Derivatives pyrrolo [2,3-d] pyrimidines, pharmaceutical composition, pyrrolo [2,3-d] pyrimidines, derivatives of pyrrole

 

(57) Abstract:

Derivatives pyrrolo [2,3-d]pyrimidines of the formula I, where B is the group NR1R2, CR1R2R11C(= CR2R12R1OCR1R2R11SCR1R2R11, CR2R11OTHER1, CR2R11OR1, COR2; R1- H, alkyl, possibly substituted by a hydroxy-group, alkoxyl, N(C1-2alkyl) - (C1-4alkyl)group; R2- alkyl, C3-8- cycloalkyl, (C1-6alkylene) C3-8- cycloalkyl, C1-10- alkylether, optionally substituted in the phenyl nucleus by alkyl; R3, R4and R6is hydrogen or alkyl; R5is phenyl, substituted with 1-3 substituents selected from fluorine, chlorine, bromine, alkyl, alkoxy, trifloromethyl, or one OH, J, NH2, NH-alkyl, Coolkill, formyl,where alkyl may be substituted by fluorine atoms, chlorine, hydroxy-group, alkoxygroup, or have one double bond; R11Is H, F, CL, CO (C1-2alkyl), COO (C1-2alkyl); R12- H or C1-4alkyl; or their pharmaceutically acceptable salts possess antagonistic activity against factor allocation corticotropin. 4 c. and 9 C.p. f-crystals, 18 PL.

The present invention relates to Pyrrhus the catfish diseases. The compounds have activity antagonists factor allocation corticotropin (FVC).

Antagonists FVC mentioned in U.S. patents NN 4605642 and 5063245 related to peptides and pyrazolinones. The importance antagonists FVC indicated in the literature, for example in U.S. patent N 5063245, which is introduced here as a reference. A list of the different manifestations of the activity of antagonists PVC can be found in the recent paper: M. J. Owens and others Pharm. Rev., so 43. page 425 - 473 (1991), which is introduced here as a reference. Based on research conducted by the authors of these two and other references, antagonists PVC is considered an effective means of treating a wide range of diseases, including stress-related diseases, for example caused by stress, depression, fear, and headache, abdominal bowel syndrome; mucous colitis; syndrome of inflamed intestine, inflammation of the colon; immune suppression; infection with human immunodeficiency virus (HIV); Alzheimer's disease; gastrointestinal diseases; anorexia nervous; associated with bleeding stress; symptoms exclusion of drugs and alcohol; addiction to the excessive use of drugs; problems related properidine. In U.S. patent N 4229453 proposed 4-aminotoluene pyrrolopyrimidine for the treatment of CNS disorders or inflammation. In: Robins, Can. J. Chem., 55, 1251 (1971) described the antibiotic tubercidin with 7-ribofuranosyl group attached to the 4-aminopyrrolidine. Publication of the German patent 3145287 refers to the three 7-bromophenyl - 5,6-dimethylpyrimidine with analgesic, sedative, anticonvulsant and anti-inflammatory activity.

The present invention relates to compounds of the formula:

(I)

and their pharmaceutically acceptable salts, where

B represents a group NR1R2, CR1R2R11C(= CR2R12R1OCR1R2R11SCR1R2R11, CR2R11OTHER1, CR2R11OR1or C(O)R2; where R1represents hydrogen, C1-C6alkyl which may be substituted by a hydroxy-group, C1-C6-alkoxygroup, N(C1-C2alkyl)(C1-C4alkyl)group and the specified C1-C6the alkyl may have one double bond,

R2represents C1-C12alkyl, C3-C8-cycloalkyl, (C1-C6alkylen) (C3-C8)cycloalkyl, C1R4and R6the same or different and represent hydrogen or C1-C6-alkyl;

R5is phenyl, independently substituted with one to three substituents, selected from the group comprising fluorine, chlorine, bromine, C1-C6alkyl, C1-C6alkoxy, trifluoromethyl, or one hydroxy-group, iodine, amino, NH(C1-C4by alkyl), COO(C1-C4by alkyl), formyl, where C1-C4alkyl and C1-C6the alkyl can be substituted by one or two fluorine atoms, chlorine, hydroxy-group, C1-C4alkoxygroup, or have one double bond;

R11represents hydrogen, fluorine, chlorine, CO(C1-C2alkyl), COO(C1- C2-alkyl); R6represents hydrogen, C1-C6-alkyl,

provided that when R5is p-bromophenyl, and at least two of R3, R4and R5are the stands, is not ethyl, ethoxy, S-ethyl, methylamino, dimethylamino or hydroxyethylamino.

For the preferred compounds of formula 1 include:

connections, which represents a group NR1R2, OCHR1R2where R1represents C1-C6-alkyl, which can be
represents benzyl or C1-C6-alkyl, and phenyl in the benzyl may be substituted C1-C6-alkyl;

connections, which represents a group CR1R2R11where R1represents C1-C6-alkyl which may be substituted by one hydroxy-group or C1-C6-alkoxygroup, R2represents benzyl or C1-C6-alkyl, where C1-C6-alkyl or phenyl in the benzyl may be substituted by one C1-C6the alkyl and R11represents hydrogen or fluorine;

connection, which is defined in paragraph 1 and R2represents C1-C6-alkyl;

connection, which is defined in paragraph 1 and R2represents benzyl which may be substituted C1-C4-alkyl;

compounds in which R3represents methyl or ethyl;

compounds in which R4and R6represent hydrogen, methyl or ethyl;

compounds in which R5represents phenyl, substituted with two or three substituents;

connection, where the Deputy is independently fluorine, chlorine, bromine, C1-C4alkoxy, trifluoromethyl, C1-C6alkyl which may be substituted by one of hydroxy, C< which represent n-butyl ethyl[2,5-dimethyl-7-(2,4, 6-trimetilfenil)-7H-pyrrolo[2,3-d]pyrimidine-4-yl]amine,

di-n-propyl[2, 5-dimethyl-7-(2,4,6-trimetilfenil) -7H-pyrrolo[2,3-d]pyrimidine-4-yl]amine,

ethyl-n-propyl[2,5-dimethyl-7-(2,4,6-trimetilfenil) -7H-pyrrolo[2,3-d]pyrimidine-4-yl]amine,

diethyl-[2,5-dimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo [2, 3-d] pyrimidine-4-yl] amine,

n-butyl-ethyl-(2,5,6-trimethyl-7-(2,4,6-trimetilfenil)-7H - pyrrolo[2,3-d] pyrimidine-4-yl]amine,

2-{ N-n-butyl-N-[2, 5-dimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo[2,3-d] pyrimidine-4-yl]amino}ethanol,

4-(1-ethylpropyl)-2,5,6-trimethyl-7- (2,4,6-trimetilfenil)-7H-pyrrolo[2,3-d]pyrimidine,

n-butyl-ethyl-[2,5-dimethyl-7-(2,4-dimetilfenil)-7H-pyrrolo [2,3-d] pyrimidine-4-yl]amine,

2,5-dimethyl-7-(2,4,6-trimetilfenil) -7H-pyrrolo[2,3-d]pyrimidine-4-yl]-(1-ethylpropyl)amine or

2-[7-(4-bromo-2,6-dimetilfenil) 2,5-dimethyl-7H-pyrrolo[2,3-d] pyrimidine-4-ylamino]butane-1-ol.

