reaction of the corresponding compounds of formula XV with R9CONH2where R9is hydrogen, C1-C6the alkyl or amine in the presence of ammonium chloride by heating at boiling point at about 240oC. Or a compound of the formula XVI may be obtained from the corresponding compounds of formula XV with R9C(OR)3where R is C1-C2the alkyl, using reaction conditions similar to conditions used in obtaining the compounds of formula II from compounds of formula III, as described above.

The compounds of formula XV by reacting excess modelinstance by the same method, what is shown in scheme 1 for the conversion of compounds VII, VIII and IX, respectively.

The compounds of formula I, where A is CR1R2R11C(=CR2R12R1, CR2R11OTHER1, CR2R11SR1or C(O)R2and R3is R9as described above in formula II, can be obtained as shown in scheme 4.

< / BR>
The compounds of formula XX, where R4, R5and R9have the above values, obtained by reaction of the corresponding compounds of formula II with potassium cyanide in dimethyl sulfoxide, react with a Grignard reagent containing the group R1as defined previously, with the formation of compounds of formula XXI. Further reaction of the compound of formula VII with a Grignard reagent containing the group R2as defined earlier, gives compound of formula IC. The corresponding compounds of formula ID, where B is CR1R2R11or C(=CR2R12R1can be obtained by conventional methods.

The compounds of formula I, where R1, R2, R3, R4or R5contains sulfoxy or sulfinil group can be obtained by oxidation of the corresponding sulfur-containing compounds, as is known in prednisonebuy, the invention includes racemic mixtures and individual diastereomers and enantiomers of such compounds.

The pharmaceutical acceptable salts of the acids get in the usual way by treatment of a solution or suspension of the free base of formula I with a chemical equivalent of a pharmaceutically acceptable acid. To highlight salts using conventional methods of concentration or crystallization. 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-, n-toluensulfonate and other related acids.

The new compound of the invention of formula I may be administered one or in combination with pharmaceutically suitable carriers, as single or multiple, up to three, for example, dose. Acceptable pharmaceutical carriers are inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions obtained by the combination of the new compounds of the formula is to tablets, powders, cakes, syrups, injectable solutions, etc., Such pharmaceutical compositions, if desired, may also 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, together with various disintegrators such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and Arabic gum. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for pelletizing. Solid compositions of a similar type may also be suitable for use as filler for soft and hard gelatin capsules. Preferred materials include 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, OCD is with diluents, such as water, ethanol, propylene glycol, 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 by standard methods known from previous works.

In addition, it is possible topical application of the compounds of the present invention in the treatment of inflammatory conditions 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 intended route of administration and other factors, such as age and weight of the patient, which is usually known to the doctor. The dose also depends on the disease being treated. The daily dose will generally vary in the range of from about 0.1 to 50 mg/kg body weight of the patient. For receprion 0.1 to about 50 mg/kg, as for gastro-intestinal diseases, loss of appetite for nervous, hemorrhagic stress, alcohol and drug dependence, fertilization and so on

Methods of testing compounds of the formula I, their activity as antagonists releasing factor corticotropin (CRF) is described in Endocrinology, 116, 1653-1659 (1985) and Peptides 10, 179-188 (1989), which determine the affinity for binding of test compounds to the CRF receptor. The affinity for binding of the compounds of formula I, expressed as IC50usually varies from about 0.2 nanomoles to about 10 micromol.

The following examples illustrate the invention. Use the following notation: Ph=phenyl, Me=methyl, tert-Bu=tert-butyl, Et=ethyl, Pr=propyl.

Example 1

3-{ (4-Methylbenzyl)-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H - pyrazolo[3,4-d]pyrimidine-4-yl]-amino}-propyl alcohol

A mixture of 4-chloro-3-methylsulfanyl-6-methyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d] pyrimidine (788 g, 2 mmole) and 3-(n-methylbenzyl)amino-1-propanol (716 mg, 4 mmole) in 10 ml of acetonitrile is boiled for 4 hours, cooled, quenched with water, diluted with hydrogen chloride and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and brine, separated, dried, UPA chromatographic column of silica gel using as eluent chloroform and get a white glassy mass.1H NMR (CDCl3): 1.79 (m, 2H), 2.38 (s, 3H), 2.52 (s, 3H), 2.54 (s, 3H), 3.56 (t, 2H), 3.86 (t, 2H), 5.12 (s, 2H), 7.20 (s, 4H), 7.51 (s, 2H) C. for 1 million13C NMR (CDCl3): 16.20, 21.13, 25.53, 29.64, 43.51, 53.88, 58.24, 127.78, 128.77, 129.33, 133.51, 136.18, 137.41, 142.93, 159.13, 164.89 'clock million on IR(KBr): 3350, 2935, 1540 cm-1. Elemental analysis for C24H24N5OSCl3:

Calculated: C at 53.69 H 4.50 N 13.04

Found: C, 53.33 H 4.44 N 12.84

Example 2

The following compound is obtained by reaction of the corresponding amine and 4-chloro-3-methylsulfanyl-6-methyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidine using the methods of Example 1 (see tab. 1).

Example 3

The following compound is obtained by reaction of the corresponding amine and 4-chloro-3-methylsulfanyl-1-(2,4-dichloro-6-trifluoromethyl-phenyl)-1H-pyrazolo [3,4-d]pyrimidine using the methods of Example 1 (see tab. 2).

Example 4

The following compound is obtained by reaction of the corresponding amine with 4-chloro-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d] pyrimidine using the methods of Example 1 (see tab. 3).

Example 5

The following compounds were obtained when the interaction of the amine and the corresponding 4-chloro-1H-pyrazolo[3,4-d] pyrimidine using the methods of Example 1.

3-{ Benz the CDCl3): 1.25 (t, 3H), 1.82 (m, 2H), 2.52 (s, 3H), 2.76 (sq. 2H), 3.58 (t, 2H), 3.87 (t, 2H), 5.15 (s, 2H), 7.25-7.4 (m, 5H), 7.50 (s, 2H) hours per million

3-{ (p-Chlorobenzyl)-[6-methyl-3-methylsulfanyl-1-(2,6-dichloro-4-triptoreline) -1H-pyrazolo[3,4-d]pyrimidine-4-yl]-amino}-propyl alcohol:

1H NMR(CDCl3): 1.83 (m, 2H), 2.52 (s, 3H), 2.55 (s, 3H), 3.59 (m, 2H), 3.88 (t, 2H), 4.36 (t, 1H), 5.12 (s, 2H), 7.2-7.4 (m, 4H), 7.76 (s, 2H), 7.2-7.4 (m, 4H), 7.76 (s, 2H), including million

3-{ benzyl-[6-methyl-3-methylsulfanyl-1-(2,6-dichloro-4-triptoreline)-1H-pyrazolo[3,4-d]pyrimidine-4-yl]-amino}-propyl alcohol:

