Aryl- and heteroaryl-substituted heterocyclic derivatives of urea, method for inhibition of raf kinase activity and pharmaceutical composition

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

EFFECT: improved method for inhibition, valuable properties of compounds and composition.

25 cl, 6 tbl

 

The present invention relates to the use of derivatives the group arelatively for the treatment of diseases mediated by raf kinase, and pharmaceutical compositions for such treatment.

The level of technology

Oncogene P21rasthe main contributor to the development and progression of solid tumors in humans and mutated in 30% of all tumors in humans (see article Bollton et al. Ann. Rep. Med. Chem., 1994, t, pp. 165-74; Bos. Cancer Res., 1989, v.49, p 4682-9). In normal, neutrogenas the form of the ras protein is a key element of the signal transduction cascade that is controlled by growth factor receptors in almost all tissues (see Avruch et al. Trends Biochem. Sci., 1994, t, pp. 279-83). In biochemical against ras is guanidoacetic-binding protein, and vzaimoprevrascheny between the GTP-bound activated form and GDF-related inactivated form is strictly controlled by endogenous GTPase activity of ras and other regulatory proteins. Mutant forms of ras are present in tumor cells, characterized by reduced endogenous GTPase activity, and, therefore, this protein transfers uncontrolled growth signalov mediated with him effectors, for example, the same enzyme as the kinase raf. This leads to malignant transformation of cells that carry mutant forms of ras (see ATU Magnuson et al. Semin. Cancer Biol., 1994, volume 5, pp. 247-53). It is shown that the inhibitory activity of the active form of ras by inhibiting signaling pathways involving kinase raf introduction of inactivating antibodies against raf kinase or through joint expression of dominant negative raf kinase or dominant negative MEK, the substrate of raf kinase, leads to reversion of transformed cells in normally growing phenotype (see article Daum et al. Trends Biochem. Sci., 1994, t, pp. 474-80; Fridman c, et al. J. Biol. Chem., 1994, t p. 30105-8). In addition, article Kolch et al. (Nature, 1991, t, pp. 426-28) have shown that inhibition of the expression of raf kinase using antisense DNA blocks cell proliferation induced membrane-associated oncogenes. Similarly, inhibition of raf kinase (antimyeloma oligonucleotide) correlate in vitro and in vivo inhibition of growth of various types of human cancers (see Monia et al. Nat. Med., 1996, Vol.2, pp. 668-75).

The invention

The present invention relates to compounds that are inhibitors of the enzyme raf kinase. Because this enzyme is an effector p21rasinhibitors of quick action can be used in pharmaceutical compositions for the treatment of human or for veterinary use, if shown inhibition of raf kinase ways, for example, in the treatment of tumors and/or tumor the growth of cells, mediated by raf kinase. First of all, such compounds applicable in the treatment of humans or animals, for example, tumors in mice, since the progression of these tumors depends on the signal transduction cascade protein ras and, therefore, sensitive interrupt this cascade, for example, by inhibiting raf kinase. Accordingly, the compounds according to the invention can find application in the treatment of solid tumors, such as carcinomas (e.g., lung, pancreas, thyroid, bladder or colon, diseases of the spinal cord or bone marrow, such as leukemia, or adenomas, for example, villous tumor (polyp of the colon).

The present invention provides compounds that usually are called derivative arelatively, including both aryl-and heteroarylboronic analogues, which inhibit the transmission signal with the participation of raf kinase. The invention also provides a method of treating diseases of the human or mammal mediated by raf kinase. Thus, the invention relates to compounds and methods for inhibiting the growth of tumor cells, mediated by raf kinase, comprising introducing the compound of the formula I:

where usually means unsubstituted or substituted aryl or heteroaryl OS is atok, up to tricyclic, with up to 30 carbon atoms containing at least one 5 - or 6-membered aromatic group containing 0-4 atoms, which is selected from the group comprising atoms of nitrogen, oxygen and sulfur. And means heteroaryl residue, which is described in more detail below.

Aryl or heteroaryl residue may include a separate cyclic structures, as well as a combination of aryl, heteroaryl and cycloalkyl structures. The substituents in these aryl or heteroaryl residues can be varied in a wide range and include halogen, hydrogen, hydrogen sulphide, cyano, nitro, amines and various carbon-containing residues, including those that contain one or more sulfur atoms, nitrogen, oxygen and/or halogen. The structure of the substituents described in more detail below.

Suitable aryl or heteroaryl residues for the group in the formula 1 include, but are not limited to, an aromatic cyclic structure containing 4-30 carbon atoms and 1 to 3 rings, of which at least one is a 5-6-membered aromatic ring. In one or more of these rings 1-4 carbon atoms may be replaced by atoms of oxygen, nitrogen and/or sulfur.

Examples of suitable aromatic cyclic structures include phenyl, pyridinyl, naphthyl, pyrimidinyl, benzothiazolyl, quinoline, from inulin, phtalimide and their combinations, such as diphenyl ether (phenoxyphenyl), diphenyl thioether (phenylthiophene), diphenylamine (phenyliminomethyl), phenylpyridinium ether (pyridiniomethyl), pyridinylmethyl, phenylpyridinium tiefer (pyridinylmethyl), phenylbenzothiazole ether (benzothiazolylthio), phenylbenzothiazole tiefer (benzothiazolylthio), phenylpyrimidine ether, vanilinovy tiefer, phenylnaphthylamine ether, pyridinylmethyl ether, pyridinylmethyl tiefer and phthalimidomethyl.

Examples of suitable heterocyclic groups include, but are not limited to, aromatic ring containing 5-12 carbon atoms, or a cyclic system containing 1-3 rings, of which at least one is aromatic, containing one or more, e.g., 1-4 carbon atom in one or more of the rings can be replaced by oxygen atoms, nitrogen or sulfur. Typically, each ring contains 3 to 7 atoms.

For example, can mean 2 - or 3-furyl, 2 - or 3-thienyl, 2 - or 4-triazinyl, 1-, 2 - or 3-pyrrolyl, 1-, 2-, 4 - or 5-imidazolyl, 1-, 3-, 4 - or 5-pyrazolyl, 2-, 4 - or 5-oxazolyl, 3-, 4 - or 5-isoxazolyl, 2-, 4 - or 5-thiazolyl, 3-, 4 - or 5-isothiazole, 2-, 3 - or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl, 1,2,3-triazole-1-, -4 - or-5-yl, 1,2,4-triazole-1-, -3 - or-5-yl, 1 - or 5-tetrazolyl, 1,2,3-oxadiazol-4 - or-5-yl, 1,,4-oxadiazol-3 - or-5-yl, 1,3,4-thiadiazole-2 - or-5-yl, 1,2,4-oxadiazol-3 - or-5-yl, 1,3,4-thiadiazole-2 - or-5-yl, 1,3,4-thiadiazole-3 - or-5-yl, 1,2,3-thiadiazole-4 - or-5-yl, 2-, 3-, 4-, 5 - or 6-2H-dipiradol, 2-, 3 - or 4-4H-dipiradol, 3 - or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6 - or 7-benzofuran, 2-, 3-, 4-, 5-, 6 - or 7-benzothiazyl, 1-, 2-, 3-, 4-, 5-, 6 - or 7-indolyl, 1-, 2-, 4 - or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6 - or 7-benzimidazolyl, 2-, 4-, 5-, 6 - or 7-benzoxazolyl, 3-, 4-, 5-, 6 - or 7-benzisoxazole, 1-, 3-, 4-, 5-, 6 - or 7-benzothiazolyl, 2-, 4-, 5-, 6 - or 7-benzisothiazolin, 2-, 4-, 5-, 6 - or 7-benzo-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7 - or 8-chinoline, 1-, 3-, 4-, 5-, 6-, 7 - or 8-ethenolysis, 1-, 2-, 3-, 4 - or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8 - or 9-acridine or 2-, 4-, 5-, 6-, 7 - or 8-hintline, or additionally, the selection substituted phenyl, 2 - or 3-thienyl, 1,3,4-thiadiazolyl, 3 perril, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc. for Example, may mean 4-were, 5-methyl-2-thienyl, 4-methyl-2-thienyl, 1-methyl-3-perril, 1-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl-1,2,4-thiadiazole-2-yl.

Suitable alkyl groups and the alkyl portion of the substituents, for example, in alkoxygroup etc. include methyl, ethyl, propyl, butyl and the like, including all linear and branched isomers such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc.,

Suitable aryl groups include, for example, phenyl and 1 - and 2-naphthyl.

Suitable cycloalkyl group include cyclopropyl, the cycle is butyl, cyclohexyl and the like, the Term "cycloalkyl"used in the text pitches, means a cyclic structure, with or without alkyl substituents, and, for example, "C4cycloalkyl" includes both cyclopropyl group, a substituted methyl group, and cyclobutyl group. In addition, the term "cycloalkyl" includes saturated heterocyclic group.

Suitable Halogens include F, Cl, Br and/or I, with the possible groups containing from one Deputy to fully replaced (when all the hydrogen atoms in the group substituted by halogen atom), in addition to possible residues of mixed substitution of different Halogens.

As shown above, these ring systems can contain or not contain substituents such as halogen, up to full substitution of the halogen. Other suitable substituents in the group include alkyl, alkoxy, carboxy, cycloalkyl, aryl, heteroaryl, cyano, hydroxy and amino. These deputies, usually referred to in the text of the application X and X'include-CN, -CO2R5, -C(O)NR5R5', -C(O)R5, -NO2, -OR5, -SR5, -NR5R5', -NR5C(O)OR5', -NR5C(O)R5'With1-C10alkyl, C2-C10alkenyl,1-C10alkoxy, C3-C10cycloalkyl, C6-C14aryl, C7-C24alkaryl,3-C13heteros is aryl, With4-C23algeterror, substituted C1-C10alkyl, substituted C2-C10alkenyl, substituted C1-C10alkoxy, substituted C3-C10cycloalkyl, substituted C4-C23algeterror and-Y-Ar.

If the Deputy X or X' is a substituted group, preferably it has one or more substituents which are independently selected from the group comprising-CN, -CO2R5, -C(O)R5, -C(O)NR5R5', -OR5, -SR5, -NR5R5', -NO2, -NR5C(O)R5', -NR5C(O)OR5'and halogen up to full substitution of the halogen.

Group R5and R5'preferably independently selected from the group including H, C1-C10alkyl, C2-C10alkenyl,3-C10cycloalkyl,6-C14aryl, C3-C13heteroaryl,7-C24alkaryl,4-C23algeterror, halogenated up to full substitution With1-C10alkyl, halogenated up to full substitution With2-C10alkenyl, halogenated up to full substitution With3-C10cycloalkyl, halogenated up to full substitution of the C6-C14aryl, halogenated up to full substitution With3-C13heteroaryl.

Bridge group Y predpochtitel the but means-O-, -S-, -N(R5)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO-, -(CH2)mS-, -(CH2)mN(R5)-, -O(CH2)m-, -CHXa-, -CXa2, -S-(CH2)m- , and-N(R5)(CH2)m-, where m=1-3, and Xameans halogen.

The group Ar is preferably means a 5 - to 10-membered aromatic ring containing 0-4 atom, which is selected from the group comprising nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by halogen, up to full substitution and optionally substituted by a group Zn1where n1=0-3.