The invention also relates to pharmaceutical compositions for the treatment of diseases caused or amplified by the factor allocation corticotropin. The composition comprises a compound of formula 1, as defined above, in an amount effective for the treatment of these diseases, and a pharmaceutically acceptable carrier. The invention relates to pharmaceutical compositions for licinianus pain; pain; cancer; irritable bowel syndrome, including Crohn's disease, mucous colitis and symptoms of irritation of the colon; deregulation of the immune system; infections caused by human immunodeficiency virus (HIV); neurovirology diseases, such as Alzheimer's disease; gastrointestinal diseases; disorders of appetite, such as anorexia nervous system; stress caused by bleeding; symptoms of drug and alcohol withdrawal symptoms; addiction to the excessive use of drugs; stress-induced psychotic States and problems of fertilization, containing the above compound of formula I is effective for the treatment of these diseases the number and pharmaceutically acceptable carrier. For the preferred compositions of the invention include compositions containing the above-mentioned preferred compounds of formula I.

The invention relates also to a method of treating diseases caused by or augmented by the factor allocation corticotropin, by introducing in need of such treatment the subject of the compounds of formula I is effective for the treatment amount and method of treatment of inflammatory diseases such as arthritis, asthma is the number of Crohn's disease, mucous colitis syndrome irritation of the colon; deregulation of the immune system; infections caused by human immunodeficiency virus (HIV); neurovirology diseases, such as Alzheimer's disease; gastrointestinal diseases; disorders of appetite, such as anorexia nervous system; caused by bleeding stress; symptoms of drug and alcohol withdrawal symptoms; addiction to the excessive use of drugs; stress-induced psychotic phenomena and related to fertilization problems, in particular depression and anxiety. The method consists in the introduction in need of such treatment the subject of the compounds of formula I effective to treat the number. To preferred methods of the invention include methods of introducing the above-mentioned preferred compounds of formula I.

The invention also relates to intermediate compounds of the formula:

(II)

where

D represents a hydroxy-group, chlorine

R4, R5and R6have the values listed in paragraph 1;

R9represents C1-C6alkyl,

and a derivative of pyrrole General formula VII:

(VII)

where

R4, R5and R6matter, the decree of the circuit.

If reference is made to the C1-C4-alkyl or C1-C6-alkyl, which may contain one or two double bonds" (see definitions R1, R2and R3), it is obvious that the alkyl is at least two carbon in the case of one double bond, at least four carbon in the case of two double bonds.

If that alkoxygroup, for example in the definitions of R1and R2may have a double bond, it is evident that the double bond is not directly linked with oxygen.

The compounds of formula I, where B represents a group NR1R2, OTHER1R2R11OCR1R2R11SCR1R2R11and R3represents hydrogen, C1-C6-alkyl, can be obtained by reaction of compounds of formula

(II)

where

D-Cl, and R4, R5and R6take the values specified above for formula 1, with the compound of the formula BH, where B takes values above. The reaction is carried out in a solvent in the presence of a base and at a temperature of 0 to 150oC. To an acceptable solvents include organic solvents such as acetonitrile, dimethylsulfoxide, acetone, alkalemia C2-C15-alcohols In case if B is a group NR1R2or NHCR1R2R11apply an excess of BH. Instead, it can be used other bases such as potassium carbonate or three(C1-C6)alkylamine. The reaction is carried out at a temperature of 75 - 150oC. If the reaction is carried out in the presence of such bases as sodium hydride or C1-C4-the potassium alkoxide is used the molar equivalent of the amine. If In - group OCR1R2R11or SCR1R2R11can be used a basis, is able to release BH, for example an alkali metal hydride such as sodium hydride or potassium or an ORGANOMETALLIC base, for example diisopropylamide sodium bis(trimethylsilyl)amide, sodium, diisopropylamide lithium bis(trimethylsilyl)amide lithium, C1-C4-alkoxide or sodium n-utillity. As the solvent used dry tetrahydrofuran, dimethylsulfoxide, methylene chloride or toluene. The reaction is carried out at a temperature of from -78oC to the boiling temperature of the reaction mixture, preferably at 0 to 80oC.

The compounds of formula I, where R3represents a group other than R9(hereinafter R10), can be obtained by the reaction of the compounds of formula I, the reasons. Acceptable bases include sodium, sodium hydroxide and the hydroxides of alkali metals such as potassium hydride, and the weaker base, such as potassium carbonate or triethylamine. The latter is usually used when R10H is represented by alkanols, C1-C6-Alcantara, an amine, such as NH(C1-C6by alkyl), or tetrahydroaluminate. Acceptable solvents include dimethylsulfoxide, acetonitrile, alkalemia C1-C6-alcohols, tetrahydrofuran, benzene, toluene or methylene chloride.

The compounds of formula II, where D is chlorine, can be obtained by reaction of the corresponding 4-hydroxy formula III with an excess of phosphorus oxychloride or thionyl chloride in the temperature range 60 - 140oC, usually at the boiling temperature of the reaction mixture. If the reaction is carried out in the solvent, the solvents suitable halogenated alkanes, for example methylene chloride or chloroform. The reaction can be carried out in the presence of a base, for example N,N-dimethylaniline, trimethylamine or potassium carbonate.

The compounds of formula III, where R9is hydrogen, can be obtained by reaction of the compound of the formula:

(IV)

where

R4, R5and R6C, preferably at the boiling temperature of the reaction mixture.

The compounds of formula III, where R9- C1-C6-alkyl (hereinafter R13), can be obtained by reaction of the compound of formula IV with R13COO-COR13in R13COOH or R13CO(OC1-C2-alkyl)3in acetic acid or acceptable organic soluble, such as ethyl acetate or toluene in the temperature range 25 - 120oC, preferably at the boiling temperature of the reaction mixture. The compounds of formula III, where R9the hydroxy - group, can be obtained by reaction of the compound of formula IV with chlorosulfonylisocyanate in an acceptable solvent in the temperature range from -78 to 100oC, preferably from -20 to 60oC, followed by acid hydrolysis. Acceptable solvents include methylene chloride, dimethylformamide, tetrahydrofuran and toluene, preferably dimethylformamide and methylene chloride. Physiopathologie compounds, where R9is hydrogen, C1-C6-alkyl or hydroxy-group, by heating in aqueous acid can be converted into compounds of formula III. Acceptable aqueous acids include 85% phosphoric acid, hydrochloric acid, sulfuric acid or acetic acid, etc is - 30oC. Or educated compounds can be heated up to 150 - 200oC with phosphorous pentoxide,N, N-dimethylcyclohexylamine.

The compounds of formula IV can be synthesized in the usual way.

The compounds of formula I, where B is the group CR1R2R11and R3is hydrogen, C1-C6-alkyl or hydroxy-group (hereinafter R14) can be obtained by the process illustrated by scheme 1, i.e., by heating the compounds of formula VI, where R14is hydrogen, C1-C6-alkyl or amino group, R1, R2, R11, R4, R5and R6take the above values and the V-group CR1R2R11with ammonium chloride and R14CONH2when boiling.

Circuit 1

< / BR>
The compounds of formula I, where B group CR1R2R11taking the values specified above for formula I, and R3takes values above with reference to formula 1, other than hydrogen, C1-C6-alkyl or hydroxy-group, can be obtained by the reaction of 2-chlorinated formula I, where R3-chlorine (formula 1-not shown ), with a nucleophile of the formula R15H in the presence or without organic or inorganic bases above SP is proxygroup and chlorine. The compounds of formula I-b can be obtained in a manner analogous to the method of transformation of compounds of formula III, the compounds of formula II, where D is chlorine.

The compounds of formula VI can be obtained according to scheme 1 based on compounds of the formula V in a manner analogous to the method of transformation of compounds of formula IV to compounds of formula III.

The compounds of formula V can be obtained by methods similar to conventional methods used for the conversion of compounds of formula IV using VCOCH2CN instead of malonitrile, where V is the group CR1R2R11.

The compounds of formula I, where B is a group C(O)R2can be obtained by reaction of compounds of formula II, where D is cyano, with a Grignard reagent containing R2group, for example R2MgCl or R2MgBr.

The compounds of formula I, where B is the group CR1R2R11C(C=CR2R12R1, CR2R11OTHER1, CR2R11OR1, CR2R11SR1or C(O)R2and R3= R9taking the values specified above for formula I, can be obtained according to scheme 2.