1H NMR (CDCl3): 1.80(m, 2H), 2.50 (s, 3H), 2.52 (s, 3H), 3.55 (t, 2H), 3.88 (t, 2H), 5.15 (s, 2H), 7.25-7.45 (m, 5H), 7.75 (s, 2H) hours per million

3-{ benzyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trimethyl-1H-pyrazolo [3,4-d]pyrimidine-4-yl]-amino}-propyl alcohol:

1H NMR (CDCl3): 1.75-1.85 (m, 2H), 1.95 (s, 6H), 2.33 (s, 6H), 2.33 (s, 3H), 2.50 (s, 6H), 3.51 (t, 2H), 3.90 (t 2H), 5.20 (s, 2H), 7.0 (s, 1H), 7.25-7.45 (m, 5H) hours per million

3-{ benzyl-[3,6-dimethyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo- [3,4-d] pyrimidine-4-yl]-amino}-propyl alcohol:

1H NMR (CDCl3): 1.84-2.0 (m, 2H), 2.41 (s, 3H), 2.51 (s, 3H), 3.55 (t, 2H), 3.91 (t, 2H), 4.99 (s, 2H), 7.3-7.5 (m, 5H), 7.47 (s, 2H) hours per million

3-{ (4-methylbenzyl)-[6-methyl-3-propyl-1-(2,4,6-trichlorophenyl)-1H - pyrazolo[3,4-d]-pyrimidine-4-yl]-amino}-propyl alcohol:

1H NMR (CDCl3):0,78 (t, 3H), 1.65-1.90 (m, 4H), 2.38 (s, 3H), 2.54 (s, 3H), 2.77 (is)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-amino}-propyl alcohol:

1H NMR (CDCl3) 1.85 (m, 2H), 2.32 (s, 3H), 2.52 (s, 3H), 3.57 (m, 2H), 3.96 (t, 2H), 4.92 (s, 2H), 5.51 (wide s, 1H), 7.1-7.2 (m, 4H), 7.50 (s, 4H) hours per million

3-{ (4-methylbenzyl)-[6-methyl-3-ethyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo - 3,4-d]pyrimidine-4-yl]-amino}-propyl alcohol:

1H NMR (CDCl3): 1.23 (t,3H), 1.78 (m, 2H), 2.34 (s, 3H), 2.50 (s, 3H), 3.54 (t, 2H), 3.85 (t, 2H), 4.90 (s, 2H), 7.15 (q, 4H), 7.48 (s, 2H) hours per million

3-{ (4-methylbenzyl)-[3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo- [3,4-d]pyrimidine-4-yl]-amino}-propyl alcohol:

1H NMR (CDCl3): 1.82 (m, 2H), 1.90 (s, 6H), 2.3 (s, 3H), 2.35 (s, 3H), 2.41 (s, 3H), 2.55 (s, 3H), 3.55 (t,2H), 3.93 (t, 2H), 4.95 (s, 2H), 6.94 (s, 2H), 7.18 (q, 4H) hours per million

3-{ benzyl-[6-chloro-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo- [3,4-d]pyrimidine-4-yl]-amino}-propyl alcohol:

1H NMR (CDCl3): 1.85 (m, 2H), 2.54 (s, 3H), 3.62 (t, 2H), 3.85 (t, 2H), 5.17 (s, 2H), 7.25-of 7.4 (m, 5H), 7.50 (s, 2H) hours per million

3-{ benzyl-[3-methylsulfanyl-6-trifluoromethyl-1-(2,4,6-trichlorophenyl)-1H - pyrazolo[3,4-d]pyrimidine-4-yl]-amino}propyl alcohol:

1H NMR (CDCl3): 1.96 (m, 2H), 2.11 (t,1H), 2.60 (s, 3H), 3.68 (q, 2H), 3.93 (t,2H), 5.22 (s, 2H), 7.2-7.4 (m,5H), 7.55 (s, 2H), including million

3-{ benzyl-[3-methylsulfanyl-1-( -naphthyl)-1H-pyrazolo[3,4-d] pyrimidine-4-yl]amino}-propyl alcohol:

1H NMR (CDCl3): 2.60 (s, 3H), 3.8-4.0 (m, 4H), 5.25 (s,2H), 7.25-7.70 (s, 10H), 7.9-8.05 (m, 2H), 8.30 (s, 1H) hours per million

ethyl-butyl-[6-chloro-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidine-4-yl]-amine:

1H NMR (CDCl3): 0.97 (t, 3H), 1.34 (t, 3H), 1.44 (m, 2H), 1.72 (m, 2H), 2.63 (s, 3H), 3.73 (DD, 2H), 3.83 (q, 2H), 7.47 (s, 2H) hours per million

butyl-[3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo[3,4-d] pyrimidine-4-yl]-ethyl-amine:

1H NMR (CDCl3): to 0.96 (t, 3H), 1.29 (t, 3H), 1.3-1.45 (m, 2H), 1.6-1.8 (m, 2H), 1.90 (s, 6H), 2.29 (s, 3H), 2.42 (s, 3H), 2.66 (s, 3H), 3.70 (DD, 2H), 3.77 (q, 2H), 6.92 (s, 2H) hours per million

the fluorine-butyl-[3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo [3,4-d]pyrimidine-4-yl]amine:

1H NMR (CDCl3): 1.00 (t, 3H), 1.3 (d, 3H), 1.6-1.72 (m, 2H), 1,90 (2 series s, 6H), 2.30 (s, 3H), 2.49 (s, 3H), 2.62 (s, 3H), 4.4-4.5 (m, 1H), 4.9 (d, 1H), 6.9 (s,2H) hours per million

[3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo[3,4-d] pyrimidine-4-yl] (1-ethylpropyl)-amine hydrochloride:

1H NMR (CDCl3): 1.08 (t, 6H), 1.83 (m, 4H), 1.90 (s, 6H), 2.35 (s, 3H), 2.60 (s, 3H), 2.75 (s, 3H), 4.0-4.15 (m,1H), 6.97 (s, 2H), 10,1 (d, 1H), 14.9 (s, 1H) hours per million

2-[3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo[3,4-d]pyrimidine-4-yl - amino]butane-1-ol hydrochloride:

1H NMR (CDCl3): 1.07 (t, 3H), 1.8-2.0 (m, 2H), 1.89 (s, 3H), 1.91 (s, 3H), 2.33 (s, 3H), 2.76 (s, 3H), 2.84 (s, 3H), 3.69 (wide s, 1H), 4.03 (wide s, 1H), 5.05 (wide s, 1H), 6.58 (Shir is lo [3,4-d]pyrimidine-4-yl]-amino}-propan-1-ol acetate

A solution of 3-{ benzyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H - pyrazolo[3,4-d] pyrimidine-4-yl] amino}-propanol (80 mg, 0.148 mmol) in 1 ml of methylene chloride is treated with acetic anhydride (38 mg, 0.37 mmol) and triethylamine (38 mg, 0.37 mmol), stirred for 15 hours at room temperature, the mixture was quenched with water, make a few drops of diluted HCl and extracted with ethyl acetate. The organic layer is neutralized aqueous sodium bicarbonate, washed with brine, separated, dried and evaporated, get a named connection in the form of oil. The oil is purified on a chromatographic column of silica gel with elution by chloroform and obtain 57 mg of the named compound as a white glassy substance.