Each Deputy Z preferably independently selected from the group comprising-CN, -CO2R5, -C(O)NR5R5', -C(O)NR5, -NO2, -OR5, -SR5, -NR5R5', -NR5C(O)OR5', -C(O)R5, -NR5C(O)R5'With1-C10alkyl, C3-C10cycloalkyl, C6-C14aryl, C3-C13heteroaryl,7-C24alkaryl,4-C23algeterror, substituted C1-C10alkyl, substituted C3-C10cycloalkyl, substituted C7-C24alkaryl and replaced With4-C23algeterror. If Z is a substituted group, this group has one or more substituents which are independently selected from the group comprising-CN, -CO2R5, -C(O)NR5R5', -ORsup> 5, -SR5, -NO2, -NR5R5', -NR5C(O)R5'and-NR5C(O)OR5'.

Aryl and heteroaryl residues in group In formula I is preferably selected from the group including

,

and

substituted or unsubstituted by halogen, up to full substitution. X has the values listed above, and n=0-3.

More preferably the aryl and heteroaryl in the group have the formula

where Y is chosen from the group comprising-O-, -S-, -CH2-, -SCH2-, -CH2S-, -CH(OH)-, -C(O)-, -CX2a, -CXaH-, -CH2O - and-co2-and Xameans halogen.

Q means six-membered aromatic ring containing 0-2 nitrogen atom, substituted or unsubstituted by halogen, up to full substitution, and Q1means mono - or bicyclic aromatic structure containing from 3 to 10 carbon atoms and 0-4 atom, which is selected from the group comprising N, O and S, unsubstituted or substituted with halogen up to complete substitution. X, Z, n and n1 have the meanings indicated above, a s=0 or 1.

In preferred embodiments the embodiment of the invention Q means phenyl or pyridinyl, n is substituted or substituted by halogen, up to full substitution and Q1selected from the group comprising phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, substituted or unsubstituted by halogen, up to full substitution, or Y-Q1means phtalimide, substituted or unsubstituted by halogen, up to full substitution. Z and X is preferably independently selected from the group comprising-R6, -OR6, -SR6and-other7where R6means hydrogen, C1-C10alkyl or C3-C10cycloalkyl, and R7preferably selected from the group including hydrogen, C3-C10alkyl, C3-C6cycloalkyl and C6-C10aryl, where R6and R7may be substituted with halogen up to full substitution.

Heteroaryl residue in formula I is preferably selected from the group including

and

where R1preferably chosen from the group comprising From3-C10alkyl, C3-C10-cycloalkyl, halogen-substituted C1-C10alkyl, up to full substitution and halogen-substituted C3-C10cycloalkyl up to full substitution, and R2means C6-C14aryl, C3-C14heteroaryl, substituted C6-C14aryl or substituted With 3-C14heteroaryl.

If R2means substituted group, the substituents preferably selected from the group including halogen, up to full substitution and Vnwhere n=0-3.

Each V is preferably independently selected from the group comprising-CN, -OC(O)NR5R5', -CO2R5, -C(O)NR5R5', -OR5, -SR5, -NR5R5', -C(O)R5, -NR5C(O)OR5', -SO2R5, -SOR5, -NR5C(O)R5', -NO2With1-C10alkyl, C3-C10-cycloalkyl,6-C14aryl, C3-C13heteroaryl,7-C24alkaryl,4-C24-algeterror, substituted C1-C10alkyl, substituted C3-C10cycloalkyl, substituted C6-C14aryl, substituted C3-C13heteroaryl, substituted C7-C24-alkaryl, substituted C4-C24algeterror.

If V denotes a substituted group, V is preferably substituted by one or more substituents which are independently selected from the group including halogen, up to full substitution, -CN, -CO2R5, -C(O)R5, -C(O)NR5R5', -NR5R5', -OR5, -SR5, -NR5C(O)R5', -NR5C(O)OR5'and-NO2.

Each of the substituents R5and R5'preferably independently selected from the group, enabling the th N, With1-C10alkyl, C3-C10cycloalkyl, C6-C14aryl, C3-C13-heteroaryl,7-C24alkaryl,4-C23algeterror, halogen-substituted C1-C10alkyl, up to full substitution, halogen-substituted C3-C10-cycloalkyl up to full substitution, halogen-substituted C6-C14aryl, up to full substitution, halogen-substituted C3-C13heteroaryl up to full substitution.

R2preferably means a substituted or unsubstituted phenyl or pyridinyl, where the substituents R2selected from the group including halogen, up to full substitution and Vn1where n=0-3.

Each V1preferably independently selected from the group comprising substituted or unsubstituted With1-C6alkyl, C3-C10cycloalkyl,6-C10aryl, -NO2, -NH2-C(O)-C1-6alkyl, -C(O)N-(C1-6alkyl)2, -C(O)NH-C1-6alkyl-O-C1-6-alkyl, -NHC(O)H, -NHC(O)OH, -N(C1-6alkyl)C(O)-C1-6alkyl, -N(C1-6-alkyl)C(O)-C1-6alkyl, -NHC(O)-C1-6alkyl, -OC(O)NH-C6-14aryl, -NHC(O)O-C1-6-alkyl, -S(O)-C1-6alkyl and-SO2-C1-6alkyl. If V1means substituted group V1preferably substituted by one or more halogen atoms up to the full Sames the deposits.

Most preferably, R2selected from substituted or unsubstituted phenyl or pyridinyl, in which the substituents denote halogen or Wn(n=0-3).

W is preferably selected from the group comprising-NO2- 1-3alkyl, -NH(O)CH3, -CF3, -Och3, -F, -Cl, -NH2, -OC(O)NH-phenyl, substituted by halogen, up to full substitution, -SO2CH3, pyridinyl, phenyl, halogen-substituted phenyl, up to full substitution With1-6alkyl substituted phenyl.

The invention also relates to compounds within the scope of General formula I described above. More specifically, these compounds include derivatives of pyrazolidine formula

prilocaine formula

and thermocline formula

where R1, R2and have the values specified above.

The present invention also relates to pharmaceutically acceptable salts of formula I. Suitable pharmaceutically acceptable salts are well known to experts in the art and include salts with inorganic bases and organic acids, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonate acid, sulfonic acid, acetic acid, t is everysunday acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts include salts of inorganic bases, such as salts with cations of alkali metals (e.g., Li+, Na+or K+), alkaline earth metals (for example, Mg+2, CA+2or VA+2), ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium cations and Quaternary ammonium cations, formed by protonation or parallelomania of triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2,2,2]octane (DABCO), 1,5-diazabicyclo-[4,3,0]non-5-ene (DBN) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).

A series of compounds of formula I have asymmetric carbon atoms and can therefore exist in the form of racemates and optically active forms. Methods of separation of mixtures of enantiomers and diastereomers well known to specialists in this field of technology. The present invention includes any selected racemic or optically active form of compounds described by formula I, which is Inga is forom kinase raf.

The compounds of formula I is obtained using known chemical reactions and procedures, some of which are suitable for use in industry. However, here represented by the following General preparative methods that experts in the art could use them for the synthesis inhibitors, and a more detailed description of these techniques is given in the experimental part, devoted to the synthesis of specific compounds.

Information confirming the possibility of carrying out the invention

General preparative methods

Heterocyclic amines are synthesized by known methods [see the books Katritzky et al. Comprehensive Heterocyclic Chemistry (the Chemistry of heterocyclic compounds), Permagon Press: Oxford, UK (1984); March, Advanced Organic Chemistry (Organic chemistry), 3rded., John Wiley:New York (1985)].

For example, as shown in scheme I, 5-aminopyrazole, substituted in position N-1 aryl or heteroaryl residues can be synthesized by reacting α-cyanomethane (2) with an appropriate aryl - or heteroeroticism (3, R2=aryl or heteroaryl). CYANOGEN (2), in turn, can be obtained by using the ion interaction of acetamidate with the corresponding allpresan, such as ester, acid halide or acid anhydride. If the remainder R1requires stabilization approach is brilliant anion, 2-aryl - and 2-heteroarylboronic can be synthesized by the reaction of Mitsunobu by the interaction of cyanomethane 2 with alcohol 5 with subsequent cyclization of simple enol ether 6 in the presence of a catalyst base with the formation of pyrilamine 7.

Scheme I

Some General methods for the synthesis of heterocyclic amines

Substituted anilines receive standard methods [see the books March, Advanced Organic Chemistry (Organic chemistry), 3rded., John Wiley:New York (1985); Larock, Comprehensive Organic Transformations (Transformations of organic compounds), VCH Publishers: New York (1989)]. As shown in scheme II, arylamine usually synthesize recovery nitroarenes using metal catalysts such as Ni, Pd or Pt, and H2or vectors hydride, such as formate, cyclohexadiene or borohydride [see the book Rylander, Hydrogenation Methods hydrogenation), Academic Press: London, UK (1985)]. Nitroarene can also be recovered directly using the effective sources of hydride, such as LiAIH4[see the book Seyden-Penne, Reduction by the Alumino - and Borohydrides in Organic Synthesis (Recovery of alumina - and borhydride in organic synthesis, VCH Publishers: New York (1991)], or by using metals with zero valency, such as Fe, Sn or Sa, in most cases in an acidic environment. There are many methods for the synthesis of nitroarenes [the m in books March, Advanced Organic Chemistry (Organic chemistry), 3rded., John Wiley:New York (1985); Larock, Comprehensive Organic Transformations (Transformations of organic compounds), VCH Publishers:New York (1989)].

Scheme II Recovery nitroarenes in arylamine

Nitroarene usually get electrophilic aromatic nitration using HNO3or an alternative source of NO2+. Before restoring nitroarene can be modified.

Thus nitroarene, substituted potentially removed by the group (F, Cl, Br and the like)may join in substitution reactions when interacting with nucleophiles, such as tilt (as shown in scheme III) or phenoxide. Nitroarene you can also enter into the condensation reaction type reaction Ullman (Ullman) (see scheme III).

Scheme III

Some reactions of nucleophilic aromatic substitution using nitroarenes

As shown in scheme IV, the urea can be obtained by the interaction heteroresistant (12) with arylamines (11). Heteroresistant can be synthesized from heteroarenes treatment with phosgene or equivalents of phosgene, such as trichloromethylcarbonate (diphosgene), bis(trichloromethyl)carbonate(triphosgene) or N,N'-carbonyldiimidazole(CDI). The isocyanate can so is e be obtained from derivatives of heterocyclic carboxylic acid, such as ether, allalone or anhydride, using a rearrangement of kurzius. Thus, the reaction of the acid derivative 16 with a source of azide and subsequent peregruppirovka lead to the formation of isocyanate. The corresponding carboxylic acid (17) can also be subjected to rearrangement of kurzius using diphenylphosphinite (DPPA) or similar reagent. In addition, the urea can be obtained by the reaction arylisocyanate (20) with the heterocyclic amine.

Scheme IV, Some methods for the synthesis of urea (Het=a heterocycle)

Ultimately, urea derivatives can be further modified using methods known to experts in this field of technology. For example, 2-aryl - and 2-heteroarylboronic can be obtained from the corresponding 2-halogentated derivatives of urea by the reaction of the cross-combinations using transition metal (as described for 2-bromothiophene 25, scheme V). Thus, the interaction of nitrile 20 with ether α-thioacetate leads to the formation of 5-substituted-3-amino-2-thiophenecarboxylate 21 (Ishizaki et al., The Japan Patent 6025221). Decarboxylation of the ester 21 can be performed by protecting the amino group, such as tert-butoxy(RE)carbamate (22), followed by saponification and acid treatment. If the protective the group using the BOC-group, the decarboxylation may be accompanied by removal of the protective group with the formation of substituted 3-tirananmongkoi salt (23). Alternative method ammonium salt 23 can be obtained by saponification of ester 21 with subsequent treatment with acid.