< / BR>
The compounds of formula II, where D is cyano and R4, R5, R6and R9agree to the above is the IDA, enter into reaction with a Grignard reagent containing R1the group receiving the above value> with the formation of the compounds of formula VII. Further reaction of compounds of formula VII with a Grignard reagent containing R2the group receiving the above value, obtain the connection formula IC. The corresponding compounds of formula ID, where B is the group CR1R2R11or C(=CR2R12R1can be obtained in the usual way. Thus, the reaction of the compounds of formula IC acid, such as concentrated sulfuric acid or hydrochloric acid to obtain the compounds of formula I, where B is the group C(=CR2R12R1. The hydrogenation of compounds where B is the group C(=CR2R12R1in the presence as catalyst of Pd/C or palladium oxide receive the compound of formula I, where B is the group CHR1R2. The reaction of compounds of formula I, where B is the group CR1R2OH, c Diethylaminoethanol sulfur or triphenylphosphine-carbon tetrachloride get compound of formula I, where B is the group CR1R2F or CR1R2Cl, respectively.

If compounds of the invention contain one or more chiral centers, it is obvious that the scope of the invention boutote-additive salts of compounds of the formula I get the usual way by treatment 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 technology concentration or crystallization. Examples of acceptable salts include acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, Hydrobromic, itestosterone, sulfamic, sulfonic acid, for example methanesulfonate, benzosulfimide, p-toluensulfonate, almond, di-p-toluoyl-L-tartaric acid and similar acids.

The new compounds of formula I can be introduced separately or in combination with pharmaceutically acceptable carriers or a single dose, or multiple, for example triple doses. Acceptable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Pharmaceutical products, created by the mixing of the new compounds of the formula I with pharmaceutically acceptable carriers, can then be readily implemented in a variety of dosage forms, for example in the form of tablets, powders, wafers, syrups, injectable solutions, etc., Such pharmaceutical preparations may contain dopolneniya can be used pills, containing various fillers, for example; sodium citrate, calcium carbonate and calcium phosphate in a mixture with a variety of resolutely, such as starch, alginic acid and certain complex silicates, together with binding means, such as polyvinylpyrrolidone, sucrose, gelatin and gum acacia. For the preparation of tablets often, in addition, may be useful lubricants, for example magnesium stearate, sodium lauryl sulfate and talc. Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules. Recommended for this purpose materials include lactose or milk sugar and high molecular weight glycols. If oral administration is desired aqueous suspensions or elixirs, the corresponding active ingredient may be mixed with a variety of sweetening agents or flavoring agents, dyes or pigments, and optionally emulsifiers or suspendresume means, as well as diluents, for example water, ethanol, propylene glycol, glycerin and mixtures thereof.

For parenteral administration can be used solutions of the new compounds of formula I in sesame is the willingness you can add the appropriate buffer system, and the liquid diluent first make isotonic by the addition of sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. Sterile water can be easily prepared with standard methods known in the art.

In addition, the compounds of the present invention can be introduced topically when treating inflammatory conditions of the skin, and this can be done by application of creams, jellies, pastes, and ointments in accordance with standard pharmaceutical practice.

The effective dosage of the compounds of the formula I differ depending on the route of administration and other factors, such as age and weight of the patient that, in General, known doctor. Dosage also depends on the nature of the underlying disease. Daily dosage generally will be in the range of 0.1 - 50 mg/kg of body weight of the subject to treatment of the patient. For the treatment of inflammatory diseases need of 0.1-100 mg/kg, for Alzheimer's required of 0.1 - 50 mg/kg, as well as in the treatment of gastrointestinal diseases, anorexia nervous system, caused by bleeding stress, etc.

50as a rule, is in the range from 0.2 nanomolar to 10 micromolar.

The following examples illustrate the invention. Use the following abbreviations: Ph is phenyl, Me is methyl, Bu is butyl, Et is ethyl, Pr is propyl.

Example 1

A. 2-Amino-4-methyl-1-(2,4,6-trimetilfenil)pyrrole-3-carbonitrile

A mixture of 2-(2-bromo-1-methylethylidene)malonitrile and 2,4,6 - trimethylaniline (17,33 g, 91,24 mmol) in 40 ml of isopropanol is stirred for 15 hours at room temperature. The reaction mixture is concentrated to dryness and diluted with chloroform and water. The chloroform layer is neutralized with dilute sodium hydroxide solution, washed with brine, separated, dried, and after concentrating obtain 33 g of a brown oily solid product. Purification of the product column chromatography on silica gel get 9,35 g (47,5%) of the title compound as an orange-yellow solid.

1H NMR (CDCl3) : 2 (s, 6H), of 2.15 (s, 3H), of 2.35 (s, 3H), 3,75 (sh.S., 2H), and 5.8 (s, 1H), 6,95 (s, 2H) h/million

C. N-/3-Cyano-4-methyl-1-(2 is th anhydride (1,41 g, 1.31 ml, 13,82 mmol) in 3 ml of acetic acid is boiled for 45 minutes, cooled, poured into crushed ice and extracted with ethyl acetate. The organic layer is neutralized, dried, and after concentrating receive 3,71 g (105%) dark pink glassy foam.

1H NMR (CDCl3) : 1,95 (s, 6H), 2,2 (s, 3H), 2,32 (s, 3H), 6,2 (s, 1H), 6,8 (sh.S., 1H, NH), 6,9 (s, 2H) h/million

C. 2,5-Dimethyl-7-(2,4,6-trimetilfenil)-3,7-dihydropyrrolo/ 2,3-d/pyrimidine-4-one

Suspension connection phase B (3.2 g, 11,38 mmol) in 3 ml of 85% phosphoric acid dipped for 30 minutes in an oil bath preheated to 130oC. the Reaction mixture is cooled, poured into crushed ice and stirred until a precipitate and melts the ice. The precipitate is filtered off, washed with water and get rmaments product brownish color (the title compound), treatment of which column chromatography on silica gel get solid tan.

1H NMR (CDCl3) : of 1.92 (s, 6H), 2,32 (s, 3H), 2,41 (s, 3H), of 2.45 (s, 3H), of 2.45 (s, 3H), 6.42 per (d, 1H), 6,95 (s, 2H) h/million

D. 4-Chloro-2,5-dimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo/2,3-d/pyrimidine

A mixture of compound stage C (1,03 g, to 3.67 mmol) and POCl3(3 ml) was boiled for 2.5 hours and then cooled. The reaction mixture was crying with the sodium carbonate and brine, dried over anhydrous sodium sulfate and after concentration to dryness obtain the title compound in the form of solids tan, purification of which on silica gel get snowy-white solid.

1H NMR (CDCl3) : 1,9 (s, 6H) to 2.35 (s, 3H), of 2.5 (s, 3H), 2,65 (s, 3H), 6,78 (s, 1H), 7 (s, 2H) h/million

Example 2

A. 2-Amino-4,5-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrrol-3 - carbonitril

A mixture of 3-hydroxy-2-Bohanon (100 g, 1,135 mol) of 2,4,6 - trimethylaniline (153,225 g 1,135 mol) and p-toluenesulfonic acid (0,67 g) in 500 ml of benzene is boiled with application to remove the water trap Dean-stark. After 2 hours add malononitrile (75 g, 1,135 mol) and the mixture is boiled for another 10 hours until you have spent the initial connection. The reaction mixture is cooled and the precipitate filtered off. The precipitate is washed with a minimal amount of ethanol. The solid is diluted with 500 ml of benzene and the product is dissolved. A certain amount of undesirable impurities remains in the precipitate, which is filtered off. Concentration of the filtrate get solid tan, recrystallization of which from ethanol snow-white crystals.

