Amide derivative and medication

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel amide derivatives of general formula [1] in any of versions (A) or (B), or its pharmaceutically acceptable salt, which possess properties of tyrosinkinase BCR-ABL inhibitor. Amide derivative of general formula [1] represents compound: , where according to Version (A) R1 represents any of the following groups (1)-(3): (1) -) -CH2-R11 [R11 represents saturated 4-6 member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom, which is substituted by group selected from group, consisting of oxo, -CH2-R111 (R111 represents saturated 5-member nitrogen-containing heterocyclic group), saturated 5-member nitrogen-containing heterocyclic group, aminomethyl, monoalkylaminomethyl, dialkylaminomethyl and (5-methyl-2-oxo-1,3-Dioxol-4-yl)methyl, and in addition, can be substituted by 1 or 2 similar or different substituents, selected from group, consisting of (C1-C4)alkyl, (C1-C4 alkoxycarbonyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, amino, carbamoyl], (2) -O-R12 [R12 represents saturated 4-6-member nitrogen-containing heterocyclic group]; and (3) - CH=R13 [R13 represents saturated 4-6-member nitrogen-containing heterocyclic group, which can contain additional nitrogen atom, and which can be substituted by 1-3 similar or different substituents, selected from group, consisting of oxo, (C1-C4)alkyl]; R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy and carbamoyl; R3 represents hydrogen, halogen; Het1 represents any of groups with the following chemical formulae [4] and [6]: [4] [6] [19] [10] Het2 represents pyridyl or pyrimidinyl. According to Version (B) R1 represents -CH2-R14 [R14 represents saturated 4-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, which can be substituted by 1-3 similar groups, selected from (C1-C4)alkyl] R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)acyl, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, nitro, carbamoyl, mono(C1-C4)alkylcarbamoyl, di(C1-C4)alkylcarbamoyl or cyano; R3 represents hydrogen or halogen; Het1 represents any of groups with the following chemical formulas [9] and [10], Het2 represents pyridyl.

EFFECT: invention can be applied for treatment of chronic myeloleukosis, acute lymphoblastic leukosis and acute myeloblastic leukosis.

6 cl, 89 ex, 3 tbl

 

The technical field to which the invention relates.

The present invention relates to amide derivative or salts thereof and pharmaceutical composition comprising the amide derivative or its salt as an active ingredient.

Because tyrosinekinase BCR-ABL (see, for example, non-patent document 1) leads to abnormal cell growth, inhibiting its activity connection applicable for the prevention or treatment of diseases caused by the activity of tyrosine kinase BCR-ABL, such as chronic myeloid leukemia, acute lymphocytic leukemia and acute myeloid leukemia (see, for example, non-patent document 2).

Background of invention

bcr is a gene contained in the 22nd chromosome human abl gene is a gene contained in the 9-th chromosome, and the Philadelphia chromosome is formed as a result of translocation 22-th and 9-th of human chromosomes. It is known that the product of the gene of the chromosome, BCR-ABL, is a protein with tyrosinase activity and continuously generating a signal for growth, causing abnormal growth of cells (see, for example, non-patent document 2).

Therefore, inhibition of tyrosine kinase activity of BCR-ABL makes it possible supression activity-dependent kinase cell growth, and a compound that inhibits this AK is Yunosti, suitable for use as a therapeutic agent for the treatment of diseases, such as chronic myelogenous leukemia, acute lymphoblastic leukemia and acute myeloblastic leukemia. Although the market as a drug with the same effect, already presents Gleevec® (see, for example, patent document 1), other drugs with the same mechanism of action, the market is not represented, and therefore required the development of more effective medicines.

Recently it was reported that, in addition to examples of blast crisis in chronic myeloid leukemia relapses often occur in patients in whom remission was achieved by the introduction of Gleevec® in BCR-ABL-positive acute lymphoblastic leukemia (see, for example, non-patent document 3). In the study of leukemia cells in patients suffering from recurrence of the disease, the detected occurrence of blast options, such as E255K (see, for example, non-patent documents 4-7). In the case of the introduction of Gleevec® in patients BCR-ABL-positive acute lymphoblastic leukemia also found the appearance of resistant cells, which basically represent the blast option E255K (see, for example, non-patent document 8). In connection with the increasing use of Gleevec® advanced growing number of resistant to it patients, and therefore requires the development of a therapy./p>

Patent document 1: unexamined application for the grant of the Japan patent No. 6-87834

Patent document 2: pamphlet form international publication WO 02/22597

Non-patent document 1: Shtivelman E, et al.: Nature 1985, 315, 550-554

Non-patent document 2: Daley G Q, et al.: Science, 1990, 247, 824-830

Non-patent document 3: Druker B J, et al.: N Engl J Med, 2001, 344, 1038-1042

Non-patent document 4: Weisberg E, et al.: Drug Resist Updat, 2001, 4, 22-28

Non-patent document 5: Gorre M E, et al.: Science, 2001, 293, 876-880

Non-patent document 6: Blagosklonny M V: Leukemia, 2002, 16, 570-572

Non-patent document 7: Hochhaus A, et al.: Leukemia, 2002, 16, 2190-2196

Non-patent document 8: Hofmann W-K, et al.: blood, 2002, 99, 1860-1862

Non-patent document 9: Deninger W N, et al.: blood, 2000, 96, 3343-3356

Non-patent document 10: J. Org. Chem., 1996, 61, 1133-1135

Non-patent document 11: J. Org. Chem., 2000, 65, 1144-1157

Non-patent document 12: Recl. Trav. Chim. Pays-Bas., 1950, 69, 673-699

Non-patent document 13: J. Heterocycl. Chem., 1970, 7, 1137-1141

Non-patent document 14: J. Am. Chem. Soc., 1999, 121, 4369-4378

Non-patent document 15: Tetrahedron Lett., 1997, 38, 8005-8008

Non-patent document 16: J. Med. Chem., 2002, 45, 3406-3417

Non-patent document 17: J. Med. Chem., 2000, 43, 3895-3905

Non-patent document 18: J. Med. Chem., 2000, 43, 1508-1518

Non-patent document 19: J. Med. Chem., 1975, 18, 1077-1088

Non-patent document 20: Bioorg. Med. Chem. Lett., 2001, 11, 2235-2239

Non-patent document 21: J. Heterocyclic Chem., 2000, 37, 1457-1462

Description of the INVENTION

The problems solved by the present invented the eat

The problem to which the present invention is directed, is to get a new amide derivative having excellent inhibitory activity against tyrosine kinase BCR-ABL, or its pharmaceutically acceptable salt.

The methods of problem solving

The authors present invention actively studied various compounds and found that the above problem can be solved by using a new amide derivative and its pharmaceutically acceptable salts (hereafter in this document referred to as "compound of the present invention"), having thus the present invention.

The present invention relates to amide derivative which is a compound represented by the following General formula [1] in any of the subsequent versions of (A), (B) or (C) or its pharmaceutically acceptable salt.

Version (A)

R1 represents any of the following groups(1)-(3):

(1) -CH2-R11 [R11 represents a saturated nitrogen-containing heterocyclic group. Saturated nitrogen-containing heterocyclic group substituted by a group selected from the group consisting of oxo, -CH2-R111 (R111 represents a saturated nitrogen-containing heterocyclic group), a saturated nitrogen-containing heterocyclic group, aminoalkyl, monoalkylamines, the dial is of illinoisil, alkoxy and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, and, in addition, may be substituted by 1 or 2 identical or different substituents selected from the group consisting of alkyl, alkoxycarbonyl, halogen, halogenoalkane, hydroxyalkyl, amino, monoalkylamines, dialkylamines, carbamoyl, monoalkylphenol and dialkylamino],

(2) -O-R12 [R12 represents a saturated nitrogen-containing heterocyclic group. Saturated nitrogen-containing heterocyclic group may be substituted by 1-3 identical or different substituents selected from the group consisting of oxo, -CH2-R121 (R121 represents a saturated nitrogen-containing heterocyclic group), a saturated nitrogen-containing heterocyclic group, aminoalkyl, monoalkylamines, dialkylaminoalkyl, alkoxy, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, alkyl, alkoxycarbonyl, halogen, halogenoalkane, hydroxyalkyl, amino, monoalkylamines, dialkylamines, carbamoyl, monoalkylphenol and dialkylamino], and

(3) -CH=R13 [R13 represents a saturated nitrogen-containing heterocyclic group. Saturated nitrogen-containing heterocyclic group may be substituted by 1-3 identical or different substituents selected from the group consisting of oxo, -CH2-R131 (R131 represents a saturated nitrogen-containing heterocyclic group), a saturated attester away heterocyclic group, aminoalkyl, monoalkylamines, dialkylaminoalkyl, alkoxy, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, alkyl, alkoxycarbonyl, halogen, halogenoalkane, hydroxyalkyl, amino, monoalkylamines, dialkylamines, carbamoyl, monoalkylphenol and dialkylamino].

R2 represents alkyl, halogen, halogenated, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, acyl, amino, monoalkylamines, dialkylamino, nitro, carbarnoyl, monoalkylammonium, dialkylammonium or cyano.

R3 represents hydrogen, halogen or alkoxy.

Het1 represents any of the groups with the following chemical formulas[2]-[8]:

Het2 represents a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or 1,2-dihydropyridine (Het2 may be substituted by 1-3 identical or different substituents selected from the group consisting of alkyl, halogen and amino).

The exception is the compound in which R11 represents pyrrolidinyl, piperidinyl, piperazinil or morpholinyl (each pyrrolidinyl, piperidinyl, piperazinil or morpholinyl substituted by a group selected from the series consisting of oxo, -CH2-R111 (R111 represents a saturated nitrogen-containing heterocyclic group), a saturated nitrogen-containing heterocyclic group, aminoalkyl, monoalkylamines, dialkylaminoalkyl is a, alkoxy and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, and, in addition, may be substituted by 1 or 2 identical or different substituents selected from the group consisting of alkyl, alkoxycarbonyl, halogen, halogenoalkane, hydroxyalkyl, amino, monoalkylamines, dialkylamines, carbamoyl, monoalkylphenol and dialkylamino); Het1 is a group of the formula [6]; and Het2 is pyrazinyl or pyridyl which may be substituted by alkyl.

Version (B)

R1 represents-CH2-R14 (R14 represents a saturated nitrogen-containing heterocyclic group. Saturated nitrogen-containing heterocyclic group may be substituted by 1-3 identical or different substituents selected from the group consisting of alkyl, alkoxycarbonyl, halogen, halogenoalkane, hydroxyalkyl, amino, monoalkylamines, dialkylamines, carbamoyl, monoalkylphenol and dialkylamino).

R2 represents alkyl, halogen, halogenated, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, acyl, amino, monoalkylamines, dialkylamino, nitro, carbarnoyl, monoalkylammonium, dialkylammonium or cyano.

R3 represents hydrogen, halogen or alkoxy.

Het1 represents any of the groups with the following chemical formulas [9] and [10]:

Het2 represents a pyridyl, pyrimid the Nile, pyrazinyl, pyridazinyl or 1,2-dihydropyridine (Het2 may be substituted by 1-3 identical or different members selected from the group consisting of alkyl, halogen and amino).

Version (C)

R1 represents any of the following groups(1)-(3):

(1) -CH2-R11 [R11 represents a saturated nitrogen-containing heterocyclic group. Saturated nitrogen-containing heterocyclic group substituted by a group selected from the group consisting of oxo, -CH2-R111 (R111 represents a saturated nitrogen-containing heterocyclic group), a saturated nitrogen-containing heterocyclic group, aminoalkyl, monoalkylamines, dialkylaminoalkyl, alkoxy, and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, and, in addition, may be substituted by 1 or 2 identical or different members selected from the group consisting of alkyl, alkoxycarbonyl, halogen, halogenoalkane, hydroxyalkyl, amino, monoalkylamines, dialkylamines, carbamoyl monoalkylphenol and dialkylamino],

(2) -O-R12 [R12 represents a saturated nitrogen-containing heterocyclic group. Saturated nitrogen-containing heterocyclic group may be substituted by 1-3 identical or different members selected from the group consisting of oxo, -CH2-R121 (R121 represents a saturated nitrogen-containing heterocyclic group), a saturated attester away heterocyclic group, aminoalkyl, monoalkylamines, dialkylaminoalkyl, alkoxy, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, alkyl, alkoxycarbonyl, halogen, halogenoalkane, hydroxyalkyl, amino, monoalkylamines, dialkylamines, carbamoyl, monoalkylphenol and dialkylamino], and

(3) -CH=R13 [R13 represents a saturated nitrogen-containing heterocyclic group. Saturated nitrogen-containing heterocyclic group may be substituted by 1-3 identical or different members selected from the group consisting of oxo, -CH2-R131 (R131 represents a saturated nitrogen-containing heterocyclic group), a saturated nitrogen-containing heterocyclic group, aminoalkyl, monoalkylamines, dialkylaminoalkyl, alkoxy, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, alkyl, alkoxycarbonyl, halogen, halogenoalkane, hydroxyalkyl, amino, monoalkylamines, dialkylamines, carbamoyl, monoalkylphenol and dialkylamino].

R2 represents alkyl, halogen, halogenated, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, acyl, amino, monoalkylamines, dialkylamino, nitro, carbarnoyl, monoalkylammonium, dialkylammonium or cyano.

R3 represents hydrogen, halogen or alkoxy.

Het1 represents any of the groups having the following formulas [9] and [10]:

Het2 represents the Oh pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or 1,2-dihydropyridine (Het2 may be substituted by 1-3 identical or different members selected from the group consisting of alkyl, halogen and amino).

Examples of preferred compounds among the compounds represented by the above General formula [1] include the following amide derivative (1)to(14) or their pharmaceutically acceptable salts:

(1) 4-(1-methylpiperidin-4-ylidenemethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(2) 4-(1-methylpiperidin-4-yloxy)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(3) 4-(1-methylpiperazin-4-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[6-(3-pyridyl)pyrimidine-4-ylamino]phenyl}benzamide,

(4) 4-(1-methylpiperazin-4-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[6-(5-pyrimidinyl)pyrimidine-4-ylamino]phenyl}benzamide,

(5) (-)-4-((S)-3-amino-2-oxopyrrolidin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(6) 4-[(S)-2-(1-pyrrolidinyl)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(7) 4-[3-dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(8) 4-[(S)-3-(1-pyrrolidinyl)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}Bentham is on,

(9) 4-{4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazine-1-ylmethyl}-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(10) 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(4-pyridyl)thiazol-2-ylamino]phenyl}benzamide,

(11) 4-[3-dimethylimidazolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(12) 4-[(R)-3-dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(13) 4-[(S)-3-dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide, and

(14) 4-[(3R,4R)-3-dimethylamino-4-ethoxypyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide.

In addition, the present invention provides the following examples of the amide derivative (1)to(37) or their pharmaceutically acceptable salts:

(1) 3-deformity-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(2) 3-ethyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(3) 4-(1-methylpiperidin-4-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(4) 3,5-dichloro-4-[(S)-3-dimethylaminopropan-1-ylmethyl]-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-silts what about]phenyl}benzamide,

(5) 3-methoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide,

(6) 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(7) 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide,

(8) 3-chloro-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(9) 3-vermeil-4-(1-methylpiperidin-4-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(10) 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]phenyl}benzamide,

(11) 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]phenyl}benzamide,

(12) 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide,

(13) 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide,

(14) 4-[4-(2-foradil)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(15) 4-[4-(2-hydroxyethyl)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(16) 4-[(R)-3-dimethylaminopropan-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-yl) - Rev. Ino]phenyl}benzamide,

(17) 4-(1-piperazinylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide,

(18) 4-(1-piperazinylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide,

(19) 4-(1-piperazinylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(20) 4-(3-carbamoylbiphenyl-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(21) 4-[(S)-3-dimethylaminopropan-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(22) 4-(3-carbarnoyl-4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(23) 4-((S)-3-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(24) 4-((R)-3-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(25) 4-[(S)-3-N,N-diethylaminopropyl-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(26) 4-[(2R,4S)-4-dimethylamino-2-methylpyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(27) 4-((S)-3-aminopiperidine)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(28) 4-[(S)-3-dimethylaminopyridine]-3-Tr is formetal-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(29) 4-((3S,4R)-3-amino-4-methylpyrrolidine-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(30) 4-[(3S,4R)-3-dimethylamino-4-methylpyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(31) 4-[(S)-3-methylaminopropyl-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(32) 4-((S)-3,4-dimethylpiperidin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(33) 4-((R)-3,4-dimethylpiperidin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(34) 4-[(3R,4R)-3-dimethylamino-4-ethoxypyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(35) 4-(1-methylpiperidin-4-yloxy)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(36) 4-(1-methylpiperidin-4-ylidenemethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide, and

(37) 4-[(R)-3-dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide.

In addition, the present invention relates to pharmaceutical compositions comprising a compound of the present invention as an active ingredient, for example an inhibitor of tyrosine kinase BCR-ABL. More specifically, the crust is ASEE the invention relates to pharmaceutical compositions, used as a therapeutic agent for the treatment of chronic myeloid leukemia, a therapeutic agent for the treatment of acute lymphoblastic leukemia or therapeutic agent for the treatment of acute myeloid leukemia.

The compound of the present invention has inhibitory activity against tyrosine kinase BCR-ABL and applicable as a drug for prevention or treatment of diseases such as chronic myelogenous leukemia, acute lymphoblastic leukemia and acute myeloblastic leukemia (see, for example, non-patent document 9).

Hereinafter the present invention will be described in detail.

The expression "nitrogen-containing saturated heterocyclic group" includes a 4-8-membered saturated ring group representing a saturated ring group containing at least one nitrogen atom as ring atoms, which may contain 1-3 identical or different members selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. If the ring atom is a nitrogen atom or a sulfur atom, nitrogen atom or sulfur atom may form the oxide. Examples of groups include pyrrolidinyl, piperidinyl, piperazinil, azetidine, morpholine, thiomorpholine, hexahydro-1H-1,4-diazepine. However, the expression "nitrogen-containing saturated gets aziklicescoe group" in relation to R13 is limited to groups where the ring atom bound to R13 through a double bond, and the neighbouring ring atoms are carbon atoms, and, for example, -CH=R13 includes piperidine-4-ylidenemethyl.

The term "alkyl" includes unbranched or branched alkyl group containing 1-10 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, n-nonyl and n-decyl. Particularly preferred are non-branched group containing 1-3 carbon atoms.

Alkyl radical "dialkylaminoalkyl", "alkoxy", "alkoxycarbonyl", "halogenoalkane", "hydroxyalkyl", "monoalkylamines", "dialkylamino", "monoalkylphenol", "dialkylamino", "alkoxyalkyl" and "hydroxyalkyl" includes the above-mentioned alkyl.

The term "halogen" includes, for example, fluorine, chlorine, bromine and iodine.

The term "halogenated" includes monohalogenated, dehalogenases and trihalomethyl, and halogen radical "halogenoalkane" includes the above-mentioned halogen. The term "halogenated" includes, for example, vermeil, 2-foretel, deformity, trifluoromethyl and 2,2,2-triptorelin.

The term "acyl" includes acyl groups containing 1 to 11 carbon atoms, for example formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl, 1-naphtol and 2-naphtol

The term "pyridyl" includes, for example, 2-pyridyl, 3-pyridyl and 4-pyridyl.

The term "pyrimidine" includes, for example, 2-pyrimidinyl, 4-pyrimidinyl and 5-pyrimidinyl.

The term "pyrazinyl" includes, for example, 2-pyrazinyl.

The term "pyridazinyl" includes, for example, 3-pyridazinyl and 4-pyridazinyl.

The term "1,2-dihydropyridines" includes, for example, 1,2-dihydropyridin-3-yl and 1,2-dihydropyridin-4-yl.

The expression "saturated cyclic amino group" includes a 4-8-membered saturated group representing a saturated cyclic amino group containing at least one nitrogen atom as the ring atom and may contain 1-3 identical or different members selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. If the ring atom is a nitrogen atom or a sulfur atom, nitrogen atom or sulfur atom may form the oxide. Examples of groups include 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinil, 1-azetidinol, 4-morpholinyl, 4-thiomorpholine, hexahydro-1H-1,4-diazepin-1-yl.

The most preferred method of carrying out the invention

The compound of the present invention can be obtained from known per se connection or intermediate product that can be easily obtained, for example, in accordance with the following method. In obtaining compounds the Oia of the present invention it is well known, what if the original compounds contain substituents that affect the conduct of the reaction, the starting compound used in the reaction after protection suitable protective groups are known per se methods. After the reaction, the protective group can be removed by known per se methods.

The method of obtaining 1

[where the values of R1, R2, R3, Het1 and Het2 defined above]

This reaction is a condensation reaction of compound [11] and the compound [12], and therefore is carried out in accordance with known per se methods used in the condensation reactions. The compound [1] can be obtained by interaction of carboxylic acid in the form of compounds [12]or its reactive derivative with an amine in the form of compounds [11]. Examples of reactive derivatives of the compound [12] include derivatives that are commonly used in reactions of amide condensation, such as gelegenheid (e.g., acid chloride, bromohydrin and so on), mixed gelegenheid, imidazole and active amide. In the case of carboxylic acids [12] is used condensing agent (for example, 1,1'-oxacillinases, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide, diethylthiophosphate, diphenylphosphoryl, iodide, 2-chloro-1-methylpyridine, hexaphosphate-benzotriazol-1-electropermeabilization and hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium), and the reaction is carried out at a temperature from-20ºC to 100ºC in the presence or in the absence of a base (e.g. organic bases such as triethylamine, N,N-aminobutiramida-N-ethylamine, N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.). The choice of solvent is not specifically limited because it does not participate in the reaction, and examples of the solvent include ethers such as tetrahydrofuran and diethyl ether; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; NITRILES such as acetonitrile and propionitrile; hydrocarbons, such as benzene and toluene; halogenated hydrocarbons such as chloroform and dichloromethane; and mixtures of these solvents. In this case, can also be used additives (for example, 1-hydroxybenzotriazole, N-hydroxysuccinimide and so on). The duration of the reaction varies depending on the kinds of source material and condensing agent and the reaction temperature, but is usually preferably the duration of the reaction is from 30 minutes to 24 hours. The amount of coupling [12], and the condensing agent is preferably 1-3 mol per mol of compound [11]. In the case of gelegenheid as the reactive derivative of the compound [12] the reaction is carried out at a temperature from-20ºC to 100ºC using pyridine dissolved the La, such as pyridine or 4-methylpyridine, or the same base or solvent, as described above. As an additive can also be added 4-dimethylaminopyridine. The duration of the reaction varies depending on the type of gelegenheid and the reaction temperature, but is usually preferably the duration of the reaction is from 30 minutes to 24 hours.

The method of obtaining the parent compound [11] for use in the method 1

Used as the source connection [11], in which Het1 is a group of the formula [6]can be obtained, for example, in the same way as described in patent document 1.