After completion of the synthesis of urea, as described above, the subsequent bromination of urea leads to the formation of the penultimate intermediate derived halogenation (25). Then the reaction cross-combination of thiophene 25 with the appropriate tributyl or trimethylation (R2=aryl or heteroaryl) in the presence of palladium leads to the formation of the desired 2-aryl - or 2-heteroarylboronic.

Scheme V Synthesis and interconversion of urea derivatives

The invention also includes pharmaceutical compositions containing a compound of formula 1 and a physiologically acceptable carrier.

The compounds can be administered orally, topically, parenterally, by inhalation or spray or under the tongue, rectally or vaginally with the use of compositions containing a uniform dose. The term "introduction by injection" includes intravenous, intramuscular, subcutaneous and parenteral injection and method injection. Skin introduction may include local application or extremely durable, the skin introduction. One or more compounds can be used in combination with one or more non-toxic pharmaceutically acceptable carriers and, if necessary, with other active componentui.

Compositions intended for oral use, get on any known in the art a method for producing pharmaceutical compositions. To impart a pleasant taste such compositions can include one or more agents chosen from the group comprising diluents, sweeteners, flavourings, colourings and preservatives. Tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. Such fillers may be inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating or dezintegriruetsja agents, for example corn starch or alginic acid; binding agents, for example magnesium stearate, stearic acid or talc. Tablets can be without shell or can be covered with well-known methods with the aim to delay disintegration and absorption in the gastrointestinal tract and thereby provide a prolonged action for a certain period of time. For example, there may be used material, ensuring the th delayed action, such as glycerylmonostearate or glycerylmonostearate. These compounds can also be obtained in a solid, rapidly absorbable form.

Compositions for oral administration, pogut to be obtained in the form of hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

The liquid suspension containing the active components in a mixture with fillers, suitable for aqueous suspensions. Such fillers are suspendresume agents, for example, sodium carboxymethyl cellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, gum tragakant and Arabian gum; dispersing and wetting agents can be natural phosphatides, for example lecithin, or condensation products of accelerated with fatty acids, for example, polyoxyethylenated, or condensation products of ethylene oxide with aliphatic alcohols, for example, heptadecafluorooctane, or condensation products of ethylene oxide with partial esters of sorbitol with fatty acids, such as polyoxyethylenesorbitan, or PR, the products of condensation of ethylene oxide with partial esters anhydromannitol with fatty acids, for example, polyethyleneterphthalate. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl-para-hydroxybenzoate, one or more dyes, one or more flavoring agents and one or more sweeteners, such as sucrose or saccharin.

Dispersible powders and granules suitable for preparation of aqueous slurry by adding water, contain the active ingredient mixed with dispersing or wetting agent, suspenders agent and one or more preservatives. An example of a suitable dispersing or wetting agents are described above components. Besides them, the composition can contain additional excipients, for example, sweeteners, flavorings and colorings.

Compounds can also be used to obtain non-aqueous compositions, for example, oil suspensions, which can be obtained by suspendirovanie active ingredients in a vegetable oil, such as peanut oil, olive oil, sesame oil or nut oil peanuts, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. To impart a pleasant taste in compositions for oral administration can add podlas Italy, mentioned above, and flavoring agents. These compositions can be protected by adding an antioxidant such as ascorbic acid.

The pharmaceutical compositions according to the invention can be manufactured in the form of water-in-oil emulsions. As the oil phase can be used vegetable oil, such as olive oil or peanut oil, or mineral oil, for example, vaseline oil, or mixtures thereof. Suitable emulsifying agents may be natural gums, for example, Arabian gum or gum tragakant, natural phosphatides, for example soy bean, lecithin, and esters or partial esters of anhydromannitol with fatty acids, for example, anhidrosis monooleate, and condensation products of these partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavorings.

Syrups and elixirs can be prepared with sweeteners, for example, glycerin, propylene glycol, sorbitol and sucrose. Such compositions may also contain means for reducing irritation, preservative, flavouring and colouring agents.

Compounds according to the invention can also be used in the form of suppositories for rectal or vaginal application. These compositions are obtained by mixing the drug with a suitable n is causing irritation filler, which is solid at ordinary temperature but becomes liquid at body temperature, i.e. will melt at rectal or vaginal introduction with the release of the drug. Such materials include coconut oil and glycols.

Compounds according to the invention can be entered using percutaneous methods known to experts in the field [see, for example, in the book Chien, Transdermal Controlled Systemic Medications (Transdermal-adjustable system medication), Marcel Dekker, Inc., (1987); Lipp et al., publication of international patent application WO 94/04157, 3.03.94]. For example, a solution or suspension of the compounds of formula I in a suitable volatile solvent of choice, containing agents promoting penetration, combined with other additives, known to specialists in this field, such as materials of the matrix and microbicides. After sterilization, the resulting mixture can be processed by known techniques in the dosage form. In addition, after processing emulsifying agents and water solution or suspension of the compounds of formula 1, you can get lotion or ointment.

Suitable solvents for the preparation of systems for percutaneous delivery to well-known specialists in this area, they include lower alcohols, such as ethanol or isopropyl alcohol; lower ketones, t is such as acetone, esters of lower carboxylic acids, such as ethyl acetate, polar ethers, such kactatdehydrogenase, lower hydrocarbons, such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane or trichloroethane. Suitable solvents may also include mixtures of one or more compounds which are selected from lower alcohols, lower ketones, esters of lower carboxylic acids, polar ethers, lower hydrocarbons, halogenated hydrocarbons.

Suitable promoting penetration agents systems for percutaneous delivery to well-known specialists in this area, they include, for example, monohydroxy - or polyhydroxystearic, such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated fatty8-C18alcohols, such as lauric alcohol or cetyl alcohol, saturated or unsaturated fatty8-C18acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl or monoglyceride esters of acetic acid, Caproic acid, lauric acid, myristic acid, stearic acid palmitinovoj acid, or diesters of saturated or unsaturated dicarboxylic acids containing up to 24 carbon atoms, such as diisopropylamide, diisobutylamine, Diisopropylamine, Diisopropylamine or Diisopropylamine. Additional materials that promote penetration include phosphatidylcholine, such as lecithin or cephalin, terpenes, amides, ketones, urea and derivatives thereof, and also ethers, such as dimethyldithiocarba and monotropy ether of diethylene glycol. Suitable compositions that promote penetration, can also include mixtures of one or more agents chosen from the group: monohydroxy - or polyhydroxystearic, saturated or unsaturated fatty8-C18alcohols, saturated or unsaturated fatty8-C18acid, saturated or unsaturated fatty esters with up to 24 carbon atoms, diesters of saturated or unsaturated dicarboxylic acids containing up to 24 carbon atoms, phosphatidylcholine, such as lecithin or cephalin, terpenes, amides, ketones, urea and derivatives thereof, and the ethers.

Suitable binder materials systems for percutaneous delivery to well-known specialists in this area, they include, for example, polyacrylates, silicones, polyurethanes, blakolmer, copolymers of styrene and butadiene, natural and synthetic is their resin. As components of the matrix can also be used cellulose ethers, derivatives of polyethylene and silicates. For increasing the viscosity of the matrix can be added for additional materials, such as viscous resin or oil.

For all schemes use stated in the description of the compounds of the formula I, the daily oral dose is preferably from 0.01 to 200 mg/kg body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion method, is preferably from 0.01 to 200 mg/kg body weight. Daily rectal dose is preferably from 0.01 to 200 mg/kg body weight. Daily vaginal dose of medicament is preferably from 0.01 to 200 mg/kg body weight. Daily local dose is preferably from 0.1 to 200 mg, with the introduction of from one to four times per day. When percutaneous introduction of a concentration preferably should provide a daily dose of from 0.01 to 200 mg/kg inhalation daily dose is preferably from 0.01 to 10 mg/kg body weight.

To a person skilled in the art it is obvious that the specific route of administration will depend on a number of factors, each of which when prescribing medicines are considered in the prescribed p is the row. However, it should also imply that individual's dose for a given patient depends on many factors including the activity of the specific compound, the age of the patient, the body weight of the patient, the General health of the patient, gender of the patient, the diet of the patient, time of administration, the administration scheme, the speed of introduction of the drug, combination of drugs, severity of illness, subject to a therapeutic treatment.

For professionals in this field it is also obvious that the optimal course of treatment, i.e. the treatment and the daily number of doses of the compounds of formula 1 or its pharmaceutically acceptable salt for a certain period of time, can be set by the person skilled in the art based on conventional medical tests.

All applications, patents and publications, cited above and below, are included as links in the text of the application, including the preliminary application for the grant of a patent Attorney Docket BAYER 9 V1, filed December 22, 1997 under serial No. 08/996181 converted on December 22, 1998

Compounds derived from known compounds (or from starting materials which, in turn, is obtained from known compounds) using General preparative methods below. The activity of the specific compound in relation to inhibition of Keene is s raf define the generally accepted method by method, described below. The following examples are given to illustrate the invention and in no way limit the scope of the invention.

Examples

All reactions carried out in a glass container, dried in a flame or in an oven, at a gauge pressure of dry argon or dry nitrogen, unless otherwise stated, under stirring on a magnetic stirrer. Sensitive to oxygen or moisture) liquids and solutions are transferred via syringe or cannula, and make the reaction vessels through rubber grommets. Unless otherwise indicated, the term "concentration under reduced pressure" refers to the use of a rotary evaporator Buchi at a pressure of approximately 1,99 kN/m2(15 mm RT. Art.).

All temperatures are given in degrees Celsius (° (C) without amendments. Unless otherwise stated, all proportions and percentages are indicated by weight.

All reagents and solvents MERCHANTABILITY used without additional purification. Thin-layer chromatography (TLC) carried out on glass plates (Whatman company®), covered with a layer of silica gel 60A F-254 with a thickness of 250 μm. The manifestation of chromatograms performed on one or more of the following ways: (a) when illuminated with UV light, (b) exposure to iodine vapor, (C) immersing the plates in a 10%solution phosphomolybdenum acid in ethanol followed by heating, (d) p is progeniem plates in a solution of cerium sulfate, followed by heating, and/or (d) immersing the plates in a solution of 2,4-dinitrophenylhydrazine in acidified ethanol followed by heating. Chromatography on a column (Express chromatography carried out on silica gel with a particle size 230-400 mesh mesh (EM Science®).