1H NMR (CDCl3): 2.0 (s, 3H), 2.03 (m, 2H), 2.45 (s, 3H), 2.60 (s, 3H), 3.74 (t, 2H), 4.10 (t, 2H), 5.1 (s, 2H), 7.2-7.4 (m, 5H), 7.50 (s, 2H) hours per million

Example 7

The following compounds were obtained when the acylation of the original example 6 from the corresponding hydroxy.

3-{ (4-methylbenzyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H - pyrazolo[3,4-d]pyrimidine-4-yl]-amino}-propan-1-ol acetate:

1H NMR (CDCl3): 1.99 (s, 3H), 1.95-2.06 (m, 2H) ,2.22 (s, 3H), 2.49 (s, 3H), 2.59 (s, 3H), 3.75 (t, 2H), 4.12 (t, 2H), 5.05 (s, 2H), 7.18 (q, 4H), 7.50 (s, 2H) hours EN-1-ol acetate:

1H NMR (CDCl3): 1.39 (t, 3H), 2.07 (s, 3H), 2.69 (s, 3H), 3.98 (q, 2H), 4.04 (t, 2H), 4.43 (t, 2H), 7.77 (s, 2H), 8.32 (s, 1H) hours per million

2-{ butyl[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H - pyrazolo[3,4-d]pyrimidine-4-yl]-amino}-ethane-1-ol acetate:

1H NMR (CDCl3): 0.98 (t,3H), 1.3-1.5 (m, 2H), 1.65-1.85 (m, 2H), 2.04 (s, 3H), 2.47 (s, 3H), 3.83 (t,2H), 4.02 (t,2H), 4.40 (t, 2H), 7.50 (s, 2H) hours per million

Example 8

4-{ N-(4-methylbenzyl)-N-(3-methoxy)propyl} amino-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine

A solution of 3-{ [4-pyrazolo[3,4-d] pyrimidine-4-yl]-amino}-propanol (96 mg, 0.15 mmol) in 1 ml dry tetrahydrofuran (THF) is treated with sodium hydride (60% in oil) (7 mg, 0.18 mmol), then add modesty methyl, the mixture is stirred for 15 hours at room temperature, quenched with water, extracted with ethyl acetate. The organic layer is dried, evaporated and receive a colorless substance that is cleaned on a chromatographic column of silica gel with elution by chloroform, and receive 60 mg of the named compound as a glassy substance.

1H NMR (CDCl3): 1.95 (m, 2H), 2.32 (s, 3H), 2.47 (s, 3H), 2.56 (s, 3H), 3.24 (s, 3H), 3.39 (t, 2H), 3.75 (t, 2H), 5.01 (s, 2H), 7.15 (q, 4H), 7.47 (s, 2H) hours per million

Example 9

The following connections receive according Metodi)] amino-3-methylsulfanyl-6-methyl-1-(2,4,6 - trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine:

1H NMR (CDCl3):1.12 (t, 3H), 1.97 (m, 2H), 2.47 (s, 3H), 2.56 (s, 3H), 3.37 (q, 2H), 3.48 (t, 2H), 3.80 (t,2H), 5.07 (s, 2H), 7.23 - 7.40 (m, 5H), 7.49 (s, 2H) hours per million

4-[benzyl-(3-methoxypropyl)] amino-3-methylsulfanyl-6-methyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine:

1H NMR (CDCl3): 2.0 (m, 2H), 2.5 (s, 3H), 2.57 (s, 3H), 3.25 (s, 3H), 3.4 (t, 2H), 3.8 (t, 2H), 5.1 (s, 2H), 7.2-7.4 (m, 5H), 7.48 (s, 2H) hours per million

Example 10

3-{ Benzyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidine-4-yl]-amino}-propan-1-ol-methylcarbamate

A solution of 3-{ benzyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)- -1H-pyrazolo[3,4-d] pyrimidine-4-yl] -amino}-propan-1-ol (100 mg, 0.191 mmol) in 2 ml of dry THF is treated with 6 mg of 60% sodium hydride in oil, contribute methyl isocyanate (39 mg, of 6.78 mmol) at room temperature, and stirred for 10 hours at this temperature, quenched with water and extracted with ethyl acetate. The organic layer is dried, evaporated and obtain 110 mg of a white substance, which was purified through column chromatography with silica gel and obtain 79 mg of the named compound as a white glassy substance.

1H NMR (CDCl3): 2.03 (m, 2H), 2.51 (s, 3H), 2.59 (s, 3H), 2.77 (d, 3H), 3.79 (t, 2H), 4.12 (t, 2H), 4.50 (wide s, 1H), 5.17 (s, 2H), 7.2-7.45 (m, 5H), 7.51 (s, 2H)hours per million

Example 11

3-{ (4-methylbenzyl)-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H - pyrazolo[3,4-d]pyrimidine-4-yl]-amino}-propan-1-ol methylcarbamate:

1H NMR (CDCl3): 2.02 (m, 2H), 2.36 (s, 3H), 2.49 (s, 3H), 2.59 (s, 3H), 2.77 (d, 3H), 3.76 (t, 2H), 4.12 (t, 2H), 4.55 (wide s, 1H), 5.12 (s, 2H), 7.29 (q, 4H), 7.50 (s, 2H) hours per million

4-[p-methylbenzyl)-3-(N-methylcarbamoylmethyl)] -amino-3-methylsulfanyl-6-methyl-1-(2,4,6-trichlorophenyl)- 1H-pyrazolo[3,4-d] pyrimidine and 4-[(p-methylbenzyl)-3-(N-methylcarbamoyl-thiopropyl)] amino-3-methylsulfanyl-6 - methyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine:

The mixture of these compounds get into the 2:1 ratio.

1H NMR (CDCl3): 2.05-2.25 (m, 2H), 2.36 (s, 3H), 2.51 (s, 3H), 2.59 (s, 1/HN), 2.60 (2/CN), 2.75 (d, 1/HN), 3.05 (d, 2/HN), 3.78 (t, 2H), 4.47 (t, 2/HN), 4.54 (t, 1/HN), 5.06 (s, 2H), 6.2 (Shir.s, 2-3H), 6.5 (Shir.s, 1/3H), 7.19 (kV, 4H), 7.51 (s, 3H) hours per million

Example 12

3-{ Benzyl-[6-methyl-3-methylsulfinyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidine-4-yl]-amino}-propyl alcohol.

A solution of 3-{ benzyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H - pyrazolo[3,4-d] pyrimidine-4-yl] -amino}propanol (42 mg, 0.077 mmol) and m-chlormadinone acid (14 mg, 0.081 mmol) in 0.5 ml of methylene chloride is stirred for 3 hours at room temperature, the reaction is quenched with water and saturated t is sodium, dried, evaporated and get the oil, which is purified on a chromatographic column of silica gel with elution with 2% methanol in chloroform, and obtain 46 mg of the named compound as a white glassy substance.

