Pyrimidine derivatives

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to the pyrimidine derivatives with general formula I and their pharmaceutically acceptable salts, which possess tyrosine kinase ZAP-70, FAK and Syk-inhibiting activity, and to their application. The compounds can be used for treatment or prevention of diseases or conditions, where the activation of tyrosine kinase ZAP-70, FAK and/or Syk is involved, e.g., heart failure, chronic obstructive pulmonary disease, Alzheimer's disease et al. In general formula (I) , X is for CR0; R0, R1, R2, R3 and R4 - each identifies independently hydrogen; C1-C8alkyl; hydroxyC1-C8 alkyl; or R3 and R4 together with the adjoined nitrogen and carbon atoms create the 5-10-term heterocyclic ring and, besides, contain 1, 2 or 3 heteroatoms, chosen from N, O and S; or R1 , R2 and R3 each identifies independently the halogen; C1-C8alcoxy; hydroxyC1-C8 alcoxy; C1-C8 alcoxy -C1-C8 alcoxy; phenyl; 5-6-term heterocyclic ring; containing 1-4 heteroatoms, chosen from N and O; nitro; carboxy; -N(C1-C8alkyl)C(O)-C1-C8 alkyl; -CONR10R11; -SO2N(R10)R11; where R10 and R11 each identifies independently the hydrogen; hydroxy; C1-C8 alkyl; C2-C8alkenyl; C3-C8cycloalkyl; C3-C8 cycloalkyl -C1-C8 alkyl; C2-C8 alcoxy -C1-C8 alkyl; hydroxy C1-C8 alcoxy -C1-C8 alkyl; hydroxyC1-C8 alkyl; or 5-10-term heterocyclic ring, containing up to two heteroatoms, chosen from N and S; or R1 and R2 together with the adjoined carbon atoms create the aryl or 5-10-term heteroaryl radical, containing one or two heteroatoms, chosen from N, O and S; or R5 and R6 identifies independently from each other the hydrogen; halogen; cyano; C1-C8 alkyl; haloC1-C8alkyl; R7, R8 and R9 identifies independently from each other the hydrogen; hydroxy; C1-C8alkyl; haloC1-C8alkyl; C1-C8alcoxy; -Y-R12, where Y means the simple link or O and R12 means C1-C4alkyl, substituted or unsubstituted 5-, 6- or 7-term heterocyclic ring, containing 1, 2 or 3 heteroatoms, chosen from N, O and S; carboxy; -N(C1-C8 alkyl)-CO-NR10R11; - -N(R10)(R11); R7 and R8 or R8 and R9, correspondingly, together with the adjoined carbon atoms create the 5- or 6-term heteroaryl containing 1, 2 or 3 heteroatoms, chosen from N; or 5- or 6- term carbocyclic ring; or R7 means hydrogen, hydroxyl, C1-C4alkyl, unsubstituted or terminally substituted hydroxyl group; C1-C8alcoxy group, unsubstituted or terminally substituted by hydroxyl, C1-C4 alcoxy group or unsubstituted or substituted C1-C4alkyl 5-6-term heterocyclic ring, containing 1-3 heteroatoms, chosen from N and O; Provided, one R1, R2 or R3 means -CON(R10)R11; or -SO2N(R10)R11.

EFFECT: therapeutic efficiency is increased.

7 cl, 14 tbl, 184 ex

 

The text descriptions are given in facsimile form.