Melting point (MP) is determined at the device Thomas-Hoover or instrument Mettler FP66 and lead without amendment. Infrared spectra with Fourier transform shoot at the spectrophotometer Mattson 4020 Galaxy Series. Proton spectra (1H) nuclear magnetic resonance (NMR) remove spectrometer General Electric GN-Omega 300 (300 MHz) using as standards Me4Si (δ is 0.00) or residual protonated solvent (CHCl3δ 7,26; Meon δ 3,30; DMSO δ 2,49). Range of carbon13To remove spectrometer General Electric GN-Omega 300 (75 MHz) using a standard solvent (CDCl3δ 77,0; MeOD-d3δ 49,0; DMSO-d6δ 39,5). Mass spectra of low-resolution (MS) and mass spectra of high resolution (HRMS) are obtained in the form of spectra, electron impact ionization (EI), and spectra ionization fast atom (FAB). Spectra of electron impact ionization (EI-MS) receive mass spectrometer Hewlett Packard 5989A, equipped with a unit for entering sample desorption chemical ionization (firm Vacumetrics). The ion source has a temperature of 250°With. Ionize the s electron impact is carried out at an electron energy of 70 eV and the current in the trap 300 µa. Mass spectra of secondary ions with capture of cesium (FAB-MS), a modern variant of the method with ionization fast atom get spectrometer Kratos Concept 1-h). Mass spectra with chemical ionization (CI-MS) get on the device Hewlett Packard MS-Engine 5989A with methane as the gas-reagent (133,32×10-4- to 333.3×10-4(1×10-4to 2.5×10-4Torr). Block direct input sample desorption chemical ionization (firm Vaccumetrics, Inc.) (DCI) operates at a pressure drop of from 0-147,1 kN/m2(0-1,5 at.), and then within 10 s at 980,6 kN/m2(10 at.), while not disappear all traces of the sample (˜1-2 minutes). Range scan in the range of 50-800 units of atomic mass (one scan for 2 seconds). HPLC-mass spectrum with electrospray (HPLC ES-MS) get on the device Hewlett Packard 1100 HPLC equipped with four-channel pump, detector with variable wavelength, column 18 and a mass spectrometer with an ion trap company Finnigan LCQ with ionization electrospray. Range scan in the range from 120-800 units of atomic mass using variable time counting the number of ions in the source. Gas-chromatographic - ion selective mass spectrum (GC-MS) get on the gas chromatograph Hewlett Packard 5890, equipped with a HP-1 methanesiliconic column (25 m × 0.2 mm; impregnation 0.33 mm) and mass-selective detector Hewlett-Packard 5971 (ionization energy 70 eV).

Elemental Ana is from perform in the laboratory Robertson Microlit Labs, Madison NJ. All connections urea characterized by NMR spectra, mass spectra of low-resolution (MS) and elemental analysis and mass spectra of high resolution (HRMS), which correspond to the given structures.

List of abbreviations

hexane
Asónacetic acid
VOStert-butoxycarbonyl
DMPU1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
DMFN,N-dimethylformamide
DMSOthe sulfoxide
DPPAdiphenylphosphoryl
EtOAcethyl acetate
EtOHethanol (100%)
Et2Odiethyl ether
Et3Nthe triethylamine
m-SRV3-chloroperoxybenzoic acid
Meonmethanol
pet. ether
(pet ether)petroleum ether (boiling point 30-60°)
THFtetrahydrofuran
TFUtriperoxonane acid
Tftrifloromethyl
acetoneacetone
hexane
CH2Cl2methylene chloride
CHCl3chloroform
t-Butert-butyl

A. General methods for the synthesis of heterocyclic amines

A1. A common method to obtain an N'-aryl-5-aminopyrazole

N'-(4-methoxyphenyl)-5-amino-3-tert-butylphenol: a Mixture of the hydrochloride of 4-methoxyphenylhydrazine (3.5 g), 4,4-dimethyl-3-oxopentanenitrile (2.5 g), EUN (30 ml) and Asón (1 ml) is refluxed for 3 h, cooled to room temperature and poured into a mixture of Et2O (100 ml) and 10% solution of Na2CO3(100 ml). The organic layer was washed with saturated NaCl solution, dried (MgSO4) and concentrate under reduced pressure. The solid residue is washed with pentane, and thus receive the desired pyrazole in the form of a solid light brown color (4,25 g):1H-NMR (DMSO-d6) δ of 1.18 (s, 9H), of 3.78 (s, 3H), 5,02 (user. s, 2H), of 5.34 (s, 1H), 6,99 (d, J=8 Hz, 2H), 7,42 (d, J=8 Hz, 2H).

A2. General method for the synthesis of 2-aryl-C-aminopurine on the basis of the reaction of Mitsunobu (Mitsunobu)

Stage 1. 4,4-dimethyl-3-(4-pyridinylmethyl)-2-pentenenitrile:

A solution of triphenylphosphine (2,93 g, and 11.2 mmol) in anhydrous THF (50 ml) is treated with diethylazodicarboxylate (1,95 g, and 11.2 mmol) and 4-pyridinylamino is ω (1.22 g, of 11.2 mmol), then stirred for 15 minutes, the resulting white suspension is treated with 4,4-dimethyl-3-oxopentanenitrile (1,00 g, to 7.99 mmol), then stirred for 15 minutes, the Reaction mixture was concentrated under reduced pressure. The residue is purified column chromatography (30% EtOAc/70% hexane), thus receive the desired nitrile in the form of a solid yellow (1,83 g, 76%): TLC (20% EtOAc/80% hexane) Rf0,13;1H-NMR (CDCl3) δ of 1.13 (s, 9H), 4,60 (s, 1 H), the 5.51 (s, 2H), 7,27 (d, 5,88 Hz, 2H), at 8.60 (d, J=6.25 Hz, 2H);13C-NMR (CDCl3) δ 27,9 (3C), 38,2, 67,5, 70,8, 117,6, 121,2 (2C), 144,5, 149,9 (2C), 180,7; CI-MS m/z (Rel. weight) 217 ((M+N)+100%).

Stage 2. 3-amino-2-(4-pyridinyl)-5-tert-butylfuran: a Solution of 4,4-dimethyl-3-(4-pyridinylmethyl)-2-pentenenitrile (1.55 g, 7,14 mmol) in anhydrous DMSO (75 ml) is treated with tertbutoxide potassium (0.88 g, 7,86 mmol) and stirred at room temperature for 10 minutes the resulting mixture was treated with EtOAc (300 ml), then successively washed with water (2×200 ml) and saturated NaCl solution (100 ml). The combined aqueous phase is extracted with EtOAc (100 ml). The combined organic phases are dried (Na2SO4) and concentrate under reduced pressure. The residue is purified column chromatography (gradient from 30% EtOAc/70% hexane to 100% EtOAc), thus receive the desired product as orange oil (0,88 is, 57%): TLC (40% EtOAc/60% hexane) Rf0,09;1H-NMR (CDCl3) δ of 1.28 (s, 9H), 3,65 (user. s, 2H), 5,79 (s, 1H), 7,30 (d, J=6.25 Hz, 2H), of 8.47 (d, J=6.25 Hz, 2H); EI-MS m/z (Rel. weight) 216 (M+30%).

A3. Synthesis of 3-amino-5-alkylthiophenes of N-BOC ester 3-amino-5-alkyl-2-thiophenecarboxylate

Stage 1. Methyl 3-(tert-butoxycarbonylamino)-5-tert-butyl-2-thiophenecarboxylate; To a solution of methyl 3-amino-5-tert-butyl-2-

thiophenecarboxylate (150 g, 0.70 mol) in pyridine (2.8 liters) at 5°add di-tert-butyl-dicarbonate (171,08 g, 0.78 mol, 1.1 equivalents), N,N-dimethylaminopyridine (86 g, 0.70 mole, 1.00 equivalent), and the resulting mixture was stirred at room temperature for 7 days. The obtained dark solution was concentrated under reduced pressure (approximately 53,328 N/m2) at approximately 20°C. the Obtained solid red dissolved in CH2Cl2(3 l) and sequentially washed with 1 m solution of N3PO4(2×750 ml), a saturated solution of NaHCO3(800 ml) and saturated NaCl solution (2×800 ml), dried (Na2SO4), concentrated under reduced pressure. The obtained solid orange dissolved in abs. EtOH (2 l) when heated at 49°C, then treated with water (500 ml), thus receive the desired product as a solid gray-white in color (163 g, 74%).1H-NMR (CDCl3δ to 1.38 (s, 9H)and 1.51 (s, 9H), of 3.84 (s, 3H), 7,68 (s, 1H), 9,35 (user. s, 1H); FAB-MS m/z (Rel. weight) 314 ((M+N)+; 45%).

Stage 2. 3-(tert-Butoxycarbonylamino)-5-tert-butyl-2-thiencarbazone acid: To a solution of methyl 3-(tert-butoxycarbonylamino)-5-tert-butyl-2-thiophenecarboxylate (90.0 g, 0,287 mol) in THF (630 ml) and Meon (630 ml) add a solution of NaOH (42.5 g, of 1.06 ml) in water (630 ml). The resulting mixture is heated at 60°C for 2 h, concentrated to approximately 700 ml under reduced pressure and cooled to 0°C. the pH Value of the solution was adjusted to 1.0 N. HCl solution (approximately 1 liter) to about 7 when the internal temperature of approximately 0°C. the resulting mixture was treated with EtOAc (4 l). The pH value of the solution was adjusted to 1 N. HCl solution (500 ml) to about 2. The organic phase is washed with saturated NaCl solution (4×1.5 l), dried (Na2SO4) and concentrated to about 200 ml under reduced pressure. The residue is treated with hexane (1 l), you get a solid light pink color (41,6 g). For re-processing of the mother liquor by using concentration-deposition pokazannoi above methods receive an additional amount of product (total of 38.4 g, total yield 93%):1H-NMR (CDCl3) δ of 1.94 (s, 9H), and 1.54 (s, 9H), 7,73 (s, 1H), 9,19 (user. s, 1H); FAB-MS m/z (Rel. weight) 300 ((M+N)+; 50%).

Stage 3. Chloride 5-tert-butyl-C-typename: a Solution of 3-(tert-butoxycarbonylamino)-5-tert-butyl-2-thiophencarboxylic acid (3.0 g, 0,010 mol) in dioxane (20 ml) is treated with HCl (4.0 M in dioxane, 12.5 ml, 0,050 mol, 5.0 equivalents) and the resulting mixture is heated at 80°C for 2 h Obtained turbid solution is cooled to room temperature, thus there is the allocation of a certain amount of sediment. The resulting suspension was diluted with EtOAc (50 ml) and cooled to -20°C. the Obtained solid is collected and dried overnight under reduced pressure to thus obtain the desired salt in a solid gray-white in color (1,72 g, 90%).1H-NMR (DMSO-d6) δ 1,31 (s, N), at 6.84 (d, J=1,48 Hz, 1H), 7,31 (d, J=1,47 Hz, 1H), 10,27 (user. s, 3H).

C. General methods of synthesis of substituted anilines

B1. General method for the synthesis of substituted aniline using nucleophilic aromatic substitution derived using halogenpoeten

3-(4-pyridylthio)aniline: To a solution of 3-aminothiophenol (3.8 ml, 34 mmol) in anhydrous DMF (90 ml) was added the hydrochloride of 4-chloropyridine (5,4 g of 35.6 mmol), then add K2CO3(16.7 g, 121 mmol). The reaction mixture was stirred at room temperature for 1.5 h, then diluted with EtOAc (100 ml) and water (100 ml). The aqueous layer was extracted with EtOAc (2#x000D7; 100 ml). The combined organic layers washed with saturated NaCl solution (100 ml), dried (MgSO4) and concentrate under reduced pressure. The residue is filtered through a layer of silica gel (gradient from 50% EtOAc/50% hexane to 70% EtOAc/30% hexane) and the resulting material was triturated with a mixture of Et2O/hexane, thus obtain the desired product (4.6 g, 66%): TLC (100% ethyl acetate) Rf0,29;1H-NMR (DMSO-d6) δ 5,41 (s, 2H), 6,64-6,74 (m, 3H), 7,01 (d, J=4,8 Hz, 2H), 7,14 (t, J=7.8 Hz, 1H), 8,32 (d, J=4,8 Hz, 2H).