1H NMR (CDCl3) : 1,68 (s, 3H), 1.93 and (s, 6H), was 2.05 (s, 3H), 2,31 (s, 3H), 3,62 (above compound is obtained in the form of a solid tan on the methodology, similar to the method of example 1A, using as starting compound connection phase A and acetic anhydride in acetic acid. The resulting product is pure and used directly in the next stage cyclization.

1H NMR (CDCl3) : of 1.75 (s, 3H), 1.8 m (s, 6H), of 1.95 (s, 3H), of 2.18 (s, 3H), 2,3 (s, 3H), 6,6 (sh.S., 1H), 6,93 (s, 2H) h/million

C. 2,5,6-Trimethyl-7-(2,4,6-trimetilfenil)-3,7-dihydropyrrolo/ 2,3-d/pyrimidine-4-one

A mixture of compound stage B (157,6 g of 0.53 mol) and 100 ml of 85% phosphoric acid is heated for 0.5 hours in an oil bath at 130oC. All original compound reacts with the formation of the target compounds. The mixture is cooled, transferred into 1200 ml of a mixture of ice water and stirred. The formed precipitate is filtered off. The precipitate is washed with water and after drying for about days get 113,22 g of the title compound in the form of brick-pink solid.

1H NMR (CDCl3) : of 1.85 (s, 6H), to 1.87 (s, 3H), of 2.34 (s, 3H), 2,41 (s, 3H), of 2.44 (s, 3H), 7 (s, 2H) h/million

Example 3

A. 2-Amino-4,5-diethyl-1-(2,4,6-trimetilfenil)-1H-pyrrol-3-carbonitril

The crude title compound obtained as an oil by the method similar to the method of example 2A 4-hydroxy-3-hexanone. The crude product is used at once)-1H-pyrrol-2 - yl/ndimethylacetamide

The title compound is obtained in the form of an oil by the method of example 1A from the product of the previous step A and acetic anhydride in acetic acid. Purification of the crude product column chromatography on silica gel using as eluent chloroform receive in the form of oil of the title compound.

1H NMR (CDCl3) : of 0.85 (t, 3H), of 1.26 (t, 3H), of 1.92 (s, 6H), are 2.19 (s, 3H), 2.23 to (K, 2H), 2,33 (s, 3H), 2,59 (K, 2H), 6,95 (s, 2H) h/million

C. 2-Methyl-5,6-diethyl-7-(2,4,6-trimetilfenil)-3,7-dihydro - pyrrolo/2,3-d/pyrimidine-4-one

The title compound is obtained as a brown solid according to the method of example 2C from a combination of the above stages B and 85% phosphoric acid. The crude product used in the subsequent chlorination reaction without further purification.

Example 4

According to the method of example 1 on the basis of relevant 2,5,6 - trialkyl-7-(2,4,6-trimetilfenil)-3,7-dihydropyrrolo/2,3-d/ pyrimidine-4-ones are obtained the following compounds:

4-Chloro-2,5,6-trimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo/2, 3-d/pyrimidine, solid tan.

1H NMR (CDCl3) : is 1.81 (s, 6H), of 1.99 (s, 3H), of 2.35 (s, 3H), of 2.46 (s, 3H), at 2.59 (s, 3H), 7,01 (s, 2H) h/million

4-Chloro-2-methyl-5,6-diethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo/ 2,3-d/pyrimidine, T2 (s, 3H), 2,62 (s, 2H), 2,92 (K, 2H), 7,02 (s, 2H) h/million

Example 5

Butyl-ethyl-/2,5-dimethyl-7-(2,4,6-trimetilfenil)- 7H-pyrrolo-/2,3-d/pyrimidine-4-yl/Amin

A mixture of 4-chloro-2,5-dimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo/2,3-d/pyrimidine (1.0 g, to 3.36 mmol) and N-ethylbutylamine (3.4 g, 33.6 mmol) in 5 ml of dimethyl sulfoxide is boiled for 1.5 hours. The mixture is cooled, treated with water and a few drops of 2 N. HCl to pH 6.5 and extracted with ethyl acetate. The organic layer is separated, washed with diluted sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated to dryness. Purification of the residue column chromatography on silica gel get 995 mg (81%) of the title compound in the form of butter.

1H NMR (CDCl3) : of 0.9 (t, 3H), of 1.23 (t, 3H), of 1.35 (m, 2H), 1.6 to 1.7 (m, 2H), 1,92 (s, 6H), 2,3 (s, 3H), and 2.4 (s, 3H), of 2.46 (s, 3H), to 3.58 (t, 2H), 3,66 (K, 2H), 6,55 (s, 1H), 6,95 (s, 2H) h /million

Corresponding chlorhydrate salt obtained in the form of white crystals after recrystallization from ethyl acetate.

1H NMR (CDCl3) : of 0.9 (t, 3H), of 1.34 (m, 5H), of 1.75 (m, 2H), and 1.9 (s, 6H), is 2.37 (s, 3H), 2,48 (s, 3H), by 2.55 (s, 3H), 3,8 - of 3.94 (m, 4H), to 7.09 (s, 2H), h/million

Example 6

According to the General method of example 5 from the corresponding amines and the corresponding 4-chloro-2,5,6-trialkyl-7-(substituted phenyl)-7H - pyrrolo/2,3-d/permafilter)-1H - pyrrol-3-yl/-2-ethylbutane-1-he

A mixture of 3-hydroxy-2-butanone (0,637 g of 7.23 mmol), 2,4,6 - trimethylaniline (0,973 g, 7.19 mmol) and p-toluene-sulfonic acids (a 0.012 g, 0.06 mmol) in 15 ml of benzene is boiled with the use of traps Dean - stark removal of water. After 3 hours add 4-ethyl-3 - oxohexanoate (1,008 g, 0,724 mmol) and the mixture boiled for a further 15 hours until complete consumption of the starting products. The mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer is dried and after preconcentration get 1,679 g brown oil after purification which column chromatography on silica gel obtained as brown oil 368 mg of the title compound and 732 mg side 2-(2-ethylbutyl)-4,5-dimethyl-1-(2,4,6 - trimetilfenil)-1H-pyrrol-3-carbonitrile in the form of a yellow solid,

1H NMR (CDCl3) (title compound) : 0,94 (t, 6H), 1,4-1,8 (m, 4H), at 1.73 (s, 3H), of 1.98 (s, 6H), of 2.25 (s, 3H), of 2.34 (s, 3H), 3 (m, 1H), 5,8 (sh.with. , 2H ), 6,99 (s, 2H) h/million

1H NMR (CDCl3) (2-(2-ethylbutyl)-4,5-dimethyl-1-(2,4,6 - trimetilfenil)-IH-pyrrol-3-carbonitril) : of 0.85 (t, 6H), 1,5-of 1.85 (m, 4H), 1,71 (s, 3H), of 1.88 (s, 6H), 1,95-2,1 (m, 1H), and 2.14 (s, 3H), of 2.34 (s, 3H), of 6.96 (s, 2H) h/million

B. N-/3-(2-Ethylbutyl)-4,5-dimethyl-1-(2,4,6-trimetilfenil)- 1H-pyrrol-2-yl/ndimethylacetamide

A mixture of l-/2-amino-4,5-dimethyl-1-(2,4,6-trimethylphenyl who belong 2 hours. The mixture is cooled, diluted with water, neutralized with a saturated solution of potassium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried, and after concentration obtained as a dark oil the title compound. Cleaning oil column chromatography on silica gel obtained as brown oil 107 mg of the title compound.