1H NMR (CDCl3): 1.88 (m, 2H), 2.54 (s, 3H), 2.73 (s, 3H), 3.5-3.7 (m, 4H), 4.3 (m, 1H), 5.15 (ABqI , JAB=16 Hz, 2H),

7.2-7.4 (m, 5H), 8.47 (AB, 2H) hours per million

Example 13

The following compounds are produced by the method of example 12, on the basis of the corresponding methylsulfonylmethane.

4-(n-butyl-ethyl)amino-3-methylsulfinyl-6-methyl-1-(2,4,6-trichlorophenyl)-1H - pyrazolo[3,4-d]pyrimidine:

1H NMR (CDCl3): 0.98 (t,3H), 1.35 (t, 3H), 1.46 (m, 2H), 1,71 (m, 2H), 2.48 (s, 3H), 3.08 (s, 3H), 3.65-4.10 (m, 4H), 7.52 (ABqI , JAB=2 Hz, 2H) hours per million

4 diethylamino-3-methylsulfinyl-6-methyl-1-(2,4,6-trichlorophenyl)- -1H-pyrazolo[3,4-d]pyrimidine:

1H NMR (CDCl3): 1.36 (t, 6H), 2.49 (s, 3H), 3.11 (s, 3H), 3.78 (m, 2H), 3.99 (m, 2H), 7.52 (ABqI , JAB=1.7 Hz, 2H) hours per million

Example 14

The following compounds are produced by the method similar to the method of example 12, on the basis of the corresponding methylsulfonylmethane and 2.5 equivalents of m-chlormadinone acid in methylene chloride. The mixture is stirred for 15 hours at room temperature.


1H NMR (CDCl3): 1.8 (m, 2H), 2.52 (s, 3H), 3.40 (s, 3H), 3.60 (t 2H), 3.90 (t, 2H), 5.16 (s, 2H), 5.16 (s, 2H), 7.2-7.4 (m, 4H), 7.50 (s, 2H) hours per million

3-{ (4-methylbenzyl)-[6-methyl-3-methylsulphonyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl]-amino}-propyl alcohol:

1H NMR (CDCl3): 1.8 (m, 2H), 2.34 (s, 3H), 2.52 (s, 3H), 3.43 (s, 3H), 3.61 (t, 2H), 3.90 (t, 2H), 5.14 (s, 2H), 7.13 (s, 4H), 7.56 (s, 2H) hours per million

4-(N-butyl-N-ethyl)amino-6-methyl-3-methylsulphonyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine:

1H NMR (CDCl3): 0.95 (t, 3H), 1.30 (t,3H), 1.37 (m, 2H), 1.69 (m, 2H), 2.47 (s, 3H), 3.42 (s, 3H), 3.85 (t, 2H), 3.93 (q, 2H), 7.53 (s, 2H) hours per million

4-N, N-diethylamino-6-methyl-3-methylsulphonyl-1-(2,4,6-trichlorophenyl)-1H- -pyrazolo[3,4-d]pyrimidine:

1H NMR (CDCl3): 1.29 (t, 3H), 2.45 (s, 3H), 3.40 (s, 3H), 3.91 (square, 2H), 7.50 (s, 1H) hours per million

2-{N-butyl-N-[6-methyl-3-methylsulphonyl-1-(2,4,6-trichlorophenyl)-1H - pyrazolo[4,3-d]pyrimidine-4-yl]amino}-ethanol:

1H NMR (CDCl3): 0.95 (t, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 2.66 (s, 3H), 2.76 (t, 2H), 3.16 (t,2H), 3.44 (s, 3H), 3.9-4.0 (m, 1H), 4.79 (t, 2H), 7.55 (s, 2H) hours per million

Example 15

Ethyl-butyl-[6-methoxy-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidine-4-yl]amine

To 1 ml of methanol is added sodium (25 mg), the mixture is stirred until complete dissolution of the sodium, obtained Rast mg, 0.21 mmol), boiled for 3 hours, then the reaction is quenched with water and extracted with ethyl acetate. The organic layer is dried, evaporated and get an oily residue, which was purified through column chromatography with silica gel and obtain 73 mg of the named compound as a colourless oil.

1H NMR (CDCl3): 0.96 (t, 3H), 1.35 (t,3H), 1.42 (m, 2H), 1.71 (m, 2H), 2.63 (s, 3H), 3,74 (DD, 2H), 3.86 (q, 2H), 3.91 (s,3H), 7.46 (s,2H) hours per million

Example 16

Dimethyl ester of 2-butyl-2-[6-methyl-3-methylsulfanyl-1-(2,4,6 - trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl]-malonic acid

A suspension of 60% sodium hydride in oil (0.240 g, 6 mmol) in 5 ml of dimethyl sulfoxide (DMCO) is treated with dimethylbutylamine (0.948 g, 6 mmol), stirred for 10 minutes, making 4-chloro-3-thiomethyl-6-methyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d] pyrimidine (1.182 g, 3 mmol), heated 1 hour at 100oC, the reaction is quenched with water and extracted with ethyl acetate. The organic layer is dried, evaporated, get the crude product in the form of oil, which is diluted with 2-propanol, evaporated to dryness and receives a yellow solid. This substance is purified on a chromatographic column of silica gel with elution of 60:40 chloroform: hexane 80:20 chloroform: hexane, get 1.349 g of the product as well oC;

1H NMR(CDCl3): 0.81 (t, 3H), 1.10-1.40 (m, 4H), 2.54-2.63 (m, 2H), 2.65 (s, 3H), 2.66 (s, 3H), 3.84 (s, 6H), 7.52 (s, 2H) hours minutes

Example 17

Diethyl ester of 2-butyl-2-[6-methyl-3-methylsulfanyl-1-(2,4,6 - trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl]malonic acid

A named connection receive according to the method of example 16, the reaction with diethyl-butylmalonate, so pl. 148-150oC;

1H NMR (CDCl3) 0.80 (t, 3H), 1.1-1.4 (m, 10H), 2.45-2.65 (m, 2H), 2.63 (s, 3H), 2.64 (s, 3H), 4.29 (q, 4H), 7.50 (s, 2H) hours per million

Example 18

Methyl ester 2-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H - pyrazolo[3,4-d]pyrimidine-4-yl] hexanoic acid

A solution of dimethyl 2-butyl-2-[6-methyl-3-methylsulfanyl-1- (2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d] pyrimidine-4-yl] malonic acid (311 mg, 0.57 mmol) in 4 ml of toluene is treated with 1.5 M diisobutylaluminium (DIBAL) (0.84 ml, 1.254 mmol), stirred for 1 hour at room temperature, contribute additional 0.3 ml of DIBAL, stirred for 15 minutes, the reaction is quenched with methanol, stirred for 1 hour, filtered through celite. The filtrate is evaporated to dryness, the residue is treated with water and chloroform. The organic layer is dried, evaporated and obtain 290 mg of crude material which is purified on a chromatographic column with silica gel when e is P>1H NMR (CDCl3): 0.87 (t, 3H), 1.2-1.5 (m, 4H), 1.96-2.10 (m, 1H), 2.1-2.3 (m, 1H), 2.68 (s, 3H), 2.69 (s, 3H), 3.71 (s, 3H), 4.22 (t, 1H), 7.50 (s, 2H) hours per million

Example 19

Ethyl ester of 2-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)- -1H-pyrazolo[3,4-d]pyrimidine-4-yl] hexanediol acid

A named connection receive according to the method of example 18 reaction of diethyl ether with 2-butyl-2-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl] malonic acid.