C. General methods for obtaining urea

Sa. Reaction of a heterocyclic amine with arylisocyanates

N-(1-(4-methoxyphenyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,3-dichlorophenyl)urea: To a solution of 1-(4-methoxyphenyl)-3-tert-butyl-5-aminopyrazole (0,342 g of 1.39 mmol) in anhydrous toluene (9 ml) was added with stirring 2,3-dichlorophenylisocyanate (0,276 ml of 2.09 mmol). The solution tightly closed and stirred in the dark for 96 h at 60°C. Then the reaction mixture was diluted with EtOAc (200 ml). The resulting mixture was sequentially washed with 1 M HCl solution (2×125 ml) and saturated NaCl solution (50 ml), dried (MgSO4) and concentrate under reduced pressure. The residue is purified column chromatography (20% EtOAc/80% hexane), and thus obtain the desired product in the form of a solid white color (0,335 g, 56%): TLC (20% EtOAc/80% hexane) Rf0,22;1H-NMR (who MCO-d 6) δ 1,24 (s, 9H), 3,79 (s, 3H), 6,33 (s, 1H), 7,05 (d, J=9 Hz, 2H), 7,28 (m, 2H), 7,38 (d, J=9 Hz, 2H), with 8.05 (dd, J=3; 6 Hz, 1H), up 8.75 (s, 1H), 9,12 (s, 1H); FAB-MS m/z 433 (M+H)+).

C1b. Reaction of a heterocyclic amine with arylisocyanates

N-(2-(4-pyridinyl)-5-tert-butyl-3-furyl)-N'-(2,3-dichlorophenyl)urea: a Solution of 3-amino-2-(4-pyridinyl)-5-tert-butylfuran (method A2, 0.10 g, 0.46 mmol) and 2,3-dichlorophenylisocyanate made (0.13 g, 0.69 mmol) in CH2Cl2stirred at room temperature for 2 hours, then treated with 2-(dimethylamino)ethylamine (of 0.081 g of 0.92 mmol) and stirred for an additional 30 minutes the mixture was diluted with EtOAc (50 ml), then successively washed with 1 N. HCl solution (50 ml), a saturated solution of NaHCO3(50 ml) and saturated NaCl solution (50 ml), dried (Na2SO4) and concentrate under reduced pressure. The residue is purified column chromatography (gradient from 10% EtOAc/90% hexane to 40% EtOAc/60% hexane), and thus obtain the desired compound in the form of solid white (0.12 g, 63%): TPL 195-198°C; TLC (60% EtOAC/40% hexane); Rf0,47;1H-NMR (DMSO-d6) δ of 1.30 (s, 9H), 6,63 (s, 1H), 7,30-to 7.32 (m, 2H), 7,58 (dm, J=6,62 Hz, 2H), 8,16 (dd, J=2.57 m, of 6.99 Hz, 1H), 8,60 (dm, J=6.25 Hz, 2H), 8,83 (s, 1H), 9,17 (s, 1H);13C-NMR (DMSO-d6) δ 28,5 (3C), 32,5, 103,7, 117,3 (2C), 119,8, 120,4, 123,7, 125,6, 128,1, 131,6, 135,7, 136,5, 137,9, 150,0 (2C), 152,2, 163,5; CI-MS m/z (Rel. weight) 404 (M+N)+, 15%), 406 (M+N+2)+ , 8%).

SS. Reaction of a heterocyclic amine with isocyanate

N-(5-tert-butyl-3-thienyl)-N'-(2,3-dichlorophenyl)urea: Pyridine (0,163 ml, 2.02 mmol) are added to the suspension chloride 5-tertbutylamine (method Is, of 0.30 g, 1.56 mmol) and 2,3-dichlorophenylisocyanate (0,32 ml, 2.02 mmol) in CH2Cl2(10 ml) for clarification of the solution and the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue partitioned between EtOAc (15 ml) and water (15 ml). The organic layer is successively washed with a saturated solution of NaHCO3(15 ml), 1 N. HCl solution (15 ml), saturated NaCl solution (15 ml), dried (Na2SO4) and concentrate under reduced pressure. Part of the residue purified preparative HPLC (Column C-18, 60% acetonitrile/40% water/0.05% of TFU), thus receive the desired urea (0,180 g, 34%): TPL 169-170 °C; TLC (20% EtOAC/80% hexane); Rf0,57; 1H-NMR (DMSO-d6) δ 1, 31 (s, 9H), 6,79 (s, 1H), 7,03 (s, 1H), 7.24 to 7,33 (m, 2H), 8,16 (dd, J=1,84, 7,72 Hz, 1H), 8,35 (s, 1H), 9,60 (s, 1H);13C-NMR (DMSO-d6) δ 31,9 (3C), 34,0, 103,4, 116,1, 119,3, 120,0, 123,4, 128,1, 131,6, 135,6, 138,1, 151,7, 155,2; FAB-MS m/z (Rel. weight) 343 ((M+N)+, 83%), 345 ((M+N+2)+, 56%), 347 (M+N+4)+, 12%).

C2. The reaction of substituted aniline with N,N'-carbonyl diimidazol followed by reaction with the heterocyclic amine

N-(1-Phenyl-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)-phenyl)urea: a Solution of 4-(4-pyridinylmethyl)aniline (0.25 g, 1.38 mmol) and N,N'-carbonyldiimidazole (0,23 g of 1.42 mmol) in CH2Cl2(11 ml) was stirred at room temperature for 2 h, then treated with 5-amino-1-phenyl-3-tert-butyl-5-pyrazole (0,30 g, 1.38 mmol) and the resulting mixture was stirred at 50°With during the night. The resulting mixture was diluted with EtOAc (25 ml), then successively washed with water (30 ml), saturated NaCl (30 ml), dried (MgSO4) and concentrate under reduced pressure. The residue is purified column chromatography (gradient from 100% SN2Cl2up to 30% acetone/70% CH2Cl2), and the resulting material was recrystallized (EtOAc/Et2O), thus receive the desired connection with the content crystallohydrates water 0.25 equivalent (0,30 g): TLC (60% acetone/40% SN2Cl2); Rf0,56;1H-NMR (DMSO-d6) δ 1,25 (s, 9H), 3,86 (s, 2H), 6,34 (s, 1H), 7,11 (d, J=8,82 Hz, 2H), 7,19 (dm, J=6.25 Hz, 2H), 7,31 (d, J=1,84 Hz, 2H), 7,35-7,51 (m, 5H), to 8.34 (s, 1H), 8,42 (dm, J=5,98 Hz, 2H), of 8.95 (s, 1H); FAB-MS m/z (Rel. weight) 426 (M+H)+, 100%).

D. Interconversion of urea derivatives

D1. The General method of electrophilic halogenation of allocatin

N-(2-bromo-5-tert-butyl-3-thienyl)-N'-(2,3-dichlorophenyl)urea: To a suspension of N-(5-tert-butyl-3-thienyl)-N'-(2,3-dichlorophenyl)is Icewine (method SS; 3.00 g, a total of 8.74 mmol) in CHCl3(200 ml) at room temperature is added slowly a solution of Br2(and 0.46 ml, 1.7 mmol) in CHCl3(150 ml) via addition funnel over 2.5 hours while the reaction mixture becomes homogeneous. Stirring is continued for 20 min, after which the data TLC indicated completion of reaction. The reaction mixture was concentrated under reduced pressure, the residue triturated (Et2O/hexane) and the resulting solid is washed (hexane), you get a commercially available brominated product in powder pink (3,45 g, 93%): TPL 180-183°C; TLC (10% EtOAC/90% hexane); Rf0,68;1H-NMR (DMSO-d6) δ of 1.28 (s, 9H), 7,27-7,31 (m, 2H), 7,33 (s, 1H), 8,11 (dd, J=3,3, 6,6 Hz, 1H), of 8.95 (s, 1H), 9,12 (s, 1H);13C-NMR (DMSO-d6) δ 31,5 (3C), 34,7, 91,1, 117,9, 120,1, 120,5, 123,8, 128,0, 131,6, 135,5, 137,9, 151,6, 155,3; FAB-MS m/z (Rel. weight) 421 ((M+N)+, 7%), 423 (M+2+N)+, 10%).

D2. The General method of carrying out reactions cross combinations initiated metals using halogen-substituted derivatives of ureas

N-(2-phenyl-5-tert-butyl-3-thienyl)-N'-(2,3-dichlorophenyl)urea: To a solution of N-(3-(2-bromo-5-tert-butyl)thienyl)-N'-(2,3-dichlorophenyl)urea (0.50 g, 1.18 mmol) and vinyltrimethylsilane (of 0.21 ml, 1.18 mmol) in DMF (15 ml) is added Pd(PPh3)2Cl2(0,082 g, 0.12 mmol) and the resulting suspension is heated at 80°With during the night. R is the promo mixture is diluted with EtOAc (50 ml) and water (50 ml) and the organic layer is successively washed with water (3× 50 ml) and saturated NaCl solution (50 ml), then dried (Na2SO4) and concentrate under reduced pressure. The residue is purified MPLC (Biotage ™; gradient from 100% hexane to 5% EtOAc/95% hexane), then purified preparative HPLC (column C-18, 70% of CH3CN/30% H2O/0.05% OF TFU). Fractions obtained by HPLC, concentrated under reduced pressure and the resulting aqueous mixture is extracted with EtOAc (2×50 ml).

The combined organic layers are dried (Na2SO4) and concentrate under reduced pressure to thus obtain a resinous semi-solid substance, which is triturated with hexane, and thus obtain the desired product in the form of a solid white color (0,050 g, 10%): TPL 171-173°C; TLC (5% EtOAc/95% hexane); Rf0,25;1H-NMR (CDCl3) δ of 1.42 (s, 9H), 6,48 (user. s, 1H), 7,01 (s, 1H), 7,10-to 7.18 (m, 2H), 7,26-7,30 (m, 1H), was 7.36 (app. t, J=7,72 Hz, 2H), 7,39 (user. s., 1H), 7,50 (dm, J=6,99 Hz, 2H), 7,16 (dd, J=2,20, 7,72 Hz, 1H);13C-NMR (CDCl3) δ 32,1 (3C), 34,8, 118,4, 118,8, 120,7, 121,1, 124,2, 127,7, 127,9, 128,2 (2C), 128,5, 129,0 (2C), 132,4, 132,5, 136,9, 153,1, 156,3; FAB-MS m/z (Rel. weight) 419 ((M+N)+, 6%), 421 (M+N+2)+, 4%).

D3. Common recovery methods nitrosoureas of allocatin

N-(1-(3-AMINOPHENYL)-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridylthio)phenyl)urea: a Solution of N-(1-(3-nitrophenyl)-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridylthio)phenyl)urea (obtained in a similar way as described in the methods A1 and CA (0,310 g, 0,635 mmol) in acetic acid (20 ml), placed in an argon atmosphere according to the method of degassing in a vacuum and purging with argon. To the resulting solution was added water (0.2 ml), then added iron powder (325 mesh; 0,354 g 6,35 mmol). The reaction mixture is intensively stirred in an argon atmosphere at room temperature for 18 h, after which TLC data indicate no in the solution of the original substance. The reaction mixture is filtered and the solid is rinsed with water (300 ml). The pH value of the resulting orange solution was adjusted to 4.5 by the addition of NaOH pellets (a white precipitate is formed). The resulting suspension is extracted with Et2O (3×250 ml), the combined organic layers washed with saturated solution of NaHCO3(2×300 ml) until the disappearance of the foam. The resulting solution was dried (MgSO4) and concentrate under reduced pressure. The obtained solid white clear column chromatography (gradient from 30% acetone/70% CH2Cl2up to 50% acetone/50% CH2Cl2), you get a product in the form of a solid white color (0,165 g, 57%): TLC (50% acetone/50% CH2Cl2Rf0,50;1H-NMR (DMSO-d6) δ 1,24 (s, 9H), 5,40 (user. s, 2H), 6,34 (s, 1H), to 6.57 (d, J=8 Hz, 2H), to 6.67 (s, 1H), 6,94 (d, J=6 Hz, 2H), 7,12 (arr. t=8 Hz, 1H), 7,47 (d, J=9 Hz, 2H), EUR 7.57 (d, J=9 Hz, 2H), 8,31 (d, J=6 Hz, 2H), 8,43 (s, 1H), 9,39 (s, 1H); FAB-MS m/z 459 (M+H)+).

