Crystalline forms and rapamycin analogues

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a composition of a rapamycin analogue for immunomodulation and antiproliferation that involves a crystalline form of the rapamycin analogue having at least one of the following structures: and a pharmaceutically acceptable carrier. What is also described a method for preparing the crystalline form of the rapamycin analogue.

EFFECT: what is described is a new form of rapamycin, which can be used in the therapeutic treatment.

38 cl, 30 ex, 11 tbl, 21 dwg

 

The text descriptions are given in facsimile form.

1. The composition of the analogue of rapamycin for immunomodulation and antiproliferative containing an effective amount of crystalline form analogue of rapamycin, with at least one of the following structures:

,

and pharmaceutically acceptable carrier.

2. The composition according to claim 1, where the analog of rapamycin has the structure of formula 1, which represents optionally, salt, derivative, or combination of them:

3. The composition according to claim 1, where the analogue of the brine is of Irina has the structure of formula 2:

4. The composition according to claim 1, where the analog of rapamycin has the formula 3:

5. The composition according to claim 1, in which the crystalline substance is a MES.

6. The composition according to claim 5, in which the MES analogue of rapamycin is selected from the group consisting of MES with acetone, ethyl acetate, methanol, ethanol, n-propanol, isopropanol, Isobutanol, tert-butanol, 2-butanol, acetonitrile, tetrahydrofuran, isobutyl acetate, n-butyl acetate, ethyl formate, n-propyl, isopropylacetate, methyl ethyl ketone, toluene, N,N-dimethylformamide, anisole, methylisobutylketone, nitromethane, propionitrile, 2-butanone (i.e., methyl ethyl ketone or MEK), 1,2-dimethoxyethane and any combination thereof.

7. The composition according to claim 1, in which the crystalline substance is desolate.

8. The composition according to claim 7, in which the crystalline substance is desolat organic solvent selected from the group consisting of acetone, ethyl acetate, methanol, ethanol, n-propanol, isopropanol, Isobutanol, tert-butanol, 2-butanol, acetonitrile, tetrahydrofuran, isobutylacetate, n-butyl acetate, ethylformate, n-propyl, isopropylacetate, methyl ethyl ketone, toluene, N,N-dimethylformamide, anisole, methylisobutylketone, nitromethane, n is Apionidae, 2-butanone (i.e. methyl ethyl ketone or MEK), 1,2-dimethoxyethane and any combination thereof.

9. A method of obtaining a crystalline form of an analog of rapamycin, including
combining analogue of rapamycin with at least one organic environment in which the analogue of rapamycin is able to crystallize to form a mixture; where the organic medium is comprised of at least one polar solvent and optionally contains at least one antibacterial; and
the incubation mixture until the analogue of rapamycin crystallizes; and
removing the crystalline analogue of rapamycin from the organic environment, and the analogue of rapamycin has at least one of the following structures:


10. The method according to claim 9, which further specified organic medium consists of at least one organic solvent for the formation of mixtures;
cause dissolution analogue of rapamycin in an organic solvent;
and
the solvent is incubated until the analogue of rapamycin crystallizes.

11. The method according to claim 10, additionally including
combining at least one antibacterial with an analogue of rapamycin and a solvent for the formation of a two-phase mixture; and
incubation of a two-phase mixture for you is to bundle phase liquid-liquid, and most of the analogue of rapamycin is in the solvent and a smaller portion of the analog of rapamycin is in antibacterial.

12. The method according to claim 11, further comprising separating an organic solvent from antibacterial.

13. The method according to claim 10, in which the organic solvent includes at least one solvent of acetone, ethyl acetate, methanol, ethanol, n-propanol, isopropanol, Isobutanol, tert-butanol, 2-butanol, acetonitrile, tetrahydro-furan, isobutylacetate, n-butyl acetate, ethylformate, n-propyl, isopropylacetate, methyl ethyl ketone, toluene, N,N-dimethylformamide, anisole, methylisobutylketone, nitromethane, propionitrile, 2-butanone, 1,2-dimethoxyethane or any combination thereof.