1H NMR (CDCl3) : to 0.88 (t, 6H), 1,4-1,8 (m, 4H), to 1.76 (s, 3H), of 1.88 (s, 3H), 1.93 and (s, 6H), of 2.25 (s, 3H), of 2.28 (s, 3H), 2,98 (s, 1H), 6.89 in (s, 2H) h/million

C. 4-(1-Ethylpropyl)-2,5,6-trimethyl-7-(2,4,6-trimetilfenil)- 7H-pyrrolo/2,3-d/pyrimidine.

A mixture of N-/3-(2-ethylbutyl)-4,5-dimethyl-1-(2,4,6-trimetilfenil)- 1H-pyrrol-2-yl/ndimethylacetamide (100 mg, 0.27 mmol), ammonium chloride (290 mg, 5,42 mmol) and ndimethylacetamide (1,635 g) is boiled for 2 hours. The mixture is cooled, diluted with water and extracted with ethyl acetate. The organic layer is dried after concentration obtained as a dark oil, 56 mg of the title compound. Cleaning oil column chromatography on silica gel get in the form of a yellow oil of the title compound.

1H NMR (CDCl3) : of 0.85 (t, 6H), 1.7 to 2 (m, 4H) and 1.83 (s, 6H), of 1.99 (s, 3H), of 2.36 (s, 3H), of 2.44 (s, 3H), 2,61 (s, 3H), 3,26 (m, 1H), 7 (s, 2H) h/million

Example 8

Butyl-ethyl-/2,5-dimethyl-7-(2,6-dimetilfenil)-7H - Pierre is acid

To a cooled to -78oC solution of n-utility (n-BuLi) (2.5 M in hexane, to 1.79 mmol) in 5 ml dry tetrahydrofuran (THF) is added a solution of 7-(4-bromo-2,6-dimetilfenil) 2,5-dimethyl-7H-pyrrolo/2,3 - d/pyrimidine-4-yl/butyl-ethyl-amine (0.7 g, and 1.63 mmol) in 5 ml dry THF and stirred for 20 minutes at the same temperature.

Select the part (1 ml) the reaction mixture is diluted with excess water, extracted with ethyl acetate, and dried after concentration obtained as a clear oil butyl-ethyl-/2,5-dimethyl-7-(2,6-dimetilfenil)- 7H-pyrrolo/2,3-d/-pyrimidine-4-yl/-Amin. The oil is treated with 1 N. HCL in methanol and concentrate to dryness. By recrystallization of the residue from ethyl acetate to obtain the corresponding HCl salt as white crystals, so pl. 146 - 150oC.

The rest of the reaction mixture is treated with excess of dry ice (-78oC) and cooling -78oC bath removed. After 30 minutes, TLC showed no starting compound, the mixture is diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried, and after concentrating receive a snow-white solid (0.55 g). By recrystallization of the product from 2-propanol get a second title compound as white crystals, so pl. 228 - Neu acid methyl ester

A mixture of 4-/4-(butyl-ethylamino)-2,5-dimethylpyrrole/2,3 - d/-pyrimidine-7-yl/3,5-dimethylbenzoic acid (0,23 g, 0,583 mmol) and 40 ml of 1 N. HCl in methanol is boiled for 3 hours (TLC shows the absence of starting compound). The mixture is concentrated to dryness. The residue is diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried, and after concentrating receive the title compound as light brown oil. Cleaning oil column chromatography on silica gel using as eluent 5% ethyl acetate in hexane get a Golden oil. The corresponding HCl salt obtained in the form of snow-white matter, so pl. 58 - 60oC.

Example 10

/4-(Butyl-ethylamino)-2,5-dimethylpyrrole/2,3 - d/pyrimidine-7-yl/-3.5 dimethylphenylamine

To a solution of 4-/4-(butyl-ethylamino)-2,5-dimethylpyrrole- /2,3-d/-pyrimidine-7-yl/-3,5-dimethylbenzaldehyde (0.1 g, 0,264 mmol) in 1 ml MeOH added sodium borohydride (0.03 g, 0,793 mmol) and stirred for 20 minutes at room temperature. The mixture is diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried, and after concentration to dryness get a clear oil. Purification of the oil by chromatography on silicar 11

Butyl-ethyl-/7-(4-vermeil-2,6-dimetilfenil) 2,6-dimethyl-7H - pyrrolo/2,3-d/pyrimidine-4-yl/Amin

A solution of 4-/4-(butyl-ethylamino)-2,5-dimethylpyrrole-/2,3 - d/pyrimidine-7-yl/-3, 5dimethylphenyl methanol (0,071 g, 0,186 mmol) in 2 ml of anhydrous methylene chloride cooled to -78oC and treated with dimethylaminoacetonitrile (0,063 g 0,39 mmol) with stirring for 1 hour at room temperature. The mixture is diluted with water and extracted with chloroform. The organic layer was washed with brine, dried, and after concentrating receive oil, purification of which on silica gel using as eluent 2% methanol in chloroform obtain the title compound in the form of snow-white matter, so pl. 163 - 165oC.

Example 12

Butyl-ethyl-/7-(4-methoxymethyl-2,6-dimetilfenil) 2,5-dimethyl - 7H-pyrrolo/2,3-d/pyrimidine-4-yl/Amin

A solution of 4-/4-(butyl-ethylamino)-2,5-dimethylpyrrole- /2,3-d/-pyrimidine-7-yl/-3, 5dimethylphenyl methanol (0.1 g, 0,265 mmol) in 1 ml of dry tetrahydrofuran is treated with sodium hydride (0,0116 g, 0,289 mmol, 60% in oil). After stirring for 10 minutes add excess methyliodide. The mixture is diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried, and after concentrating receive Mac is 81 g (78%) of the title compound as a white glassy foam.

Example 13

/7-(4-Aminomethyl-26-dimetilfenil) 2,5-dimethyl-7H - pyrrolo-/2,3-d/pyrimidine-4-yl/butyl-ethylamine

To a solution of 4-/4-(butyl-ethylamino)-2,5-dimethylpyrrole-/2,3 - d/pyrimidine-7-yl/-3,5-dimethylbenzaldehyde (0.2 g, 0,528 mmol) in 2 ml of methanol add cyanoborohydride sodium (0,023 mmol), ammonium acetate (0,407 g, 5,28 mmol) and sodium sulfate. After stirring 1 hour the mixture was concentrated to remove methanol, the residue is dissolved in water, saturated sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried, and after concentrating receive oil. Purification of the oil on a column of silica gel using as eluent 10% methanol in chloroform receive the title compound as a clear oil. Collected di-HCl salt as a white substance, so pl. 158 - 160oC.

Example 14

Butyl-ethyl-/7-(4-methoxyethyl-2,6-dimetilfenil) 2,5-dimethyl - 7H-pyrrolo/2,3-d/pyrimidine-4-yl/Amin

The title compound is obtained according to the method of example 12 using as initial products 1-4-/4-(butylamino) -2,5-dimethylpyrrole/2,3-d/pyrimidine-7-yl/-3, 5dimethylphenyl ethanol, sodium hydride and methyliodide. In table. II the data 1H NMR of compounds obtained by methods which, analogichnym methods of examples 8 to 13, compounds of formulae (example 14), are presented in table. III.

Example 16

A. According to the methods similar to the methods of examples 8 to 13, the reaction of n-BuLi with 4-chloro-2,5-dimethyl-7-(2,6-dimethyl-4-bromo - or 2,4-dimethyl-6-bromophenyl)-7H-pyrrolo/2,3-d/pyrimidine followed by treatment of the appropriate electrophile, the compounds presented in table. IV.

B. According to the General method of example 5 by using as starting compounds of the appropriate amine and the appropriate 4-chloro-2,5-dimethyl-7-(substituted phenyl)-7H-pyrrolo/2,3-d/pyrimidine (compound listed in table. IV, and other related compounds) in DMSO obtained compounds are shown in table. V.

Example 17

According to the methods similar to the methods of examples 8 to 13, the reaction of an excess of n-BuLi with 4-(substituted amino)-2,5-dimethyl-7-(2,4,6 - triple-substituted phenyl)-7H-pyrrolo-/2,3-d/pyrimidine followed by quenching the reaction of an appropriate electrophile, the compounds presented in table. VI.