<> D4. General methods for the acylation of amine-containing allocation

N-(1-(3-acetamidophenyl)-3-tert-butyl-5-pyrazolyl)-N'-(4-phenoxyphenyl)urea: To a solution of N-(1-(3-AMINOPHENYL)-3-tert-butyl-5-pyrazolyl)-N'-(4-phenoxyphenyl)urea (obtained in a similar way as described in the methods A1, Sa and D3; 0,154 g, 0,349 mmol) in CH2Cl2(10 ml) is added pyridine (0.05 ml), then add acetylchloride (0,030 ml, 0,417 mmol). The reaction mixture is stirred in an argon atmosphere at room temperature for 3 h, after which TLC data indicate the absence of the original substance. The reaction mixture was diluted with CH2Cl2(20 ml) and then the resulting solution was sequentially washed with water (30 ml) and saturated NaCl solution (30 ml), dried (MgSO4) and concentrate under reduced pressure. The resulting residue is purified column chromatography (gradient from 5% EtOAc/95% hexane to 75% EtOAc/25% hexane), thus receive the product in a solid white color (0,049 g, 30%): TLC (70% EtOAc/30% hexane) Rf0,32;1H-NMR (DMSO-d6) δ of 1.26 (s, 9H), was 2.05 (s, 3H), 6.35mm (s, 1H), 6,92-6,97 (m, 4H), 7,05-to 7.18 (m, 2H), 7,32 was 7.45 (m, 5H), to 7.64-7,73 (m, 2H), scored 8.38 (s, 1H), 9,00 (s, 1H), 10,16 (s, 1H); FAB-MS m/z 484 (M+H)+)

The following compounds are synthesized according to the General methods described above (see tab. 1-5).

Examples of biological tests

Analysis of raf kinase in vitro

In the analysis of the kinase in vitro kinase raf incubated with MEK protein in 20 mm Tris-HCl buffer solution, pH of 8.2, containing 2 mm 2-mercaptoethanol and 100 mm NaCl. Then prepare a 10 mm concentrated solution (reference solution) compounds in DMSO. To 20 μl of protein solution raf+MEK add 5 ál of water or diluted with water to the original mortar joints. Kinase reaction initiated by adding 25 μl of [γ-33P]ATP (1000-3000 RSPV min/pmol) in 80 mm Tris-HCl buffer solution, pH 7.5, containing 120 mm NaCl, 1.6 mm DTT, 16 mm MgCl2. The reaction mixture was incubated at 32°usually within 22 minutes Then the reaction mixture is applied on phosphocellulose filters, washed free label 1%solution of phosphoric acid and the inclusion of the33P protein is determined quantitatively in the liquid scintillator. For high-performance analysis of a greater Isla samples using a 10 μm solution of ATP and 0.4 μm solution of MEK. In some experiments kinase reaction is stopped by adding an equal amount of buffer laemmli's method. The samples boiled for 3 min and the proteins separated by electrophoresis in a 7.5%gel according to the method of laemmli's method. The gels are fixed, dried, and placed on the photographic plate (Fuji). The degree of phosphorylation determined using analytical system Fujix Bio-lmaging.

All are listed as examples of compounds have values IC50in the range from 1 nm to 10 μm.

Analysis of cell growth in vitro

For analysis of growth lines in vitro human tumor cells, including NST and DLD-1, but not limited to containing the mutant genes K-ras, are used in standard assays of proliferation with growth of the anchor substrate on plastic or bhasyakara growth on soft agar. Line human tumor cells, receive the firm was ATSS (Rockville MD) and support in RPMI medium with 10%V / V heat inactivated fetal calf serum and 200 mm glutamine. Culture medium and additives are firm Gibco/BRL (Gaitherburg, MD) with the exception of fetal calf serum (firm JRH Biosciences, Lenexa, KS). In the standard analysis of cell proliferation in the growth of the anchor substrate cells (3×103) were seeded in 96-well plates to cell cultures and for fixing the holes left overnight at 37°in an incubator with 5%CO2. With the organisations retitrement in the environment by the method of dilution and add to the wells of the 96-well plate with cell cultures. Usually the cells are left to grow for 5 days with fresh mortar joints on the third day. Proliferation is controlled by measuring the metabolic activity of standard colorimetric XTT analysis (firm Boehringer Mannheim) using a standard reader for tablets for the ELISA plate reader at OD 490/560 or definition for inclusion in the DNA3H-thymidine at 8 h of culture using3H-thymidine (1 µci), for example, by transfer of the cells of the collector cells on glass fiber filters with subsequent measurement, including3H-thymidine by the number of pulses in the liquid scintillator.

For bezyakina growth of cells in a 0.4%agarose (Seaplaque) in complete RPMI medium in the amount from 1×103up to 3×103placed in 24-hole plates, layering on the bottom layer, containing only 0,64%agar in complete medium RPMI. Then add the solutions of the analyzed compounds obtained by the method of serial dilutions in complete medium, and incubated at 37°in an incubator with 5%CO2within 10-14 days with fresh medium containing the analyzed connection with an interval of 3-4 days. Number and average size of colonies recorded using computer image analysis and special software (Image Pro Plus, media Cybernetics).

Table 6 shows data on the biological activity of the compounds of the tab is CI 3-5.

58
Table 6.
Data on the biological activity of the compounds.
POS.IC50, mcmPOS.IC50, mcmPOS.IC50, mcmPOS.IC50, mcm
42<161<180from 1 to 599<1
43<162<181<1100<1
44from 5 to 1063from 1 to 58210101from 5 to 10
45<164from 5 to 10831010210
46<165108410103from 1 to 5
47<166from 5 to 108510104from 5 to 10
48<167from 1 to 5861010 from 5 to 10
49<168from 1 to 58710106from 5 to 10
50<169from 1 to 588from 1 to 5107from 1 to 5
51<170from 1 to 589from 5 to 10108<1
52<171from 1 to 59010109from 1 to 5
53<172from 1 to 59110110<1
54<1731092<1111from 5 to 10
551074<193from 1 to 5112<1
561075from 1 to 594<1113from 1 to 5
57<176from 1 to 595<1114from 5 to 10
<177<196from 1 to 5115<1
59from 1 to 578<197from 1 to 5116from 1 to 5
60<179from 1 to 598from 5 to 10117from 1 to 5

Data analysis show that the compounds of formula 1 have activity as inhibitors of raf kinase and inhibitors of the growth of tumor cells.

Analysis of in vivo

Analysis of in vivo inhibitory effects of compounds on tumor (e.g., solid tumor), mediated by raf kinase, carried out by the following method.

The mice CDI nu/nu (age 6-8 weeks) injected subcutaneously in the flank of 1×106cell adenocarcinoma of human colon. Beginning about 10 days, when the tumor size is 50-100 mg, animals injected intraperitoneally, intravenously or orally defined doses of 10, 30, 100 or 300 mg/kg of the compounds according to the invention. Within 14 days to impose certain dose once a day; tumor size was measured with calipers twice a week.

In addition, the inhibitory activity of the compounds of the raf kinase and, therefore, tumor (e.g., solid tumor), mediated by what nesoi raf, can be demonstrated in vivo by the method described in the article Monia et al. (Nat. Med., 1996, Vol.2, pp. 668-75).

The above examples can be repeated with the same results, replacing described in General or more specific reagents and/or conditions (reaction) according to the present invention for the compounds or conditions described in the preceding examples.

From the above description, the specialist in the art can easily establish the characteristic features of the present invention without going beyond the scope and nature of the invention may create variations and modifications of the invention to adapt it to a variety of tasks and conditions.

1. The compound of the formula I

where a means heteroaryl chosen from the group including

and

In the mean substituted or unsubstituted phenyl, naphthyl, pyridinyl, pyrimidinyl or indolyl, and if means a substituted group, it is substituted by one or more substituents which are independently selected from the group including halogen, up to full substitution and Xnwhere n is 0-3 and each X is independently selected from the group including1-C10alkyl, -CN, -NO2With1/sub> -C10alkyl substituted by halogen, up to full substitution With1-C10alkoxy, phenyl, pyridinyl and Y-Ar, while Y represents-O-, -S-, -N(R5)-, -(CH2)m-, -(CH2)mO-, -O(CH2)m-, -(CH2)mS - and-S-(CH2)m-, m=1-3, and Ar means a 5-10 membered aromatic structure containing 0-2 atom selected from the group comprising nitrogen, oxygen and sulfur, which is unsubstituted or substituted by halogen, up to full substitution, or by selecting substituted Zn1where n1 is from 0 to 2, and each Z is independently selected from the group comprising-CN, -CO2R5a, -C(O)NR5aR5a', -NO2, OR5a, -SR5a, -NR5aR5a', -C(O)R5a, -NR5aC(O)R5a'C1-C10alkyl, phenyl, pyridinyl and C1-C10alkyl substituted by halogen, up to full substitution where R5aand R5a'independently selected from the group including H, C1-C10alkyl, C2-C3alkenyl, phenyl, pyridinyl, were, With1-C10alkyl substituted by halogen, up to full substitution, phenyl, substituted by halogen, up to full substitution

R1selected from the group including3-C10alkyl, C3-C5cycloalkyl and trifluoromethyl, and

R2means C6-C14aryl, -CH2-C6-C14aryl, substituted C6-C14aryl, substituted-CH2-C6-C14aryl, pyridyl or substituted pyridyl, where if R2means a substituted group, it is substituted by one or more substituents which are independently selected from the group including halogen, up to full substitution and Vnwhere n=0-3 and each V is independently selected from the group comprising-OR5, -NR5R5', -OC(O)NR5R5', -SO2R5, -NR5C(O)R5', -NO2With1-C10alkyl and C1-C10alkyl substituted by halogen, up to full substitution, where each R5and R5'independently selected from the group including H, C1-C10alkyl, C6-C14aryl, C6-C14aryl substituted by halogen, up to full substitution of the pyridyl and methylpyridyl,

or pharmaceutically acceptable salts of the compounds of formula I.

2. The compound according to claim 1, wherein R2means phenyl or pyridinyl, optionally substituted-NO2, -OH, -NH2, -Och3With1-C6the alkyl, C1-C6the alkyl substituted by halogen, up to full substitution, -NHC(O)-C1-6by alkyl, -SO2-C1-6the alkyl or-O-C1-6the alkyl and substituted by one or two atoms,- F,- Cl, or both halogen.

3. The compound according to claim 2, characterized In that means is romantic cyclic structure, which is chosen from the group including

or

which is substituted or not substituted with halogen up to full substitution, and X is independently selected from the group comprising-CN, -NO2With1-With10alkyl, -CF3, phenyl, pyridinyl and-Y-Ar, where Y represents-O-, -S-, -NH-, -NCH3-, -NC2H5-, -CH2-, -CH2O-, -CH2S-, -OCH2-or-SCH2and Ar denotes phenyl, pyridinyl, pyrimidinyl, naphthyl, chinoline, ethenolysis, benzothiazolyl, thiazolyl, imidazolyl, thiophenyl or phtalimide, which are unsubstituted or substituted with halogen up to the full replacement or may be substituted Zn1where P1 denotes from 0 to 3 and each Z is independently selected from the group comprising-CN, -CO2R5a, -C(O)NR5aR5a', -NO2, -OR5a, -SR5a, -NR5aR5a', -C(O)R5a, -NR5aC(O)R5a'C1-C10alkyl, phenyl, and C1-C10alkyl substituted by halogen, up to full substitution, where R5aand R5a'independently selected from the group comprising H and C1-C6alkyl.