Used as the source connection [11], in which Het1 represents a group of formula[4], [5], [7] or [9], can be obtained in the following way:

[where values Het1 and Het2 as defined above; R4 and R5 can be the same or different from each other and represent an alkyl or hydroxy; R6, R7 and R8 represent alkyl; and X1 represents a halogen]

Stage 1

This reaction is a reaction cross-combination, in which the connection is used [13] and organoboron compound [14] or ORGANOTIN compound [15], and may be conducted by known per se methods. For example, the above reaction is carried out at 20ºC-200ºc is manageable is a suitable solvent in the presence of palladium catalyst. As the palladium catalyst is usually used tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium and dichlorobis(tri-ortho-tolylphosphino)palladium. The choice of solvent is not specifically limited because it does not participate in the reaction, and examples of the solvent include ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; hydrocarbons, such as benzene, toluene and xylene; organic amines such as pyridine and triethylamine; and mixtures of these solvents. When using compounds [14] requires the addition of a base (e.g. sodium hydroxide, potassium carbonate, tribalista and so on). The duration of the reaction varies depending on the nature of the source material and the reaction temperature, but generally is preferably from 1 hour to 48 hours.

Stage 2

This reaction is a reaction for reduction of aromatic nitro compounds [16] to the amino group, and therefore is carried out in accordance with known per se methods used in the reactions of recovery. The method includes, for example, a method of processing zinc or tin under acidic conditions. In accordance with the method of catalytic reduction, for example, can be carried out hydrogenation with ISOE what Itanium as a catalyst of platinum, of Raney Nickel, platinized carbon (Pt-C), palladium carbon (Pd-C) or complex of ruthenium. In addition, the quality of the example can be represented by the use of sulfide, such as dithionite sodium, and method of recovery by ammonium formate or hydrazine in the presence of a metal catalyst.

Used as starting material the compound [13], in which Het1 is a group of the formula [4]can be obtained, for example, through the implementation of the interaction of 2,4-dichloropyridine (obtained, for example, in accordance with a modification of the method described in non-patent document 12) 2-methyl-5-nitroaniline in accordance with the method according to J.P. Wolfe et al. using a palladium catalyst (see non-patent documents 10 and 11). When Het1 is a group of the formula [5], the connection can be obtained, for example, through the implementation of the interaction of 1-bromo-3-yogashala with 2-methyl-5-nitroaniline. When Het1 is a group of the formula [7], the connection can be obtained, for example, through the implementation of the interaction of 2,6-dichloropyrazine with 2-methyl-5-nitroaniline. When Het1 is a group of the formula [9], the connection can be obtained, for example, by performing interaction 4,6-dichloropyrimidine with 2-methyl-5-nitroaniline. The choice of solvent is not specifically limited, the village is olcu he is not involved in the reaction, and examples of the solvent include ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; hydrocarbons, such as benzene, toluene and xylene; and mixtures of these solvents. The reaction is carried out at 70ºC-100ºC in the presence of a base. Examples of the palladium catalyst include Tris(dibenzylideneacetone)dipalladium(0), palladium acetate(II) and three(ortho-tolylphosphino)palladium(0). Generally, the amount of palladium is preferably from 0.5 mol.% up to 4 mol.% relative to the halogenated amine. As a ligand of palladium catalyst can be used, for example, 1,3-bis(diphenylphosphino)propane, 1,1'-bis(diphenylphosphino)ferrocene and (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [(±)-BINAP]. Examples of the base include tert-piperonyl sodium tert-piperonyl potassium, cesium carbonate, potassium carbonate and sodium carbonate. The duration of the reaction varies depending on the nature of the source material and the reaction temperature, but generally is preferably from 1 hour to 36 hours.

The compound [13] can also be obtained by interaction of 2,4-dichloropyridine, for example, when Het1 is a group of the formula [4], or by implementing interaction 4,6-dichloropyrimidine, for example, when Het1 is a group of the formula [9], 2-methyl-5-nitroaniline at 20ºC-200ºc is manageable in a suitable solvent or in the absence of rest is rites in the presence or in the absence of base. Examples of the base include pyridine, triethylamine, N,N-aminobutiramida-N-ethylamine, potassium carbonate, sodium bicarbonate and potassium hydroxide. The choice of solvent is not specifically limited because it does not participate in the reaction, and examples of the solvent include ethers such as tetrahydrofuran, disutility ether and 1,4-dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; hydrocarbons, such as benzene and toluene; alcohols, such as ethylene glycol and 2-methoxyethanol; halogenated hydrocarbons such as chloroform and dichloromethane; dimethylsulfoxide; and mixtures of these solvents. The duration of the reaction varies depending on the nature of the source material and the reaction temperature, but generally is preferably from 1 hour to 24 hours.

Used as source material connection [16a] (compound [16], in which Het1 is a group of the formula [4]) can be obtained, for example, as follows:

[where the values of R4, R5, R6, R7, R8 and Het2 as defined above, and X2 and X3 are halogen].

Stage 1

This reaction is a reaction cross-combination, which uses the connection [17] and organoboron compound [14] or ORGANOTIN compound [15], and can be conducted in a similar manner as described above.

Stage 2

Connect the tion [19] is obtained by halogenation of the compound [18]. Therefore, the reaction is carried out according to known per se techniques. Usually the reaction is carried out using the acid chloride phosphoric acid, bromohydrin phosphoric acid, pentachloride phosphorus or pentabromide phosphorus with or without using a solvent. The choice of solvent is not specifically limited because it does not participate in the reaction, and examples of the solvent include ethers such as tetrahydrofuran, disutility ether and 1,4-dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; and mixtures of these solvents. The reaction is usually carried out at a temperature from room temperature to 130ºC, and the duration of reaction is usually preferably ranges from 20 minutes to 24 hours.

Stage 3

Connection [16a] can be obtained by interaction of the compound [19] with the compound [20] in accordance with the above method using a palladium catalyst (see, for example, non-patent documents 10 and 11).

The compound [11a] (compound [11], in which Het1 is a group of the formula [4]) can be obtained by interaction of the compound [19] with the compound [21] according to the above method using a palladium catalyst (see, for example, n the patent documents 10 and 11) to obtain the compound [22] and removing the protective groups from the compound [22].

[where values Het2 and X3 are defined above and R9 is a protective group].

Stage 1

The original connection [21] can be obtained by protection of 2,4-diaminotoluene the introduction of a suitable protective group according to known per se techniques. Examples of the protective group include acylphosphate, such as benzoyl, acetyl and formyl, and urethane derivatives type, such as benzyloxycarbonyl, tert-butoxycarbonyl and 2,2,2-trichlorocyanuric. Connection [22] can be obtained by interaction of the compound [19] with the compound [21] using a palladium catalyst.

Stage 2

In the reaction of removing the protective groups from the compound [22] the protective group of the acyl type is removed by hydrolysis using an acid or alkali or removed by addition of ammonia or hydrazine. The examples used for hydrolysis of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and examples of the base include inorganic bases such as sodium hydroxide and potassium hydroxide. The choice of solvent is not specifically limited because it does not participate in the reaction, and examples of the solvent include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and 1,4-dioxane; water; and mixtures of these solvents. T is mperature reaction ranges from 0ºC to 100ºC, and the duration of reaction is usually from several minutes to 24 hours. If the protective group is a derivative of urethane type, the protective group can be removed by hydrogenation using a palladium catalyst or by adding hydrochloric acid, triperoxonane acid, trimethylsilylmethyl or boron TRIFLUORIDE, depending on the nature of the protective group.

Connection [11b]used as the starting compound [11], in which Het1 is a group of the formula [10]can be obtained in accordance with the method similar to that described, for example, non-patent document 13, to obtain the compound [16b], followed by reduction of the aromatic nitro group to the amino group, as presented later in this document.

[where is Het2 as defined above].

The method of obtaining the parent compound [12] for use in the method 1

The compound [12a]used as the starting compound [12]can be obtained, for example, as follows:

[where the values of R2, R3, and R12 are defined above and X4 is a halogen].

Stage 1

Connection [25] can be obtained by education essential connection between halogenated aryl [23] and alcohol [24]. This reaction is particularly the reaction of nucleophilic substitution of compounds [23] and alcohols and is conducted according to known per se techniques. The above reaction is carried out in a suitable solvent in the presence of a base. Examples of preferred bases include any commonly used base (e.g. pyridine, triethylamine), alkoxides of alkali metals (for example, tert-piperonyl potassium), metal hydride (e.g. sodium hydride) and inorganic bases (e.g. potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide). The choice of solvent is not specifically limited because it does not participate in the reaction, and examples of the solvent include ethers such as tetrahydrofuran and 1,4-dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; NITRILES such as acetonitrile and propionitrile; hydrocarbons, such as benzene and toluene; dimethylsulfoxide; water; and mixtures of these solvents. The reaction temperature is usually from-78ºC to 200ºc is manageable. The duration of the reaction varies depending on the nature of the source material and the reaction temperature, but generally is preferably from 30 minutes to 24 hours. In addition, in such substitution reactions as a catalyst copper powder, copper halide(I) or copper alkoxide. As an alternative method for obtaining compounds [25] of the halogenated aryl [23] and alcohol [24] can be used a method using a palladium catalyst p is A. Aranyos, et al. or G. Mann, et al. (see, for example, non-patent documents 14 and 15).

Stage 2

The compound [12a] can be obtained by hydrolysis of the compound [25]. The reaction is usually carried out in a suitable solvent in the presence of acid or base. The examples used for hydrolysis of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and formic acid, and examples of the base include inorganic bases such as sodium hydroxide and potassium hydroxide. Examples of the reaction solvent include alcohols such as methanol, ethanol and ethylene glycol; ethers such as tetrahydrofuran and 1,4-dioxane; water; and mixtures of these solvents. The reaction temperature ranges from 0ºC to 200ºc is manageable, and the duration of reaction is usually preferably from 30 minutes to 24 hours.

Connection [12b]used as the starting compound [12]can be obtained, for example, as follows:

[where the values of R2, R3 and R13 are defined above; R10 represents alkyl; and Q represents dialkoxybenzene salt or dialkoxybenzene].

Stage 1

This reaction is a reaction of the Wittig or Horner reaction of Ammonia organophosphorus compounds [26] and the compound [27], and then is carried out in accordance with known per se methods, such as the reaction of the Wittig or Horner reaction of Ammonia. The reaction is carried out in a suitable solvent in the presence of a base at a temperature from-78ºC to about 150ºc. Examples of the base include n-utility, sodium hydride, ethoxide sodium tert-piperonyl potassium and diisopropylamide lithium. The choice of solvent is not specifically limited because it does not participate in the reaction, and examples of the solvent include ethers such as tetrahydrofuran and 1,2-dimethoxyethane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; alcohols such as methanol and ethanol; hydrocarbons such as n-hexane, benzene and toluene; halogenated hydrocarbons such as chloroform and dichloromethane; dimethylsulfoxide; and mixtures of these solvents. The duration of the reaction varies depending on the nature of the source material and condensing means and the reaction temperature, but generally is preferably from 30 minutes to 24 hours.

Used as starting material the compound [26] represents a halide salt alkyl(Triaryl)phosphonium or alkyl(dialkoxy)phosphoryl, each of which may be obtained in accordance with a modification of the method described in non-patent documents 16 and 17.

Stage 2

Connection [12b] can be obtained by hydrolysis of compounds [28]. The reaction is usually carried out in a suitable p is storytale in the presence of acid or base. The examples used for hydrolysis of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and examples of the base include inorganic bases such as sodium hydroxide and potassium hydroxide. Examples of the reaction solvent include alcohols such as methanol, ethanol and ethylene glycol; ethers such as tetrahydrofuran and 1,4-dioxane; water; and mixtures of these solvents. The reaction temperature ranges from 0ºC to 100ºC, and the duration of reaction is usually preferably from 30 minutes to 24 hours.

Connection [12c]used as the starting compound [12]can be obtained, for example, as follows:

[where the values of R2, R3, R10, R11, R14 and Q defined above].

Stage 1

This reaction is a reaction of the Wittig or Horner reaction of Ammonia organophosphorus compounds [26] and the compound [29] or the compound [30] and can be carried out in accordance with the modification of the General method for the synthesis of compounds [28] of the above compounds [26].

Stage 2

Connection [12c] can be obtained by hydrolysis of compound [31] to obtain compounds [32], followed by reduction of the compound [32]. Alternatively, the compound [12] can be obtained by restoring the connection [31] to obtain compounds [33] followed what idolism compounds [33]. The hydrolysis reaction is carried out in accordance with the modification of the General method for the synthesis of compounds [12b] of the above compounds [28]. The reduction can be carried out in accordance with known per se methods.

In addition, if R11 or R14 represents a saturated cyclic amino group, the compound can be obtained, for example, in accordance with the following method:

[where the values of R2, R3 and R10 are defined above; R15 is a saturated cyclic amino group; X5 represents a leaving group such as Cl, Br, I, pair-toluensulfonate, methanesulfonate].

Stage 1

Connection [36] can be obtained by condensing compounds [34] (which can be obtained, for example, in accordance with a modification of the method described in non-patent document 18) with saturated cyclic amine [35] (where the leaving group X5 is a leaving group such as halogen, pair-toluensulfonate, methanesulfonate). This reaction is a nucleophilic substitution reaction of compound [34] and amines and is conducted according to known per se techniques. This reaction is carried out in a suitable solvent using an excess of amine or in the presence of a base. Examples of preferred bases include pyridi is, the triethylamine, N,N-aminobutiramida-N-ethylamine, potassium carbonate and sodium bicarbonate. The choice of solvent is not specifically limited because it does not participate in the reaction, and examples of the solvent include ethers such tetrahydrofuran and diethyl ether; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; NITRILES such as acetonitrile and propionitrile; hydrocarbons, such as benzene and toluene; alcohols such as methanol and ethanol; water; and mixtures of these solvents. The reaction temperature usually ranges from 0ºC to 100ºC. The duration of the reaction varies depending on the nature of the source material and the reaction temperature, but generally is preferably from 30 minutes to 24 hours.

Stage 2

Connection [12d] can be obtained by hydrolysis of compounds [36].

This reaction is a reaction of hydrolysis of esters and can be carried out in accordance with the modification of the General method for the synthesis of compounds [12b] of the above compounds [28].

The method of obtaining 2

[where the values of R1, R2, R3, Het1 and Het2 are defined above; X6 represents Cl, Br, I or SR16 (where R16 represents alkyl)].

The compound [1] can be obtained by interaction of the compound [37] with the compound [38]. The reaction is carried out at 20ºC-200ºc is manageable in the absence of solvent or in a suitable p is storytale in the presence or in the absence of base. Examples of the base include pyridine, triethylamine, N,N-aminobutiramida-N-ethylamine, potassium carbonate, sodium bicarbonate and potassium hydroxide. The choice of solvent is not specifically limited because it does not participate in the reaction, and examples of the solvent include ethers such tetrahydrofuran, disutility ether and 1,4-dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; hydrocarbons, such as benzene and toluene; alcohols, such as ethylene glycol and 2-methoxyethanol; halogenated hydrocarbons such as chloroform and dichloromethane; dimethylsulfoxide; and mixtures of these solvents. The duration of the reaction varies depending on the nature of the source material and the reaction temperature, but generally is preferably from 1 hour to 24 hours.

In addition, compound [1] can be obtained by interaction of the compound [37] with the compound [38] in accordance with a method using a palladium catalyst, as described for the method of obtaining 1 (see, for example, non-patent documents 10 and 11).

Connection [37]used as a starting compound can be obtained, for example, by condensation of 2,4-diaminotoluene with carboxylic acid as the compound [12] or its reactive derivative in accordance with a modification of the method of obtaining 1.

Connection [38], BL is used as a starting compound, can be obtained in accordance with method 4 described here and later in this document, using 2,6-dibromopyridine, for example, when Het1 is a group of formula [2]; 3,5-dibromopyridine, for example, when Het1 is a group of the formula [3]; 2,4-dibromopyridine, for example, when Het1 is a group of the formula [4]; 1,3-dibromobenzene with, for example, when Het1 is a group of the formula [5]; 2,4-dichloropyrimidine, for example, when Het1 is a group of the formula [6]; and 2,6-dichloropyrazine, for example, when Het1 is a group of the formula [7]. When Het1 is a group of the formula [4], the compound [38] can also be obtained in accordance with the method described for the above-mentioned method of obtaining 1.

The method of obtaining 3

[where the values of R1, R2, R3 and Het2 as defined above].

The compound [1a] (compound [1], where Het1 is a group of the formula [6]) can be obtained by interaction of the compound [39] or its salts of addition of an acid with the compound [40]. The reaction is carried out at 20ºC-200ºc is manageable in a suitable solvent. The choice of solvent is not specifically limited because it does not participate in the reaction, and examples of the solvent include alcohols such as methanol, ethanol, 2-propanol and 2-methoxyethanol. Connection [40] is used 1-2 times, preference is sustained fashion 1-1,2-fold, molar amount relative to 1 mole of compound [39]. The duration of the reaction varies depending on the nature of the source material and the reaction temperature, but generally is preferably from 30 minutes to 30 hours. In the case of salt you add acid compounds [39] the reaction can be carried out with addition of a suitable base (e.g. potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, and so forth).

Connection [39]used as a starting compound can be obtained in the form of a loose salt or salt adding acid by interaction of the compound [37] with cyanamide as described in the document (see, for example, non-patent document 19).

Connection [40]used as a starting compound can be obtained, for example, in accordance with a modification of the method described in patent document 1.

The method of obtaining 4

[where the values of R1, R2, R3, R4, R5, R6, R7, R8, Het1 and Het2 are defined above; and X7 represents a halogen].

This reaction is a reaction of the cross-combinations using connection [41] and organoboron compounds [14] or ORGANOTIN compounds [15] and can be carried out according to known per se techniques. For example, this reaction is s carried out at 20ºC-200ºc is manageable in a suitable solvent in the presence of palladium catalyst. As the palladium catalyst is usually used tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium and dichlorobis(tri-ortho-tolylphosphino)palladium. The choice of reaction solvent is not specifically limited because it does not participate in the reaction, and examples of the solvent include ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; hydrocarbons, such as benzene, toluene and xylene; organic amines such as pyridine and triethylamine; and mixtures of these solvents. In the case of compounds [14] requires the addition of a base (e.g. sodium hydroxide, potassium carbonate, tribalista and so on). The duration of the reaction varies depending on the nature of the source material and the reaction temperature, but generally is preferably from 1 hour to 48 hours.

Connection [41]used as a starting compound can be obtained, for example, by interaction of the compound [37] with 4-hydroxy-2-methylthiopyridine, when Het1 is a group of the formula [4], or by interaction of the compound [37] with 4-hydroxy-2-methylthiopyrimidine and processing of the reaction product of the acid chloride phosphoric acid (see, for example, non-patent dock is ment 20), when Het1 is a group of the formula [6], or by conducting the reaction as described in the document (see, for example, non-patent document 21) using connection [37] and 2,4-dichloropyrimidine, when Het1 is a group of the formula [6].

The method of obtaining 5

[where the values of R2, R3 and R15, Het1 and Het2 are defined above; and X8 is a halogen].

Stage 1

This reaction is carried out by condensation of compound [11] and the acid chloride [42] in accordance with the method described for the method of obtaining 1.

Stage 2

The compound [1b] (compound [1], where R1 represents-CH2-R15) can be obtained by condensing compounds [43] Amin [35]. This reaction is a condensation reaction of the acid chloride and amines and is conducted according to known per se techniques. This reaction is carried out in a suitable solvent using an excess of amine or in the presence of a base. Examples of suitable bases include pyridine, triethylamine, N,N-aminobutiramida-N-ethylamine, potassium carbonate and sodium bicarbonate. The choice of solvent is not specifically limited because it does not participate in the reaction, and examples of the solvent include ethers such as tetrahydrofuran, diethyl ether and 1,3-dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide NITRILES, such as acetonitrile and propionitrile; hydrocarbons, such as benzene and toluene; alcohols such as methanol and ethanol; water; and mixtures of these solvents. The reaction temperature usually ranges from 0ºC to 100ºC. The duration of the reaction varies depending on the nature of the source material and the reaction temperature, but generally is preferably from 30 minutes to 24 hours.

The method of obtaining 6

[where the values of R1, R2, R3 and Het2 as defined above; and X9 represents a halogen].

The compound [1c] (compound [1], in which Het1 is a group of the formula [10]) can be obtained by interaction of the compound [44] and the compound [45] or its salt add the acid with the formation of rings. This reaction can be carried out in accordance with known per se methods as the method of synthesis of a derivative of 2-aminotriazole (see, for example, non-patent document 13).

Amide derivative according to the present invention can be applied as a medicinal product in free base form, but it can also be applied in the form of pharmaceutically acceptable salts obtained according to known per se techniques. These salts include salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid and phosphoric acid,and organic acid salts, such as acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, para-toluensulfonate acid, benzolsulfonat acid and methanesulfonamide acid.

Hydrochloride amide derivative according to the present invention can be obtained, for example, by dissolving the amide derivative according to the present invention in a solution of hydrogen chloride in alcohol, ethyl acetate, or a simple ester.

As shown below in this document the test examples, the compound of the present invention has a high inhibitory activity against tyrosine kinase BCR-ABL compared to pyrimidine derivatives, disclosed in detail in patent document 1. Therefore, the compound of the present invention can be used as a preventive or therapeutic agent for the treatment of diseases involving tyrosine kinase BCR-ABL, such as chronic myeloid leukemia, acute lymphocytic leukemia and acute myeloid leukemia.

In the case of the introduction of the compounds of the present invention as a drug it can be administered to a mammal, including humans, either alone or in the form of pharmaceutical compositions in which the compound of the present invention and pharmaceutically acceptable non-toxic and inert the media contained in the relation for example, from 0.1% to 99.5%, or preferably 0.5% by 90%.

For the preparation of compositions using one or more auxiliaries, such as fillers or solid, semi-solid or liquid diluents. Is desirable introduction pharmaceutical composition in dosage form for a single admission. The pharmaceutical composition of the present invention can be administered intravenously, orally, directly in the target tissue, topically (e.g., transdermal or rectal. Of course that is used dosage form suitable for the above-described techniques. It is desirable oral administration.

It is desirable to select the dosage of the compound acting as an inhibitor of tyrosine kinase BCR-ABL or a therapeutic agent for the treatment of chronic myeloid leukemia, take into account the condition of the patient, age, body weight, performance and disease severity and other factors such as route of administration; but, usually, for adults, the number of compounds of the present invention ranges from 0.1 mg/person up to 1000 mg/person per day, and preferably from 1 mg/person up to 500 mg/person per day.

In some cases, it is sufficient fewer, and, on the contrary, in some cases, require large quantities. They can be put the m divide the total dose into two or three doses per day.

EXAMPLES

The present invention will be described below in more detail by reference examples, examples, test examples and examples of formulations of the compounds of the present invention, which, however, the present invention is not limited.

Reference example 1

Hydrochloride 3-ethyl-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride

Stage 1

Ethyl-3-iodide-4-methylbenzoate

40,61 g of 3-iodine-4-methylbenzoic acid suspended in 406 ml of ethanol and was added to 9.1 ml of concentrated sulfuric acid and then the mixture was heated under reflux for 24 hours. After removal of the solvent under reduced pressure the residue was mixed with water with ice, podslushivaet aqueous saturated sodium hydrogen carbonate solution and then was extracted twice with ethyl acetate. The extracts are then washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent drove under reduced pressure to get 44,44 g of the crude product as a brown oily product.

Stage 2

Ethyl-4-methyl bromide-3-iodobenzoate

44.4 g of ethyl-3-iodide-4-methylbenzoate obtained in stage 1, was dissolved in 550 ml of carbon tetrachloride was added to 25.3 g of N-bromosuccinimide and 355 mg of benzoyl peroxide and then heated reaction solution under reflux under the influence of light from the incandescent lamp (1500 watts) for 8 hours. Insoluble substances were removed by filtration, and then drove the solvent in the filtrate under reduced pressure to get 56,99 g of the crude product as a reddish-purple crystals.