14. The method according to claim 11, in which antibacterial includes at least one antibacterial from cyclohexane, heptane, hexane, n-octane, isooctane, methylcyclohexane or any combination thereof.

15. The method according to claim 9, in which the incubation is carried out at a temperature of from about -10°to about 10°C.

16. The method according to claim 9, further comprising a suspension of crystalline analogue of rapamycin.

17. The method according to claim 9, further comprising mixing the above-mentioned mixture, while the analogue of rapamycin crystallizes.

18. The method according to claim 9, further comprising nasyscennosti.

19. The method according to claim 9, in which the analogue of rapamycin combined with the organic medium is a crystalline form.

20. The method according to claim 9, further comprising combining the mixture with the second organic medium, and in which encubierta mixture includes a second organic environment.

21. The method according to claim 9, in which the analogue of rapamycin combined with the organic medium is in amorphous form.

22. The method according to claim 9, in which the organic medium is a pharmaceutically acceptable solvent that is acceptable to obtain the pharmaceutical composition skills.

23. The method according to claim 9, further comprising a characterization of crystalline analogue of rapamycin as having a powder x-ray diffraction pattern with a peak at approximately 5.2, 10,5, 13,3, to 15.8, 16.5 and/or 19,1.

24. The method according to item 23, where the powder x-ray diffraction pattern essentially as shown in figure 14A.

25. The method according to claim 9, further comprising a characterization of crystalline analogue of rapamycin as having a powder x-ray diffraction pattern with a peak at about 5,4, 10,8, 11,8, 16,9, and/or 17.9.

26. The method according A.25, where the powder x-ray diffraction pattern essentially as shown in figure 16.

27. The method according to claim 9, additionally including a characterization of the crystal is tax rapamycin as having a powder x-ray diffraction pattern with a peak at approximately 5.1, 10,2, 16,3, 17,1, 19,2, 20,1 and/or 20,5.

28. The method according to item 27, where the powder x-ray diffraction pattern essentially as shown in figure 15A.

29. The method according to claim 9, further comprising a characterization of crystalline analogue of rapamycin as having a powder x-ray diffraction pattern with a peak at about 5,3, 7,2, 10,5, 15,8, 16,6, 19,1 and/or 21,2.

30. The method according to clause 29, where the powder x-ray diffraction pattern essentially as shown in figure 12A.

31. The method according to claim 9, further comprising a characterization of crystalline analogue of rapamycin as having a powder x-ray diffraction pattern with a peak at approximately 5.2, 10,5, 10,8, 15,7, 16.5 and/or 19,0.

32. The method according to p, where the powder x-ray diffraction pattern essentially as shown in figure 17A.

33. The method according to claim 9, further comprising a characterization of crystalline analogue of rapamycin as having a powder x-ray diffraction pattern with a peak at about 5,8, 9,6, 11,7, 13,6, 15,9, 17,4, 20,6 and/or 23.5.

34. The method according to p, where the powder x-ray diffraction pattern essentially as shown in figure 18A.

35. The method according to claim 9, further comprising a characterization of crystalline analogue of rapamycin as having a powder x-ray diffraction pattern with a peak at primerno,3, 10,5, 13,3, 15,8, and/or 16,6.