1H NMR (CDCl3): 0.88 (t, 3H), 1.20 (t,3H), 1.2-1.5 (m,4H), 2.0-2.1 (m, 1H), 2.1-2.3 (m, 1H), 2.67 (s, 3H), 2.69 (s, 3H), 4.19 (q, 2H), 4.39 (t, 1H), 7.50 (s, 2H) hours per million

Example 20

Methyl ester 2-ethyl-2-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidine-4-yl]-hexanoic acid

A solution of methyl ester 2-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl] -hexanoic acid (217 mg, 0.445 mmol) in 1 ml DMCO treated with 60% sodium hydride in oil (46 mg, 1.15 mmol), stirred for 20 minutes at room temperature, make ethyliodide (0.2 ml), stirred for 15 hours at room temperature, the reaction is quenched with brine and extracted with ethyl acetate. The organic layer is washed twice with brine, separated, dried, evaporated and get 233 mg of crude material, is 146 mg of the above compound in the form of not-quite-white solid.

1H NMR (CDCl3): 0.74 (t, 3H), 0.83 (t, 3H), 1.2-1.4 (m, 2H), 2.1-2.55 (m, 4H), 2.64 (s, 3H), 2.70 (s, 3H), 3.74 (s, 3H), 7.51 (s, 2H) hours per million

Example 21

4-(1-ethyl-pentyl)-6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H - pyrazolo[3,4-d] pyrimidine and 3-[6-methyl-3-methylsulfanyl-1- (2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl]heptane-3-ol

A solution of methyl ester 2-ethyl-2-[6-methyl-3-methylsulfanyl-1-(2,4, 6-trichlorophenyl)-1H-pyrazolo[3,4-d] pyrimidine-4-yl] -hexanoic acid (89 mg, 0.173 mmol) in 2 ml of dimethylformamide (DMF) is treated idestam lithium, boiled for 5 hours, pay an additional amount iodotope lithium (433 mg), additionally heat the mixture for 1 hour, neutralized with acid and extracted with ethyl acetate. The organic layer was washed with brine, dried, evaporated and obtain 79 mg of crude material, which contains two main components, which are separated through column chromatography into two fractions. One faction shows the pure component 3-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d] pyrimidine-4-yl] -heptane-3-ol and the other fraction is a mixture of these compounds at a weight ratio of 55 to 45.

1H NMR (CDCl3for 3-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d] pyrimidine-4-yl]-heptane-3-UP>1H NMR (CDCl3for mixtures of the aforementioned compounds: 1.4-2.4 (m, 10H), 1.6-1.8 (m, 0.55 2H), 1.8-2.0 (m, 0.55 2H), 2.0-2.2 (m, 0.45 2H), 2.2-2.4 (m, 0.45 2H), 2.665 (C, 0.55x3H), 2.672 (C, 0.HN), 2.686 (C, 0.HN), 2.718 (0.HN), 3.34 (m, 0.55 H), 5.79 (s, 0.45 H), 7.49 (s, 0.HN), 7.51 (s, 0.HN) hours per million

Example 22

A. 2-(2-ethyl-butyl)-3-ethoxy-but-2-enitel

A mixture of 4-ethyl-3-oxo-hexanenitrile (1.013 g, 7.28 mmol), acetic anhydride (1.5 ml) and triethyl-orthoacetate (1.240 g, 7.64 mmol) boil overnight, treated with ethyl acetate and water. Layers ethyl acetate and brine share. The organic layer is dried, evaporated and receive absorbance 1.262 g dry oil, which was directly used for the next reaction.

1H NMR (CDCl3) of 0.8-1.0 (m, 6H), of 1.44 (T, 3H), 1,4-1,8 (m, 4H), 2,61 (s, 3H), 3,03 (m, 1H), 4,28 (kV, 2H) hours per million

B. 1-[5-amino-3-methyl-1-(2,4,6-trimetilfenil)-1H-pyrazole-4-yl]- -2-ethyl-butane-1-he

A mixture of 2-(2-ethyl-butyl)-3-ethoxy-but-2-onitrile (407 mg, 1.94 mmol) and trimethylpyrazine (280 mg, 1.86 mmol) in 5 ml of methanol is boiled for 5 hours, the reaction is quenched with water and extracted with ethyl acetate. The organic layer is dried, evaporated and receive 584 mg of brown oil, which was purified through column chromatography with silica gel with elution with hexane: chloroform 1:1 and obtain 222 mg yellow solid.

C. 4-(1-ethyl-propyl)-6-methyl-3-methyl-1-(2,4,6-trimetilfenil)-1H - pyrazolo[3,4-d]pyrimidine

A mixture of 1-[5-amino-3-methyl-1-(2,4,6-trimetilfenil)-1H-pyrazole-4-yl] -2-ethyl-butane-1-it (598 mg, 1.91 mmol), ndimethylacetamide (2,311 g, 39.1 mmol) and ammonium chloride (2.057 g, 38.5 mmol) boiled for 5 hours, make additional 2,029 g ndimethylacetamide, conduct additional heating for 16 hours (TLC shows some amount of source material). 3 Quiroga additionally added to the mixture still 2,049 g ndimethylacetamide, heated 16 hours and GC-mass spectrometry indicates the end of the reaction. The mixture is quenched with water and extracted with ethyl acetate. The organic layer is dried, evaporated to dryness and get a brown oil, which was purified through column chromatography with silica gel and obtain 221 mg of the above compound in the form of butter.

1H NMR (CDCl3): 0.86 (t 6H), 1.70-1.85 (m, 2H), 1.91 a (s, 6H), 1.90-2.05 is (m, 2H), 2.34 (s, 3H), 2.70 (s, 3H), 2.74 (s, 3H), 3.15-3.30 (m, 1H), 6.98 (s, 2H) hours per million

Example 23

4-(1-methoxymethyl-propoxy)-3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H - pyrazolo[3,4-d]pyrimidine

A mixture of 1-methoxy-2-butanol (208 mg, 1.99 mmol) and sodium hydride (53 mg, 1.33 mmol) in dry THF (1 ml) is stirred for 10 minutes at room temperature, treated with 4-chlorine is the first temperature, the reaction is quenched with water and extracted with ethyl acetate. The organic layer is dried, evaporated and get the oil, which is purified on a chromatographic column of silica gel with elution by chloroform and obtain 185 mg of the above compound in the form of not-quite-white solid.