Stage 3

Ethyl-3-iodide-4-(4-methylpiperazin-1-ylmethyl)benzoate

to 57.0 g of ethyl-4-methyl bromide-3-iodobenzoate obtained in stage 2, was dissolved in 570 ml of anhydrous tetrahydrofuran and after the addition of 22.8 g of potassium carbonate with stirring at room temperature dropwise within 20 minutes was added a solution of 12.1 g of N-methylpiperazine in 70 ml of tetrahydrofuran. After stirring at room temperature for 4 hours, the insoluble matter was removed by filtration and drove the solvent in the filtrate under reduced pressure. The residue was purified by the method of column chromatography on silica gel with getting to 32.9 g of the desired compound as a yellow oily product.

Stage 4

Ethyl-4-(4-methylpiperazin-1-ylmethyl)-3-(trimethylsilylethynyl)benzoate

To of 3.77 g of ethyl-3-iodide-4-(4-methylpiperazin-1-ylmethyl)benzoate obtained in stage 3, has consistently added 34 mg dichloride bis(triphenylphosphine)palladium(II), 19 mg of copper iodide(I), 1.65 ml trimethylsilylacetamide and 38 ml of triethylamine and heated the reaction solution under reflux at 80ºC for 2 hours in argon atmosphere. The reaction solution cooling and air, insoluble substances were removed by filtration, the insoluble matter was washed with ethyl acetate, and then drove the solvent in the filtrate under reduced pressure. To the residue was added ethyl acetate and sequentially washed with a mixture of 5% ammonia, water and saturated salt solution, and then drove the organic layer under reduced pressure. The residue was purified by the method of column chromatography on silica gel with getting 2,60 g of the desired compound as a yellow oily product.

Stage 5

Ethyl-3-ethyl-4-(4-methylpiperazin-1-ylmethyl)benzoate

2,60 g ethyl-4-(4-methylpiperazin-1-ylmethyl)-3-(trimethylsilylethynyl)benzoate obtained in stage 4, was dissolved in 13 ml of methanol was added 3.0 g of potassium carbonate and then stirred the mixture at room temperature for 1 minute. After removal of the solvent under reduced pressure to the reaction mixture were added ethyl acetate and water and the separated aqueous layer. The organic layer was twice washed with water and saturated saline and then dried over anhydrous magnesium sulfate and drove away the solvent under reduced pressure. The residue was dissolved in 26 ml of ethanol and was added 260 mg of 10% palladium carbon, and then was first made the mixture at room temperature under a pressure of 4 ATM for 15 hours. The catalyst was removed by filtration and drove RA is the solvent in the filtrate under reduced pressure to get to 1.83 g of the crude product as a yellow oily product.

Stage 6

3-Ethyl-4-(4-methylpiperazin-1-ylmethyl)benzoic acid

to 1.83 g of ethyl-3-ethyl-4-(4-methylpiperazin-1-ylmethyl)benzoate obtained in stage 5, was dissolved in 20 ml of ethanol was added 10 ml of 1N. an aqueous solution of sodium hydroxide and then the mixture was heated under reflux for 2 hours. The reaction solution was neutralized by adding 10 ml of 1N. hydrochloric acid while cooling on ice. After the distillation of water under reduced pressure, water azeotrope was removed by adding to the residue of toluene to obtain 2.16 g of the crude product as a yellow crystal.

Stage 7

Hydrochloride 3-ethyl-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride

2.16 g of 3-ethyl-4-(4-methylpiperazin-1-ylmethyl)benzoic acid obtained in stage 6, was dissolved in 8.3 ml of thionyl chloride and the mixture was heated under reflux for 16 hours. After cooling the reaction solution in the air to the reaction solution was added diethyl ether, the precipitated crystal was collected by filtration, and then washed with diethyl ether to obtain the crude product.

Reference example 2

The dihydrochloride of 4-(4-methylpiperazin-1-ylmethyl)-3-cryptoperidiniopsoid

Stage 1

Ethyl-4-methyl-3-cryptomelane

This compound was obtained in the same way as described in reference example 1 (stage 1), except that the o they used 4-methyl-3-triftorperasin acid.

Pale yellow oily product

Stage 2

Ethyl-4-methyl bromide-3-cryptomelane

This compound was obtained in the same way as described in reference example 1 (stage 2), except that used ethyl-4-methyl-3-cryptomelane obtained in stage 1.

Pale yellow oily product

Stage 3

Ethyl-4-(4-methylpiperazin-1-ylmethyl)-3-cryptomelane

This compound was obtained in the same way as described in reference example 1 (step 3), except that used ethyl-4-methyl bromide-3-cryptomelane obtained in stage 2.

Yellowish-brown oily product

Stage 4

The dihydrochloride of 4-(4-methylpiperazin-1-ylmethyl)-3-triftorperasin acid

This compound was obtained in the same way as described in reference example 1 (step 6), except that used ethyl-4-(4-methylpiperazin-1-ylmethyl)-3-cryptomelane, obtained in stage 3, and the reaction solution was acidified (pH 3) by adding concentrated hydrochloric acid instead of 1H. of hydrochloric acid.

Pale brown crystals

Melting point 233-238ºC (decomposition)

Stage 5

The dihydrochloride of 4-(4-methylpiperazin-1-ylmethyl)-3-triftormetilfullerenov

This compound was obtained the same way, as described in reference example 1 (step 7), except that used the dihydrochloride of 4-(4-methylpiperazin-1-ylmethyl)-3-triftorperasin acid, obtained in stage 4, and the reaction mixture was heated under reflux for 24 hours.

Colourless crystals

Reference example 3

The dihydrochloride of 3-methoxy-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride

This compound was obtained in the same way as described in reference example 2 (stages 2-5), except that in stage 2 used methyl-3-methoxy-4-methylbenzoate.

Colourless crystals

Reference example 4

The dihydrochloride of 3-chloro-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride

This compound was obtained in the same way as described in reference example 2, except that in stage 1 used 3-chloro-4-methylbenzoic acid.

Colourless crystals

Reference example 5

The dihydrochloride of 4-(4-ethylpiperazin-1-ylmethyl)-3-triftormetilfullerenov

This compound was obtained in the same way as described in reference example 2, except that in stage 2 used N-ethylpiperazin.

Colourless crystals

Reference example 6

Hydrochloride 3,5-dichloro-4-[(S)-3-dimethylaminopropan-1-ylmethyl]benzoyl chloride

Stage 1

Methyl-3,5-dichloro-4-methylbenzoate

This is connected to the e was obtained in the same way, as described in reference example 1 (stage 1), except that used 3,5-dichloro-4-methylbenzoic acid (unexamined patent application for the grant of the Japan patent (Kokai) No. 6-192196), the solvent used methanol, and the crude product was purified by the method of column chromatography on silica gel.

Pale-yellow crystals

Melting point 49-50ºC

Stage 2

Methyl-4-methyl bromide-3,5-dichlorobenzoate

This compound was obtained in the same way as described in reference example 1 (stage 2), except that used methyl-3,5-dichloro-4-methylbenzoate obtained in stage 1, and the reaction mixture was heated under reflux for 2 hours.

Orange crystals

Melting point 63-65ºC

Stage 3

Methyl-3,5-dichloro-4-[(S)-3-dimethylaminopropan-1-ylmethyl]benzoate

This compound was obtained in the same way as described in reference example 1 (step 3), except that used methyl-4-methyl bromide-3,5-dichlorobenzoate obtained in stage 2, and (S)-(-)-3-dimethylaminopyridine, and the reaction was carried out at room temperature for 17 hours.

Pale yellow oily product

Stage 4

3,5-Dichloro-4-[(S)-3-dimethylaminopropan-1-ylmethyl]benzoic acid

This compound was obtained in the same way as described in the reference p is the iMER 1 (stage 6), except that used methyl-3,5-dichloro-4-[(S)-3-dimethylaminopropan-1-ylmethyl]benzoate, obtained in stage 3, the solvent used methanol, and after adding to the residue methanol and stirring the obtained mixture of the insoluble substance was removed by filtration and drove the solvent in the filtrate under reduced pressure to obtain the desired connection.

Pale orange amorphous substance

Stage 5

Hydrochloride 3,5-dichloro-4-[(S)-3-dimethylaminopropan-1-ylmethyl]benzoyl chloride

This compound was obtained in the same way as described in reference example 1 (step 7), except that used 3,5-dichloro-4-[(S)-3-dimethylaminopropan-1-ylmethyl]benzoic acid obtained in stage 4, and the processing after the reaction was that thionyl chloride drove away under reduced pressure, and twice repeated the operation of adding toluene to the residue, followed by azeotropic removal of thionyl chloride.

Pale-yellow crystals

The melting point of 210-219ºC (decomposition)

Reference example 7

The hydrochloride of 4-(1-methylpiperidin-4-ylidenemethyl)-3-triftormetilfullerenov

Stage 1

Ethyl-4-dimethoxyphosphoryl-3-cryptomelane

6.20 g ethyl-4-methyl bromide-3-triftoratsetata (reference example 2 (stage 2)) was dissolved in 12 ml trimethylol the ITA and the mixture was heated under reflux for 4 hours in argon atmosphere. After completion of the reaction was thrice repeated operation of adding toluene to the residue, followed by azeotropic removal of trimethylphosphite. The residue was purified by the method of column chromatography on silica gel with getting 4,96 g of the desired compound as a yellow oily product.

Stage 2

Ethyl-4-(1-methylpiperidin-4-ylidenemethyl)-3-cryptomelane

In an argon atmosphere 624 mg of 60% sodium hydride washed twice with n-hexane, was added to the solution 4,96 g ethyl-4-dimethoxyphosphoryl-3-triftoratsetata obtained in stage 1, and 1.60 ml of N-methylpiperidine dissolved in 50 ml of 1,2-dimethoxyethane, and then gradually heated the mixture up to 85ºC and was heated under reflux for 1 hour. The reaction solution was cooled in the air, mixed with water with ice, and then was extracted twice with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel with getting 3,21 g of the desired compound as a yellow oily product.

Stage 3

4-(1-Methylpiperidin-4-ylidenemethyl)-3-triftorperasin acid

This compound was obtained in the same way as described in reference example 1 (step 6), except that the objects of study were ethyl-4-(1-methylpiperidin-4-ylidenemethyl)-3-cryptomelane, obtained in stage 2.

Yellow amorphous substance

Stage 4

The hydrochloride of 4-(1-methylpiperidin-4-ylidenemethyl)-3-triftormetilfullerenov

This compound was obtained in the same way as described in reference example 1 (step 7), except that used 4-(1-methylpiperidin-4-ylidenemethyl)-3-triftorperasin acid, obtained in stage 3, and the processing after the reaction was that thionyl chloride drove away under reduced pressure, and twice repeated the operation of adding toluene to the residue, followed by azeotropic removal of thionyl chloride.

Greenish-brown amorphous substance

Reference example 8

The hydrochloride of 4-(1-methylpiperidin-4-ylmethyl)-3-triftormetilfullerenov

Stage 1

Ethyl-4-(1-methylpiperidin-4-ylmethyl)-3-cryptomelane

of 1.57 g of ethyl-4-(1-methylpiperidin-4-ylidenemethyl)-3-triptoreline (reference example 7 (stage 2)) was dissolved in 32 ml of methanol and was added 78 mg of 10% palladium carbon, and then was first made the mixture at room temperature under a pressure of 1 ATM for 24 hours. The catalyst was removed by filtration and drove the solvent in the filtrate under reduced pressure. The mixture was again dissolved in 32 ml of methanol and was added 78 mg of 10% palladium carbon, and then was first made the mixture at room temperature under a pressure of 1 ATM for 4 the aces. Then was added 78 mg of palladium charcoal and was first made the mixture at room temperature under a pressure of 1 ATM for 24 hours. Additionally added 78 mg of palladium charcoal and was first made the mixture at room temperature under a pressure of 1 atmosphere for 19 hours. The catalyst was removed by filtration and drove the solvent in the filtrate under reduced pressure to obtain 1.54 g of the desired compound in the form of green oily product.

Stage 2

4-(1-Methylpiperidin-4-ylmethyl)-3-triftorperasin acid

This compound was obtained in the same way as described in reference example 1 (step 6), except that used ethyl-4-(1-methylpiperidin-4-ylmethyl)-3-cryptomelane obtained in stage 1, the crude product was mixed with methanol and stirred, insoluble substances were removed by filtration, the filtrate is kept under reduced pressure, and then led the remainder by adding acetonitrile.

Colourless crystals

Melting point 247-250ºC (decomposition)

Stage 3

The hydrochloride of 4-(1-methylpiperidin-4-ylmethyl)-3-triftormetilfullerenov

This compound was obtained in the same way as described in reference example 1 (step 7), except that used 4-(1-methylpiperidin-4-ylmethyl)-3-triftorperasin acid, extracting the combining stage 2, and the processing after the reaction was that thionyl chloride drove away under reduced pressure, and then twice repeated the operation of adding toluene to the residue, followed by azeotropic removal of thionyl chloride.

Pale green crystals

Melting point 157-164ºC (decomposition)

Reference example 9

Hydrochloride 3-deformity-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride

Stage 1

Tert-butyl-3-iodide-4-methylbenzoate

26,20 g of 3-iodine-4-methylbenzoic acid are suspended in 500 ml of tert-butyl alcohol was added 43,65 g of di-tert-butyl-dicarbonate, and then stirred the mixture at room temperature. To the mixture was added 1.22 g of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 10 minutes and then the mixture was heated under reflux for 4 hours. After removal of the solvent under reduced pressure the residue was mixed with ethyl acetate and additionally drove away under reduced pressure. After adding to the residue 10 ml of ethyl acetate and 30 ml of n-hexane the mixture was mixed. Insoluble substances were removed by filtration and drove the solvent in the filtrate under reduced pressure. To the residue was added 30 ml of n-hexane and carried out with a mixture of the above operation. The residue was purified by the method of column chromatography on silica gel with getting 22,01 g tre the connection has been created in the form of a colorless oily product.

Stage 2

Tert-butyl 3-formyl-4-methylbenzoate

7,00 g of tert-butyl-3-iodide-4-methylbenzoate obtained in stage 1, was dissolved in 200 ml of anhydrous tetrahydrofuran and the mixture was stirred while cooling in a bath of dry ice/acetone in an argon atmosphere. Dropwise at an internal temperature of 66ºC or below was added to 15.5 ml of n-utility (1,6M solution in n-hexane). After stirring for 5 minutes dropwise within 5 minutes was added 3.4 ml of N,N-dimethylformamide and the mixture was stirred for 50 minutes. This slowly was added dropwise 100 ml of water. The mixture was heated to room temperature and then was extracted with ethyl acetate. The mixture was dried over anhydrous magnesium sulfate and drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel with getting 3,76 g of the desired compound as colorless crystals.

The melting point of 53-55ºC

Stage 3

Tert-butyl-3-deformity-4-methylbenzoate

3,76 g of tert-butyl 3-formyl-4-methylbenzoate obtained in stage 2, was dissolved in 17 ml of anhydrous methylene chloride, was added at room temperature a 2.71 ml TRIFLUORIDE diethylaminoethyl (DAST), and then was stirred for 7 hours. The reaction mixture was mixed with ethyl acetate, washed with aqueous saturated sodium bicarbonate and dried over anhydrous magnesium sulfate,and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel with receipt of 3.10 g of the desired compound as a pale yellow oily product.

Stage 4

Tert-butyl-4-methyl bromide-3-deformationof

This compound was obtained in the same way as described in reference example 1 (stage 2), except that used tert-butyl-3-deformity-4-methylbenzoate, obtained in stage 3.

Stage 5

Tert-butyl-3-deformity-4-(4-methylpiperazin-1-ylmethyl)benzoate

This compound was obtained in the same way as described in reference example 1 (step 3), except that used tert-butyl-4-methyl bromide-3-deformationof obtained in stage 4.

Colorless oily product

Stage 6

3-Deformity-4-(4-methylpiperazin-1-ylmethyl)benzoic acid

This compound was obtained in the same way as described in reference example 1 (step 6), except that used tert-butyl-3-deformity-4-(4-methylpiperazin-1-ylmethyl)benzoate obtained in stage 5, the obtained crude product was mixed with methanol and stirred, insoluble substances were removed by filtration, the filtrate is kept under reduced pressure, and then led the remainder by adding acetonitrile.

Colourless crystals

Melting point 160-167ºC (razlozheny is m)

Stage 7

Hydrochloride 3-deformity-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride

This compound was obtained in the same way as described in reference example 1 (step 7), except that used a 3-deformity-4-(4-methylpiperazin-1-ylmethyl)benzoic acid obtained in stage 6.

Colourless crystals

Melting point 217-222ºC (decomposition)

Reference example 10

Hydrochloride 3-vermeil-4-(1-methylpiperazin-4-ylmethyl)of benzoyl chloride

Stage 1

Tert-butyl-4-methyl bromide-3-iodobenzoate

This compound was obtained in the same way as described in reference example 1 (stage 2), except that used tert-butyl-3-iodide-4-methylbenzoate (reference example 9 (step 1)).

Purple oily product

Stage 2

Tert-butyl-3-iodide-4-(1-methylpiperidin-4-ylidenemethyl)benzoate

This compound was obtained in the same way as described in reference example 7 (stages 1 and 2), except that used tert-butyl-4-methyl bromide-3-iodobenzoate obtained in stage 1.

Pale yellow oily product

Stage 3

Tert-butyl 3-formyl-4-(1-methylpiperidin-4-ylidenemethyl)benzoate

This compound was obtained in the same way as described in reference example 9 (stage 2), except that used tert-butyl-3-iodide-4-(1-methylpiperidin-4-ylidene who yl)benzoate, obtained in stage 2, and the obtained product has not been cleared.

Stage 4

Tert-butyl-3-hydroxymethyl-4-(1-methylpiperidin-4-ylidenemethyl)benzoate

of 4.75 g of tert-butyl 3-formyl-4-(1-methylpiperidin-4-ylidenemethyl)benzoate obtained in stage 3, was dissolved 47.5 ml of anhydrous methanol and stirred the mixture with water cooling with ice. To this was added 689 mg of sodium borohydride and the mixture was stirred under cooling for 3.5 hours. The reaction mixture was mixed with ice water and saturated sodium hydrogen carbonate solution and then was extracted three times with ethyl acetate and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel with getting to 2.41 g of the desired compound as a yellow amorphous substance.

Stage 5

Tert-butyl-3-hydroxymethyl-4-(1-methylpiperidin-4-ylmethyl)benzoate

to 2.41 g of tert-butyl 3-hydroxymethyl-4-(1-methylpiperidin-4-ylidenemethyl)benzoate obtained in stage 4, was dissolved in methanol and added 241 mg of 10% palladium carbon, and then was first made the mixture at room temperature under a pressure of 4 ATM for 2 hours. Added 241 mg of 10% palladium charcoal and additionally was first made the mixture at room temperature under a pressure of 4 bar within 12 hours. The catalyst was removed by filtration and d is balali to the filtrate 482 mg of 10% palladium charcoal, and then again was first made the mixture at room temperature under a pressure of 4 ATM for 22 hours. The catalyst was removed by filtration and drove away the solvent under reduced pressure obtaining of 2.34 g of the desired compound as a pale green amorphous substance.

Stage 6

Tert-butyl-3-vermeil-4-(1-methylpiperidin-4-ylmethyl)benzoate

982 mg DAST was dissolved in 10 ml of anhydrous dichloromethane and the mixture was stirred while cooling in a bath of dry ice/acetone in an argon atmosphere. Dropwise for 3 hours was added a solution of 1.77 g of tert-butyl 3-hydroxymethyl-4-(1-methylpiperidin-4-ylmethyl)benzoate obtained in stage 5, in 18 ml of anhydrous dichloromethane and stirred the reaction mixture for 2 hours. After heating to room temperature, to the reaction solution was added a saturated solution of sodium bicarbonate to separate the water layer. The aqueous layer was twice subjected to extraction with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel with getting 954 mg of the crude product as a yellow oily product.

Stage 7

3-Vermeil-4-(1-methylpiperidin-4-ylmethyl)benzoic acid

This compound was obtained in the same way as from ogino in reference example 1 (step 6), except that used tert-butyl-3-vermeil-4-(1-methylpiperidin-4-ylmethyl)benzoate obtained in stage 6, the water drove, was added to the residue methanol, insoluble substances were removed by filtration, and then drove the solvent in the filtrate under reduced pressure.

White amorphous substance

Stage 8

Hydrochloride 3-vermeil-4-(1-methylpiperidin-4-ylmethyl)of benzoyl chloride

This compound was obtained in the same way as described in reference example 1 (step 7), except that used a 3-vermeil-4-(1-methylpiperidin-4-ylmethyl)benzoic acid obtained in stage 7, and the processing after the reaction was that thionyl chloride drove away under reduced pressure, and then twice repeated the operation of adding toluene to the residue, followed by azeotropic removal of thionyl chloride.

Orange amorphous substance

Reference example 11

The hydrochloride of 4-(1-methylpiperidin-4-yloxy)-3-triftormetilfullerenov

Stage 1

4-(1-Methylpiperidin-4-yloxy)-3-cryptomathematical

of 6.68 g of tert-butoxide potassium suspended in 40 ml of anhydrous tetrahydrofuran, with stirring, with water cooling with ice dropwise over 35 minutes was added a solution of 6.85 g of 1-methyl-4-hydroxypiperidine in 20 ml of anhydrous tetrahydrofuran, and optionally stirred mixture during the course the e 30 minutes. At the same time, 7.50 g of 4-fluoro-3-triftormetilfosfinov was dissolved in 40 ml of anhydrous tetrahydrofuran, the mixture was stirred while cooling in a bath of dry ice/acetone and was added dropwise previously prepared solution at an internal temperature of 70ºC. After adding dropwise, the reaction solution was stirred over night, as he naturally was heated to room temperature. The reaction solution was cooled on ice, was added a saturated aqueous solution of ammonium chloride and water, and then drove away the solvent under reduced pressure. The residue was twice subjected to extraction with ethyl acetate. The extracts are then washed with water and saturated saline solution, dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel with getting 7,31 g of the desired compound as colorless crystals.

The melting point of 66-69ºC

Stage 2

4-(1-Methylpiperidin-4-yloxy)-3-triftorperasin acid

1.0 g of 4-(1-methylpiperidin-4-yloxy)-3-triftormetilfosfinov obtained in stage 1, was dissolved in 20 ml of ethanol, was added 17.6 ml 1N. an aqueous solution of sodium hydroxide and the mixture was heated under reflux for 24 hours. After removal of the solvent under reduced pressure the residue is obavljale water. The aqueous layer was once washed with diethyl ether and neutralized by adding to 17.6 ml of 1N. hydrochloric acid while cooling with ice. After the distillation of water under reduced pressure three times repeated the operation is added to the residue methanol, followed by azeotropic removal of water. After adding methanol and stirring the insoluble substance was removed by filtration and drove the solvent in the filtrate under reduced pressure. The obtained crude crystal was washed with acetonitrile to obtain 0.96 g of the desired compound as colorless crystals.

Melting point 254ºC (decomposition)

Stage 3

The hydrochloride of 4-(1-methylpiperidin-4-yloxy)-3-triftormetilfullerenov

800 mg of 4-(1-methylpiperidin-4-yloxy)-3-triftorperasin acid, obtained in stage 2, suspended in anhydrous toluene and successively added to 0.94 ml of thionyl chloride and 80 μl of anhydrous N,N-dimethylformamide, and then the mixture was heated under reflux for 18 hours. After stirring under cooling with water with ice, the precipitated crystals were collected by filtration, and then washed with toluene to obtain 500 mg of the desired compound as colorless crystals.