4. The compound according to claim 1, characterized In that means

where Y is chosen from the group comprising-O-, -S-, -CH2-, -SCH2-, -CH2S-, -CH2On - and-OCH2/sub> ,

Q means phenyl or pyridinyl, substituted or not substituted with halogen up to full replacement, and

Q1selected from the group comprising phenyl, pyridinyl, naphthyl, pyrimidinyl, chinoline, ethenolysis, imidazolyl and benzothiazolyl, unsubstituted or substituted by halogen, up to full substitution, X, Z, n and n1 are defined in claim 1.

5. Compound selected from the group including

N-(1-phenyl-3-tert-butyl-5-pyrazolyl)-N'-(2,3-dichlorophenyl)urea;

N-(1-(4-AMINOPHENYL)-3-tert-butyl-5-pyrazolyl)-N'-(2,3-dichlorophenyl)urea;

N-(1-(2-were)-3-tert-butyl-5-pyrazolyl)-N'-(2,3-dichlorophenyl)urea;

N-(1-(2-pyridinyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,3-dichlorophenyl)urea;

N-(1-(5-trifluoromethyl-2-pyrimidinyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,3-dichlorophenyl)urea;

N-(1-(3-forfinal)-3-tert-butyl-5-pyrazolyl)-N'-(2,3-dichlorophenyl)urea;

N-(1-(4-chlorophenyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,3-dichlorophenyl) urea;

N-(1-(4-methanesulfonyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,3-dichlorophenyl)urea;

N-(1-(4-nitrophenyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,3-dichlorophenyl)urea;

N-(1-(3-methoxyphenyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,3-dichlorophenyl)urea;

N-(1-(3-tryptophanyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,3-dichlorophenyl)urea;

N-(1-(4-methoxyphenyl)-3-tert-butyl-5-piraso who yl)-N'-(2,3-dichlorophenyl)urea;

N-(1-(4-isopropylphenyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,3-dichlorophenyl)urea;

N-(1-(3-AMINOPHENYL)-3-tert-butyl-5-pyrazolyl)-N'-(2,3-dichlorophenyl)urea;

N-(1-(3-nitrophenyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,3-dichlorophenyl)urea;

N-(1-phenyl-3-tert-butyl-5-pyrazolyl)-N'-(3-trifter, 4-chlorophenyl)urea;

N-(1-phenyl-3-tert-butyl-5-pyrazolyl)-N'-(4-tryptophanyl)urea;

N-(1-phenyl-3-tert-butyl-5-pyrazolyl)-N'-(2,4-differenl)urea;

N-(1-phenyl-3-tert-butyl-5-pyrazolyl)-N'-(3-forfinal)urea;

N-(1-phenyl-3-tert-butyl-5-pyrazolyl)-N'-(3-cyanophenyl)urea;

N-(1-phenyl-3-tert-butyl-5-pyrazolyl)-N'-(4-nitrophenyl)urea;

N-(1-(3-acetamidophenyl)-3-tert-butyl-5-pyrazolyl)-N'-(4-phenoxyphenyl)urea;

N-(1-(3-AMINOPHENYL)-3-tert-butyl-5-pyrazolyl)-N'-(4-phenoxyphenyl)urea;

N-(1-(3-nitrophenyl)-3-tert-butyl-5-pyrazolyl)-N'-(4-phenoxyphenyl)urea;

N-(1-phenyl)-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea;

N-(1-(4-pyridinyl)-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea;

N-(1-(2,5-dichlorophenyl)-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea;

N-(1-(4-forfinal)-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea;

N-(1-(2-were)-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)mochaui is a;

N-(1-(3-forfinal)-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea;

N-(1-(4-methanesulfonyl)-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea;

N-(1-(4-nitrophenyl)-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea;

N-(1-(3-methoxyphenyl)-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl) phenyl)urea;

N-(1-(3-AMINOPHENYL)-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl) phenyl)urea;

N-(1-(3-nitrophenyl)-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea;

N-(1-(3-AMINOPHENYL)-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridylthio)phenyl)urea;

N-(1-(3-nitrophenyl)-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridylthio)phenyl)urea;

N-(1-(3-(2,3-dichlorophenylamino)phenylmethyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,3-dichlorophenyl)urea;

N-(1-(3-hydroxyphenylethyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,3-dichlorophenyl)urea;

N-(2-phenyl-5-tert-butyl-3-thienyl)-N'-(2,3-dichlorophenyl)urea;

and

N-(2-(4-pyridinyl)-5-tert-butyl-3-furyl)-N'-(2,3-dichlorophenyl)urea.

6. The compound according to claim 1, wherein R1means tert-butyl and R2means substituted or unsubstituted phenyl.

7. The compound according to claim 4, wherein Q denotes phenyl, Q1means phenyl or pyridinyl, Y represents-O-, -S - or-CH2and X Osnach the em Cl, F, NO2or CF3.

8. The connection according to claim 7, wherein R1means tert-butyl.

9. The compound according to claim 1, characterized in that it has the formula

where In denotes phenyl, pyridinyl or pyrimidinyl substituted by one or more substituents which are independently selected from the group including halogen, up to full substitution and Xnwhere n is 0-2 and each X is independently selected from the group comprising-CN, -NO2With1-10alkyl, C1-10alkyl substituted by halogen, up to full substitution, and-Y-Ar, where Y represents-O-, -S -, and -(CH2)m-, m=1-3, and Ar denotes phenyl or pyridinyl that is unsubstituted or substituted with halogen up to the full replacement or may be substituted Zn1where n1 denotes from 0 to 3 and each Z is independently selected from the group comprising-CN, -CO2R5a, -C(O)NR5aR5a', -NO2, -OR5a, -SR5a, -NR5aR5a', -C(O)R5a, -NR5aC(O)R5a'With1-C10alkyl, phenyl and C1-C10alkyl substituted by halogen, up to full substitution, where R5aand R5a'independently selected from the group comprising H and C1-C6alkyl; and

R2means phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl or substituted feast is Meinel, moreover, if R2means a substituted group, it is substituted by one or more substituents independently selected from the group comprising halogen, up to full substitution and V, where V is chosen from the group comprising-OR5, -NR5R5', -SO2R5, -NR5C(O)R5', -NO2With1-C10alkyl, C1-C10alkyl substituted by halogen, up to full substitution, -OC(O)NH phenyl, where each of R5and R5'independently denotes H or C1-C10alkyl,

or its pharmaceutically acceptable salt.

10. The connection according to claim 9, wherein R2selected from substituted or unsubstituted representatives of the group, including phenyl and pyridinyl.

11. The compound according to claim 1, characterized in that it has the formula

where In denotes phenyl, pyridinyl or pyrimidinyl substituted by one or more substituents which are independently selected from the group including halogen, up to full substitution and Xnwhere n is 0-2 and each X is independently selected from the group comprising-CN, -NO2With1-10alkyl, C1-10alkyl substituted by halogen, up to full substitution, and-Y-Ar, where Y represents-O-, -S -, and -(CH2)m-, m=1-3, and Ar denotes phenyl or pyridinyl;

R2means phenyl, substituted phenyl, pyridinyl, Zam is on pyridinyl, pyrimidinyl or substituted pyrimidinyl, and if R2means a substituted group, it is substituted by one or more substituents independently selected from the group comprising halogen, up to full substitution and V, where V is chosen from the group comprising-OR5, -NR5R5', -SO2R5, -NR5C(O)R5', -NO2C1-C10alkyl, C1-C10alkyl substituted by halogen, up to full substitution, -OC(O)NH phenyl, where each of R5and R5'independently denotes H or C1-C10alkyl,

or its pharmaceutically acceptable salt.

12. Connection claim 11, wherein R2selected from substituted or unsubstituted representatives of the group, including phenyl and pyridinyl.

13. The compound according to claim 1, characterized in that it has the formula

where In denotes phenyl, pyridinyl or pyrimidinyl substituted by one or more substituents which are independently selected from the group including halogen, up to full substitution and Xnwhere n is 0-2 and each X is independently selected from the group comprising-CN, -NO2With1-10alkyl, C1-10alkyl substituted by halogen, up to full substitution, and-Y-Ar, where Y represents-O-, -S -, and -(CH2)m-, m=1-3, and Ar denotes phenyl or pyridinyl;

R2Osnach the em phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl or substituted pyrimidinyl, and if R2means a substituted group, it is substituted by one or more substituents independently selected from the group comprising halogen, up to full substitution and V, where V is chosen from the group comprising-OR5, -NR5R5', -SO2R5, -NR5C(O)R5', -NO2With1-C10alkyl, C1-C10alkyl substituted by halogen, up to full substitution, -OC(O)NH phenyl, where each of R5and R5'independently denotes H or C1-C10alkyl,

or its pharmaceutically acceptable salt.

14. The connection 13, wherein R2selected from substituted and unsubstituted representatives of the group, including phenyl and pyridinyl.

15. A method of inhibiting raf kinase in the body of a mammal, comprising introducing the compound of the formula I

where a means heteroaryl chosen from the group including

and

In the mean substituted or unsubstituted phenyl, naphthyl, pyridinyl, pyrimidinyl or indolyl, and if means a substituted group, it is substituted by one or more substituents, coorientation selected from the group including halogen, up to full substitution and Xnwhere n is 0-3 and each X is independently selected from the group comprising-CN, -NO2With1-C10alkyl, C1-C10alkoxy substituted by halogen, up to full substitution With1-C10alkyl, phenyl, pyridinyl and Y-Ar; Y represents-O-, -S-, -N(R5)-, -(CH2)m-, -(CH2)mO-, -(CH2)mS-, -O(CH2)m-, -S-(CH2)m-, m=1-3, and Ar means a 5-10 membered aromatic structure containing 0-2 atom selected from the group comprising nitrogen, oxygen and sulfur, which is unsubstituted or substituted by halogen, up to full substitution or by selecting substituted Zn1where n1 is from 0 to 3 and each Z is independently selected from the group comprising-CN, -CO2R5a, -C(O)NR5aR5a', -NO2, -OR5a, -SR5a, -NR5aR5a', -C(O)R5a, -NR5aC(O)R5a'C1-C10alkyl; substituted by halogen, up to full substitution With1-C10alkyl; phenyl, pyridinyl, where R5aand R5a'independently selected from the group including H, C1-C10alkyl, C2-C3alkenyl, phenyl, pyridinyl, were, With1-C10alkyl substituted by halogen, up to full substitution, phenyl, substituted by halogen, up to full substitution

R1choose from the town is uppy, include3-C10alkyl, C3-C5cycloalkyl and trifluoromethyl, and

R2means6-C14aryl, substituted-CH2-C6-C14aryl, substituted-CH2-With6-C14aryl, pyridyl or substituted pyridyl, where if R2means a substituted group, it is substituted by one or more substituents which are independently selected from the group including halogen, up to full substitution and Vnwhere n=0-3 and each V is independently selected from the group comprising-CN, -OR5, -NR5R5', -OC(O)NR5R5', -SO2R5, -NR5C(O)R5', -NO2With1-C10alkyl substituted by halogen, up to full substitution With1-C10alkyl, where each R5and R5'independently selected from the group including H, C1-C10alkyl, C6-C14aryl, C6-C14aryl substituted by halogen, up to full substitution of the pyridyl and methylpyridyl,

or pharmaceutically acceptable salts of the compounds of formula I.