1H NMR (CDCl3): 1.02 (9 t, 3H), 1.7-1.9 (m, 2H), 1.90 (s,3H), 1.91 (s, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 2.62 (s, 3H), 3.41 (s, 3H), 3.5-3.89 (m, 2H), 5.64 (m, 1H), 6.94 (s, 2H) hours per million

Example 24

A. 2-(2-ethyl-hexanoyl)-3-methoxy-but-2-ene-nitrile

A named connection receive according to the method of example 22A by the reaction of 4-ethyl-3-oxo-Octan-nitrile, acetic anhydride and triethylorthoformate with the formation of a brown oil, which was purified on silica gel and receive a mixture of two isomers in the form of a light brown oil.

1H NMR (CDCl3): 0,8-0,95 (m, 6H), 1,1-1,8 (m, 8H), 2,62 (group 2, 3H), 3,0-3,2 (m, 1H), 4,0 (two) hours per million

B. 1-[5-amino-3-methyl-1-(2,4,6-trimetilfenil)-1H-pyrazole-1-yl] 2-ethyl-hexane-1-he

A named connection receive according to the method of example 22B from 2-(2-ethyl-hexanoyl)-3-methoxy-but-2-ene-nitrile and trimethylpyrazine in the form of a yellow oil.

1H NMR (CDCl3): 0,85-1,0 (m, 6H), 1,20-1,40 (m, 4H), 1,40-1,70 (m, 2H), 1.70 to of 1.85 (m, 2H), 2,026 (s, 3H), at 2,033 (s, 3H), 2,32 (s, 3H), 2, irazola[3,4-d]pyrimidine

A named connection receive according to the method of example 22C of 1-[5 - amino-3-methyl-1-(2,4,6-trimetilfenil)-1H-pyrazole-4-yl]-2-ethyl - hexane-1-she and ndimethylacetamide in the form of a light oil.

1H NMR (CDCl3): 0,86 (t, 6H), 1,2-1,4 (m, 4H), 1.7 to 1.9 (m, 2H), 1,9-2,0 (m, 2H), 1.91 a (s, 3H), 1.93 and (s, 3H), of 2.36 (s, 3H), 2,70 (s, 3H), 2,74 (s, 3H), 3,24-to 3.35 (m, 1H), 6,99 (s, 2H) hours per million

The following methods illustrate the raw materials used in the above examples.

Methodology A

5-Amino-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazole - 4-carboxamide

A mixture of bis(methylthio)methyltrienolone (7.800 g, 50 mmol) and 2,4,6-trichlorophenylhydrazine (10.575 g, 50 mmol) in 250 ml of methanol is boiled for 2.5 hours, cooled, water is added, the precipitation is filtered off and get 14.323 g (81,5% yield) of the named compound as a white solid.

1H NMR (CDCl3): 2.6 (s, 3H), 5.5 (wide s, 2H), 7.5 (s, 2H) hours per million

When recrystallization of a small amount of solid matter from chloroform obtain white crystals, so pl. 198-199oC. Elemental analysis for C11H9Cl3N4OS:

Calculated: C 37.57 H 2.58 N 15.93

Found: C 37.54 H 2.51 N 15.73

Method B.

1. 5-Amino-3-methylsulfanyl-1-(2,6-dichloro-4-trifter etodo method A from 2,6-dichloro-4-triftormetilfullerenov. 1H NMR (CDCl3): 2.58 (s, 3H), 5.25 (wide s, 2H), 7.72 (s, 2H) hours per million

2. 5-amino-3-methylsulfanyl-1-(2,4,6-trimetilfenil)-1H-pyrazole-4-carboxamide

The named compound obtained as white solid according to the method of Method A from 2,4,6-trimethylpyrazine.

1H NMR (CDCl3) 1.98 (s, 6H), of 2.25 (s, 3H), 2.5 (s,3H),5,2 (wide s, 2H), 7.9 (s, 2H) hours per million

3. 5-amino-3-methylsulfanyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl) -1H-pyrazole-4-carbonitrile

A named connection get method method A from bis (methylsulfanyl)metromanila and 2,6-dichloro-4 - triftormetilfullerenov.1H NMR (CDCl3): of 2.5 (s, 3H), 4.5 (s, 2H), 7.75 (s, 2H) hours per million

4. 5-amino-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carbonitrile

Named substance obtained as an orange solid material so pl. 208.5-209.5oC method A method of ethoxymethylenemalononitrile and 2,4,6-trichlorophenylhydrazine.

1H NMR (CDCl3) 4.5 (wide s, 2H), 7.5 (s, 2H), 7.7 (s, 1H) hours per million

The method C

5-Amino-3-methylsulfanyl-1-(2,6-dichloro-4-triptoreline)-1H - pyrazole-4-carboxamide

A mixture of 5-amino-3-methylsulfanyl-1-(2,6-dichloro-4-triptoreline)-1H - pyrazole-4-carbonitrile (2.7 g, 7.35 mmol), 30% hydrogen peroxide (10 ml), gidromolot not quite white solid. The filtrate is diluted with water and extracted with ethyl acetate. The organic layer is dried, evaporated and allocate additional product in the form of not-quite-white solid. These two parts are combined and obtain 1.4 g of the desired compound, which is identical with the originally named connection methods B.

Procedure D

5-amino-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carboxamide

To the cooled concentrated sulfuric acid (10 ml) was added in portions of 5-amino-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carbonitrile (4.000 g, 13.9 mmol) for 45 minutes, stirred for 1 hour at room temperature, poured onto ice with stirring, the solution is neutralized with 15% NaOH in a bath with ice. The resulting precipitated precipitate is filtered off and obtain 3.57 g of yellow solid.1H NMR (CDCl3): 5.3 (wide s, 2H), 5.6 (wide s, 2H), 7.5 (s, 2H), 7.7 (s, 1H) hours per million

Method E

Amide 2-cyano-3-(N'-2,4,6-trichlorophenylhydrazine)-but-2-ene acid

A mixture of amide 2-cyano-3-ethoxy-but-2-ene acid (616 mg, 4 mmol) and trichlorophenylhydrazine (730 mg, 4 mmol) in 15 ml of ethanol and 3 ml of chloroform is boiled for 6 hours and get 754 mg of the named compound as a white solid, so pl. 204-206oC.1H NMR (CDCl3) 2.35 (s, 3H), 6.95 Ino)Penta-2-ene acid

A named connection receive in the form of a yellow solid according to the method similar to method E from amide 2-cyano-3-methoxyphenyl-2-ene acid.1H NMR (CDCl3): 1.2 (t, 3H), 3.0 (q, 2H), 4.0 (s, 3H), 5.5 (wide s, 1H), 6.0 (wide s,1H) hours per million

Method G

3,6-Dimethyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-ol

A mixture of amide 2-cyano-3-(N'-2,4,6-trichlorophenylhydrazine)but-2-ene acid (0.620 g, 2.02 mmol) and ndimethylacetamide (1 g, 16.95 mmol) is boiled for 15 hours. The mixture is cooled, diluted with water and extracted with chloroform. The organic layer is separated, dried, evaporated and get 0.325 g (47%) of the titled compound as a brown solid.1H NMR (CDCl3): 2.5 (s, 3H), 2.7 (s, 3H), 7.5 (s, 2H) hours per million

Method H

3-Ethyl-6-methyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-ol

Raw material these compounds are obtained as a brown solid according to the method of method C and used without purification in the next stage.