36. The method according to claim 9, where the analogue of rapamycin has the structural formula 1:

37. The method according to claim 9, where the analogue of rapamycin has the structural formula 2:

38. The method according to claim 9, where the analogue of rapamycin has the structural formula 3:



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention relates to macrocyclic compounds of formula (I), which can be used as inhibitors of NS3 protease of hepatitis C virus (HCV), to their synthesis and their application for treatment or prevention of HCV infection. Compound of formula (I) and its pharmaceutically acceptable salt, in which is selected from group, consisting of group of cycles, whose value is given in i.1 of the formula, with being substituted with from 0 to 4 substituents, selected from W, R5 or oxo; with said substituents W and R5 being located on one or more ring atoms, selected from C and N; R1 is selected from group, consisting of -CO2R10 and -CONR10SO2R6; R2 is selected from group, consisting of C1-C6 alkyl and C3-C6 alkenyl; R3 is selected from group, consisting of H, C1-C8 alkyl and C3-C8 cycloalkyl; R5 is selected from group, consisting of H, halogen atoms, -OH, C1-C6 alkoxy, C1-C6 alkyl, -CN, -CF3, -OCF3, -C(O)OH, -C(O)CH3, C1-C6halogenalkyl, phenyl, naphthyl and -O-phenyl; R6 is selected from group, consisting of C3-C6 cycloalkyl and said R6 are substituted with from 0 to 2 independently selected substituents W; Y is selected from group, consisting of -C(O)-, -OC(O)-, -C(O)N(D)L- and -LN(D)C(O)-, where D is selected from group, consisting of H and C1-C6 alkyl, is selected from group, consisting of direct bond, groups -G-(C1-C6 alkylene)- and (C1-C6 alkylene)-G-, where said G stands for -O-, said alkylene and alkenylene are substituted with from 0 to 4 substituents E, independently selected from group, consisting of C1-C6 alkyl, and said D and E can together form 3-6-membered ring, containing from 0 to 3 N atoms; Z is selected from group, consisting of -C(O)- and direct bond; M is selected from group, consisting of C1-C12 alkylene and C2-C12 alkenylenes, and said M is substituted with from 0 to 2 substituents RA, independently selected from group, consisting of C1-C6 alkyl, =CH2, and 2 adjacent substituents R71 can together with atoms, which they are bound to, form 3-6-membered ring, containing from 0 to 3 heteroatoms, selected from group, consisting of N and O; X is selected from group, consisting of -O-, -CH2O-, -NHC(O)O-, -CH2NHC(O)O-, -C≡CCH2O-, -C(O)O-, -(CH2)3O-, -OC(O)NH-, (CH2)2C(O)NH-, -C(O)NH- and direct bond; each W is independently selected from group, consisting of halogen atoms, -OR10, C1-C6 alkyl, -CN, -CF3, -CO2R10, C1-C6 halogenalkyl, phenyl and naphthyl; and each R10 is independently selected from group, consisting of H and C1-C6alkyl.

EFFECT: method improvement.

19 cl, 138 ex

FIELD: chemistry.

SUBSTANCE: present invention describes methods of producing 32-deoxorapamycin from 32-iodo- or 32-hydroxyrapamycin, in which the hydroxy group is substituted with an arylthiocarbonate or an arylthiocarbamate residue, in the presence of tris(trimethylsilyl)silane and α,α'-azoisobutyronitrile in an organic solvent.

EFFECT: efficient method of producing said compounds.

5 cl, 4 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: disclosed an analogue of 17-desmethylrapamycin, having a structure described in the claim, or a pharmaceutically acceptable derivative thereof. The invention also relates to methods of producing and extracting 17-desmethylrapamycin analogue. 17-desmethylrapamycin analogues are used in preparing medicine for treating cancer. The invention also discloses a pharmaceutical composition based on 17-desmethylrapamycin analogues for treating cancer and autoimmune disorders.

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25 cl, 8 dwg, 8 tbl, 11 ex

FIELD: medicine.

SUBSTANCE: invention refers to a single-stage method for producing a compound of formula I from the compound of formula ASC including interaction of a compound of formula ASC with the appropriate chlorinating agent in an organic solvent in the presence of a base, and segregating the compound of formula I from the reaction mixture, at that use of protective groups in the given method is not required.

EFFECT: new single-stage method for producing compound of formula I is developed.

7 cl, 1 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of the formula , where R1 and R2 are different independent groups and are selected from the group consisting of OR3 and N (R3') (R3"); or R1 and R2 are different groups connected through a single bond and selected from the group consisting of O and NR3; R3, R3', and R3" are independently selected from the group consisting of H, phenyl, substituted phenyl, where substituents are independently selected from the group consisting of C1-C6 alkyl, halogen; R4 and R4': (a) independently selected from the group consisting of H, OH, a group of the formula ; R5, R6, and R7 are independently selected from the group consisting of OCH3; R8 and R9 are joined by (i) a single bond and represent CH2 or (ii) double bond and are CH; R15 are selected from the group consisting of C=O; n is equal to 2. The invention also refers to method for obtaining these compounds.