Example 18

4-Deut-Butoxy-1-(2,5,6-trimetilfenil)-7-(2,4,6-trimetilfenil)- 7H-pyrrolo/2,3-d/pyrimidine

Sodium hydride (0,114 g, 4.77 mmol, 60% in oil) was washed with hexane and then obrabativala/2,3-d/pyrimidine 0.5 g, to 1.59 mmol) and 5 ml of anhydrous tetrahydrofuran and stirred for 2 hours. The mixture is concentrated to dryness, dissolved in ethyl acetate and water. The organic layer was separated, washed with brine and after preconcentration get a clear oil. The oily residue is purified column chromatography on silica gel using as eluent 20% ethyl acetate in hexane and get a clear oil, crystallization of which is in a deep vacuum obtain 0.45 g (80,5%) of snow-white solid. By recrystallization of the product from isopropanol get Golden crystals, so pl. 178 - 180oC.

Example 19

According to the General procedure of example 18 from the corresponding alcohol or thiol and 4-chloro-2,5,6-trimethyl-7-(2,4,6-trimetilfenil)-7H - pyrrolo/2,3-d/pyrimidine or 4-chloro-2,5-dimethyl-7-( 2,4,6 - trimetilfenil)-7H-pyrrolo/2,3-d/pyrimidine obtained compounds are shown in table. VII.

Example 20

A. 2,5, 6-Trimethyl-7-(2,4,6-trimetilfenil)-7H - pyrrolo/2,3-d/-pyrimidine-4-carbonitrile

A mixture of 4-chloro-2,5,6-trimethyl-7-( 2,4,6-trimetilfenil)-7H - pyrrolo/2,3-d/pyrimidine (10 g, 31.9 per mmol) and potassium cyanide (20,75 g, 319 mmol) in 100 ml of dimethyl sulfoxide is heated on an oil bath at 130oC for several days. The mixture is diluted with water and extrage get being 9.61 g (99%) of a brown solid product. By recrystallization of the product from isopropanol get 6,34 g (65%) of the title compound as a pale Golden crystals, so pl. 188 - 190oC.

1H NMR (CDCl3) : 1,8 (s, 6H), 2,07 (s, 3H), of 2.36 (s, 3H), of 2.5 (s, 3H), 2,65 (s, 3H), 7(s, 2H).

Century 2-Methyl-1-/2,5,6-trimethyl-7-( 2,4,6-trimetilfenil)-7H - pyrrolo/2,3-d/pyrimidine-4-yl/butane-1-he

To a solution of the second-butylacrylamide (1.5 ml, 3 mmol, 2 M in diethyl ether) in 24 ml of dry tetrahydrofuran at room temperature add 2,5,6-trimethyl-7-(2,4,6-trimetilfenil)-7H - pyrrolo/2,3-d/pyrimidine-4-carbonitrile (0,814 g, to 2.67 mmol) and stirred for 5 hours. The mixture is diluted with 2 ml of 2 N. HCl, neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer is dried and after concentrating receives a yellow solid product. Purification of the product column chromatography on silica gel using chloroform as eluent get 0,884 g (90%) of the title compound as yellow crystals, so pl. 133 - 135oC.

Example 21

/2,5,6-Trimethyl-7-(2,4,6-trimetilfenil)-7H - pyrrolo/2,3-d/-pyrimidine-4-yl/propane-1-he

1-/2,5,6-trimethyl-7- (2,4,6-trimetilfenil)-7H-pyrrolo/- /2,3-d/pyrimidine-4-yl/pentane-1-he

Synthesized according to the General procedure of example 20B on the basis of 2,5,6 BuLi.

Example 22

/2,5,6-Trimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo/2,3-d/- pyrimidine-4-yl/propane-1-ol

To a solution of 2,5,6-trimethyl-7-(2,4,6-trimetilfenil)-7H - pyrrolo/2,3-d/pyrimidine-4-yl/propane-1-she (0.3 g, 0.89 mmol) in 10 ml of methanol, add borgerende (NaBH4) (0,169 g, 4,47 mmol) and the mixture stirred for 15 minutes at room temperature. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried and after preconcentration get 0,291 g (96%) of the title compound as light yellow crystals. By recrystallization of the crystals from isopropanol receive light yellow crystals with so pl. 143-144oC.

Example 23

According to the method described in example 22, the recovery of the relevant ketopropionic NaBH4received the following connections:

1-/2,5,6-trimethyl-7-( 2,4,6-trimetilfenil)-7H - pyrrolo/2,3-d/-pyrimidine-4-yl/pentane-1-ol and

2-methyl-1-/2,5,6-trimethyl-7-( 2,4,6-trimetilfenil)-7H - pyrrolo/2,3-d/pyrimidine-4-yl/butanol.

Example 24

By the method similar to the method of example 12, reaction of a corresponding alcohol derivative with NaH followed by reaction with alkyllithium received the following connections:

4-( 1-Methoxypropyl)-2,5,6-trimethyl-7-(2,4,6-trimetilfenil) -7H-pyrrolo/2,3-d/pyrimidinyl)-2,5,6-trimethyl-7-(2,4,6 - trimetilfenil)-7H-pyrrolo/2,3-d/pyrimidine.

Example 25

/2,5,6-Trimethyl-7-(2,4,6-trimetilfenil)-7H - pyrrolo/2,3-d/ pyrimidine-4-yl/pentane-3-ol

To a solution of 1-/2,5,6-trimethyl-7-(2,4,6-trimetilfenil)-7H - pyrrolo/2,3-d/pyrimidin-4-yl/propane-1-it (0,22 g, 0,656 mmol) in 10 ml dry THF was added when 0oC ethylmagnesium (0,787 mmol, of 0.39 ml, 2M in THF) and stirred for 1 hour at room temperature. To the mixture diluted HCl, neutralized with an aqueous solution of NaOH and extracted with ethyl acetate. The organic layer is dried and concentrated receives a yellow solid product. By recrystallization of the product from a mixture of ethyl ether-ethyl acetate get snow-white crystals, so pl. 164 - KZT 166.5oC.

Example 26

/2,5,6-Trimethyl-7-(2,4,6-trimetilfenil)-7H - pyrrolo/2,3-d/pyrimidine-4-yl/hexane-3-ol

The title compound was synthesized according to the method described in example 25, the reaction of 1-/2,5,6-trimethyl-7-(2,4,6-trimetilfenil)-7H - pyrrolo/2,3-d/pyrimidine-4-yl/propane-1-one with n-propylaniline.

Example 27

(1-Ethyl-1-forproper)-2,5,6-trimethyl-7-(2,4,6-trimetilfenil) -7H-pyrrolo/2,3-d/pyrimidine

The title compound was synthesized according to the method described in example 11, the reaction of 3-/2,5,6-trimethyl-7-(2,4,6-trimetilfenil)-7H - pyrrolo/2,3-d/pyrimidine-4-yl/pentane-3-ol with diethylaminosulfur
A mixture of 3-/2,5,6-trimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo/ 2,3-d/pyrimidine-4-yl/pentane-3-ol (0,041 g, 0,122 mmol), concentrated sulfuric acid (by 0.055 g of 0.56 mmol) and acetic acid (0,136 g of 2.27 mmol) boil for 1 hour, cooled, diluted with water, alkalinized 2 N. NaOH to pH 10 and extracted with ethyl acetate. The organic layer was washed with brine, dried, and after concentration to dryness obtain 43 mg of the title compound as a clear oil. Cleaning oil column chromatography on silica gel get the title compound in the form of white matter with so pl. 59 - 61oC.