The method I

Amide 2-cyano-3-(N'-2,4,6-trichlorophenylhydrazine)Gex-2-ene acid

A named connection receive in the form of a yellow solid according to the method of practice E of 2-cyano-3-methoxy-Gex-2-ene acid.1H NMR (CDCl3): 1.07 (t, 3H), 1.71 (m, )-1H-pyrazolo-4-carboxamid

A solution of amide 2-cyano-3-(N'-2,4,6-trichlorophenylhydrazine)-Gex-2-ene acid (of 1,920 g, 5.552 mmol) and ndimethylacetamide (3.262 g at 55.20 mmol) boil for 3 hours, cooled, treated with 20 ml water, the precipitate is filtered off and get 2.024 g of a beige solid, which was dissolved in ethyl acetate and water. The organic layer is separated, dried, evaporated and get 1.685 g of the named compound.1H NMR (CDCl3): 1.02 (t, 3H), 1.82 (m, 2H), 2.75 (t, 2H), 5.4 (wide s, 1H), 5.55 (wide s, 1H), 7.5 (s, 2H) hours per million

Method K

3-n-Propyl-6-methyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d] pyrimidine-4-ol

These connection Methods J (1.617 g, 4.85 mmol) and ndimethylacetamide (3.203 g, 5.42 mmol) boiled for 5 hours. Liquid chromatography (TLC) shows that all starting material had been consumed. The mixture is cooled, quenched with water. The precipitation is filtered off and get a beige solid, which was dissolved in chloroform and water. The organic layer is separated, dried, evaporated and get 1.617 g brown oil named connection.1H NMR (CDCl3): 0.95 (t, 3H), 1.84 (m, 2H), 2.44 (s, 3H), 2.95 (t, 2H), 7.48 (s, 2H), 11.15 (wide s, 1H) hours per million

The method L

5-Amino-1-naphthyl-3-methylsulfanyl-1H-pyrazole-4-carboxamide

A named connection get the visine.1H NMR (CDCl3): 2.6 (s, 3H), 4.0 (s, 1H), 5.3 (wide s, 1H), 5.45 (Tyr s, 1H), 7.45-7.6 (m, 5H), 7.9-8.05 (m, 2H) hours per million

Method M

3,6-Dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo[3,4-d]pyrimidine-4-ol

A mixture of amide 2-cyano-3-ethoxy-but-2-ene acid (573 mg, 3.72 mmol), hydrochloride 2,4,6-trimethylpyrazine (695 mg, 3.72 mmol), triethylamine (377 mg, 3.73 mmol) in 5 ml of methanol is boiled for 15 hours, cooled, diluted with water and extracted with ethyl acetate. The organic layer is dried, evaporated and receive 434 mg brown solid which is used directly for the next reaction. Brown solid is treated with ndimethylacetamide (1.600 g, 27 mmol), boiled for 15 hours, cooled, diluted with water and extracted with ethyl acetate. The organic layer is dried, evaporated and receive 400 mg of a dark red solid, which was purified through column chromatography with silica gel with elution by chloroform and obtain 110 mg of a yellowish-brown solid substances called compounds.1H NMR (CDCl3): 2.0 (s, 3H), 2.3 (s, 3H), 2.45 (s, 3H), 2.65 (s, 3H), 7.0 (s, 2H) hours per million

Methodology N

6-Methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-ol

A mixture of 5-amino-1-(2,4,6-trichlorophenyl)-3-methylthiazole-4 - amount of methanol. The precipitation is filtered off and get 4.343 g (58%) of these substances in the form of a brown solid material. 1H NMR (CDCl3): 2.5 (s, 3H), 2.65 (s, 3H), 7.5 (s, 2H), 12.2 Shir s, 1H) hours per million

Methodology O

6-Methyl-3-methylsulfanyl-1-(2,6-dichloro-4-trifluoromethyl- (phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-ol

The named compound are obtained from 66% yield as a yellow solid according to the method of method N.1H NMR (CDCl3): 2.5 (s, 3H), 2.65 (s, 3H), 7.75 (s, 2H), 11.5 (wide s, 1H) hours per million

Methodology P

6-Methyl-3-methylsulfanyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo [3,4-d] pyrimidine-4-ol

A mixture of 5-amino-3-methylsulfanyl-1-(2,4,6-trimetilfenil)-4-carboxamide (340 mg, 1.17 mmol) and ndimethylacetamide (691 mg, 11.7 mmol) boiled for 9 hours, quenched with water and extracted with ethyl acetate. The organic layer is dried, evaporated and get the named compound as a brown solid (74% yield.

1H NMR (CDCl3): 2.0 (s, 6H), 2.3 (s, 3H), 2.5 (s, 3H), 2.6 (s, 3H), 7.0 (s, 2H), 11.7 (wide s, 1H) hours per million

Methodology Q

6-Methyl-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-ol

The named compound are obtained from 91% yield as a yellowish brown solid according to the method of method P of 5-amino-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carbol)-1H-pyrazolo[3,4-d] pyrimidine-4-ol

The named compound are obtained from 75% yield according to the method of Method P of 5-amino-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4 - carboxamide and formamide.1H NMR (CDCl3): 2.65 (s, 3H), 7.55 and 7.60 (group 2, 2H), 7.8 (s, 0.5 H), 8.15 and 8.25 (2 groups s, 1H), 12.0 (Shir s, 0.5 H) hours per million

3-Methylsulfanyl-1-(2,6-dichloro-4-triptoreline)-1H-pyrazolo[3,4-d] pyrimidine-4-ol

The named compound are obtained from 83% yield as a white solid by the method of P from 5-amino-3-methylsulfanyl)-1-(2,4-dichloro-6-triptoreline)-1H-pyrazole-4 - carboxamide and formamide.1H (CDCl3); 2.6 (s, 3H), 7.72 (s, 2H), 8.0 (c, 1H), 12.1 (wide s, 1H) hours per million

3-Methylsulfanyl-1-( -naphthyl)-1H-pyrazolo[3,4-d]pyrimidine-4-ol

The named compound are obtained from 64% yield according to the method of method P in the form of a brown solid from 5-amino-3-methylsulfanyl-1-( -naphthyl)-1H-pyrazole-4-carboxamide and formamide.1H NMR (CDCl3): 2.7 (s, 3H), 7.2-7.7 (m, 5H), 7.7-8.1 (m, 3H) hours per million