EFFECT: obtaining new compounds which can be used in medicine as neurodefensive and neurogenerative, antiproliferative and anti-inflammatory drugs.

43 cl, 7 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 39-desmethoxy rapamycin derivatives of the formula (I): where: X is CH2; R1 is a keto group; R2 is OMe; R3 is OH or OMe; R4 and R5 are each independently H; R6 is -C(O)R7, -(CH2)2-O- [CR21R22-O]a-C(O)-R23; -CR21R22-O-C(O)-R23; R7 is (CR8R9)m(CR10R11)PCR12R13R14; or R7 contains two groups selected from -PO(OH)2, -CF2PO(OH)2, -OH, -COOH and -NH2; or R7 contains at least one functional group selected from COOH, OH and -NH2; R8 and R9 are each independently C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkylnyl, any of which can be substituted with -PO(OH)2, -CF2PO(OH)2, -OH, -COOH or -NH2 groups; or R8 and R9 are each independently H, trifluoromethyl or F; R10, R11, R12 and R14 are each independently C1-C4 alkyl, C2-C4 alkenyl; R13 is independently selected from H, OH, C1-C4 alkyl and C2-C4 alkenyl; R21 is H; R22 is H; R23 is R7; a equals 0; m and p are each independently equal to 0; provided that the functional group R7 does not contain more than 12 carbon atoms and contains at least one OH functional group; or to a pharmaceutically acceptable salt thereof. The invention also pertains to a method of obtaining the said compounds and a pharmaceutical composition based on the said compounds.

EFFECT: new compounds are obtained and described, which can be used in medicine in treating cancer and/or B-lymphocytic malignant growths.

22 cl, 5 tbl, 6 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for regiospecific synthesis of rapamycin 42-ester derivatives of formula , where R is ketal isopropylidene substituted with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid, linear or branched C1-C10 alkyl, which possibly contains a halogen, C2-C8 alkenyl, or phenyl, where the said method involves acylation of 42-hydroxyrapamycin with an acyl donor in the presence of lipase. The invention also relates to regiospecific preparation of rapamycin 42-ester from ketal isopropylidene substituted with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid in the presence of lipase.

EFFECT: increased output of the product under mild conditions.

13 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to the amorphous form of the 42-ester of rapamycin and 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid. The invention also relates to methods of obtaining the amorphous form and to pharmaceutical compositions containing this amorphous form and having immunosuppressive, anti rejection, antifungal, antiphlogistic and antiproliferative activity.

EFFECT: increased solubility and bioavailability.

24 cl, 7 dwg, 6 tbl, 7 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention proposes a method for purifying macrolide compounds. Invention describes a method for isolation of macrolide in a purified state that involves the following steps: (a) treatment of an unpurified macrolide or crude macrolide with a solvent not mixing with water; (b) not obligatory concentrating the mixture; (c) treatment with gaseous ammonia to precipitate impurities; (d) separation of impurities; (e) not obligatory concentration of macrolide-containing phase; (f) carrying out chromatography on silica gel column in not obligatory reversed-phase, or with preliminary treatment with silver and elution of macrolide; (g) preparing macrolide in the essential purified form; (h) not obligatory repeat of steps (f) and (g) for preparing macrolide in the essential purified form. Macrolide is represented preferably as tacrolimus, immunomycin or syrolimus. Proposed method provides preparing macrolides of high purity degree by simplified technology.

EFFECT: improved isolating and purifying method.

8 cl, 2 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

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EFFECT: improved method for synthesis.