Melting point 242ºC (decomposition)

Reference example 12

4-[(R)-3-Dimethylaminopropan-1-ylmethyl)-3-cryptomelane the Naya acid

This compound was obtained in the same way as described in reference example 2 (stages 1-4), except that in stage 3 used (R)-(+)-3-dimethylaminopyridine, in stage 4, the reaction solution was neutralized (pH 7) by adding 1N. hydrochloric acid instead of concentrated hydrochloric acid, and the crude product was purified by the method of column chromatography on silica gel.

Colourless crystals

Melting point 206-209ºC (decomposition)

Reference example 13

4-[4-(Tert-butoxycarbonyl)piperazine-1-ylmethyl]-3-triftorperasin acid

This compound was obtained in the same way as described in reference example 2 (stages 1-4), using in stage 3 N-(tert-butoxycarbonyl)piperazine. However, in stage 4 the reaction was carried out at room temperature for 3 hours; the reaction solution was neutralized (pH 7) by adding 1N. hydrochloric acid instead of concentrated hydrochloric acid, and then extracted with ethyl acetate; and the resulting crude product is obtained by purification according to the method of column chromatography on silica gel, washed with n-hexane.

Colourless crystals

Melting point 131-136ºC (decomposition)

Reference example 14

4-[4-(2-Foradil)piperazine-1-ylmethyl]-3-triftorperasin acid

Stage 1

Ethyl-4-[4-(2-hydroxyethyl)piperazine-1-ylmethyl]-3-Tr is formatives

This compound was obtained in the same way as described in reference example 2 (step 3), except that used 1-(2-hydroxyethyl)piperazine.

Yellow oily product

Stage 2

Ethyl-4-[4-(2-foradil)piperazine-1-ylmethyl]-3-cryptomelane

4,50 g ethyl-4-[4-(2-hydroxyethyl)piperazine-1-ylmethyl]-3-triftoratsetata obtained in stage 1, was dissolved in 90 ml of anhydrous dichloromethane and the mixture was stirred while cooling in a bath of dry ice/acetone in an argon atmosphere. Dropwise within 20 minutes solution was added a 4.03 g DAST in 50 ml of anhydrous dichloromethane and stirred the reaction solution for 10 minutes. The reaction solution was stirred for 1 hour while cooling with ice, and then stirred at room temperature for 2 hours. The reaction solution was podlachian (pH 9) by addition of ice and 100 ml of aqueous saturated solution of sodium bicarbonate, and then remove insoluble substances by filtration. The filtrate was subjected to extraction with ethyl acetate and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel to obtain 2.16 g of the desired compound as a yellow oily product.

Stage 3

4-[4-(2-Foradil)piperazine-1-ylmethyl]-3-triptime Ventana acid

This compound was obtained in the same way as described in reference example 1 (step 6), except that used ethyl-4-[4-(2-foradil)piperazine-1-ylmethyl]-3-cryptomelane obtained in stage 2, and after neutralization of the aqueous layer was extracted with ethyl acetate, the separated aqueous layer was mixed with saturated salt solution, was subjected to extraction with ethyl acetate, optionally mixed with sodium chloride, and then was extracted five times with ethyl acetate.

Colourless crystals

Melting point 152-155ºC (decomposition)

Reference example 15

4-{4-[2-(Tert-butyldimethylsilyloxy)ethyl]piperazine-1-ylmethyl}-3-triftorperasin acid

Stage 1

Ethyl-4-[4-(2-(tert-butyldimethylsilyloxy)piperazine-1-ylmethyl)-3-cryptomelane

2,82 g ethyl-4-[4-(2-hydroxyethyl)piperazine-1-ylmethyl]-3-triftoratsetata (reference example 14 (stage 1)) was dissolved in anhydrous N,N-dimethylformamide and consistently added to 1.33 g of imidazole and 1.42 g of tert-butyldimethylchlorosilane, and then stirred the mixture at room temperature for 1 hour. The reaction mixture was mixed with water, then was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel with the teachings 3,70 g of the desired compound as a pale yellow oily product.

Stage 2

4-[4-(2-Tert-butyldimethylsilyloxy-1-ylmethyl)-3-triftorperasin acid

This compound was obtained in the same way as described in reference example 1 (step 6), except that used ethyl-4-[4-(2-tert-butyldimethylsilyloxy-1-ylmethyl)-3-cryptomelane obtained in stage 1, as a solvent, and after neutralization used ethanol, the aqueous layer was twice subjected to extraction with ethyl acetate, and the organic layer was washed with saturated salt solution.

Pale yellow amorphous substance

Reference example 16

4-[1-Tert-butoxycarbonyl-2-carbamoylbiphenyl-4-ylmethyl]-3-triftorperasin acid

Stage 1

Ethyl-4-(3-carbamoylbiphenyl-1-ylmethyl)-3-cryptomelane

This compound was obtained in the same way as described in reference example 2 (step 3), except that used 2-carbamoylbiphenyl.

Colorless oily product

Stage 2

Ethyl-4-[1-tert-butoxycarbonyl-2-carbamoylbiphenyl-4-ylmethyl]-3-cryptomelane

of 3.07 g of ethyl-4-(3-carbamoylbiphenyl-1-ylmethyl)-3-triftoratsetata obtained in stage 1, and 0.20 g of 4-dimethylaminopyridine was dissolved in 34 ml of acetonitrile and added to 1.96 g of di-tert-butyl-dicarbonate, and then stirred the mixture at room temperature for chasov. The precipitated crystal was collected by filtration, and then washed with a small amount of acetonitrile with the receipt of 2.08 g of the desired compound as colorless crystals.

Melting point 124-125ºC

Stage 3

4-[1-Tert-butoxycarbonyl-2-carbamoylbiphenyl-4-ylmethyl]-3-triftorperasin acid

2,84 g ethyl-4-[1-tert-butoxycarbonyl-2-carbamoylbiphenyl-4-ylmethyl]-3-triftoratsetata obtained in stage 2, suspended in 15 ml of methanol was added 10 ml of 1N. an aqueous solution of sodium hydroxide, and then stirred the reaction solution at room temperature for 18 hours. The reaction solution was neutralized by adding 10 ml of 1N. of hydrochloric acid. The precipitated crystal was collected by filtration, and then washed with water to obtain of 2.51 g of the desired compound as colorless crystals.

The melting point of 230-233ºC (decomposition)

Reference example 17

4-[(S)-3-Tert-butoxycarbonylamino-2-oxopyrrolidin-1-ylmethyl]-3-triftorperasin acid

Stage 1

Ethyl-4-[(S)-3-tert-butoxycarbonylamino-2-oxopyrrolidin-1-ylmethyl]-3-cryptomelane

669 mg (S)-3-tert-butoxycarbonylamino-2-it (J. Med. Chem., 1999, 42, 3557-3571) was dissolved in 30 ml of tetrahydrofuran/N,N-dimethylformamide (9/1) and the mixture was stirred under cooling on ice. Was added 60% sodium hydride and paramashiva and mix for 20 minutes. Was added dropwise a solution (3 ml), ethyl-4-methyl bromide-3-triftoratsetata (reference example 2 (stage 2)) in tetrahydrofuran and then stirred at room temperature for 6 hours after removal of the ice bath. The reaction solution was poured into a saturated aqueous solution of ammonium chloride, then was extracted twice with ethyl acetate, dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel with getting 867 mg of the desired compound as pale yellow crystals.

The melting point of 93-95ºC

Stage 2

4-((S)-3-Tert-butoxycarbonylamino-2-oxopyrrolidin-1-ylmethyl)-3-triftorperasin acid

829 mg of ethyl-4-((S)-3-tert-butoxycarbonylamino-2-oxopyrrolidin-1-ylmethyl)-3-triftoratsetata obtained in stage 1, was dissolved in 5 ml of methanol and was added to 2.9 ml of 1N. an aqueous solution of sodium hydroxide, and then stirred the reaction solution at room temperature for 20 hours. The reaction solution was neutralized by the addition of 2.9 ml of 1N. hydrochloric acid and kept off the methanol under reduced pressure. The residue was mixed with water, then was extracted with ethyl acetate, and then dried over anhydrous magnesium sulfate. The solvent drove under reduced pressure to obtain 800 mg of the desired is soedineniya in the form of a pale yellow amorphous substance.

Reference example 18

4-Methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]aniline

Stage 1

3-Dimethylamino-1-(5-pyrimidinyl)-2-propen-1-he

6,01 g of N,N-dimethylformamidine was added 1.54 g of 5-acetylpyridine (Khim. Geterotsikl. Soedim., 1981, (7), 958-962) and the mixture was heated under reflux for 15 hours. After cooling the reaction solution in air was added a small amount of diisopropyl ether and collecting the precipitated crystal by filtration to obtain 1.52 g of the desired compound as reddish brown crystals.

Melting point 133-135ºC

Stage 2

1-(2-Methyl-5-nitrophenyl)guanidine

To 135 g of nitrate 1-(2-methyl-5-nitrophenyl)guanidine (unexamined patent application for the grant of the Japan patent (Kokai) No. 6-87834) was directly added 21 g of sodium hydroxide in 1.0 l of cold water solution, and then stirred at room temperature for 10 minutes. The crystals were filtered, washed with plenty of water, and then dried by air flow at 60ºC to obtain 102 g of the desired compound as pale yellow crystals.

The melting point of 135-142ºC

Stage 3

1-Methyl-4-nitro-2-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]benzene

To 1.51 g of 3-dimethylamino-1-(5-pyrimidinyl)-2-propen-1-she received in stage 1, was added 1.66 g of 1-(2-methyl-5-nitrophenyl)guanidine, polucen is th at stage 2, and then was stirred at 120ºC for 2 hours. To the mixture was added 2-propanol, collecting the crystals by filtration, and then washed with 2-propanol and diethyl ether obtaining of 1.95 g of the desired compound as pale brown crystals.

Melting point 200-203ºC

Stage 4

4-Methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]aniline

18,50 g of 1-methyl-4-nitro-2-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]benzene obtained in stage 3, suspended in 1.3 l of tetrahydrofuran/methanol (1/1) and was added in an argon atmosphere 7,40 g of 10% palladium charcoal. Under stirring at room temperature was added 9,06 ml of formic acid, and then heated reaction solution under reflux for 1 hour. After cooling the reaction solution in air, the catalyst was removed by filtration, washed with methanol and drove the solvent in the filtrate under reduced pressure. The residue was dissolved in chloroform. For separation of the aqueous layer to the residue was added a saturated aqueous solution of sodium bicarbonate. The aqueous layer was twice subjected to extraction with chloroform. The organic layers were combined and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. Amorphous substance obtained by purification of the residue by the method of column chromatography on Sealy is agile, was led by adding chloroform to the receipt of $ 11.97 g of the desired compound as pale yellow crystals.

Melting point 164-167ºC

Reference example 19

3-[4-(5-Bromopyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline

Stage 1

5-Bromonicotinate

To 5,00 g 5-bromonicotinic acid was added 74 ml of thionyl chloride and the mixture was heated under reflux for 6 hours. After removal of the solvent under reduced pressure, the crystals washed with diisopropyl ether and collected by filtration to obtain 4.09 g of the desired compound as colorless crystals.

The melting point of 72-74ºC

Stage 2

3-Acetyl-5-bromopyridin

1.24 g of powdered magnesium chloride suspended in 13 ml of toluene and successively added 6.2 ml of triethylamine and 2.93 g of diethylmalonate. After stirring at room temperature for 1.5 hours dropwise within 15 minutes was added to the suspension 4,08 g 5-bromonicotinate obtained in stage 1, in 10 ml of toluene and then stirred at room temperature for 2 hours. After neutralization by adding 40 ml of 1N. hydrochloric acid was separated the aqueous layer. Then the aqueous layer was subjected to extraction with diethyl ether, combined organic layers, and then drove away the solvent under reduced pressure. It received maslany what this product was added dimethyl sulfoxide/water (17 ml/0.7 ml), and then was stirred with heating at 150-160ºC for 2 hours. The reaction solution was cooled in air, and then added water. Then the precipitated crystals were collected by filtration. The precipitated crystals were dissolved in ethyl acetate, then washed with water and saturated aqueous sodium bicarbonate, and then dried over anhydrous magnesium sulfate. Added to 0.60 g of activated carbon (Kyoryoku Shirasagi MOIWY433), was kept for 10 minutes, removed, activated carbon by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by the method of column chromatography on silica gel with getting 0,89 g of the desired compound as pale yellow crystals.

Melting point 87-89,5ºC

Stage 3

1-(5-Bromopyridin-3-yl)-3-dimethylamino-2-propen-1-he

To 859 mg of 3-acetyl-5-bromopyridine obtained in stage 2, was added 563 mg of N,N-dimethylformamidine and the mixture was heated under reflux for 1 hour. After air cooling, the reaction solution was directly purified by the method of column chromatography on silica gel. The obtained crude crystals were washed with diethyl ether and then collected by filtration to obtain 860 mg of the desired compound as yellow crystals.

Melting point 131-131,5ºC

Stage 4

2-[4-(5-Bromopyridin-3-the l)pyrimidine-2-ylamino]-1-methyl-4-nitrobenzene

To 833 mg of 1-(5-bromopyridin-3-yl)-3-dimethylamino-2-propen-1-she received at stage 3, and 634 mg of 1-(2-methyl-5-nitrophenyl)guanidine (reference example 6 (stage 2)) was added 7 ml of 2-propanol and the mixture was heated under reflux for 17 hours. After cooling the reaction solution to air the precipitated crystals were collected by filtration and washed with diethyl ether to obtain 823 mg of the desired compound as pale yellow crystals.

Melting point 206-208ºC

Stage 5

3-[4-(5-Bromopyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline

To 807 mg of 2-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-1-methyl-4-nitrobenzene obtained in stage 4, was added 5 ml of concentrated hydrochloric acid and stirring with heating at 55ºC was added a solution of 2.36 g two-water chloride tin(II) in 3.5 ml of concentrated hydrochloric acid. The mixture was gradually heated to 100ºC and additionally stirred at 100ºC for 15 minutes. After cooling the reaction solution in air was added water and was podslushivaet solution by adding 10% aqueous sodium hydroxide solution. After adding chloroform and stirring for some time, insoluble substances were removed by filtration and the separated aqueous layer. The aqueous layer was further subjected to extraction with chloroform, and the organic layers were combined and thenali the solvent under reduced pressure after drying over anhydrous sodium sulfate. The residue was purified by the method of column chromatography on silica gel to obtain the crude product. The crude product was led by addition of diethyl ether/ethyl acetate and collecting the crystals by filtration to obtain 528 mg of the desired compound as yellow crystals.

The melting point of 129.5-130ºC

Reference example 20

4-Methyl-3-[6-(3-pyridyl)pyrimidine-4-ylamino]aniline

Stage 1

2-[6-Chloropyrimidine-4-ylamino]-1-methyl-4-nitrobenzene

2.64 g of 2-methyl-5-nitroaniline and 10,33 g of 4,6-dichloropyrimidine was stirred with heating at 110ºC for 16 hours. After air cooling, the reaction solution was dissolved in methanol. For separation of the aqueous layer was added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. Then the aqueous layer was twice subjected to extraction with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel to obtain the crude product. The crude product is washed with diisopropyl ether to obtain 3,61 g of the desired compound as yellow crystals.

Melting point 161-163ºC

Stage 2

1-Methyl-4-nitro-2-[6-(3-pyridyl)pyrimidine-4-ylamino]benzene

a 2.00 g of 2-[6-chloropyrimidine-4-ylamino]-1-m is Tyl-4-nitrobenzene, obtained in stage 1, was dissolved in 80 ml of tetrahydrofuran, was sequentially added to 1.22 g of diethyl(3-pyridyl)borane and 870 mg tetrax(triphenylphosphine)palladium(0), and then stirred the mixture at room temperature in argon atmosphere. To the mixture was added 1.27 g of potassium hydroxide and 10 ml of water, and then heated reaction solution under reflux for 6 hours. The reaction mixture was mixed with water, then was extracted three times with ethyl acetate, dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The crude crystals were washed with ethyl acetate to obtain 1,43 g of the desired compound as brown crystals.

The melting point of 187-192ºC

Stage 3

4-Methyl-3-[6-(3-pyridyl)pyrimidine-4-ylamino]aniline

1.85 g of 1-methyl-4-nitro-2-[6-(3-pyridyl)pyrimidine-4-ylamino]benzene obtained in stage 2, suspended in 74 ml of anhydrous methanol was added 555 mg of 10% palladium charcoal. In an atmosphere of argon was added 3.80 g of ammonium formate and the mixture was heated under reflux at a bath temperature of 90ºC for 4 hours. The catalyst was removed by filtration and drove the solvent in the filtrate under reduced pressure. The residue was mixed with water and twice subjected to extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then Athena and the solvent under reduced pressure. The residue was led by addition of ethyl acetate with the receipt of 1.41 g of the desired compound as pale yellow crystals.

The melting point of 176 179ºC

Reference example 21

4-Methyl-3-[6-(5-pyrimidinyl)pyrimidine-4-ylamino]aniline

Stage 1

1-Methyl-4-nitro-2-[6-(5-pyrimidinyl)pyrimidine-4-ylamino]benzene

3.28 g of 2-[(6-chloro)pyrimidine-4-ylamino]-1-methyl-4-nitrobenzene (reference example 20 (stage 1)) was dissolved by heating in 130 ml of anhydrous ethanol. Added 1,69 g dihydroxy(5-pyrimidinyl)borane, and then spent a deaeration followed by purging with argon. Consistently added of 5.82 g of potassium carbonate and 2.15 g tetrax(triphenylphosphine)palladium(0), and then the mixture was heated under reflux for 7.5 hours. The reaction mixture was mixed with water, then was extracted twice with ethyl acetate, dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was led by adding chloroform/methanol to obtain 808 mg of the desired compound in the form of buff crystals.

Melting point 257-261ºC (decomposition)

Stage 2

4-Methyl-3-[6-(5-pyrimidyl)pyrimidine-4-ylamino]aniline

This compound was obtained in the same way as described in reference example 20 (stage 3), except that used 1-methyl-4-nitro-2-[6-(5-pyrimidyl)p is rimidine-4-ylamino]benzene, obtained in stage 1, and the reaction was conducted for 1.5 hours.

Yellow crystals

Melting point 98-102ºC (decomposition)

Reference example 22

4-Methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]aniline

Stage 1

2-[(4-Chloro)pyridine-2-ylamino]-1-methyl-4-nitrobenzene

To 2.00 g of 2,4-dichloropyridine, and 2.26 g of 2-methyl-5-nitroaniline, 121 mg of palladium(II)acetate, 336 mg (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [(±)-BINAP] and 6,16 g of cesium carbonate was added 120 ml of toluene and then the mixture was stirred with heating at 70ºC for 23 hours in argon atmosphere. After removing insoluble substances by filtration drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel to obtain the crude product. The crude product was washed with diethyl ether to obtain 1.22 g of the desired compound as yellow crystals.

Melting point 130-133ºC

Stage 2

1-Methyl-4-nitro-2-[4-(5-pyrimidinyl)pyridine-2-ylamino]benzene

To 120 ml of deaerated mixture of tetrahydrofuran/water (1/1), was added 1.73 g of 2-[4-chloropyridin-2-ylamino]-1-methyl-4-nitrobenzene obtained in stage 1, 890 mg dihydroxy(5-pyrimidinyl)borane, 3,10 g of potassium carbonate, and 1.15 g tetrax(triphenylphosphine)palladium(0) and the stirred mixture heated at 80ºC for 46 hours in argon atmosphere. DL the separation of the aqueous layer of the reaction solution was diluted with ethyl acetate, and then the aqueous layer was further subjected to extraction with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel to obtain the crude product. The crude product was washed with diethyl ether to obtain 820 mg of the desired compound as orange crystals.

Melting point 229-230ºc is (decomposition)

Stage 3

4-Methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]aniline

163 mg of 1-methyl-4-nitro-2-[4-(5-pyrimidinyl)pyridine-2-ylamino]benzene obtained in stage 2, was dissolved in 32 ml of tetrahydrofuran/methanol (1/1) and was added 98 mg of 10% palladium charcoal. In addition, it was added 284 mg of ammonium formate and the mixture was heated under reflux at a bath temperature of 90ºC for 40 minutes. The catalyst was removed by filtration and drove the solvent in the filtrate under reduced pressure. For separation of the aqueous layer to the residue were added water and ethyl acetate. The aqueous layer was further subjected to extraction with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel to obtain 149 mg of the desired connected to the I in the form of pale yellow crystals.

The melting point of 179-180ºC

Reference example 23

4-Methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]aniline

Stage 1

1-Methyl-4-nitro-2-[4-(3-pyridinyl)pyridine-2-ylamino]benzene

This compound was obtained in the same way as described in reference example 22 (step 2), except that used diethyl(3-pyridyl)borane, and the crude product is obtained by purification according to the method of column chromatography on silica gel, was led by addition of chloroform/methanol.

Orange crystals

The melting point of 170-173ºC (decomposition)

Stage 2

4-Methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]aniline

To 126 mg of 1-methyl-4-nitro-2-[4-(3-pyridinyl)pyridine-2-ylamino]benzene obtained in stage 1, was added 1 ml of concentrated hydrochloric acid and stirring with heating at 60ºC solution was added 465 mg two-water chloride tin (II) in 1 ml of concentrated hydrochloric acid. The mixture was gradually heated to 100ºC and additionally stirred at 100ºC for 40 minutes. After cooling the reaction solution in air was added water and was podslushivaet solution by adding 10% aqueous sodium hydroxide solution. The reaction solution was thrice subjected to extraction with ethyl acetate and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. Received n the purified crystals were washed with a small amount of chloroform, and then collected by filtration to obtain 93 mg of the desired compound as pale yellow crystals.

Melting point 183-186ºC

Reference example 24

The dihydrochloride of 1-methylpiperazin-2-carboxamide

Stage 1

4-Tert-butoxycarbonyl-1-methylpiperazin-2-carboxamide

A solution of 6.00 g of 4-tert-butoxycarbonylmethyl-2-carboxamide and 3.28 g of 37% aqueous formaldehyde solution in 60 ml of methanol was cooled on ice and added 16,66 g triacetoxyborohydride sodium, and then stirred at room temperature for 24 hours after removal of the ice bath. The reaction solution was again cooled on ice was added 3.28 g of 37% aqueous formaldehyde and 16,66 g triacetoxyborohydride sodium. After stirring at room temperature for 16 hours the reaction solution was diluted with water with ice, podslushivaet aqueous saturated sodium hydrogen carbonate solution and then was extracted three times with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel with getting 5,42 g of the desired compound as colorless crystals.

Melting point 137-138ºC

Stage 2

The dihydrochloride of 1-methylpiperazin-2-carboxamide

of 5.40 g of 4-tert-bout xianbei-1-methylpiperazin-2-carboxamide, obtained in stage 1, was dissolved in 29 ml of methanol, was added 48 ml of hydrochloric acid/methanol (Reagent 10, Tokyo Chemical Industry Co., Ltd.) and the mixture was heated under reflux for 6 hours. The reaction solution was concentrated under reduced pressure and dried under reduced pressure to get 5,97 g of the crude product in the form of blue-green oily product.