Example 29

The compounds listed in table. VIII, where B is the group CH(OAc) (CHMeEt), and the mixture of the two isomers of 4-(1-ethylbutyl)-2,5,6 - trimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo/2,3-d/-pyrimidine and 4- (1-n-propylphenyl)-2,5,6-trimethyl-7-(2,4,6-trimetilfenil)-7H - pyrrolo/2,3-d/pyrimidine (see tab. VIII, where B is the group C(= CHEI)(Et) and C(= CHMe)(n-Pr ) synthesized by the method similar to the method described in example 28.

Example 30

(1-Ethylbutyl)-2,5,6-trimethyl-7-(2,4,6-trimetilfenil)-7H - pyrrolo/3,3-d/pyrimidine

A mixture of two isomers: 4-(1-ethylbutyl)-2,5,6-trimethyl-7- (2,4,6-trimetilfenil)-7H-pyrrolo/2,3-d/pyrimidine and 4-(1-n - propylphenyl)-2,5,6-trimethyl-7-(2,4,6-trimetilfenil)-7H - pyrrolo/2,3-d/feast of the Sabbath.2). The mixture is filtered through celite. The filtrate is washed with brine, dried, and after concentrating obtain 119 mg of oil. Cleaning oil column chromatography on silica gel using as eluent 7% ethyl acetate in hexane obtain 31 mg (46%) of the title compound in the form of snow-white crystals, so pl. 100 - 102oC.

Example 31

/2,5,6-Trimethyl-7-( 2,4,6-trimetilfenil)-7H-pyrrolo/2,3 - d/pyrimidine-4-yl/propane-1-it oxime

A mixture of 1-/2,5,6-trimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo/2,3 - d/pyrimidine-4-yl/propane-1-it (0,598 g 1,783 mmol), hydroxylamine hydrochloride (0,37 g, 6,36 mmol), sodium acetate (0,439 g, are 5.36 mmol) in MeOH (30 ml) is stirred 24 hours at room temperature and then concentrated to dryness. The residue is diluted with water and extracted with ethyl acetate. The organic layer is dried and after preconcentration get 0,657 g white vitreous product. Purification of the product column chromatography on silica gel get in divided form E- (white crystals, so pl. 162 - 164oC, the configuration was confirmed by x-ray diffraction analysis) and Z-isomer (white crystals, so pl. 84 - 87oC) and a mixture of E - and Z-isomer (so pl. 150 - 190oC).

Example 32

1-/2,5,6-Trimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo/2, 3-d/-pyrimidin-1-it is in the presence of 10% Pd/C according to the General method shown in example 28, received the title compound.

Example 33 /2,5,6-Trimethyl-7-(2,4,6-trimetilfenil)-7H - pyrrolo/2,3-d/-pyrimidine-4-ylmethyl/formamid

A mixture of 2,5,6-trimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo/2,3 - d/pyrimidine-4-carbonitrile (1 g, 3,29 mmol) and Al alloy-Ni (1:1, 1 g) in 70% formic acid (10 ml) is stirred for 1 hour at room temperature. The mixture is filtered through celite, washed with 100 ml water and 100 ml of ethyl acetate. The organic layer is separated, dried, and after concentrating receive light green oil. Cleaning oil column chromatography on silica gel using as eluent 2% methanol in chloroform obtain 0.96 g (86,5%) of the title compound in the form of a solid colour such as snow. By recrystallization of the product from ethyl acetate to obtain light yellow crystals, so pl. 202 - 204oC.

Example 34

N/2,5,6-Trimethyl-7-(2,4,6 - trimetilfenil)-7H-pyrrolo-/2,3-d/-pyrimidine-4-ylmethyl/ndimethylacetamide

A mixture of 2,5,6-trimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo/2,3 - d/pyrimidine-4-carbonitrile (0.5 g, of 1.64 mmol) and 10% Pd/C (0.5 g) in ethanol hydronaut 5 hours under a pressure of 55 pounds per square inch (3,9 kg/cm2). The mixture is filtered through celite and concentration of the filtrate obtain 0.5 g (98,8%) N/2,5,6-trimethyl-7-(2,4,6-trimetilfenil)- 7H-midin-4 - ylmethyl/amine (0.2 g, 0,648 mmol), acetic anhydride (0,132 g, 1.3 mmol), triethylamine (0,132 g, 1.3 mmol) in anhydrous methylene chloride (1 ml) is stirred for 1 hour at room temperature. The mixture is diluted with water and extracted with methylene chloride. The organic layer is separated, dried and after preconcentration get 0,217 g (95,6%) of the title compound in the form of a solid color light tan. Purification of the product column chromatography on silica gel using as eluent 5% methanol in chloroform obtain 0.2 g (88.1 per cent) of the title compound as white crystals, so pl. 140 - 143oC.

In table. VIII the data 1H NMR of the compounds described in examples 20 to 34.

Example 35

A. 1-/2-Amino-4,5-dimethyl-1-(2,4,6-trimetilfenil)-1H - pyrrol-3-yl/-2-ethylbutane-1-he

A mixture of 3-hydroxy-2-butanone (0,637 g of 7.23 mmol), 2,4,6 - trimethylaniline (0,973 g, 0,719 mmol) and p-toluenesulfonic acid (0.12 g) in 15 ml of benzene is boiled for 3 hours with trap Dean-stark. To the reaction mixture add a solution of (Et)2CHCOCH2CN (1,008 g of 7.24 mmol) and boil for about a day. The mixture is cooled and diluted with water ethyl acetate. The organic layer was separated, washed with water, aqueous sodium carbonate solution and brine, dried, and after concentrated the use of chloroform as an eluent selected 0,368 g of target compound.

1H NMR (CDCl3) : of 0.94 (t, 6H), 1.5 and 1.8 (m, 4H), at 1.73 (s, 3H), of 1.98 (s, 6H), and 2.26 (s, 3H), of 2.34 (s, 3H), 3 (m, 1H), 5,78 (sh. S., 2H), 6,99 (s, 2H) h/million

C. N-/3-(2-Ethylbutyl)-4,5-dimethyl-1-(2,4,6-trimetilfenil)- 1H-pyrrol-2-yl/ndimethylacetamide

A mixture of the title compound of example 35A (0,326 g, 1 mmol) and acetic anhydride (to 0.108 g, 1.05 mmol) in acetic acid (5 ml) is boiled for 2 hours. The mixture is concentrated to dryness, diluted with water and extracted with ethyl acetate. The organic layer was washed with aqueous solution of sodium carbonate and brine, and dried after concentration get a dark oil. Cleaning oil column chromatography on silica gel obtained as brown oil 107 mg of the title compound.

1H NMR (CDCl3) : to 0.88 (t, 6H), of 1.6-1.8 (m, 4H), to 1.76 (s, 3H), of 1.88 (s, 3H), 1.93 and (s, 3H), of 2.25 (s, 3H), of 2.28 (s, 3H), 2,9-3 (m, 1H), 6.89 in (s, 2H) h/million

C. 4-(1-Ethylpropyl)-2,5,6-trimethyl-7-(2,4,6-trimetilfenil)- 7H-pyrrolo/2,3-d/pyrimidine

A mixture of the title compound of example 35V (100 mg, 0.27 mmol) and ammonium chloride (1.6 g ndimethylacetamide boiled for 2 hours. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried and concentrated obtain the target compound, cleaning which column chromatography on silica gel get the title compound as a yellow mA 7 (C, 2H) h/million

The following preparative examples illustrate the synthesis of intermediate compounds.

Preparative example 1

By applying the General method of example 1A based on the corresponding anilines of the obtained compounds are shown in table. IX.

Preparative example 2

According to the General method of example 2A on the basis of 3-hydroxy-2-butanone or 4-hydroxy-3-hexanone and the corresponding aniline compounds obtained, are presented in table. X.

Preparative example 3

According to the General procedure of examples 1B and 1C on the basis of the corresponding compounds of preparative examples 1 and 2, the compounds shown in table. XI.