26 cl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to novel crystalline forms of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrol-2,5-dione acetate salt, their use for the treating the diseases mediated by T-lymphocytes or PKC, to a pharmaceutical compositions thereof, and a method for preparing them. The presented crystalline forms have: a strong diffraction peak at the angle of 2θ making 21.5° for the A form, or a strong diffraction peak at the angle of 2θ making 9.7° for the B form. The mentioned crystalline forms can be prepared by dissolving 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrol-2,5-dione in 2-propanol at higher temperature, and then cooling after salt formation for preparing the A form, or dissolving 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrol-2,5-dione in ethyl acetate at higher temperature and then cooling after salt formation for preparing the B form.

EFFECT: there are prepared novel crystalline form of the biologically active compound with the improved properties, which may be effectively used in medicine.

11 cl, 8 ex, 11 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to application of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form or in form of pharmaceutically acceptable salt (FTY720) for treatment of autoimmune disease of disorder, where dose of FTY720 during initial period of 4 days constitutes 0.5 mg/1 mg/1.5mg/2 mg, respectively, where after that treatment is continued with day dose equal 0.5 mg.

EFFECT: invention relates to set, containing day units of drug forms of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form or in form of pharmaceutically acceptable salt (FTY720) for treatment of autoimmune disease of disorder.

5 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition applicable for oral administration contains an S1P receptor agonist and mannitol with the composition representing a solid dosage form. Mannitol has a particle specific surface area 1 to 7 m2/g, and the S1P receptor agonist is specified from 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720), its pharmaceutically acceptable salt and FTY720-phosphate.

EFFECT: compositions under the invention are characterised by a high level of distribution uniformity of said S1P receptor agonist, and applicable for oral administration in the solid dosage form, eg in the form of a tablet or a capsule.

14 cl, 39 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: method for preparing a pharmaceutical composition consists in mixing an S1P receptor agonist - 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable salt with sugar alcohols; the mixture is milled and/or granulated, and then mixed with an oil agent. The method under invention is implemented on high-speed automated equipment and enables producing the compositions with high-level distribution uniformity of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable salt in the composition applicable for oral administration of said S1P receptor agonist.

EFFECT: preparing the pharmaceutically acceptable salt in the composition applicable for oral administration of said S1P receptor agonist.

15 cl, 39 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents the use of sodium metaarsenite in preparing an oral dosage form of a pharmaceutical composition for inflammation treatment in a mammal.

EFFECT: use of sodium metaarsenite in preparing the oral dosage form of the pharmaceutical composition for inflammation treatment in a mammal.

6 cl, 7 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new amino alcohol derivatives or to their pharmaceutically acceptable salts: In formula I (a):

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EFFECT: invention refers to a pharmaceutical drug applicable as an immunodepressant in graft rejection and containing said compounds.

8 cl, 3 tbl, 45 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new 1H-pyrrolo[3,4-b]quinoline-3,9(2H, 4H)-dione derivatives of general formula 1

wherein R1=Alk, Ar; R2=H, Alk, halogen; R3=H, Alk, halogen; R4=H, Alk, halogen; R5=H, Alk, halogen; R6=CH2Ar, R7=Ar, Also, the invention refers to a method for preparing them.

EFFECT: there are prepared new 1H-pyrrolo[3,4-b]quinoline-3,9(2H, 4H)-dione derivatives possessing anti-tuberculosis activity.

3 cl, 1 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: recipient of a cadaver kidney graft is examined to compare recipient's and donor's HLA alloepitopes. The alloepitopes found in the donor, but not found in the recipient are recovered. It is followed by comparing the recipient's HLA-DR antigens and the recovered alloepitopes, the derived combinations are compared with the following combinations: A9C-DR7; A10C- DR3; A10C-DR6; A28C-DR1; Bw4-DR6; B8C-DR3; B12C-DR2; B27C-DR5. Detecting said combinations enables stating an adequacy of the preventive application of monoclonal antibodies blocking an alpha-chain of an interleukin-2 receptor molecule. The preventive application of the monoclonal antibodies blocking an alpha-chain of the interleukin-2 receptor molecule shall be indicated to the patients with said combinations.