Reference example 25

The dihydrochloride of 3-dimethylaminomethylene

Stage 1

1-Tert-butoxycarbonyl-3-dimethylaminomethylene

To a solution of 920 mg of 1-tert-butoxycarbonyl-3 - aminomethylpyridine in 18 ml of methanol was sequentially added to 5.66 ml of acetic acid, 4.12 g of 37% aqueous formaldehyde 3.14 g triacetoxyborohydride sodium, and then stirred at room temperature for 20 hours. The reaction solution was podslushivaet by adding saturated aqueous sodium hydrogen carbonate solution and three times was subjected to extraction with ethyl acetate. The organic layers were combined, washed with water, and then dried over anhydrous magnesium sulfate. Then drove the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel with getting 673 mg of the desired compound as colorless oily product.

Stage 2

The dihydrochloride of 3-dimethylaminomethylene

This was soedineniya the same way as described in reference example 24 (stage 2), except that used 1-tert-butoxycarbonyl-3-dimethylaminomethylene obtained in stage 1.

Pale yellow oily product

Reference example 26

The dihydrochloride (S)-3-N,N-diethylaminopropylamine

Stage 1

(S)-1-Benzyloxycarbonyl-3-N,N-diethylaminopropyl

To a solution of 1.40 g (S)-3-amino-1-benzyloxycarbonylglycine (J. Med. Chem., 1992, 35, 1764-1773) in 28 ml of tetrahydrofuran under stirring with cooling on ice was added 2.6 g of potassium carbonate and 1.0 ml of ethyliodide, and then was stirred for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with water, then was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel with getting 0,70 g of the desired compound as a yellow oily product.

Stage 2

The dihydrochloride (S)-3-N,N-diethylaminopropylamine

700 mg of (S)-1-benzyloxycarbonyl-3-N,N-diethylaminopropylamine obtained in stage 1, was dissolved in 28 ml of methanol and was added 70 mg of 10% palladium carbon, and then was first made the mixture at room temperature under a pressure of 3 ATM for 2 hours. The catalyst was removed by filtration and added to the filtrate 10 ml of 10% with what Laney acid/methanol, and then concentrated under reduced pressure to obtain 576 mg of the crude product.

Reference example 27

Hydrochloride (S)-3-(1-pyrrolidinyl)pyrrolidine

Stage 1

(S)-1-benzyl-3-(1-pyrrolidinyl)pyrrolidin

a 2.00 g (R)-1-benzyl-3-pair-of colorselectionmodel (J. Med. Chem., 1992, 35, 4205-4208) was dissolved in 12 ml of ethanol was added 1.63 g of pyrrolidine, and then stirred the mixture at 140ºC for 20 hours in a sealed vessel. The reaction solution was concentrated under reduced pressure, mixed with water, then was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel to obtain 0.97 g of the desired compound as a brown oily product.

Stage 2

Hydrochloride (S)-3-(1-pyrrolidinyl)pyrrolidin

0.97 g (S)-1-benzyl-3-(1-pyrrolidinyl)pyrrolidine obtained in stage 1, was dissolved in 30 ml of ethanol and added 4,21 ml of 1N. of hydrochloric acid. Added 1.68 g of 10% palladium carbon, and then was first made the mixture at room temperature under normal pressure during the night. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain 0.74 g of the crude product in the form of a slightly reddish oily product.

The background is the first example 28

The dihydrochloride of (3S,4S)-3-dimethylamino-4-ethoxypyrrolidine

Stage 1

(3S,4S)-1-tert-butoxycarbonyl-3-dimethylamino-4-hydroxypyrrolidine

This compound was obtained in the same way as described in reference example 25 (stage 1), except that used the (3S,4S)-1-tert-butoxycarbonyl-3-hydroxy-4-methylaminopropane (Tetrahedron: Asymmetry, 2001, 12, 2989-2997), the reaction was conducted for 1 hour while cooling on ice, the reaction solution was podslushivaet by adding 1N. an aqueous solution of sodium hydroxide, methanol mostly drove away under reduced pressure, and then was extracted twice with ethyl acetate.

Colorless oily product

Stage 2

(3S,4S)-1-tert-butoxycarbonyl-3-dimethylamino-4-ethoxypyrrolidine

To a suspension 448 mg of 60% sodium hydride in 5 ml of anhydrous N,N-dimethylformamide was added to 1.59 g methyliodide dropwise under stirring with cooling on ice was added a solution of 2.15 g of (3S,4S)-1-tert-butoxycarbonyl-3-dimethylamino-4-hydroxypyrrolidine obtained in stage 1, dissolved in 10 ml of anhydrous N,N-dimethylformamide, and then stirred at room temperature for 1 hour after removal of the ice bath. The reaction solution was cooled on ice and was added dropwise thereto 1% aqueous solution of acetic acid, and then twice subjected to a mixture of ethyl acetate extraction. Organic SL and United, was washed with saturated saline and then dried over anhydrous sodium sulfate. Then drove the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel to obtain 1.10 g of the desired compound as colorless oily product.

Stage 3

The dihydrochloride of (3S,4S)-3-dimethylamino-4-ethoxypyrrolidine

This compound was obtained in the same way as described in reference example 24 (stage 2), except that used the (3S,4S)-1-tert-butoxycarbonyl-3-dimethylamino-4-ethoxypyrrolidine obtained in stage 2, and the reaction was carried out at 80ºC for 1.5 hours.

Yellow oily product

Reference example 29

The dihydrochloride (2R,4S)-4-dimethylamino-2-methylpyrrolidine

Stage 1

(2R,4R)-1-tert-butoxycarbonyl-2-methyl-4-para-colorselectionmodel

To a solution of 1.02 g of (2R,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-methylpyrrolidine (J. Med. Chem., 1988, 31, 1598-1611) in 10 ml of anhydrous dichloromethane was added 1.7 ml of triethylamine and of 1.16 g of para-toluensulfonate, and then stirred the mixture at room temperature over night. The reaction mixture was mixed with water and then was extracted twice with ethyl acetate. The organic layers were combined, sequentially washed with water, 1N. hydrochloric acid and 1N. aqueous solution of sodium hydroxide, dried in the sodium sulfate, and then drove the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel to obtain 1.54 g of the desired compound as colorless oily product.

Stage 2

(2R,4S)-1-tert-butoxycarbonyl-4-dimethylamino-2-methylpyrrolidine

To 1,99 g of (2R,4R)-1-tert-butoxycarbonyl-2-methyl-4-pair-of colorselectionmodel obtained in stage 1, was added 50 ml of dimethylamine (2M solution in methanol), and then stirred the mixture at 140ºC overnight in a sealed vessel. The reaction solution was concentrated under reduced pressure and then the residue was purified by the method of column chromatography on silica gel with getting 874 mg of the desired compound as a brown oily product.

Stage 3

The dihydrochloride (2R,4S)-4-dimethylamino-2-methylpyrrolidine

This compound was obtained in the same way as described in reference example 24 (stage 2), except that used the (2R,4S)-1-tert-butoxycarbonyl-4-dimethylamino-2-methylpyrrolidine obtained in stage 2, and the reaction was carried out at 80ºC for 2 hours.

Brown oily product

Reference example 30

(S)-3-N-tert-butoxycarbonyl-N-methylaminopropyl

Stage 1

(S)-1-benzyl-3-N-tert-butoxycarbonyl-N-methylaminopropyl

of 0.67 g (S)-1-benzyl-3-methylaminopropane (J. Med. Chem., 1992, 35,4205-4213) was dissolved in 5 ml of dichloromethane, solution was added di-tert-BUTYLCARBAMATE in 5 ml dichloromethane and stirred the mixture at room temperature over night. The reaction solution was concentrated under reduced pressure, and then the crude product was purified by the method of column chromatography on silica gel with getting to 0.80 g of the desired compound as colorless oily product.

Stage 2

(S)-3-N-tert-butoxycarbonyl-N-methylaminopropyl

0,80 g (S)-1-benzyl-3-N-tert-butoxycarbonyl-N-methylaminopropane obtained in stage 1, was dissolved in 18 ml of ethanol, was added 1.10 g of 10% palladium carbon, and then was first made the mixture at room temperature under normal pressure during the night. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure obtaining at 0.42 g of the desired compound as colorless oily product.

Reference example 31

4-methyl bromide-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Stage 1

4-methyl bromide-3-triftorperasin acid

To 60,0 g of 4-methyl-3-triftorperasin acid was added to 600 ml of isopropylacetate. Under stirring at room temperature was sequentially added a solution of 133.0 g of sodium bromate in 420 ml of water and the solution of 91.7 g of hydrosulfite of sodium in 180 ml of water. The mixture was gradually heated from 30ºC to 50 the C with an interval of 10ºC and stirred until the disappearance of the staining reaction solution. The aqueous layer was separated and removed, the organic layer was added a solution of 133.0 g of sodium bromate in 420 ml of water and the solution of 91.7 g of hydrosulfite of sodium in 180 ml of water, and then gradually heated the mixture up to 60ºC, as described above. After separation the organic layer was additionally added to the solution 133.0 g of sodium bromate in 420 ml of water and the solution of 91.7 g of hydrosulfite of sodium in 180 ml of water and gradually heat the mixture as described above to a temperature of phlegmy. After completion of the reaction, the reaction solution was separated, the organic layer was twice washed with 5% aqueous sodium thiosulfate solution and twice with 15% salt solution, dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. To the residue was added 120 ml of n-heptane, and the mixture was stirred, and then collecting the crystals by filtration to obtain 50.0 g of the desired compound as colorless crystals.

Melting point 140-143ºC

Stage 2

4-methyl bromide-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

of 7.69 g of 4-methyl bromide-3-triftorperasin acid, obtained in stage 1, suspended in 154 ml of anhydrous dichloromethane. While stirring with cooling on ice, was added dropwise 6,59 ml oxalicacid and 0.1 ml of anhydrous N,N-dimethylformamide. The mixture was additionally stirred with cooling on ice for 3 h, the owls, and then concentrating the reaction solution under reduced pressure. To the residue was added 70 ml of anhydrous 1,4-dioxane and then added to 7.00 g of 4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]aniline (reference example 18) and 4,18 g of potassium carbonate and then stirred at room temperature for 18 hours. To the reaction solution was added to 175 ml of water and vigorously stirred mixture for 1 hour. Then the precipitate was collected by filtration and then washed with water, a small amount of acetonitrile, ethyl acetate and diisopropyl ether to obtain 8,10 g of the desired compound as pale yellow crystals.

Melting point 198-202ºC (decomposition)

Reference example 32

4-(Piperazine-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that used piperazine in an amount of 10 equivalents relative to the starting material.

Pale-yellow crystals

Melting point 208-213ºC

Reference example 33

4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-[4-methyl-3-theoreticity]benzamid

Stage 1

4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-(3-amino-4-were)benzamid

1.04 g of 2,4-diaminotoluene, 104 mg of 4-dimethylaminopyridine S4,9 ml of N,N-aminobutiramida-N-ethylamine was dissolved in 40 ml of acetonitrile. While stirring with cooling on ice four portions was added 3,70 g of the dihydrochloride of 4-(4-methylpiperazin-1-ylmethyl)-3-triftormetilfullerenov (reference example 2). After stirring for 1 hour and chased off the solvent under reduced pressure and diluted with water. The reaction solution was podslushivaet aqueous saturated sodium hydrogen carbonate solution and then was extracted twice with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified by the method of column chromatography on silica gel with receipt of 2.56 g of the desired compound as a pale brown amorphous substance.

Stage 2

4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-[3-(3-benzoylthiourea)-4-were]benzamid

To a solution of 0.21 g of ammonium thiocyanate in 1.5 ml of acetone with stirring at room temperature was added dropwise a solution of 0.35 g of benzoyl chloride in 0.5 ml of acetone. After heating the mixture under reflux for 15 minutes was added dropwise a solution of 1.00 g of 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-(3-amino-4-were)benzamide obtained in stage 1 in 4 ml of acetone and additionally mixture was heated under reflux for 15 minutes. The reaction solution was cooled in air to room temperature, and then diluted with water. The solution of the active ingredient is GDI was subjected to extraction with ethyl acetate and dried over anhydrous magnesium sulfate. Then drove the solvent under reduced pressure and the residue was purified by the method of column chromatography on silica gel with obtaining and 0.98 g of the desired compound as colorless crystals.

Melting point 127-129ºC

Stage 3

4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-[4-methyl-3-theoreticity]benzamid

To a solution of 960 mg of 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-[3-(3-benzoylthiourea)-4-were]benzamide obtained in stage 2, in 10 ml of methanol was added 4 ml of 1N. an aqueous solution of sodium hydroxide. The mixture was heated under reflux for 2 hours, then drove a large part of the solvent under reduced pressure and diluted with water. The reaction solution was acidified by adding 6 ml of 1N. hydrochloric acid, and then podslushivaet by adding 28% aqueous ammonia. The precipitated crystals were collected by filtration to obtain 718 mg of the desired compound as colorless crystals.

Melting point 215-216ºC (decomposition)

Reference example 34

The dihydrochloride of 3-dimethylaminopyridine

Stage 1

1-(Tert-butoxycarbonyl)-3-dimethylaminoacetyl

This compound was obtained in the same way as described in reference example 25 (stage 1), except that used 1-tert-butoxycarbonyl-3-aminoamides.

Stage 2

The dihydrochloride of 3-dimethy is aminoacridine

This compound was obtained in the same way as described in reference example 25 (stage 2), except that used 1-tert-butoxycarbonyl-3-(dimethylamino)azetidin obtained in stage 1.

Colorless oily product

Reference example 35

The dihydrochloride (S)-3-dimethylaminomethylene

Stage 1

(R)-1-tert-butoxycarbonyl-3-dimethylaminomethylphenol

This compound was obtained in the same way as described in reference example 25 (stage 1), except that used the (R)-3-aminomethyl-1-(tert-butoxycarbonyl)pyrrolidin.

Stage 2

The dihydrochloride (S)-3-dimethylaminomethylene

This compound was obtained in the same way as described in reference example 25 (stage 2), except that used the (R)-1-tert-butoxycarbonyl-3 - dimethylaminomethylphenol obtained in stage 1.

Colorless oily product

Reference example 36

The dihydrochloride of (R)-3-dimethylaminomethylene

Stage 1

(S)-1-tert-butoxycarbonyl-3-dimethylaminomethylphenol

This compound was obtained in the same way as described in reference example 25 (stage 1), except that used the (S)-3-aminomethyl-1-(tert-butoxycarbonyl)pyrrolidin.

Stage 2

The dihydrochloride of (R)-3-dimethylaminomethylene

This connection we shall do the same way as described in reference example 25 (stage 2), except that used the (S)-1-tert-butoxycarbonyl-3-dimethylaminomethylphenol obtained in stage 1.

Pale yellow oily product

Reference example 37

The dihydrochloride (3R,4R)-3-dimethylamino-4-ethoxypyrrolidine

This compound was obtained using (3R,4R)-1-tert-butoxycarbonyl-3-hydroxy-4-methylaminopropane (Tetrahedron: Asymmetry, 2001, 12, 2989-2997) in accordance with the method of reference example 28 (stages 1-3).

Colorless oily product

The structural formula and the properties of the following compounds of reference examples 38-81 presented in table 1.

Reference example 38

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 39

3-Iodide-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 40

3-Chloro-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 41

3-Fluoro-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 42

4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 43

4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 44

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(2-pyrazinyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 45

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide

Reference example 46

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide

Reference example 4

4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide

Reference example 48

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(1,2-dihydropyridin-4-yl)pyrimidine-2-ylamino]-4-were}benzamide

Reference example 49

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridinyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 50

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 51

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide

Reference example 52

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]phenyl}benzamide

Reference example 53

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[2-(3-pyridinyl)pyridine-6-ylamino]phenyl}benzamide

Reference example 54

3-Bromo-4-(4-methylpiperazin-1 and the methyl)-N-{4-methyl-3-[3-(3-pyridinyl)pyridine-5-ylamino]phenyl}benzamide

Reference example 55

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[3-(3-pyridyl)phenylamino]phenyl}benzamide

Reference example 56

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[2-(3-pyridyl)pyrazin-6-ylamino]phenyl}benzamide

Reference example 57

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[5-(3-pyridyl)-1,2,4-triazine-3-ylamino]phenyl}benzamide

Reference example 58

3-Methyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 59

4-(4-Methylpiperazin-1-ylmethyl)-3-nitro-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 60

3-Methoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 61

3,5-Dibromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 62

3,5-Dimethoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 63

3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 64

3-Bromo-4-(4-ethylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 65

3-Bromo-4-[4-(n-propyl)piperazine-1-ylmethyl]-N-{4-methyl-3-[4-(3-pyridyl)pyrim the DIN-2-ylamino]phenyl}benzamide

Reference example 66

3-Bromo-4-(N,N-dimethylaminomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 67

3-Bromo-4-(N,N-diethylaminomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 68

3-Bromo-4-(1-pyrrolidinyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 69

3-Bromo-4-piperidinomethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 70

3-Bromo-4-morpholinomethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 71

3-Bromo-4-(CIS-3,5-dimethylpiperazine-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 72

3-Bromo-4-(4-methyl-hexahydro-1H-1,4-diazepin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 73

3-Bromo-4-(1-piperazinylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 74

4-[4-(Tert-butoxycarbonyl)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 75

4-(1-Piperazinylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 76

3-Methoxycarbonyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)PIR is midin-2-ylamino]phenyl}benzamide

Reference example 77

3-Cyano-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 78

The hydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 79

The hydrochloride of 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Reference example 80

The hydrochloride of 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide

Reference example 81

Methanesulfonate of 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Compounds of reference examples 38-81 were obtained in accordance with the above-described method of obtaining 1.

Reference example 82

4-methyl bromide-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

The desired compound was obtained using 4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline (patent document 1) in the same way as described in Ref is cnom example 31.

Example 1

3-Deformity-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

1.98 g of 4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]aniline (reference example 18) was dissolved in 35 ml of anhydrous pyridine and added 2,90 g of the hydrochloride of 3-deformity-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride (reference example 9), and then stirred at room temperature for 2 hours. To the reaction mixture were added ice water and saturated aqueous sodium hydrogen carbonate solution, and then subjected the mixture to extraction with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The crude crystals were washed with chloroform/diethyl ether (1/1) to obtain 2.66 g of the desired compound as pale brown crystals.

Melting point 206-207ºC

Example 2

Hydrochloride 3-deformity-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

2.66 g of 3-deformity-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 1) are suspended in 26 ml of ethanol and added 4,88 ml of 1N. hydrochloric acid, and then stirred the mixture with heating in a bath at 70ºC and dissolved. The solvent is kept under reduced pressure, and then PR is mawali the crude crystals from ethanol to obtain 2,80 g of the desired compound.

Buffy crystals

Melting point 264ºC (decomposition)

Elemental analysis (for C29H30F2N8O·HCl·0,6EtOH)

Calculated (%): C, 59,59; H, 5,73; N, 18,41

Found (percent): C, 59,59; H, 5,71; N, 18,53

Example 3

3-Ethyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 1, except that used the hydrochloride of 3-ethyl-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride (reference example 1), and the reaction was carried out at room temperature for 2 hours and the crude product was purified by the method of column chromatography on silica gel.

Yellow crystals

Melting point 131-134ºC

Example 4

Hydrochloride 3-ethyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 3-ethyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 3), and the obtained crude crystals were washed with ethyl acetate.

Yellow crystals

Melting point 253-255ºC (decomposition)

Elemental analysis (for C30H34N8O·HCl·2,1H2O)

Calculated (%): C, 60,36; H, 6,62; N, 18,77

Found (percent): C, 60,10; H, of 6.31; N, 18,75

Example 5

4-(1-Methylpiperidin-4-ylidene the l)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 1, except that used the suspension of the hydrochloride of 4-(1-methylpiperidin-4-ylidenemethyl)-3-triftormetilfullerenov (reference example 7) in anhydrous tetrahydrofuran, and the reaction was carried out at room temperature for 21 hours.

Yellow crystals

Melting point 234-239ºC (decomposition)

Example 6

The hydrochloride of 4-(1-methylpiperidin-4-ylidenemethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-(1-methylpiperidin-4-ylidenemethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 5), and the obtained crude crystals are then washed with ethanol and diethyl ether.

Pale-yellow crystals

Melting point 202-206ºC (decomposition)

Elemental analysis (for C30H28F3N7O·HCl·H2O)

Calculated (%): C, 58,68; H, 5,09; N, 15,97

Found (percent): C, 58,42; H, to 4.92; N, 16,10

Example 7

4-(1-Methylpiperidin-4-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 1, except that used the suspension of the hydrochloride of 4-(1-methylpiperidin-4-ylmethyl)-3-is diftormetilirovaniya (reference example 8) in anhydrous tetrahydrofuran, the reaction was carried out at room temperature for 21 hours, and the obtained crude crystals were washed with ethyl acetate.

Pale-yellow crystals

The melting point of 230-233ºC (decomposition)

Example 8

The hydrochloride of 4-(1-methylpiperidin-4-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-(1-methylpiperidin-4-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 7), and the obtained crude crystals are then washed with ethanol and diethyl ether.

Pale-yellow crystals

Melting point 227-231ºC (decomposition)

Elemental analysis (for C30H30F3N7O·HCl·0,5H2O)

Calculated (%): C, 59,35; H, 5,31; N, 16,15

Found (percent): C, 59,02; H, 5,20; N, 16,08

Example 9

4-(1-Methylpiperidin-4-yloxy)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 1, except that used the hydrochloride of 4-(1-methylpiperidin-4-yloxy)-3-triftormetilfullerenov (reference example 11), the reaction was carried out at room temperature overnight, and the crude product was purified by the method of column chromatography on silica gel.

Bleu is but yellow crystals

The melting point of 187-191ºC

Example 10

The hydrochloride of 4-(1-methylpiperidin-4-yloxy)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-(1-methylpiperidin-4-yloxy)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 9), and the obtained amorphous substance was led by adding ethanol/diisopropyl ether.

Yellow crystals

Melting point 275ºC or higher

Elemental analysis (for C29H28F3N7O2·HCl·0,3H2O)

Calculated (%): C, 57,53; H, is 4.93; N, 16,19

Found (percent): C, 57,34; H, 4,99; N, of 16.05

Example 11

3,5-Dichloro-4-[(S)-3-dimethylaminopropan-1-ylmethyl]-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 1, except that used hydrochloride 3,5-dichloro-4-[(S)-3-dimethylaminopropan-1-ylmethyl]benzoyl chloride (reference example 6), the reaction was carried out at room temperature for 66 hours, the crude product was purified by the method of column chromatography on silica gel, and the resulting crude crystals were washed with ethyl acetate.

Yellow crystals

Melting point 215-223ºC (decomposition)

Example 12

Hydrochloride (-)for 3,5-dichloro-4-[(S-3-dimethylaminopropan-1-ylmethyl]-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 3,5-dichloro-4-[(S)-3-dimethylaminopropan-1-ylmethyl]-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 11), and the obtained amorphous substance was led by adding ethyl acetate/ethanol.

Buffy crystals

Melting point 161-170ºC (decomposition)

[α]D20: -10,03° (c=0,538, methanol)

Elemental analysis (for C29H30Cl2N8O·HCl·0,06CH3CO2C2H5·1,7H2O)

Calculated (%): C, 54,04; H, 5,09; N, 17,24

Found (percent): C, 54,41; H, to 5.56; N, 16,94

Example 13

3-Methoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide

This compound was obtained in the same way as described in example 1, except that used 3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-methyl aniline (reference example 19) and the dihydrochloride of 3-methoxy-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride (reference example 3), the reaction was carried out at room temperature for 17 hours, and the crude product was purified by the method of column chromatography on silica gel.