Preparative example 4

According to the General method of Example 1D on the basis of the corresponding compounds of preparative example 3, the compounds shown in table. XII.

Examples preparative forms of the pharmaceutical composition

Example 1

Coated tablets for oral administration

Ingredients - Number*mg

2-[7-(4-bromo-2,6 - dimetilfenil) 2,5-dimethyl-7H-pyrrolo[2,3-d] pyrimidine-4-yl]-butane - 1-ol (active agent) - 20,0

hydroxypropylcellulose (Klucel EF) (covering agent) - 6,0

lactose, anhydrous (fill the would-loosening agent) - 40,0

magnesium stearate (lubricating agent) - 3,6

valium magnesium (lubricating agent) - 0,4

doonally calcium phosphate (base for tablets) - 7,0

All 200,0

*Quantities of ingredients are given for 1 tablet.

Example 2

Capsules for oral administration

Ingredients - Number**mg

2-[7-(4-propyl-2,6-dimetilfenil) 2,5 - dimethyl-7H-pyrrolo[2,3-d] pyrimidine-4-ylamino]-butane-1-ol (active agent) - USD 128.0

lactose, anhydrous (filler or diluent) - 160,5

pre gelatinizing starch (filler) - 112,5

sodium crosscarmellose (baking powder) - 9,0

magnesium stearate (lubricating agent) - 9,0

All 419,0

**Quantities of ingredients are given to one party for the manufacture of gelatin capsules.

Example 3

The solution for parenteral injection (one injection)

Ingredients - Number***mg

4-(1-ethylpropoxy)-2, 5,6-trimethyl-7 (2,4,6-trimetilfenil)-7H-pyrrolo[2,3-d] pyrimidine (active agent) - 10,2

methylparaben, U. S. P. (antimicrobial preservative) - 1,8

propylparaben, U. S. P. (antimicrobial preservative) - 0,2

sodium hydroxide, U. S. P. q.s.ph, alkalizing agent - 9,0

water for injection, U. S. P. q.ASS="ptx2">

Example test

Compounds of the present invention were tested for activity as antagonists FVC by the techniques described in Endocrinology, 116, 1653-1659 (1985) and Peptides, 10, 179 - 188 (1985). Obtained for the compounds of magnitude IR50presented in table 1.

Example 6, where R3and R4represents methyl, B represents NR1R2; and NR1R2, R5and R6represent the values listed in the table. 2.

Example 15 where B is a NEtBu; R3and R1represents methyl, R6represents H; and R5represents a 2-R2'-4-R4'-6-were, where R2' and R4' take the values listed in the table. 3.

Example 16B and 17, where B represents NR1R2;

R3and R4represent methyl;

R6represents H; and R5represents a 2-R2'-4-R4'-6-methyl-phenyl, where NR1R2; R2' and R4' take the values listed in the table. 4

Example 18 and 19, where R3represents methyl;

R5represents a 2-methyl-4-R4'-6-were, and B, R4, R6and R4' take the values listed in the table. yet a 2,4,6-trimetilfenil;

and B takes the values listed in the table. 6.

1. Derivatives pyrrolo [2,3-d]pyrimidines of General formula I

< / BR>
or their pharmaceutically acceptable salt,

where In represents a group NR1R2, CR1R2R11C(=CR2R12R1OCR1R2R11SCR1R2R11, CR2R11OTHER1, CR2R11OR1, COR2where R2represents hydrogen, C1- C6alkyl which may be substituted by a hydroxy-group, WITH1- C6-alkoxygroup, N(C1- C2alkyl) (C1- C4alkyl)group and a specified WITH1- C6the alkyl may have one double bond;

R2is1- C12alkyl, C3- C8-cycloalkyl, (C1- C6-alkylen) (C3- C8-cycloalkyl,1- C10alkylether, optionally substituted in the phenyl nucleus WITH1- C6by alkyl;

R3, R4and R6the same or different and represent hydrogen or C1- C6-alkyl;

R5is phenyl, independently substituted with one to three substituents, selected from the group comprising fluorine, chlorine, bromine, C1- C6alkyl, C1- C6SUB> - C4by alkyl), formyl, where C1- C4alkyl and C1- C6the alkyl can be substituted by one or two fluorine atoms, chlorine, hydroxypoly,1- C4-alkoxygroup, or have one double bond;

R11represents hydrogen, fluorine, chlorine, (C1- C2alkyl), COO(C1- C2alkyl);

R12is hydrogen, C1- C4alkyl,

provided that when R5is p-bromophenyl, and at least two of R3, R4and R5are the stands, is not ethyl, ethoxy, S-ethyl, methylamino, dimethylamino or hydroxyethylamino.

2. Connection on p. 1, which represents a group NR1R2, OCHR1R2where R1is1- C6-alkyl, which may be mixed with one hydroxy-group, WITH1- C2-alkyloxy and may contain one double bond, and R2represents benzyl or1- C6-alkyl, and phenyl in the benzyl may be substituted WITH1- C6-alkyl.

3. Connection on p. 1, which represents a group CR1R2R11where R1is1- C6-alkyl which may be substituted WITH one1- C6- THE C6-alkyl or phenyl in the benzyl may be substituted WITH one1- C6the alkyl and R11represents hydrogen or fluorine.

4. Connection on p. 1, which is defined in paragraph 1 and R2is1- C6-alkyl.

5. Connection on p. 1, which is defined in paragraph 1 and R2represents benzyl which may be substituted WITH1- C4-alkyl.

6. The compound according to any one of paragraphs.1 to 5, in which R3represents methyl or ethyl.

7. The compound according to any one of paragraphs.1 - 6, where R4and R6represent hydrogen, methyl or ethyl.

8. The compound according to any one of paragraphs.1 to 7, in which R5represents phenyl, substituted with two or three substituents.

9. Connection on p. 8, wherein said Deputy is independently fluorine, chlorine, bromine, C1- C4alkoxy, trifluoromethyl, C1- C6alkyl which may be substituted by one of hydroxy, C1- C4alkoxy or fluorine, and may have one double bond.

10. Connection on p. 1, which is n-butyl ethyl[2,5-dimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo[2,3-d] pyrimidine-4-yl] amine, di-n-propyl[2,5-dimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo[2,3-d] pyrimidine-4-ilmatieteen)-7H-pyrrolo[2,3-d] pyrimidine-4-yl] amine, n-butyl ethyl[2,5,6-trimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo[2,3-d] pyrimidine-4-yl] amine, 2-{N-n-butyl-N-[2,5-dimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo[2,3-d] pyrimidine-4-yl] amino] ethanol, 4-(1-ethylpropyl)-2,5,6-trimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo[2,3-d] pyrimidine, n-butyl ethyl[2,5-dimethyl-7-(2,4-dimetilfenil)-7H-pyrrolo[2,3-d] pyrimidine-4-yl] amine, 2,5-dimethyl-7-(2,4,6-trimetilfenil)-7H-pyrrolo[2,3-d] pyrimidine-4-yl] -(1-ethylpropyl)amine, or 2-[7-(4-bromo-2,6-dimetilfenil)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-ylamino]butane-1-ol.

11. Pharmaceutical composition having antagonistic activity against factor allocation corticotropin, including an active agent and pharmaceutically acceptable carriers, characterized in that it contains as active agent a compound of formula I under item 1 in a pharmaceutically effective amount.

12. Pyrrolo[2,3-d]pyrimidines of General formula II

< / BR>
where D represents a hydroxy-group, chlorine;

R4, R3and R6have the values listed in paragraph 1;

R9is1- C6alkyl.

13. Derived pyrrole General formula VII

< / BR>
where R4, R3and R6have the values listed in paragraph 1;

R16represents hydrogen.

 

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< / BR>
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< / BR>
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