3-Methylsulfanyl-6-trifluoromethyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidine-4-ol

Named substance obtained as white solids with so pl. 220-229oC 61% yield according to the method of method P of 5-amino-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carboxamide and trifluorophenyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidine

A mixture of 5-amino-3-methylsulfanyl-1-(2,4,6-tryptophanyl)-1H - pyrazole-4-carboxamide (1.0 g, 2.84 mmol) and propionamide (2.100 g, 28.77 mmol) is heated for 15 hours at 200oC, the reaction is quenched with water and extracted with ethyl acetate. The organic layer is dried, evaporated and receive 600 mg of crude material, which contains the desired product, and an unidentified compound. The crude product is treated with 1.5 ml of phosphorus oxychloride, boiled for 3 hours, cooled, poured into ice water and stirred. The precipitation is filtered off and get 712 mg of the named compound as a brown solid.1H NMR (CDCl3): 1.3 (t, 3H), 2.7 (s, 3H), 3.0 (q, 2H), 7.5 (s, 2H) hours per million

Method S

4-Chloro-3-methylsulfanyl-6-methyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]peridinin

A mixture of 3-methylsulfanyl-6-methyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidine-4-ol (3.700 g, 9.85 mmol) and phosphorus oxychloride (18.115 g, 11 ml) was boiled for 4 hours, cooled, poured on ice water, stirred for 10 minutes. The precipitation is filtered off and get a brown solid, which is kept in vacuum and get 3.718 g (96% yield).1H NMR (CDCl3): 2.65 (s, 3H), 2.7 (s, 3H), 7.5 (s, 2H) hours per million

Methodology T

By the method of S on the basis of what can be found in the table. 4.

Biological activity

The activity of compounds of formula I are antagonists of CRF was determined by the method described Endcrinlogy, 116, 1653-1659 (1985) and Peptides 10, 1979-188 (1989).

The results are presented below in table. 5. Used the following abbreviation:

Ph is phenyl,

Me is methyl,

t-Bu is tert-butyl,

Et is ethyl,

Pr is propyl.

1. Pyrazolopyrimidine General formula I

< / BR>
and their pharmaceutically acceptable salts,

where a is a group NR1R2or CR'1R'2R11; R1means hydrogen or C1-C6-alkyl which may be substituted by one or two substituents R6independently from each other selected from the group consisting of hydroxy, fluorine, chlorine, C1-C6-alkoxy, NH2, NH(C1-C4-alkyl), N(C1-C2-alkyl) (C1-C4-alkyl), S (C1-C6-alkyl), OC(O)NH(C1-C4-alkyl), COOH, SH, or C2-C6alkenyl; or C2-C6-quinil;

R2represents a C1-C6-alkyl which can be substituted by the Deputy selected from the group containing hydroxy, C1-C6-alkoxy, N(C1-C2-alkyl) (C1-C4-alkyl); or C2-C6-Alden from one to three substituents, such as chlorine, fluorine, or C1-C4-alkyl, or one Deputy, such as C1-C6-alkoxy, trifluoromethyl, nitro, amino; or (C1-C4-alkylen)hetaryl, where the above-mentioned hetaryl means thienyl, possibly substituted by chlorine, benzothiazyl, pyridyl, chinoline, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrrolidinyl, 1-benzylpiperidine, tetrahydropyranyl; or (C1-C4-alkylen)cyclopropyl; or NR1R2form hetaryl selected from the group consisting of pyrrolidyl, possibly substituted benzyl group, pyrrolidinyl, possibly substituted benzyl and hydroxy-group, imidazolyl, pyrrolyl, diazolidinyl, thiomorpholine, R'1is hydrogen, C1-C6-alkyl; R'2- C1-C6-alkyl; R3is hydrogen, C1-C6-alkyl, O-(C1-C6-alkyl), S(C1-C4-alkyl); R4represents a C1-C6-alkyl, or S(O)n(C1-C6-alkyl), where n is 0,1 or 2; R5means 2,4,6-substituted phenyl, where the substituents independently selected from the group consisting of chlorine, C1-C6-alkyl and trifluoromethyl; R11is hydrogen, hydroxy, or COO(C1-C2-alkyl), provided that the group CR'1R'21-C6-alkyl.

2. Connection on p. 1, in which R1represents C1-C4-alkyl, (C2-C4-alkylene)O(C1-C4-alkyl or C2-C4-hydroxyalkyl.

3. Connection PP.1 to 3, in which R2means C1-C5-alkyl.

4. Connection PP.1 to 3, where R2means benzyl, phenylethyl, p-tormentil, p-Chlorobenzyl, p-nitrobenzyl, p-methylbenzyl, p-active compounds, (2-thienyl)methyl, (2-thienyl)ethyl, (2-furanyl)methyl, 2-(4-chloranil)methyl, (2-benzofuranyl)methyl, (2-benzothiazyl)methyl, (2-thiazolyl) methyl or (2-benzothiazolyl) methyl.

5. Connection PP.1 to 4, in which R3means methyl, ethyl, methoxy, chlorine,

6. Connection PP.1 to 5, in which R4represents methylthio, methylsulfinyl or methylsulphonyl,

7. Connection on p. 1 representing: 3-{(4-methylbenzyl)-[3,6-dimethyl-1-(2,4,6-trimetilfenil)-IH-pyrazolo[3,4-d] pyrimidine-4-yl] -amino}-propan-1-ol; diethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-IH-pyrazolo[3,4-d] pyrimidine-4-yl]-amine; 2-{butyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-IH-pyrazolo[3,4-d] pyrimidine-4-yl] -amino} -ethanol; dibutil-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-IH-pyrazolo[3,4-d]pyrimidine-4-yl] -amine; butyl-Alfani-1-(2,4,6-trichlorophenyl)-IH-pyrazolo[3,4-d] pyrimidine-4-yl]-amine; butyl-cyclopropylmethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-IH-pyrazolo[3,4-d] pyrimidine-4-yl] -amine; di-1-propyl[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-IH-pyrazolo[3,4-d] pyrimidine-4-yl] -amine; diallyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-IH-pyrazolo[3,4-d]pyrimidine-4-yl] -amine; butyl-ethyl-[6-chloro-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-IH-pyrazolo[3,4-d] pyrimidine-4-yl] -amine; butyl-ethyl-[6-methoxy-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-IH-pyrazolo[3,4-d] pyrimidine-4-yl]-amine; propyl-ethyl-[3,6-dimethyl-1-(2,4,6-trimetilfenil)-IH-pyrazolo [3.4-d]pyrimidine-4-yl] -amine; and 4-(1-ethylpropyl)-6-methyl-3-methylsulfanyl-1-(2,4,6-trimetilfenil)-IH-pyrazolo[3.4-d]peridinin.

 

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in which

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