Pale-yellow crystals

The melting point of 168-171ºC

Example 14

The hydrochloride of 3-methoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide

This compound was obtained in the same paragraph the same time, as described in example 2, except that used 3-methoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide (example 13), and the obtained amorphous substance was led by adding ethyl acetate.

Pale-yellow crystals

The melting point of 168-169ºC (decomposition)

Elemental analysis (for C30H32BrN7O2·HCl·0,3CH3CO2C2H5·0,6H2O)

Calculated (%): C, to 55.42; H, 5,46; N, 14,50

Found (percent): C, to 55.42; H, the 5.45; N, 14,11

Example 15

4-(4-Ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 1, except that used the dihydrochloride of 4-(4-ethylpiperazin-1-ylmethyl)-3-triftormetilfullerenov (reference example 5), the reaction was carried out at room temperature for 20 hours, and the crude product was washed with warm methanol and then diethyl ether.

Pale-yellow crystals

The melting point of 240-244ºC (decomposition)

Example 16

The hydrochloride of 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrim the DIN-2-ylamino]phenyl}benzamide (example 15).

Pale-yellow crystals

Melting point 256-259ºC (decomposition)

Elemental analysis (for C30H31F3N8O·HCl)

Calculated (%): C, 58,77; H, 5,26; N, 18,28

Found (percent): C, 59,47; H, 5,32; N, 18,19

Example 17

4-(4-Ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide

This compound was obtained in the same way as described in example 1, except that used 3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-methyl aniline (reference example 19) and the dihydrochloride of 4-(4-ethylpiperazin-1-ylmethyl)-3-triftormetilfullerenov (reference example 5), the reaction was carried out at room temperature for 24 hours, and amorphous substance obtained by purification according to the method of column chromatography on silica gel, was led by adding chloroform/diethyl ether (1/1).

Pale-yellow crystals

Melting point 178-179ºC

Example 18

The hydrochloride of 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide (example 17), and the obtained amorphous substance was vykristallizovyvalas from ethanol.

B is edno-yellow crystals

Melting point 166-172ºC (decomposition)

Elemental analysis (for C31H31BrF3N7O·HCl·0,5H2O)

Calculated (%): C, 53,19; H, 4.75 V; N, 14,01

Found (percent): C, 52,89; H, 4,79; N, 14,05

Example 19

3-Chloro-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 1, except that used the dihydrochloride of 3-chloro-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride (reference example 4), and the reaction was carried out at room temperature for 18 hours.

Pale-yellow crystals

The melting point of 210-227ºC (decomposition)

Example 20

The hydrochloride of 3-chloro-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 3-chloro-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 19), and the obtained amorphous substance was vykristallizovyvalas from ethanol.

Pale-yellow crystals

Melting point 197-200ºc is manageable

Elemental analysis (for C28H29ClN8O·HCl)

Calculated (%): C, 59,47; H, to 5.35; N, 19,81

Found (percent): C, 59,73; H, 5,38; N, 19,90

Example 21

3-Vermeil-4-(1-methylpiperidin-4-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This is Obedinenie was obtained in the same way, as described in example 1, except that used hydrochloride 3-vermeil-4-(1-methylpiperidin-4-ylmethyl)of benzoyl chloride (reference example 10), the reaction was carried out at room temperature for 3 days, and amorphous substance obtained by purification according to the method of column chromatography on silica gel, vykristallizovyvalas of ethyl acetate.

Pale-yellow crystals

The melting point of 162-164ºC

Example 22

4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 1, except that used 4-methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]aniline (reference example 22) and the dihydrochloride of 4-(4-methylpiperazin-1-ylmethyl)-3-triftormetilfullerenov (reference example 2), and the obtained crude crystals were washed with ethyl acetate.

Pale-yellow crystals

Melting point 277ºC (decomposition)

Example 23

The hydrochloride of 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]phenyl}benzamide (example 22).

Bescot the haunted crystals

Melting point 203-206ºC (decomposition)

Elemental analysis (for C30H30F3N7O·HCl·0,3H2O)

Calculated (%): C, 59,71; H, 5,28; N, 16,25

Found (percent): C, 59,52; H, of 5.34; N, 16,37

Example 24

4-(4-Ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 1, except that used 4-methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]aniline (reference example 22) and the dihydrochloride of 4-(4-ethylpiperazin-1-ylmethyl)-3-triftormetilfullerenov (reference example 5), and the obtained crude crystals were washed with ethyl acetate.

Pale-yellow crystals

Melting point 256-258ºC (decomposition)

Example 25

The hydrochloride of 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]phenyl}benzamide (example 24).

Colourless crystals

Melting point 254-256ºC (decomposition)

Elemental analysis (for C31H32F3N7O·HCl·0,6H2O)

Calculated (%): C, 59,77; H, of 5.53; N, 15,74

Found (percent): C, 59,63; H, of 5.34; N, 15,63

Example 26

4-(4-Ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)Piri is in 2-ylamino]phenyl}benzamide

200 mg of 4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]aniline (reference example 23) suspended in 4 ml of acetonitrile and consistently added 78.8 mg of 4-dimethylaminopyridine and 484 μl of N,N-aminobutiramida-N-ethylamine. While stirring with cooling on ice was added 383 mg of the dihydrochloride of 4-(4-ethylpiperazin-1-ylmethyl)-3-triftormetilfullerenov (reference example 5), and then stirred at room temperature for 2 hours. To the reaction solution were added water three times and subjected the mixture to extraction with ethyl acetate. The organic layers were washed with saturated salt solution and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel to obtain 93 mg of the desired compound as pale yellow crystals.

Melting point 227-229ºC (decomposition)

Example 27

The hydrochloride of 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide (example 26).

Colourless crystals

The melting point of 230-235ºC (decomposition)

Elemental analysis (for C32H33F3N6·HCl)

Calculated (%): C, 62,89; H, 5,61; N, of 13.75

Found (percent): C, 63,30; H, 5,70; N, 13,65

Example 28

4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 26, except that used the dihydrochloride of 4-(4-methylpiperazin-1-ylmethyl)-3-triftormetilfullerenov (reference example 2), 5 times carried out the extraction with chloroform, and the crude crystals obtained by purification according to the method of column chromatography on silica gel, washed with ethyl acetate.

Pale-yellow crystals

Melting point 241-242ºC (decomposition)

Elemental analysis (for C31H31F3N6O·0,4H2O)

Calculated (%): C, 65,57; H, 5,64; N, 14,80

Found (percent): C, 65,31; H, 5,70; N, the 14.90

Example 29

Methanesulfonate of 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide

to 1.21 g of 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide (example 28) suspended in 20 ml of methanol and was added to 140 μl methanesulfonic acid, and then stirred under heating. Insoluble substances were removed by filtration under heating and drove the solvent in the filtrate under reduced pressure. The residue was led by adding isopropanol and collected by the filter is the obtaining of 1.33 g of the desired compound as pale yellow crystals.

Melting point 189-191ºC

Elemental analysis (for C31H31F3N6O·CH3SO3H·0,3H2O)

Calculated (%): C, 58,05; H, 5,42; N, 12,69

Found (percent): C, 58,05; H, and 5.30; N, 12,71

Example 30

4-(1-Methylpiperazin-4-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[6-(3-pyridyl)pyrimidine-4-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 1, except that used 4-methyl-3-[6-(3-pyridyl)pyrimidine-4-ylamino]aniline (reference example 20) and the dihydrochloride of 4-(4-methylpiperazin-1-ylmethyl)-3-triftormetilfullerenov (reference example 2), the reaction was carried out at room temperature for 92 hours, and the obtained crude crystals were washed with ethyl acetate.

Colourless crystals

The melting point of 253 254ºC (decomposition)

Example 31

The hydrochloride of 4-(1-methylpiperazin-4-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[6-(3-pyridyl)pyrimidine-4-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-(1-methylpiperazin-4-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[6-(3-pyridyl)pyrimidine-4-ylamino]phenyl}benzamide (example 30), and the obtained crude crystals are then washed with ethanol and diethyl ether.

Pale-yellow crystals

Melting point 190-194ºC (decomposition)

Elemental analysis (for C30H30F3N7O·HCl·2,5H2O)

Calculated %): C, 56,03; H, 5,64; N, 15,25

Found (percent): C, 55,67; H, USD 5.76; N, 15,11

Example 32

4-(1-Methylpiperazin-4-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[6-(5-pyrimidinyl)pyrimidine-4-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 1, except that used 4-methyl-3-[6-(5-pyrimidinyl)pyrimidine-4-ylamino]aniline (reference example 21) and the dihydrochloride of 4-(4-methylpiperazin-1-ylmethyl)-3-triftormetilfullerenov (reference example 2), the reaction was carried out at room temperature for 17 hours, and the obtained crude crystals were washed with ethyl acetate.

Pale-yellow crystals

Melting point 257-267ºC (decomposition)

Example 33

The hydrochloride of 4-(1-methylpiperazin-4-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[6-(5-pyrimidinyl)pyrimidine-4-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-(1-methylpiperazin-4-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[6-(5-pyrimidinyl)pyrimidine-4-ylamino]phenyl}benzamide (example 32), and the obtained crude crystals are then washed with ethanol and diethyl ether.

Pale-yellow crystals

Melting point 203-207ºC (decomposition)

Elemental analysis (for C29H29F3N8O·HCl·4H2O)

Calculated (%): C, better than anticipated at 51.90; H, 5,71; N, 16,70

Found (percent): C, 52,50; H, of 5.68; N, 16,24

Example 34

4-[4-(2-CFT is ratil)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

In an argon atmosphere 1,71 g of 4-[4-(2-foradil)piperazine-1-ylmethyl]-3-triftorperasin acid (reference example 14) was dissolved in 14 ml of anhydrous N,N-dimethylformamide was added 1.56 g of iodide, 2-chloro-1-methylpyridine, and then stirred at room temperature for 10 minutes. Consistently added 1.50 g of 4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]aniline (reference example 18) and 1.13 ml of N,N-aminobutiramida-N-ethylamine, and then stirred at room temperature for 1 hour. To the reaction solution was added 300 ml of water and then was extracted with ethyl acetate. To the aqueous layer was added 200 ml of saturated sodium hydrogen carbonate solution and then was extracted with a mixture of ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography and washed crude crystals of diethyl ether/ethyl acetate to obtain 1.68 g of the desired compound as pale yellow crystals.

Melting point 207-209ºC (decomposition)

Example 35

Hydrochloride 4-[4-(2-foradil)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-[4-(2-foradil)PIP the Razin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 34), and the obtained crude crystals were washed with ethanol.

Pale-yellow crystals

Melting point 213-233ºC (decomposition)

Elemental analysis (for C30H30F4N8O·HCl·0,2H2O)

Calculated (%): C, 56,77; H, 4,99; N, 17,66

Found (percent): C, 56,62; H, 4,99; N, 17,77

Example 36

4-[4-(2-Hydroxyethyl)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Stage 1

4-{4-[2-(tert-butyldimethylsilyloxy)ethyl]piperazine-1-ylmethyl}-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 34, except that used 4-{4-[2-(tert-butyldimethylsilyloxy)ethyl]piperazine-1-ylmethyl}-3-triftorperasin acid (reference example 15), and amorphous substance obtained by purification according to the method of column chromatography, vykristallizovyvalas from diethyl ether/ethyl acetate.

Pale-yellow crystals

Melting point 193-198ºC (decomposition)

Stage 2

4-[4-(2-Hydroxyethyl)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

2,03 g of 4-{4-[2-(tert-butyldimethylsilyloxy)ethyl]piperazine-1-ylmethyl}-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide obtained in stage 1, was dissolved in 25 ml of anhydrous tetrahydrofuran, is then stirred with cooling on ice. Added 5,74 ml of tetrabutylammonium fluoride (1M solution in tetrahydrofuran) and stirred the mixture for 5 minutes, and then stirred at room temperature for 22 hours. The reaction solution was diluted with ethyl acetate and washed with water. The aqueous layer was washed four times was subjected to extraction with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel to obtain 890 mg of the desired compound as pale yellow crystals.

The melting point of 188-192ºC

Example 37

Hydrochloride 4-[4-(2-hydroxyethyl)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-[4-(2-hydroxyethyl)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 36).

Pale-yellow crystals

Melting point 248-255ºC (decomposition)

Elemental analysis (for C30H31F3N8O2·HCl·0,2H2O)

Calculated (%): C, 56,95; H, 5,16; N, 17,71

Found (percent): C, 56,80; H, is 5.06; N, 17,71

Example 38

Hydrochloride (+)-4-[(R)-3-dimethylaminopropan-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]f the Nile}benzamide

Stage 1

4-[(R)-3-dimethylaminopropan-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 34, except that used 4-[(R)-3-dimethylaminopropan-1-ylmethyl]-3-triftorperasin acid (reference example 12), after adding to the reaction solution, water and saturated aqueous solution of sodium bicarbonate and the mixture was stirred, and then the precipitated crystals were collected by filtration and washed with water.

Yellow crystals

Stage 2

Hydrochloride (+)-4-[(R)-3-dimethylaminopropan-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-[(R)-3-dimethylaminopropan-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide obtained in stage 1, and the obtained crude crystals successively washed with diisopropyl ether and diethyl ether.

Pale-yellow crystals

Melting point 178ºC (decomposition)

[α]D20: +9,75° (c=1,025, methanol)

Elemental analysis (for C30H31F3N8O·HCl·1,5H2O)

Calculated (%): C, 56,29; H, the 5.51; N, 17,51

Found (percent): C, 56,11; H, 5,43; N, 17,60

Example 39

4-(1-Piperazinylmethyl)-3-trif ormetal-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide

Stage 1

4-[4-(Tert-butoxycarbonyl)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide

This compound was obtained in the same way as described in example 34, except that used 4-[4-(tert-butoxycarbonyl)piperazine-1-ylmethyl]-3-triftorperasin acid (reference example 13) and 3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-methyl aniline (reference example 19).

Pale-yellow crystals

Stage 2

4-(1-Piperazinylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide

To 214 mg of 4-[4-(tert-butoxycarbonyl)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide obtained in stage 1, was added 1.5 ml triperoxonane acid, and then stirred at room temperature for 1 hour. The mixture was podlachian (pH 9) by addition to the reaction solution, 10 ml of 10% aqueous sodium hydroxide solution, and was twice extracted with ethyl acetate, and then dried over anhydrous magnesium sulfate. The solvent is kept at reduced pressure. The residue was purified by the method of column chromatography on silica gel and vykristallizovyvalas the crude product from diethyl ether/ethyl acetate to obtain 99 mg of the desired compound as pale yellow crystals.

Temperature the tour melting 195-197ºC (decomposition)

Example 40

The hydrochloride of 4-(1-piperazinylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-(1-piperazinylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide (example 39), and the obtained amorphous substance was led by addition of chloroform/diethyl ether/methanol.

Pale-yellow crystals

Melting point 176-182ºC (decomposition)

Elemental analysis (for C29H27BrF3N7O·HCl·1,5H2O)

Calculated (%): C, 50,48; H, a 4.53; N, 14,21

Found (percent): C, 50,25; H, 4,21; N, 13,91

Example 41

4-(1-Piperazinylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide

Stage 1

4-[4-(Tert-butoxycarbonyl)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 34, except that used 4-[4-(tert-butoxycarbonyl)piperazine-1-ylmethyl]-3-triftorperasin acid (reference example 13) and 4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]aniline (reference example 23), and the crude crystals obtained by purification according to the method of column chromatography on silica gel, vykristallizovyvalas from n-hexane/utilize the ATA.

Stage 2

4-(1-Piperazinylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 39 (stage 2), except that used 4-[4-(tert-butoxycarbonyl)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide obtained in stage 1.

Example 42

The hydrochloride of 4-(1-piperazinylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-(1-piperazinylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide (example 41), and the obtained amorphous substance was led by adding isopropanol.

Pale-yellow crystals

Melting point 190-195ºC (decomposition)

Elemental analysis (for C30H29F3N6O·HCl·0,36(CH3)CHOH·1,9H2O)

Calculated (%): C, 57,64; H, of 5.89; N, 13,40

Found (percent): C, 58,02; H, vs. 5.47; N, 12,97

Example 43

Triptorelin 4-(1-piperazinylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Stage 1

4-[4-(Tert-butoxycarbonyl)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in the ore 34, except that used 4-[4-(tert-butoxycarbonyl)piperazine-1-ylmethyl]-3-triftorperasin acid (reference example 13).

Pale-yellow crystals

Melting point 182-186ºC (decomposition)

Stage 2

Triptorelin 4-(1-piperazinylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

To 1.54 g of 4-[4-(tert-butoxycarbonyl)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide obtained in stage 1, was added 15 ml triperoxonane acid, and then stirred at room temperature for 1 hour. Triperoxonane acid chased off under reduced pressure and then the residue was purified by the method of column chromatography on NH-silica gel (Chromatorex (Fuji Silysia Chemical Co., Ltd.), elwira chloroform → chloroform/methanol (10/1)). The obtained amorphous substance was vykristallizovyvalas from ethyl acetate to obtain 1.23 g of the desired compound.

Pale-yellow crystals

Melting point 199-202ºC (decomposition)

Elemental analysis (for C28H27F3N8O·CF3CO2H·2H2O)

Calculated (%): C, 51,58; H, to 4.62; N, 16,04

Found (percent): C, 51,71; H, 4.26 deaths; N, 16,13

Example 44

4-(3-Carbamoylbiphenyl-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Stage 1

4-[4-(Tert-butoxycarbonyl)-3-carbamoylbiphenyl-1-elmet the l]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 34, except that used 4-[1-tert-butoxycarbonyl-2-carbamoylbiphenyl-4-ylmethyl]-3-triftorperasin acid (reference example 16), and the reaction was carried out at room temperature for 6 hours.

Pale-yellow crystals

Melting point 206-209ºC (decomposition)

Stage 2

4-(3-carbamoylbiphenyl-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

To 1.52 g of 4-[4-tert-butoxycarbonyl-3-carbamoylbiphenyl-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide obtained in stage 1, was added to 6.0 ml triperoxonane acid, and then stirred at room temperature for 1 hour. Triperoxonane acid drove away under reduced pressure, the residue was dissolved in ethyl acetate, sequentially washed with aqueous saturated sodium hydrogen carbonate solution and water and dried over anhydrous magnesium sulfate, the solvent is kept under reduced pressure and then the residue was purified by the method of column chromatography on silica gel with getting 963 mg of the desired compound as pale yellow crystals.

Melting point 235-238ºC

Example 45

The hydrochloride of 4-(3-carbamoylbiphenyl-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidine is l)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-(3-carbamoylbiphenyl-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 44).

Pale-yellow crystals

Melting point 205-208ºC

Elemental analysis (for C29H28F3N9O2·HCl·1,3H2O)

Calculated (%): C, 53.47 USD; H, 4,89; N, 19,35

Found (percent): C, 53,11; H, to 4.92; N, 19,79

Example 46

(-)-4-((S)-3-amino-2-oxopyrrolidin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Stage 1

4-[(S)-3-(tert-butoxycarbonylamino)-2-oxopyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

800 mg of 4-[(S)-3-(tert-butoxycarbonylamino)-2-oxopyrrolidin-1-ylmethyl]-3-triftorperasin acid (reference example 17) was dissolved in 7 ml of anhydrous N,N-dimethylformamide and consistently added to 0.67 ml of N,N-aminobutiramida-N-ethylamine and 1.00 g of hexaflurophosphate 1H-benzotriazol-1-electroparadise (PyBOP), and then stirred at room temperature for 30 minutes. Was added 4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]aniline (reference example 18) and the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with water and then was extracted with ethyl acetate. The organic layer placentas is tion washed with aqueous saturated sodium hydrogen carbonate solution and water, and then was dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified by the method of column chromatography on silica gel to obtain 453 mg of the desired compound as a pale yellow amorphous substance.

Stage 2

(-)-4-((S)-3-amino-2-oxopyrrolidin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

To 439 mg of 4-[(S)-3-(tert-butoxycarbonylamino)-2-oxopyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide obtained in stage 1, was added 2.0 ml triperoxonane acid, and then stirred at room temperature for 1 hour. Triperoxonane acid chased off under reduced pressure and then the residue was dissolved in water and washed with diethyl ether. The mixture was podslushivaet by adding to the aqueous layer saturated aqueous solution of sodium bicarbonate, then twice was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure, then the residue was purified by the method of column chromatography, was led by adding to the obtained amorphous substance ethyl acetate and collected by filtration to obtain 244 mg of the desired compound as yellow crystals.

Melting point 156-159ºC (decomposition)

[α]D20: -2,13° (c=0,352, methanol)

Elemental analysis (for C28H25F3N8O·0,5CH3CO2C2H5·0,5H2O)

Calculated (%): C, 58,53; H, 4,91; N, 18,20

Found (percent): C, 58,99; H, 4,88; N, 17,76

Example 47

4-[(S)-3-dimethylaminopropan-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

To a solution of 6.00 g of 4-methyl bromide-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (reference example 31) in 60 ml of anhydrous N,N-dimethylformamide was added 1.51 g (S)-(-)-3-dimethylaminopyridine and 1.83 g of potassium carbonate and then stirred at room temperature for 14 hours. To the reaction solution were added water and saturated aqueous sodium hydrogen carbonate solution, was extracted with a mixture of ethyl acetate and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified by the method of column chromatography on silica gel with receipt of 4.57 g of pale yellow crystals.

The melting point of 179-183ºC (decomposition)

Example 48

Hydrochloride (-)-4-[(S)-3-dimethylaminopropan-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-[(S)-3-dimethylaminopropan-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (note the p 47), and the obtained crude crystals were washed with isopropanol.

Pale-yellow crystals

The melting point of 154-158ºC (decomposition)

[α]D20: -10,25° (c=0,546, methanol)

Elemental analysis (for C30H31F3N8O·HCl·2,5H2O)

Calculated (%): C, 54,75; H, 5,67; N, 17,03

Found (percent): C, 54,72; H, 5,38; N, 16,96

Example 49

4-(3-Carbarnoyl-4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that used the dihydrochloride of 1-methylpiperazin-2-carboxamide (reference example 24), and sodium carbonate is used in an amount of 10 equivalents relative to the starting material.

Pale-yellow crystals

Melting point 248-253ºC

Example 50

The hydrochloride of 4-(3-carbarnoyl-4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-(3-carbarnoyl-4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 49).

Pale-yellow crystals

Melting point 203-208ºC

Elemental analysis (for C30H30F3N9O2·HCl·1,7H2O)

Calculated (%): C, 53,56; H, 5,15; N, 18,74

Found (percent): C, 53,53; H, to 4.98; N, 18,46

Example 1

4-[(S)-2-(1-pyrrolidinyl)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that used the (S)-(+)-2-(1-pyrrolidinyl)pyrrolidin.

Pale-yellow crystals

Melting point 147-152ºC (decomposition)

Example 52

Hydrochloride (-)-4-[(S)-2-(1-pyrrolidinyl)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-[(S)-2-(1-pyrrolidinyl)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 51).