EFFECT: improved outcome of the cadaver kidney grafting that is combined with reducing the price of the method.

1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, more specifically to haematology, and is applicable for immune response modulation, particularly for prevention of acute graft-versus-host disease following marrow allografting. Donor multipotent mesenchymal stromal cells recovered from bone marrow, cultured on a human blood plasma medium enriched in platelet lysate are introduced intravenously in the amount of 1x106 grafted cells per one kg of patient's body weight at the moment of leukocyte recovery in patient's peripheral blood following marrow allografting min. 1.0×109/l.

EFFECT: method provides effective prevention of acute graft-versus-host disease following marrow allografting.

5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel isoquinolinone derivatives of formula (I) , wherein R1 is selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (CH2)a-X-Ar and (CR101R102)a-X-Ar, where said (C1-C6)alkyl is optionally substituted with 1, 2 or 3 groups independently selected from -(C1-C6)alkoxy, -halogen, -OH, -heterocycloalkyl, (C3-C7)cycloalkyl and -NR8R9; R2 is selected from H and (C1-C6)alkyl; R is selected from H, (C1-C6)alkyl and (CH2)d-Y; provided that when R3 is (CH2)d-Y, R2 is selected from H; R4 and R5 are independently selected from H, (C1-C6)alkyl and halogen; R is (C3-C7)cycloalkyl; R7 is H; Ar is phenyl or heteroaryl, optionally substituted with 1, 2 or 3 groups independently selected from -(C1-C6)alkyl, -(CH2)e-O-(C1-C6)alkyl, -(CH2)e-S(O)f(C1-C6)alkyl, -(CH2)e-N(R10)-(C1-C6)alkyl, -(CH2)e-Z-(C1-C6)alkyl, -halogen, heterocycloalkyl, -C(O)NR8R9, -NR8R9 and -C(O)OH, where (C1-C6)alkyl in each case is independently optionally substituted with 1, 2 or 3 groups, independently selected from -NRI2R13; X is selected from a single bond; Y is NR16R17, where R16 and R17 together with a nitrogen atom with which they are bonded form a 5-7-member ring, optionally containing an additional heteroatom NR27, where said ring is optionally substituted on the carbon atom with 1 or 2 substitutes independently selected from -(C1-C6)alkyl, where said -(C1-C6)alkyl is optionally substituted with -OH; and where R27 is selected from H and (C1-C6)alkyl, where said (C1-C6)alkyl is optionally substituted with -OH; Z is selected from C(O)N(R18); R8 and R9 are independently selected from H and (C1-C6)alkyl, where said (C1-C6)alkyl is optionally substituted with 1, 2 or 3 groups, independently selected from NR19R20; or R8 and R9 together with the nitrogen atom with which they are bonded form a 5-6-member ring, optionally containing an additional heteroatom, selected from NR21; R12 and R13 are independently selected from H and (C1-C6)alkyl, where said (C1-C6)alkyl is optionally substituted with -(C1-C6)alkoxy, -OH; or R12 and R13 together with the nitrogen atom with which they are bonded form a 5-6-member ring optionally containing an additional heteroatom selected from NR24; R10, R18, R19, R20, R21, R22, R23 and R24 are independently selected from H and (C1-C6)alkyl; a is selected from 1, 2, 3, 4, 5 and 6; d equals 0 or 1; e equals 0; f is independently selected from 1 and 2; where the heterocycloalkyl is a 5-6-member non-aromatic cyclic ring bonded at a C atom, having 1-2 NR28 atoms; optionally having one double bond; the heteroaryl is a 6-member aromatic ring containing 1 N atom; R is selected from H, (C1-C6)alkyl and -C(O)O-(C1-C6)alkyl; R101 is (C1-C6)alkyl; R102 is H; or pharmaceutically acceptable salts thereof or N-oxides. The invention also relates to methods of producing said compounds and use thereof as a p38 kinase inhibitor.

EFFECT: improved method.

13 cl, 4 dwg, 1 tbl, 128 ex

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