1. The compound of the formula I

where X is CR0;

R0, R1, R2, R3and R4each independently of one another denotes hydrogen;

With1-C8alkyl; hydraxis1-C8alkyl;

or R3and R4form together with the nitrogen atoms and the carbon to which they are attached, a 5-10 membered heterocyclic ring and, in addition, contain 1, 2 or 3 heteroatoms selected from N, O and S;

or R1, R2and R3each independently of one another denotes halogen; C1-C8alkoxy; hydraxis1-C8alkoxy; C1-C8alkoxy-C1-C8alkoxy; phenyl; 5-6-membered heterocyclic ring containing 1-4 heteroatoms selected from N and O; nitro; carboxy;

-N(C1-C8alkyl)C(O)-C1-C8alkyl; -CONR10R11; -SO2N(R10R11; where R10and R11each independently of one another denotes hydrogen; hydroxy; C1-C8alkyl, C2-C8alkyl; C3-C8cycloalkyl; C3-C8cycloalkyl-C1-C8alkyl; C1-C8alkoxy-C1-C8alkyl; guide axis 1-C8alkoxy-C1-C8alkyl; hydraxis1-C8alkyl; or a 5-10 membered heterocyclic ring containing up to two heteroatoms selected from N and S;

or R1and R2form together with the carbon atoms to which they are attached, aryl, or 5-10-membered heteroaryl moiety containing one or two heteroatoms selected from N, O and S; or

R5and R6independently of one another denote hydrogen; halogen; cyano; C1-C8alkyl; Galos1-C8alkyl;

R7, R8and R9each independently of one another denotes hydrogen; hydroxy; C1-C8alkyl; Galos1-C8alkyl; C1-C8alkoxy; -Y-R12where Y represents a simple bond or O and R12stands With1-C4alkyl, substituted or unsubstituted 5-, 6 - or 7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O and S; carboxy; -N(C1-C2alkyl)-CO-NR10R11; -N(R10)(R11);

R7and R8or R9and R10respectively form together with the carbon atoms to which they are attached, a 5 - or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N; or a 5-or 6-membered carbocyclic ring,

or R7denotes hydrogen, hydroxyl, C1-C 4alkyl, unsubstituted or terminal substituted hydroxyl group; C1-C8alkoxygroup, unsubstituted or terminal substituted by hydroxyl,1-C4alkoxygroup or unsubstituted or substituted C1-C4the alkyl 5-6-membered heterocyclic ring containing 1-3 heteroatom selected from N and O;

provided that one of R1, R2or R3represents-CON(R10R11; or-SO2N(R10R11,

in free form or in salt form.

2. The method of obtaining the compounds of formula I according to claim 1, which is subjected to the interaction of the compound of formula II

where R1, R2, R3, R4, R5, R6and X have the meanings indicated in claim 1 and Y represents a leaving group;

with the compound of the formula III

where R7, R8and R9have the meanings indicated in claim 1;

and produce the compound of formula I in free form or in salt form, and optionally convert the compound of formula I obtained in free form into the desired salt or Vice versa.

3. The compound according to claim 1 in free form or in the form of pharmaceutically acceptable salts designed to produce pharmaceutical composition having Inga is yuusei activity against tyrosine kinase ZAP-70, F and Syk.

4. Pharmaceutical composition having inhibitory activity against tyrosine kinase ZAP-70, F and Syk containing compound of the formula I according to claim 1 or its pharmaceutically acceptable salt in combination with one or more pharmaceutically acceptable carriers or diluents.

5. The use of the compounds of formula I according to claim 1 in free form or in the form of pharmaceutically acceptable salts as active ingredients in pharmaceutical compositions intended for the treatment or prevention of a disease or condition, which plays a role or is involved activation of the tyrosine kinase ZAP-70, F and/or Syk.

6. The use of the compounds of formula I according to claim 1 in free form or in the form of pharmaceutically acceptable salts for preparing a medicinal product intended for treating or preventing a disease or condition, which plays a role or is involved activation of the tyrosine kinase ZAP-70, F and/or Syk.