Pale yellow amorphous substance

[α]D20: -11,00° (c=0,509, methanol)

Elemental analysis (for C33H35F3N8O·HCl·0,5H2O)

Calculated (%): C, 59,86; H, 5,63; N, 16,92

Found (percent): C, 59,66; H, of 5.89; N, 16,61

Example 53

4-[3-Dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that used the dihydrochloride of 3-dimethylaminomethylene (reference example 25), and potassium carbonate was used in an amount of 5 equivalents relative to recognize the aqueous material.

Yellow crystals

Melting point 174-181ºC (decomposition)

Example 54

Hydrochloride 4-[3-dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-[3-dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 53).

Pale-yellow crystals

Melting point 142-152ºC (decomposition)

Elemental analysis (for C30H31F3N8O·HCl·H2O)

Calculated (%): C, 57,10; H, 5,43; N, 17,76

Found (percent): C, 57,41; H, 5,79; N, 17,53

Example 55

4-((S)-3-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that used the (S)-(+)-2-methylpiperazin.

Yellow crystals

Melting point 193 -196 ° C

Example 56

Hydrochloride (+)-4-((R)-3-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Stage 1

4-((R)-3-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that use is isovale (R)-(-)-2-methylpiperazin.

Pale-yellow crystals

Stage 2

Hydrochloride (+)-4-((R)-3-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-((R)-3-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide obtained in stage 1.

Yellow crystals

Melting point 254-258ºC

[α]D20: +9,63° (c=0,498, methanol)

Elemental analysis (for C29H29F3N8O·HCl·0,3C2H5OH·H2O)

Calculated (%): C, 55,85; H, 5,46; N, 17,97

Found (percent): C, 55,93; H, 5,33; N, 18,08

Example 57

Hydrochloride (-)-4-[(S)-3-N,N-diethylaminopropyl-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Stage 1

4-[(S)-3-N,N-diethylaminopropyl-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that used dihydrochloride (S)-3-N,N-diethylaminopropylamine (reference example 26), and potassium carbonate used in the amount of 6 equivalents relative to the starting material.

Pale-yellow crystals

Stage 2

Hydrochloride (-)-4-[(S)-3-N,N-diethylaminopropyl-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-yl) - Rev. Ino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-[(S)-3-N,N-diethylaminopropyl-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide obtained in stage 1.

Pale-yellow crystals

Melting point 200-202ºC

[α]D20: -9,74° (c=0,513, methanol)

Elemental analysis (for C32H35F3N8O·HCl·2,5H2O)

Calculated (%): C, 56,01; H, of 6.02; N, 16,33

Found (percent): C, 56,27; H, 5,94; N, 15,96

Example 58

Hydrochloride (-)-4-[(S)-3-(1-pyrrolidinyl)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Stage 1

4-[(S)-3-(1-pyrrolidinyl)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that used hydrochloride (S)-3-(1-pyrrolidinyl)pyrrolidine (reference example 27), and potassium carbonate used in the amount of 3.8 equivalents relative to the starting material.

Yellow crystals

Stage 2

Hydrochloride (-)-4-[(S)-3-(1-pyrrolidinyl)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-[(S)-3-(1-pyrrolidinyl)pyrrole the Jn-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide, obtained in stage 1.

Yellow crystals

The melting point of 168-171ºC

[α]D20: -12,20° (c=1,016, methanol)

Elemental analysis (for C32H33F3N8O·HCl·3H2O)

Calculated (%): C, 55,45; H, of 5.82; N, 16,17

Found (percent): C, 55,44; H, of 5.48; N, 16,06

Example 59

Hydrochloride 4-[(3S,4S)-3-dimethylamino-4-ethoxypyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Stage 1

4-[(3S,4S)-3-dimethylamino-4-ethoxypyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that used dihydrochloride (3S,4S)-3-dimethylamino-4-ethoxypyrrolidine (reference example 28), and potassium carbonate was used in an amount of 5 equivalents relative to the starting material.

Pale-yellow crystals

The melting point of 187-190ºC (decomposition)

Stage 2

Hydrochloride 4-[(3S,4S)-3-dimethylamino-4-ethoxypyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-[(3S,4S)-3-dimethylamino-4-ethoxypyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide obtained in stage 1. The crude crystal is washed with isopropanol.

Pale-yellow crystals

Melting point 155-161ºC (decomposition)

Elemental analysis (for C31H33F3N8O·HCl·0,2i-D·1,5H2O)

Calculated (%): C, of 55.64; H, 5,70; N, 16,43

Found (percent): C, 55,59; H, lower than the 5.37; N, 16.69 per

Example 60

Hydrochloride (-)-4-[(2R,4S)-4-dimethylamino-2-methylpyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Stage 1

4-[(2R,4S)-4-dimethylamino-2-methylpyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that used dihydrochloride (2R,4S)-4-dimethylamino-2-methylpyrrolidine (reference example 29), and potassium carbonate was used in an amount of 5 equivalents relative to the starting material.

Pale-yellow crystals

Stage 2

Hydrochloride (-)-4-[(2R,4S)-4-dimethylamino-2-methylpyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-[(2R,4S)-4-dimethylamino-2-methylpyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide obtained in stage 1.

Yellow crystals

The melting point of 188-193ºC

[α]D20: -51,87° (c=0,347, methanol)

Element is the analysis (for C31H33F3N8O·HCl·0,5C2H5OH·2H2O)

Calculated (%): C, 55,23; H, 6,13; N, 16,62

Found (percent): C, to 55.42; H, 6,10; N, 16,96

Example 61

4-((S)-3-aminopiperidine)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Stage 1

4-[(S)-3-tert-butoxycarbonylamino-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that used the (S)-(-)-3-tert-butoxycarbonylamino (Synthetic Communications 1998, 28, 3919-3926).

Pale yellow amorphous substance

Stage 2

4-((S)-3-aminopiperidine)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 46 (stage 2), except that used 4-[(S)-3-tert-butoxycarbonylamino-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide obtained in stage 1, carried out the extraction of a mixed solution of chloroform/methanol (10:1), kept the solvent, and then washed obtained crude crystals diethyl ether.

Pale-yellow crystals

Melting point 163-167ºC

Example 62

Hydrochloride (+)-4-((S)-3-aminopiperidine)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Canoaaeyea was obtained in the same way, as described in example 2, except that used 4-((S)-3-aminopiperidine)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 61).

Pale-yellow crystals

Melting point 193-199ºC

[α]D20: +28,31° (c=0,438, methanol)

Elemental analysis (for C29H29F3N8O·HCl·2,1H2O)

Calculated (%): C, 54,69; H, 5,41; N, 17,59

Found (percent): C, 54,33; H, of 5.40; N, 18,05

Example 63

4-[(S)-3-dimethylaminopyridine]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

To a suspension of 1.47 g of 4-((S)-3-aminopiperidine)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 61) in 30 ml of methanol was sequentially added 3 ml of acetic acid, 2 ml of 37% aqueous formaldehyde and 1.66 g of triacetoxyborohydride sodium, and then stirred at room temperature for 14 hours. The mixture was podslushivaet by adding to the reaction solution, saturated aqueous sodium hydrogen carbonate solution and was extracted twice with ethyl acetate. The organic layers were combined, washed with water and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel with receipt of 0.62 g of the desired compound as pale yellow crystals.

Temperature plavini the 160-162ºC

Example 64

Hydrochloride (+)-4-[(S)-3-(dimethylamino)piperidinomethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-[(S)-3-(dimethylamino)piperidinomethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 63), and the obtained crude crystals were washed with acetone.

Pale-yellow crystals

Melting point 195-198ºC

[α]D20: +15,92° (c=0,314, methanol)

Elemental analysis (for C31H33F3N8O·HCl·2H2O)

Calculated (%): C, 56,15; H, 5,78; N, 16,90

Found (percent): C, 55,45; H, 5,80; N, 17,30

Example 65

4-((3S,4R)-3-amino-4-methylpyrrolidine-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Stage 1

4-[(3S,4R)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that used the (3S,4R)-3-tert-butoxycarbonylamino-4-methylpyrrolidine (Tetrahedron: Asymmetry, 1997, 8, 883-887).

Pale-yellow crystals

Melting point 191-201ºC

Stage 2

4-((3S,4R)-3-amino-4-methylpyrrolidine-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This is the compound was obtained in the same way, as described in example 46 (stage 2), except that used 4-[(3S,4R)-3-tert-butoxycarbonylamino-4-methylpyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide obtained in stage 1, and the extraction was performed mixed solution of chloroform/ methanol (10/1).

Pale-yellow crystals

Melting point 148-155ºC (decomposition)

Example 66

4-[(3S,4R)-3-dimethylamino-4-methylpyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 63, except that used 4-((3S,4R)-3-amino-4-methylpyrrolidine-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 65).

Pale-yellow crystals

Melting point 153-156ºC (decomposition)

Example 67

Hydrochloride (-)-4-[(3S,4R)-3-dimethylamino-4-methylpyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-[(3S,4R)-3-dimethylamino-4-methylpyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 66).

Pale-yellow crystals

Melting point 164-174ºC (stage what the group)

[α]D20: -2,43° (c=0,493, methanol)

Elemental analysis (for C31H33F3N8O·HCl·0,5H2O)

Calculated (%): C, 58,53; H, to 5.55; N, 17,62

Found (percent): C, 58,50; H, 5,73; N, 17,38

Example 68

(-)-4-[(S)-3-methylaminopropyl-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Stage 1

4-{(S)-3-[N-tert-butoxycarbonyl-N-methylamino]pyrrolidine-1-ylmethyl}-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that used the (S)-3-[N-tert-butoxycarbonyl-N-methylamino]pyrrolidine (reference example 30).

Yellow crystals

Stage 2

(-)-4-[(S)-3-methylaminopropyl-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

0,99 g 4-{(S)-3-[N-tert-butoxycarbonyl-N-methylamino]pyrrolidine-1-ylmethyl}-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide obtained in stage 1, was dissolved in 15 ml of dichloromethane was added 10 ml triperoxonane acid, and then stirred at room temperature for 1 hour. The reaction mixture was neutralized by adding 20% aqueous sodium hydroxide solution and then was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate, and then Athena and the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel with getting 0,70 g of the desired compound crystals are flesh-colored.

Melting point 142-149ºC (decomposition)

[α]D20: -7,14° (c=1,007, methanol)

Elemental analysis (for C29H29F3N8O·HCl·0,6H2O)

Calculated (%): C, 66,75; H, 5,31; N, 19,54

Found (percent): C, up 66,78; H, and 5.30; N, 19,37

Example 69

Hydrochloride (-)-4-((S)-3,4-dimethylpiperidin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Stage 1

4-((S)-3,4-dimethylpiperidin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 63, except that used 4-((S)-3-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 55).

Yellow crystals

Stage 2

Hydrochloride (-)-4-((S)-3,4-dimethylpiperidin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-((S)-3,4-dimethylpiperidin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide obtained in stage 1.

Yellow crystals

The melting point of 187-193ºC

[α]D20: -5,27° (c=0,379, methanol)

elementry analysis (C30H31F3N8O·HCl·2,6H2O)

Calculated (%): C, 54,60; H, of 5.68; N, 16,98

Found (percent): C, 54,46; H, 5,46; N, the value of 16,81

Example 70

4-((R)-3,4-dimethylpiperidin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 63, except that used 4-((R)-3-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 56 (stage 1)).

Yellow powder

Melting point 246-249ºC (decomposition)

Example 71

Hydrochloride (+)-4-((R)-3,4-dimethylpiperidin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-((R)-3,4-dimethylpiperidin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 70).

Pale-yellow crystals

Melting point 186-194ºC

[α]D20: +5,42° (c=0,369, methanol)

Elemental analysis (for C30H31F3N8O·HCl·0,4C2H5OH·2H2O)

Calculated (%): C, 54,77; H, 5,88; N, 17,04

Found (percent): C, 55,04; H, the 5.65; N, 16,74

Example 72

4-{4-[(5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazine-1-ylmethyl}-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

Stage 1

4-methyl bromide-5-methyl-1,3-dioxol-2-he

To 403 mg of 4-chloromethyl-5-methyl-1,3-diox the l-2-she and 525 mg of sodium bromide was added 0.8 ml of anhydrous N,N-dimethylformamide, and then at room temperature for 1.5 hours. To the reaction solution was added 1.2 ml of anhydrous acetone, the mixture was additionally stirred at room temperature for 1 hour, and then remove insoluble substances by filtration. Insoluble substances thrice washed with 0.8 ml of anhydrous acetone and used the obtained pale-yellow solution in the following reaction.

Stage 2

4-{4-[(5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazine-1-ylmethyl}-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

To a suspension of 1.22 g of 4-(piperazine-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (reference example 32) in 5 ml of anhydrous N,N-dimethylformamide was added 222 mg of potassium bicarbonate and with stirring at room temperature was added dropwise a solution of 4-methyl bromide-5-methyl-1,3-dioxol-2-she received at stage 1, in acetone. After stirring at room temperature for 10 hours, the reaction solution was diluted with water and then was extracted 5 times with ethyl acetate. The organic layers were washed with water and dried over anhydrous magnesium sulfate, and then drove away the solvent under reduced pressure. The residue was purified by the method of column chromatography on silica gel with receipt of 1.00 g of the desired compound as a pale yellow amorphous the substances.

Example 73

Hydrochloride 4-{4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazine-1-ylmethyl}-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-{4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazine-1-ylmethyl}-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 72), and the obtained crude crystals were washed with methanol.

Pale-yellow crystals

Melting point 218-226ºC (decomposition)

Elemental analysis (for C33H31F3N8O4·HCl·3H2O)

Calculated (%): C, 56,86; H, 4,63; N, 16,07

Found (percent): C, 56,55; H, 4,70; N, 16,14

Example 74

4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(4-pyridyl)thiazol-2-ylamino]phenyl}benzamide

To 697 mg of 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-[4-methyl-3-theoreticity]benzamide (reference example 33), was added 3 ml of ethanol, 1.5 ml of water and 1.5 ml of 1N. hydrochloric acid and the mixture was heated on an oil bath at 65ºC. Added 6 ml of an aqueous solution 421 mg hydrobromide 4-bromoacetophenone (J. Heterocycl. Chem., 1970, 7, 1137-1141) and the mixture was stirred for 2 hours. After air cooling, the reaction solution was diluted with water, podslushivaet by adding saturated aqueous sodium hydrogen carbonate solution and then was extracted with what ethyl acetate and dried over anhydrous magnesium sulfate. Then drove the solvent under reduced pressure and the residue was purified by the method of column chromatography on silica gel with getting 701 mg of the desired compound as colorless crystals.

Melting point 226-227ºC

Example 75

The hydrochloride of 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(4-pyridyl)thiazol-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(4-pyridyl)thiazol-2-ylamino]phenyl}benzamide (example 74).

Pale-yellow crystals

Melting point 186-188ºC

Elemental analysis (for C29H29F3N6OS·HCl·H2O)

Calculated (%): C, 56,08; H, 5,19; N, 13,53

Found (percent): C, 56,37; H, 5,26; N, 13,25

Example 76

4-[3-Dimethylimidazolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that used the dihydrochloride of 3-dimethylaminopyridine (reference example 34), and potassium carbonate was used in an amount of 5 equivalents relative to the starting material.

Yellow crystals

The melting point of 169-173ºC (decomposition)

Example 77

Hydrochloride 4-[3-dimethylimidazolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)PI is kidin-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-[3-dimethylimidazolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 76).

Pale-yellow crystals

Melting point 159-167ºC (decomposition)

Elemental analysis (for C29H29F3N8O·HCl·H2O)

Calculated (%): C, 56,45; H, 5,23; N, 18,16

Found (percent): C, 56,35; H, 5,04; N, 17,90

Example 78

4-[(R)-3-dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that used dihydrochloride (S)-3-dimethylaminopyridine (reference example 35), and potassium carbonate was used in an amount of 5 equivalents relative to the starting material.

Yellow crystals

Melting point 159-164ºC (decomposition)

Example 79

Hydrochloride 4-[(R)-3-dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-[(R)-3-dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 78), and the crude crystal is s washed with isopropanol.

Pale-yellow crystals

Melting point 114-122ºC (decomposition)

Elemental analysis (for C31H33F3N8O·HCl·0,5i-D·0,5H2O)

Calculated (%): C, 58,61; H, 5,97; N, 16,67

Found (percent): C, 58,73; H, by 5.87; N, to 16.31

Example 80

4-[(S)-3-dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that used the dihydrochloride of (R)-3-dimethylaminopyridine (reference example 36), and potassium carbonate was used in an amount of 5 equivalents relative to the starting material.

Yellow crystals

Melting point 158-163ºC (decomposition)

Example 81

Hydrochloride 4-[(S)-3-dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-[(S)-3-dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 80), and the crude crystals were washed with isopropanol.

Pale-yellow crystals

Melting point 114-122ºC (decomposition)

Elemental analysis (for C31H33F3N8O·HCl·0,5i-D·0,2H2O)

Calculated (%): C, 59,08; H, 5,86; N, 16,96

Found (percent): C, 59,02; H, 5,79; N, 16,62

p> Example 82

4-[(3R,4R)-3-dimethylamino-4-ethoxypyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that used dihydrochloride (3R,4R)-3-dimethylamino-4-ethoxypyrrolidine (reference example 37), and potassium carbonate was used in an amount of 5 equivalents relative to the starting material.

Pale-yellow crystals

Melting point 185-188ºC

Example 83

Hydrochloride 4-[(3R,4R)-3-dimethylamino-4-ethoxypyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 2, except that used 4-[(3R,4R)-3-dimethylamino-4-ethoxypyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 82), and the crude crystals were washed with isopropanol.

Pale-yellow crystals

Melting point 166-170ºC

Elemental analysis (for C31H33F3N8O·HCl·1,5H2O)

Calculated (%): C, 55,56; H, to 5.57; N, 16,72

Found (percent): C, 55,53; H, 5,19; N, 16,77

Example 84

4-(1-Methylpiperidin-4-yloxy)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 1, except for the CSOs, they used 4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline (patent document 1), and hydrochloride of 4-(1-methylpiperidin-4-yloxy)-3-triftormetilfullerenov (reference example 11).

Example 85

4-(1-Methylpiperidin-4-ylidenemethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 1, except that used 4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline (patent document 1), and hydrochloride of 4-(1-methylpiperidin-4-ylidenemethyl)-3-triftormetilfullerenov (reference example 7).

Example 86

4-[(R)-3-dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same way as described in example 47, except that used 4-methyl bromide-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide (reference example 82) and the dihydrochloride (S)-3-dimethylaminopyridine (reference example 35), and potassium carbonate was used in an amount of 5 equivalents relative to the starting material.

Structural formulas of the compounds of examples 1-86 presented in table 2.

Test example 1

The effect of inhibiting the growth of cells

Cells K562 and U937 cells (purchased from American Type Culture Collection) were cultured in medium RPMI-1640 (manufactured by Sigma)containing 10% vol. (v/v) fetal calf serum (FCS) (manufactured by Sigma) (RPMI-1640/FCS). Cells K562 and U937 cells were seeded with a density of 5000 cells/100 μl/well and 4000 cells/100 μl/well into each well of 96-well microtiter plate (manufactured by Costar), respectively. The microplate was incubated in a CO2 incubator overnight. Received a solution of the test drug in dimethyl sulfoxide (DMSO) (produced by Nacalai Tesque) at concentrations 1000 times greater than the test concentration (0; 0,00001-1 μm). The resulting solution was diluted 500 times with medium RPMI-1640/FCS, and then added to the wells 100 ál of diluent. The microplate was incubated in a CO2 incubator. After 72 hours, each well was added 20 μl of a set for counting cells in Cell counting Kit-8 (5 mmol/l of WST-8, 0.2 mmol/l 1-methoxy-PMS, 150 mmol/l NaCl) (produced by Dojindo). After the formation of color in the reaction mixture in a CO2 incubator for 3 hours was determined by optical density formazan, arr is organized by restoring the WST-8, at 450 nm using a multi-level counter ARVOsx (produced by Wallac).

If containing 0.1% DMSO medium RPMI-1640/FCS optical density of the area in which plant cells after culturing in a CO2 incubator for 72 hours, defined as the rate of inhibiting the growth of cells equal to 0%, and the optical density of the site, which was not sown cells, defined as the rate of inhibiting the growth of cells equal to 100%, then the value of the decimal logarithm of the concentration calculated as the decimal logarithm of the ratio (the rate of inhibition/(100 - rate of inhibition)and graphically determine the IC50 value (μm). The results are presented in table 3.

As a control medications used 4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide (see patent document 1).

Table 3
Tested medicinescells K562 (IC50 value, µm)the U937 cells (a value of IC50, μmCoefficient (U937 cells/cells K562)
Example 20,0028155357
Example 4 0,00202814000
Example 60,00124,33583
Example 80,000984,64694
Example 100,00218,13857
Example 120,0056the 4.7839
Example 140,00792,0253
Example 160,00114,13727
Example 180,00484,6958
Example 200,00262911154
Example 210,0063426667
Example 23 0,00115,04545
Example 250,0018the 3.82111
Example 270,00252,61040
Example 290,00171,4824
Example 310,00692,1304
Example 330,0084111310
Example 350,0034113235
Example 370,0014107143
Example 380,00198,94684
Example 400,00394,41128
Example 42 0,00681,4206
Example 430,0011a 3.93,545
Example 450,0031154839
Example 460,019291526
Example 480,0040123000
Example 500,0046163478
Example 520,0040a 3.9975
Example 540,0096161667
Example 550,0022104545
Example 560,00464,4957
Example 57 0,00585,6966
Example 580,00479,42000
Example 590,0081131605
Example 600,00504,0800
Example 620,00141,61143
Example 640,00433,7860
Example 670,00776,5844
Example 680,00245,82417
Example 690,0022104545
Example 710,00616,71098
Example 73 0,0023the 9.74217
Example 750,00592,7458
Example 770,018>100>13699
Example 790,0059204348
Example 810,0047>100>27778
Control medicines0,1517,8136,9

From the results shown in table 3, it is seen that the compounds of the present invention typically possess a greater compared with the control drug's ability to inhibit the growth of cells. Also used in test example 1, K562 cells are BCR-ABL-positive cells, which were obtained from the pleural effusion of a patient with chronic myeloid leukemia in the late stage, which was subjected to transformation in the acute form. The U937 cells are malignant BCR-ABL-negative cells, which were received from pale is that with histiocytomas lymphoma. From the values of the coefficient of inhibiting the growth of cells (U937 cells/cells K562) shows that compared with the control drug compounds of the present invention are safer medicines (from 20 to 8000 times or more). Moreover, the compounds of the present invention is also able to inhibit the growth of expressing E255K cells, and therefore it can be assumed that they possess a sufficient effect of inhibiting autophosphorylation against mutant kinases that can be discovered in the future. Accordingly, the compounds of the present invention is extremely useful as a therapeutic agent for diseases such as chronic myelogenous leukemia, acute lymphoblastic leukemia and acute myeloblastic leukemia.

Example composition 1

Tablet (tablet for oral administration)

The composition of the tablets (80 mg): compound of example 15.0 mg
corn starch46.6 mg
crystalline cellulose24,0 mg
the methylcellulose4.0 mg
magnesium stearate0.4 mg

Mixed powder of this composition is compressed in accordance with a conventional manner and formed with reception of tablets for oral administration.

Example composition 2

Tablet (tablet for oral administration)

The composition of the tablets (80 mg): compound of example 25.0 mg
corn starch46.6 mg
crystalline cellulose24,0 mg
the methylcellulose4.0 mg
magnesium stearate0.4 mg

Mixed powder of this composition is compressed in accordance with a conventional manner and formed with reception of tablets for oral administration.

Industrial applicability

Due to the fact that the connection of the present invention is, as described above, a compound with excellent inhibitory activity against tyrosine kinase BCR-ABL, the pharmaceutical composition comprising the compound of the present invention as an active ingredient, can be used as an inhibitor of tyrosine kinase BCR-ABL, a therapeutic agent for the treatment of chronic myeloid leukemia therapeutic agent for the treatment of acute myeloid leukemia and a therapeutic agent for the treatment of acute lymphoblastic leukemia in mammals, including humans.

1. Amide derivative, representing a compound of the General formula [1] in any of the versions (a) And (b), or its pharmaceutically acceptable salt:

Version (A)
R1is any of the following groups (1)to(3):
(1) -CH2-R11[R11represents a saturated 4-6 membered nitrogen-containing heterocyclic group optionally containing an additional nitrogen atom; a saturated 5-6-membered nitrogen-containing heterocyclic group optionally containing an additional nitrogen atom, which is substituted by a group selected from the group consisting of oxo, -CH2-R111(R111represents a saturated 5-membered nitrogen-containing heterocyclic group), a saturated 5-membered nitrogen-containing heterocyclic group, aminomethyl, monoalkylamines, dialkylaminomethyl and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, and, in addition, may be substituted by 1 or 2 identical or different substituents selected from the group consisting of (C1-C4)alkyl, (C1-C4) alkoxycarbonyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, amino, carbamoyl],
(2) -O-R12[R12represents a saturated 4-6 membered nitrogen-containing heterocyclic group], and
(3) -CH=R13[R13pre is is a saturated 5-6-membered nitrogen-containing heterocyclic group, which may contain an additional nitrogen atom and which may be substituted by 1-3 identical or different substituents selected from the group consisting of oxo, (C1-C4)alkyl];
R2is a (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy and carbarnoyl;
R3represents hydrogen, halogen;
Hetl is any one of groups with the following chemical formulas [4] and [6]:

Het2 represents a pyridyl or pyrimidinyl, provided that excluded the compounds in which R11is pyrrolidinyl, piperidinyl, or piperazinil or morpholinyl (each pyrrolidinyl, piperidinyl, piperazinil or morpholinyl substituted by a group selected from the group consisting of oxo, -CH2-R111(R111represents a saturated 5-membered nitrogen-containing heterocyclic group), a saturated 5-membered nitrogen-containing heterocyclic group, aminomethyl, monoalkylamines, dialkylaminomethyl and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, and, in addition, may be substituted by 1 or 2 identical or different substituents selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, g is lagena, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, amino, carbamoyl);
Het1 is a group of the formula [6] and Het2 represents pyridyl.
Version ()
R1represents-CH2-R14[R14represents a saturated 4-6 membered nitrogen-containing heterocyclic group optionally containing an additional nitrogen atom; a saturated 5-6-membered nitrogen-containing heterocyclic group which may be substituted by 1-3 identical groups selected from (C1-C4)alkyl];
R2is a (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)acyl, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, nitro, carbarnoyl, mono(C1-C4)allylcarbamate, di(C1-C4)allylcarbamate or cyano;
R3represents hydrogen or halogen;
Het1 represents any of the groups with the following chemical formulas [9] and [10]:

Het2 represents a pyridyl;

2. Amide derivative according to claim 1, which represents a compound selected from the group consisting of the following compounds (1), (5), (6), (8), (9), (12) and (13), or its pharmaceutically acceptable salt:
(1) 4-(1-methylpiperidin-4-ylidenemethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(5) (-)-4-((3)-3-amino-2-oxopyrrolidin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(6) 4-[(S)-2-(1-pyrrolidinyl)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(8) 4-[(S)-3-(1-pyrrolidinyl)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(9) 4-{4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazine-1-ylmethyl}-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(12) 4-[(R)-3-dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide and
(13) 4-[(S)-3-dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

3. Amide derivative, representing a compound selected from the group consisting of the following compounds (1)to(44), or its pharmaceutically acceptable salt:
(1) 3-deformity-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(2) 3-ethyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
3) 4-(1-methylpiperidin-4-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(4) 3,5-dichloro-4-[(S)-3-dimethylaminopropan-1-ylmethyl]-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(5) 3-methoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide,
(6) 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(7) 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide,
(8) 3-chloro-4-(4-methylpiperazin-1-ylmethyl)-]N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(9) 3-vermeil-4-(1-methylpiperidin-4-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(10) 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]phenyl}benzamide,
(11) 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]phenyl}benzamide,
(12) 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide,
(13) 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide,
(14) 4-[4-(2-foradil)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(15) 4-[4-(2-hydroxyethyl)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(16)4-[(R)-3-dimethylaminopropan-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(17) 4-(1-piperazinylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide,
(18) 4-(1-piperazinylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridinyl)pyridine-2-ylamino]phenyl}benzamide,
(19) 4-(1-piperazinylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(20) 4-(3-carbamoylbiphenyl-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(21) 4-[(S)-3-dimethylaminopropan-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(22) 4-(3-carbarnoyl-4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(23) 4-((S)-3-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(24) 4-((R)-3-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(25) 4-[(S)-3-N,N-diethylaminopropyl-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(26) 4-[(2R,4S)-4-dimethylamino-2-methylpyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(27) 4-((S)-3-aminopiperidine)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(28) 4-[(S)-3-(dimethylamino)piperidinomethyl]-3-trifluoromethyl-N-{4-meta the-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(29) 4-((3S,4R)-3-amino-4-methylpyrrolidine-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(30) 4-[(3S,4R)-3-dimethylamino-4-methylpyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(31) 4-[(S)-3-(methylamino)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(32) 4-((S)-3,4-dimethylpiperidin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(33) 4-((R)-3,4-dimethylpiperidin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(34) 4-[(3R,4R)-3-dimethylamino-4-ethoxypyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(35) 4-(1-methylpiperidin-4-yloxy)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,
(36) 4-(1-methylpiperidin-4-ylidenemethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide, and
(37) 4-[(R)-3-dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-1N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide.
(38) 4-(1-methylpiperazin-4-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[6-(3-pyridyl)pyrimidine-4-ylamino]phenyl}benzamide,
(39) 4-(1-methylpiperazin-4-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[6-(5-pyrimidinyl)pyrimidine-4-ylamino]phenyl}benzamide,
(40) 4-(4-methylpiperazin-1-metil)-3-trifluoromethyl-N-{4-methyl-3-[4-(4-pyridyl)thiazol-2-ylamino]phenyl}benzamide,
(41) 4-[3-dimethylimidazolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(42) 4-(1-methylpiperidin-4-yloxy)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,
(43) 4-[3-dimethylaminomethylene-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino] phenyl} benzamide,
(44) 4-[(3R,4R)-3-dimethylamino-4-ethoxypyrrolidine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide.

4. Pharmaceutical composition having the properties of an inhibitor of the tyrosine kinase BCR-ABL, including as an active ingredient amide derivative according to any one of claims 1 to 3, or its pharmaceutically acceptable salt.

5. The inhibitor of the tyrosine kinase BCR-ABL, which represents an amide derivative according to any one of claims 1 to 3, or its pharmaceutically acceptable salt.

6. Therapeutic agent for the treatment of chronic myeloid leukemia, acute lymphocytic leukemia and acute myeloid leukemia, comprising as an active ingredient amide derivative according to any one of claims 1 to 3, or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a novel anhydrous tetomilast type A crystalline form, having powder X-ray diffraction spectrum essentially the same as the powder X-ray diffraction spectrum having characteristic peaks at 2θ = 10.5°, 13.1°, 18.4°, 21.9° and 25.8°, pharmaceutical compositions based thereon and synthesis methods thereof.

EFFECT: considerable advantages in terms of industrial production owing to significantly better filterability.

8 cl, 14 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to synthetic cytoskeleton-active compounds which are from the family of natural latrunculin A or latrunculin B and have structural formulae

and described in the formula of invention. Present invention also relates to a pharmaceutical composition containing said compounds and a pharmaceutically acceptable carrier. The invention also pertains to a method of preventing or treating diseases and conditions associated with actin polymerisation. In one embodiment of the invention, high intraocular pressure, such as during primary open angle glaucoma, is treated using the method. The method involves administering a therapeutically effective amount of the cytoskeleton-active compound of formula I or II to a subject, where the said amount is sufficient for acting on a cytoskeleton, for example through actin polymerisation inhibition.

EFFECT: compounds are highly effective.

16 cl, 75 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrole derivatives of formula (I): , where R1 denotes hydrogen; R2 denotes adamantine which is unsubstituted or substituted with a hydroxy group or halogen; R3 denotes trifluoromethyl, pyrazole, triazole, piperidine, pyrrolidine, hydroxymethylpiperidine, benzylpiperazine, hydroxypyrrolidine, tert-butylpyrrolidine, hydroxyethylpiperazine, hydroxypiperidine or thiomorpholyl group; R4 denotes cyclopropyl, tert-butyl, -CH(CH3)2CH2OH, methyl, -CF3 or -(CH2)nCF3 group, where n equals 1 or 2; R5 denotes hydrogen or lower alkyl which is unsubstituted or substituted with a halogen, as well as pharmaceutically acceptable salts thereof.

EFFECT: compounds and pharmaceutical compositions containing said compounds can inhibit 11β-hydroxysteroid dehydrogenase of the form 1 (11-BETA-HSD-1) and can be used to treat diseases such as type II sugar diabetes type and metabolic syndrome.

17 cl, 99 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula I: and their pharmaceutically acceptable salts, in which R1-R4 have values, given in item 1 of invention formula. Said compounds possess inhibiting activity with respect to 11-beta-hydroxysteroid-dehydrogenase and can be applied for production of medications, intended for treatment and prevention of diabetes, especially, diabetes of II type, obesity, malnutrition and hypertension.

EFFECT: development of efficient method of obtaining formula I compounds and based on them pharmaceutical composition.

25 cl, 1 tbl, 149 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) in form of base or a pharmaceutically acceptable addition salt with an acid. The disclosed compounds have β-amyloid peptide(β-A4) formation inhibiting properties. In formula (I), R1 denotes: C1-6-alkyl or phenyl; where said phenyl groups are substituted with two substitutes selected from halogen atoms; R1 and R2' independently denote a hydrogen atom or a hydroxy group; R3 denotes C1-6-alkyl; one or another of radicals R4 and R5 is a group Z and one or another of radicals R4 and R5 is a -C(X)R6 group; G denotes a single bond; Y denotes a single bond, an oxygen atom, a sulphur atom, a C1-4-alkylene group; A and B independently denote a hydrogen atom, a halogen, trifluoromethyl, trifluoromethoxy group; provided that if Y denotes a single bond or an oxygen atom and if group Z is a type group, A does not denote a hydrogen atom; X denotes an oxygen atom; R6 denotes a C1-6alkoxy group. The invention also relates to a method for synthesis of formula (I) compounds, to a medicinal agent and a pharmaceutical composition based on said compounds, and to use of formula (I) compounds in preparing the medicinal agent.

EFFECT: increased effectiveness of using said derivatives.

6 cl, 1 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula

, in which A is a counter ion, a=1-3, b=0-3, X=1-6C alkyl, R1=1-6C alkyl, one or R2 and R3 is 1-6C alkyl and the other is XN+Hb(R1)3-b, or R2 and R3 form a methylenedioxy group, one or R4 and R5 is a halogen and the other is a halogen-substituted 1-6C alkyl, or R4 and R5 are bonded to form a 6-10C aromatic ring or a substituted 6-10C aromatic ring in which the substitute is selected from 1-6C alkoxy, halogen and halogen-substituted 1-6C alkyl. The invention also relates to a method of measuring content of analysed substance capable of ensuring proportional colour change as a result of a reaction in a biological fluid, involving the following steps: ensuring availability of the disclosed tetrazolium salt as an indicator and determination of concentration of the said analysed substance in the biological fluid using the said tetrazolium salt which is used as an indicator.

EFFECT: agents are highly effective.

24 cl, 7 dwg, 1 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula I and to their pharmaceutically acceptable acid addition salts. The compounds of the present invention exhibit the properties of glycine carrier 1 (GlyT-1) inhibitors. In formula I , R1 represents -OR1', -SR1' or morpholinyl; R1' represents lower alkyl, halogen-substituted lower alkyl, or represents -(CH2)n-lower cycloalkyl; R2 represents -S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2 or CN; X1 represents CR3 or N; X2 represents CR3' or N; R3/R3' independently represent hydrogen, halogen, lower alkyl, CN, NO2, -S(O)2-phenyl, -S(O)2-lower alkyl, -S(O)2-pyridine-2, 3 or 4-yl, phenyl optionally substituted with one or two substitutes specified from the group consisting of NO2 or halogen, or represent halogen-substituted lower alkyl, or represent -C(O)-lower alkyl; n has a value of 0, 1 or 2. The invention also concerns a drug containing one or more compounds of the invention and pharmaceutically appropriate excipients.

EFFECT: preparation of the compounds exhibiting the properties of glycine carrier inhibitors.

20 cl, 1 tbl, 133 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where R1 is selected from group, including: phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, lower alkoxy group, halogen or lower halogenalkyl; naphtyl; tetrahydronaphtyl; C3-7cycloalkyl; -(CHR3)m-phenyl, where m stands for 1, 2, or 3; and phenyl is unsubstituted or mono-, di- or tri-substituted with lower alkoxy group, and where R3 is independently selected from hydrogen and lower alkyl; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur, and heteroaryl is mono-, di- or tri-substituted independently with lower alkoxy group; and R2 is selected from group including: n-butyl; phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, halogen or lower alkoxy group; heteroaryl, where term "heteroaryl" relates to aromatic 5-member ring, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; unsubstituted or mono-, di- or tri-substituted independently with lower alkoxy group; -C(O)-NR4R5; where R4 and R5 stand for lower alkyl or together with nitrogen atom, to which they are bound, form 5-member heterocycle, which can additionally contain heteroatom, selected from N or S, and to their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, able to inhibit DPP-IV.

13 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: compound has general formula (where R1 and R3 are identical or different, and each denotes a hydrogen atom or C1-6alkyl; R2 denotes, for example, 5,5-dimethyl-1,3-dioxan-2-yl, 5,7-dioxaspiro[2.5]oct-6-yl, 1,5,9-trioxaspiro [5.5]undec-3-yl, 2,2-dimethyl-1,3-dioxan-5-yl etc; R4, R5, R6 and R7 each denotes a hydrogen atom, a halogen atom, C1-6 alkyl, C1-6 halogenalkyl, C1-6 alkoxy, C1-6 halogenalkoxy etc, and W1 denotes a single bond, methylene or ethylene, or salt thereof.

EFFECT: compound has excellent inhibiting activity towards secretion of gastric hydrochloric acid and more effectively in preserving inhibiting activity towards secretion of gastric hydrochloric acid, can maintain pH in the stomach for a long period of time, is safe and has acceptable physical and chemical resistance.

40 cl, 4 tbl, 97 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: compounds have formula (lb) in which R1 denotes (1) -N(R1A)SO2-R1B, (2) -SO2NR1CR1D, (3) -COOR1E, (4) -OR1F, (5) -S(O)mR1G; (6) -CONR1HR1J, (7) -NR1K COR1L, or (8) cyano, where m equals 0, 1 or 2;X denote a bond or a spacer which contains 1-3 atoms as the backbone chain; ; R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1K and R1L each independently denotes (1) a hydrogen atom, (2) a C1-8alkyl group which can have a substitute (substitutes) selected from a group comprising [1] a hydroxy group, [2] a carboxy group, [3] a C1-6alkoxy group which can be substituted with a halogen and [4] a mono- or disubstituted amino substituted C1-8alkyl group or (3) tetrahydropyran, piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl, and where R1C and R1D, or R1H and R1J together with a nitrogen atom to which they are bonded can form piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl; ring A is a benzene ring or a pyridine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl, nitro, C1-6alkoxy and halogen; ring B is a benzene ring, a pyridine ring or a pyrazine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl; R51 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (2) benzene, pyrazole, pyridine, isoxazole, thiophene, benzothiazole, each of which can have a substitute (substitutes) selected from a group comprising C1-4alkokyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl and halogen; R52 denotes a hydrogen atom; R53 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (3) benzene, pyrazole, pyridine, thiophene, benzodioxane, cyclohexan or tetrahydropyran, each of which can have a substitute (substitutes) selected from a group comprising [1] hydroxy group, [2] cyano, [3] carbamoyl, [4] aminocarbonyl, substituted with one or two substitutes selected from (a) hydroxy group, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group, (e) carboxyl and (f) C1-6alkoxycarbonyl, [5] carboxy, [6] halogen, [7] C1-6alkoxy, [8] C1-6alkylsulphonyl, [9] amino, [10] C1-6acylamino, [11] alkyl-sulphonylamino, [12] cyclic aminocarbonyl and [13] C1-8 hydrocarbon group substituted with 1 or 2 substitutes selected from (a) hydroxy, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group and (e) aminocarbonyl, substituted with a C1-8 hydrocarbon group; to salts thereof, N-oxide thereof and solvate thereof. The invention also relates to a pharmaceutical composition based on said compound, having antagonistic activity towards CCR5, to use of formula (1b) compound to produce an agent for preventing or treating CCR5 related diseases. Novel compounds which have anti CCR5 activity are obtained and described. Said compounds are therefore useful in preventing and/or treating CCR5 related diseases, for example various inflammatory diseases, immunological diseases etc.

EFFECT: wider field of use of the compounds.

7 cl, 11 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: tricyclic compounds of formula I: $ substituted with heterocycle are disclosed, or pharmaceutically acceptable salt or solvate of specified compound, isomer or racemic mixture, where stands for optional double link, dotted line stands for link or does not stand for link, which results in double or single link according to requirements of valency and where A, B, G, M, X, J, n, Het, R3, R10, R11, R32 and R33 and other substituents are such as indicated in formula of invention. Invention also relates to pharmaceutical compositions, which contain them, method of thrombin receptor or cannabinoid receptor inhibition, and to method for treatment of disease related to thrombosis, atherosclerosis, restenosis, hypertension, stenocardia, arrhythmia, cardiac failure and cancer by administration of specified compounds.

EFFECT: production of compounds having properties of antagonists of thrombin receptors.

33 cl, 6 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new compounds of formula (1) or its pharmaceutically acceptable salts, with properties of antagonist CXCR2 of human neutrophils receptor. In formula (1) R1 represents a group selected from C1-8alkyl; where this group is possibly substituted with 1 substituent, independently selected from phenyl or 5-6-unit heteroaryl, containing 1-2 heteroatoms selected from N, S; where phenyl and heteroaryl are possibly substituted by 1, 2 or 3 substitutors, independently selected from halogeno, cyano, -OR4, -COOR7, -SO2R10, C1-6alkyl; X represents -CH2-, oxygen, sulfur; R2 represents C3-7carbocyclil, possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4; or R2 represents 5-unit ring, containing 2 heteroatoms, selected from O, -NR8, and where this ring is possibly substituted with 1 substituent, independently selected from C1-3alkyl; or R2 represents group, selected from C1-8alkyla, where this group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-C1-6alkylcarbamoyl, N,N-di(C1-6alkyl)carbamoyl, carboxy, -NR8COR9 and -CONR5R6; R3 represents group -NR5R6, or R3 represents phenyl, possibly condensed with 6-unit heterocyclil, containing nitrogen, naphthyl, 4-8-unit monocyclic heterocyclil, containing 1-3 heteroatoms, selected from N, O, S, possibly condensed with benzole ring or 3-unit nitrogen-containing ring, where heteroring may be non-saturated, partially or fully saturated, and one or more than one circular atom of carbon may form carbonyl group, and where each phenyl or heterocyclil group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, phenyl, 5-6-unit heteroaryl, containing 1-2 atoms of nitrogen, -OR4, -NR5R6, -CONR5R6, -COR7, -COR20, -COOR7, -NR8COR9, -SO2R10, -SO2NR5R6 or C1-6alkyl [possibly additionally substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR20, -COOR20, -NR18R19, -CONR18R19, phenyl or 5-6-unit of monocyclic heteroaryl, containing 1-2 heteroatoms O, N, S, or 10-unit bicyclic heteroaryl, containing 1 heteroatom O, where heteroring may be partially or fully saturated, and where each phenyl or heteroaryl is group possibly substituted with 1 or 2 substituents, independently selected from halogeno, cyano, nitro, -OR20, -NR5R6, -COOR7, -NR8COR9, 6-unit heterocyclil, containing two heteroatoms, selected from O and N, 5-unit heteroaryl, containing 3 heteroatoms N, C1-6alkyl (possibly additionally substituted with 1 substituent, independently selected from halogeno, cyano, nitro, -OR20, -COOR20; or R3 represents group, selected from C3-7carbocyclil, C1-8alkyl, where this group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6; R4 represents hydrogen; R5 and R6 independently represent hydrogen or group, selected from C1-6alkyl and monocyclic 6-unit saturated heterocyclil containing 1 heteroatom N; where C1-6alkyl is possibly substituted with 1 substituent, independently selected from -NR15R16; or R5 and R6 together with atom of nitrogen, to which they are linked, form 4-7-unit saturated heterocyclic circukar system, possibly containing additional heteroatom, selected from oxygen, -SO(n)- (where n equals 0, 1 or 2) and atoms of nitrogen; R10 represents hydrogen or group, selected from C1-6alkyl; and each of R7, R8, R9, R15, R16, R17 independently represents hydrogen, C1-6alkyl; R18, R19 and R20 represent hydrogen or group, selected from C1-6alkyl, where this group is possibly substituted with 1 substituent, independently selected from -NR8R9, -CONR8R9.

EFFECT: production of new compounds, which may find application in production of medicinal agent for use in treatment of diseases and disorders mediated with chemokines, such as asthma, allergic rhinitis, chronic obstructive pulmonary disease, inflammatory intestine disease, irritable colon syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis or psoriasis, and also for treatment of cancer.

12 cl, 155 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula (Ia) or their pharmaceutically acceptable salts, tautomers, or N-oxides, for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases. In formula (Ia) X stands for group R1-A-NR4; A stands for link, C=O, or NRg(C=O, where R8 stands for hydrogen or C1-3 alkyl; Y stands for link or alkylene chain, made of 1, 2 or 3 atoms of carbon; R1 stands for carbocyclic or heterocyclic group, containing from 3 to 12 circular units; or saturated C1-8hydrocarbyl group, optionally substituted with one or more substituents selected from halogen (for instance, fluorine), hydroxygroups, C1.4alkoxygroups, and carbocyclic or heterocyclic groups, and where 1 or 2 atoms of hydrocarbyl group carbon may be optionally substituted with atom or group selected from O, S, NH, SO, SO2; R2 stands for hydrogen or methyl; R3 is selected from hydrogen and carbocyclic or heterocyclic groups, containing from 3 to 6 circular units; and R4 stands for hydrogen or methyl. Specified carbocyclic and heterocyclic groups are determined in formula of invention and may be optionally substituted with groups specified in invention formula. Objects of invention are also a pharmaceutical composition based on proposed compounds, their application to produce medicinal agents and methods of their application.

EFFECT: production of pharmaceutical composition based on proposed compounds for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases.

48 cl, 6 tbl, 254 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

EFFECT: novel heterocyclic derivatives of formula I, having aspartyl protease inhibiting properties, are obtained.

16 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

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