7. Method of inhibiting tyrosine kinase ZAP-70, F and/or Syk, which is administered a therapeutically effective amount of the compounds of formula I according to claim 1 or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes novel derivatives of triazolo[4,5-d]pyrimidine of the general formula (I): wherein R1 means (C3-C5)-alkyl that can be substituted with halogen atom; R2 means phenyl that can be substituted with fluorine atom; R3 and R4 are similar and mean hydroxy-group; R means XOH wherein X means -CH2, -OCH2CH2 or a bond, or their pharmaceutically acceptable salt or solvate of solvate of such salt under condition that when X means -CH2 or a bond then R1 doesn't mean propyl group; when X means -CH2 and R1 means -CH2CHCF3, butyl or pentyl groups then phenyl group at R2 must be substituted with fluorine atom; when X means -OCH2CH2 and R1 means propyl then phenyl group at R2 must be substituted with fluorine atom. Also, invention describes a pharmaceutical composition based on these compounds, method for their synthesis and novel intermediate compounds of the formula (II) , (V) and R-(R*,R*)-2,3-dihydroxybutanedioate (1:1) of compound of the formula (III): . Also, invention relates to a method for treatment of diseases mediated by P2T-receptors, such as myocardium infarction, prophylaxis or propagation of tumors and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions, improved method of synthesis.

15 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) or their pharmaceutically acceptable salts or solvates possessing properties of modulator of activity of insulin-like growth factor-1 (IGF-1) receptors, their synthesis and using. These compounds can be used in cancer treatment also. In the general formula (I) R1 represents a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom chosen from nitrogen, oxygen or sulfur atom and wherein this ring is optionally substituted with at least a substitute chosen from (C1-C6)-alkyl, (C1-C6)-alkoxy-group (each can be optionally substituted with at least one substitute chosen from halogen atom, hydroxyl and trifluoromethyl group), halogen atom, cyano-group, hydroxyl, (C1-C6)-alkoxycarbonyl, -C(O)NR7N8, and unsaturated 5-6-membered ring that can comprise at least one heteroatom chosen from nitrogen atom, and wherein this ring is optionally substituted with at least one substitute chosen from (C1-C6)-alkyl, (C1-C6)-alkoxy-group (each can be optionally substituted with at least one substitute chosen from halogen atom, hydroxyl and trifluoromethyl group), halogen atom and cyano-group; R2 represents (C1-C4)-alkyl group; R3 represents hydrogen atom or halogen atom; R4 represents 5-membered heteroaromatic ring comprising at least one ring heteroatom chosen from nitrogen atom, and wherein this ring is optionally substituted with at least one substitute chosen from (C1-C6)-alkyl, (C1-C6)-alkoxy-group (each can be optionally substituted with at least one substitute chosen from halogen atom, hydroxyl and trifluoromethyl group),(C3-C6)-cycloalkyl; each R7 and R8 represents independently hydrogen atom, or R7 and R8 in common with nitrogen atom to which they are bound form 4-6-membered saturated heterocycle.

EFFECT: improved method of synthesis and preparing, valuable medicinal properties of compounds and pharmaceutical composition.

24 cl, 102 ex

FIELD: organic chemistry, chemical technology, fungicides.

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EFFECT: improved method of synthesis.

3 cl, 1 sch, 6 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions, improved method of inhibition, improved method of synthesis of compounds.

15 cl, 2 sch, 133 ex

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wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

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The invention relates to new compounds of General formulas I, II, III

< / BR>
or their pharmaceutically acceptable salts, in which the dotted lines indicate optional double bonds; A is-CR7or N; - - NR1R2, -CR1R2R11, -C(= CR2R12R1, -NHCHR1R2, -ОСHR1R2, -SCHR1R2, -CHR2OR12,

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FIELD: medicine, oncology, organic chemistry, antibiotics.

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EFFECT: valuable medicinal properties of combination.

14 cl

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EFFECT: valuable medicinal properties and enhanced effectiveness of agent.

7 cl, 18 ex

FIELD: medicine, oncology, pharmacy.

SUBSTANCE: invention relates to drugs and concerns docetaxel as a drug used in accessory therapy for treatment of metastatic cancer breast in combination with doxorubicin and cyclophosphamide. Proposed combination of drugs provides the enhanced viability coefficient in patients with superexpressed glands ER, PR and/or HER2.

EFFECT: enhanced effectiveness of treatment.

6 cl, 36 ex

FIELD: medicine, oncology.

SUBSTANCE: the present innovation refers to treating malignant neoplasms being capable for metastasing. The method for treating malignant neoplasms deals with introducing medicinal preparation as peptide of γ-D-Glu-D-Trp formula. Before introducing the preparation mentioned one should locally irradiate the tumor.

EFFECT: higher efficiency of therapy.

5 ex, 15 tbl

FIELD: medicine.

SUBSTANCE: method involves subcutaneously introducing Recormon at a dose of 10000 U one day before beginning chemotherapy treatment. Next to it, Recormon is introduced at the same dose every week during 6 weeks. Patient having bone metastases additionally intravenously receive 4 mg of Zometa injected during 30 min or 2 mg of Bondronat during 120 min.

EFFECT: increased and stabilized blood hemoglobin concentration.

2 cl

FIELD: biochemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel using inhibitors of dipeptidyl peptidase IV (DPIV) - isoleucylthiazolidine, isoleucylcyanopyrrolidine and valylpyrrolidine and their corresponding pharmaceutically acceptable acid-additive salts used in treatment and prophylaxis of colony-forming tumor cells and/or metastasis. Enumerated compounds decreased adhesion of rat tumor pulmonary cells and resulted to decrease amount of colonies of tumor cells in them and reduced metastasis.

EFFECT: valuable medicinal anticancer properties of inhibitors.

3 cl, 6 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: method involves applying biphosphonates for producing preparations and treating osteoblastic (osteosclerotic) metastases connected with prostate cancer.

EFFECT: enhanced effectiveness in inhibiting abnormal osteoblast proliferation.

5 cl, 3 tbl

FIELD: medicine, oncology.

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EFFECT: higher efficiency of therapy.

1 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to using dicarboxylic acids of the general formula (2): R-CONH-OH (2) wherein R means -HO-HNCO, -HO-NHCOCH-(OH)CH(OH), -HOOC-CH2CH2, -HO-OCCH=CH as inhibitors of metastasis and agents enhancing chemotherapeutic activity of antitumor preparations. Also, invention relates to a method for enhancing effectiveness of cytostatics in carrying out cytostatic chemotherapy of tumors. Method is carried out by using cytostatics in combination with derivatives of dicarboxylic acids of the formula (2). Also, invention relates to a method for inhibition of metastasizing process. Method is carried out by effect of the known cytostatics and derivatives of dicarboxylic acid of the formula (2) on tumor. Proposed substances provide enhancing antitumor and anti-metastatic activity of known cytostatics based on using derivatives of dicarboxylic acids.

EFFECT: valuable medicinal properties of agents and preparations, enhanced effectiveness of metastasizing inhibition.

4 cl, 4 dwg, 7 ex

FIELD: medicine, oncology.

SUBSTANCE: one should carry out endoliquor therapy, moreover, after surgical removal of cerebral tumor, in early post-surgical period, it is necessary to fulfill catheterization of subarachnoidal cerebrospinal space at L4-L5 level and apply an endolumbar catheter. Then one should sample 5 ml cerebrospinal fluid and mix it with methothrexate at the dosage of 5 mg and hydrocortisone suspension at the dosage of 50 mg. The mixture should be incubated for 30 min at 37° C to be introduced into subarachnoidal space through endolumbar catheter by flow-type technique. There are 5 such infusions during one therapeutic course at 3-d-long interval. Totally, it is necessary to conduct 3 mentioned courses in combination with 5 cycles of adjuvant systemic polychemotherapy at injecting cytostatics upon autoblood. Application of such complex therapy enables to stabilize generalized tumoral process, increase relapse-free and metastases-free periods and prolong patient's life duration.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine, cardiosurgery.

SUBSTANCE: in addition to conventional therapy it is necessary to introduce 5-oxymethyl uracil per 500 mg thrice daily for 5 d before operation and for 14 d after operation. The innovation provides efficient rehabilitation due to complex - antioxidizing, cardiotonic and antiphlogistic action of 5-oxymethyl uracil.

EFFECT: higher efficiency.

1 ex

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