16. The method according to item 15, wherein R2means phenyl or pyridinyl, optionally substituted-NO2, -OH, -NH2, -Och3With1-C6the alkyl, C1-C6the alkyl substituted by halogen, up to full substitution, -NHC(O)-C1-6by alkyl, -SO2-C1-6by alkyl, -O-C1-6 the alkyl and substituted by one or two atoms,- F,- Cl, or both halogen.

17. The method according to item 15, characterized In that means an aromatic cyclic structure, up to tricyclic, which is chosen from the group including

which is substituted or not substituted with halogen up to full substitution, and X is independently selected from the group comprising-CN, -NO2With-1With10alkyl, -CF3, phenyl, pyridinyl and-Y-Ar, where Y represents-O-, -S-, -NH-, -NCH3-, NC2H5-, -CH2-, -CH2O-, -CH2S-, -OCH2-or-SCH2and Ar denotes phenyl, pyridinyl, pyrimidinyl, naphthyl, chinoline, ethenolysis, benzothiazolyl, thiazolyl, imidazolyl, thiophenyl or phtalimide, which are unsubstituted or substituted with halogen up to the full replacement or may be substituted Zn1where n1 denotes from 0 to 3 and each Z is independently selected from the group comprising-CN, -CO2R5a, -C(O)NR5aR5a', -NO2, -OR5a, -SR5a, -NR5aR5a', -C(O)R5a, -NR5aC(O)R5a'C1-C10alkyl, phenyl, and C1-C10alkyl substituted by halogen, up to full substitution, where R5aand R5a'independently selected from the group comprising H and C1-C6alkyl.

18. The method according to clause 15 of the notable that means

where Y is chosen from the group comprising-O-, -S-, -CH2-, -SCH2-, -CH2S-, -CH2O -, and-OCH2,

Q means phenyl or pyridinyl, substituted or not substituted with halogen up to full replacement, and

Q1selected from the group comprising phenyl, pyridinyl, naphthyl, pyrimidinyl, chinoline, ethenolysis, imidazolyl and benzothiazolyl, substituted or not substituted with halogen up to full substitution, X, Z, n and n1 are defined in claim 1.

19. The method according to p, wherein Q denotes phenyl, Q1means phenyl or pyridinyl, Y represents-O-, -S - or-CH2and X is Cl, F, NO2or CF3.

20. The method according to item 15, wherein the administered compound is one of formula

or

where In denotes phenyl, pyridinyl or pyrimidinyl substituted by one or more substituents which are independently selected from the group including halogen, up to full substitution and Xnwhere n is 0-2 and each X is independently selected from the group comprising-CN, -NO2With1-10alkyl, C1-10alkyl substituted by halogen, up to full substitution, and-Y-Ar, where Y represents-O-, -S -, and -(CH2)m-, m=1-3, and Ar denotes phenyl or pyridinyl, which are what I'm not substituted or substituted by halogen, up to full substitution or can be substituted Zn1where n1 denotes from 0 to 3 and each Z is independently selected from the group comprising-CN, -CO2R5a, -C(O)NR5aR5a', -NO2, -OR5a, -SR5a, -NR5aR5a', -C(O)R5a, NR5aC(O)R5a'With1-C10alkyl, phenyl and C1-C10alkyl substituted by halogen, up to full substitution, where R5aand R5a'independently selected from the group comprising H and C1-C6alkyl; and

R2means phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl or substituted pyrimidinyl, and if R2means a substituted group, it is substituted by one or more substituents independently selected from the group comprising halogen, up to full substitution and V, where V is chosen from the group comprising-OR5, -NR5R5', -SO2R5, -NR5C(O)R5', -NO2With1-C10alkyl, C1-C10alkyl substituted by halogen, up to full substitution, -OC(O)NH phenyl, where each of R5and R5'independently denotes H or C1-C10alkyl,

or its pharmaceutically acceptable salt.

21. The method according to claim 20, wherein R2selected from substituted or unsubstituted representatives of the group, including phenyl or pyridinyl.

22. The method according to item 15, characterized t is m, that enter the compound of the formula

where In denotes phenyl, pyridinyl or pyrimidinyl substituted by one or more substituents which are independently selected from the group including halogen, up to full substitution and Xnwhere n is 0-2 and each X is independently selected from the group comprising-CN, -NO2With1-10alkyl, C1-10alkyl substituted by halogen, up to full substitution, and-Y-Ar, where Y represents-O-, -S -, and -(CH2)m-, m=1-3, and Ar denotes phenyl or pyridinyl; and

R2means phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl or substituted pyrimidinyl, and if R2means a substituted group, it is substituted by one or more substituents independently selected from the group comprising halogen, up to full substitution and V, where V is chosen from the group comprising-OR5, -NR5R5', -SO2R5, -NR5C(O)R5', -NO2With1-C10alkyl, C1-C10alkyl substituted by halogen, up to full substitution, -OC(O)NH phenyl, where each of R5and R5'independently denotes H or C1-C10alkyl,

or its pharmaceutically acceptable salt.

23. The method according to item 22, wherein R2selected from substituted and unsubstituted representatives of groups, including the setup portion of phenyl and pyridinyl.

24. Pharmaceutical composition having inhibitory activity against protein kinase in the body of the mammal containing the compound according to claim 1 and a pharmaceutically acceptable carrier.

25. Pharmaceutical composition having inhibitory activity against protein kinase in the body of the mammal containing the compound according to claim 2 and a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: organic chemistry of natural compounds, medicine.

SUBSTANCE: invention relates to new taxanes with carbonate substitute at C7 of the general formula (I) given in the invention description wherein R2 means benzoyloxy group; R7 means -COO; R9 means -CO; R10 means -OH; R14 means hydrogen atom (H); X3 means (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl or 5-membered heteroaromatic group wherein heteroatom is represented by oxygen (O) or sulfur (S) atom; X5 means -COX10, -COOX10 wherein X10 means (C1-C6)-alkyl, (C2-C6)-alkenyl, phenyl or 5-membered heteroaromatic group wherein heteroatom is represented by oxygen (O) or sulfur (S) atom, and Ac means acetyl. Proposed compounds possess an anti-tumor activity.

EFFECT: valuable medicinal properties of compounds.

61 cl, 1 tbl, 5 ex

FIELD: organic chemistry of natural compounds, medicine, oncology.

SUBSTANCE: invention relates to new compounds - C7-ester-substituted taxanes of the general structural formula:

wherein R2 represents benzoyloxy-group; R7 represents R7aCOO-; R10 represents hydroxy-group; X3 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among oxygen (O), nitrogen (N) and sulfur (S) atoms; X5 represents -COX10 wherein X10 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, phenyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among O, N and S; or it (X5) represents -COOX10 wherein X10 represents (C1-C8)-alkyl or (C2-C8)-alkenyl; R7a represents (C1-C20)-alkyl or (C2-C20)-alkenyl; Ac represents acetyl group. These compounds possess an anti-tumor activity. Also, invention relates to a method for inhibition of tumor growth in mammals and to a pharmaceutical composition based on synthesized compounds. Invention provides preparing new derivatives of taxanes possessing the enhanced anti-tumor activity and reduced toxicity as compared with taxol and taxoter.

EFFECT: improved and valuable medicinal properties of compounds.

39 cl, 4 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to derivatives of taxane of the general formula (I):

wherein R2 means acyloxy-group; R7 means hydroxy-group; R9 means keto-group; R10 means carbonate; R14 means hydrogen atom; X3 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl substituted optionally with nitro-group or 5-6-membered heteroaromatic group comprising heteroatoms taken among oxygen (O), nitrogen (N) or sulfur (S) atoms; X5 means -C(O)X10, -C(O)OX10 or -CONHX10 wherein X10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl, furyl, pyridyl or thienyl; Ac means acetyl. Also, invention describes a pharmaceutical composition based on taxanes and a method for inhibition of a tumor growth.

EFFECT: improved inhibiting method, valuable medicinal properties of compounds.

98 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to novel trifluoromethylpyrrole carboxamides of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C4)-alkyl; R2 means (C1-C4)-alkyl, (C1-C4)-halogenalkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, cyano-group or (C1-C6)-alkylcarbonyl; A means the group of the formula:

, or wherein R3 means (C1-C6)-alkyl, (C1-C6)-halogenalkyl, (C2-C6)-alkenyl, (C3-C7)-cycloalkyl, (C1-C4)-alkyl-(C3-C7)-cycloalkyl, (C4-C7)-cycloalkenyl, (C1-C4)-alkyl-(C4-C7)-cycloalkenyl, phenyl, naphthyl or phenoxy-group, or substituted phenyl, or substituted phenoxy-group wherein substituted represent 1-3 groups taken independently among an order comprising halogen atom, (C1-C4)_alkyl, (C1-C4)-alkoxy-, cyano-group, (C1-C4)-alkylcarbonyl, (C1-C4)-halogenalkyl, (C1-C4)-halogenalkoxy-, methylenedioxy-, difluoromethylenedioxy-group or phenyl; R4 means hydrogen, halogen atom or (C1-C4)-alkyl; each among R5, R6 and R7 means (C1-C6)-alkyl. Compounds of the formula (I) are used for control of phytopathogen organisms or for prophylaxis in damaging cultured plants by these organisms.

EFFECT: valuable properties of compounds.

10 cl, 3 tbl, 1 sch, 12 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new taxanes of the general formula (I)

wherein R2 means benzoyloxy-group; R7 means hydroxyl (OH); R9 means keto-group; R10 means R10aCOO-; R10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl or 5-6-membered heteroaromatic group wherein heteroatom represents oxygen atom (O), sulfur atom (S) or nitrogen atom (N); R14 means hydrogen atom (H); X3 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl substituted possibly with nitro-group (-NO2), 5-6-membered heteroaromatic group wherein heteroatom represents O, S or N; X5 means -COX10, -COOX10; X10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl or 5-6-membered heteroaromatic group wherein heteroatom represents O, S, N; Ac means acetyl. Compounds of the formula (I) elicit antitumor activity.

EFFECT: valuable medicinal properties of compounds.

68 cl, 1 tbl, 6 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention relates to substituted thienocycloalk(ene)ylamino-1,3,5-triazines of the general formula (I): wherein R1 means hydrogen atom; R2 means hydrogen atom, formyl or alkylcarbonyl, group N(R1R2) denoting dialkylaminoalkylideneamine; R3 means unsubstituted or halogen-substituted alkyl; Z means one of the following thienocycloalkyl groups: and wherein A1, A2 and A3 mean alkylene. Also, invention describes a method for synthesis of indicated compounds and intermediate compounds used in the synthesis. Compounds can be used as herbicides.

EFFECT: improved method for synthesis, valuable agricultural properties of compounds.

8 cl, 4 tbl, 5 ex

New compounds // 2261245

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): wherein m = 0, 1, 2 or 3; each R1 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C6)-halogenalkoxy-group, -NR9R10, (C3-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group or (C1-C6)-alkyl; X represents -O- or CH2-, OCH2-, CH2O-, CH2NH-, NH-; Y represents nitrogen atom (N) or group CH under condition that when X represents -O- or CH2O-, CH2NH- or NH-group then Y represents group CH; Z1 represents a bond or group (CH2)q wherein q = 1 or 2; Z2 represents a bond or group CH2 under condition that both Z1 and Z2 can't represent a bond simultaneously; Q represents -O- or sulfur atom (S) or group CH2 or NH; R2 represents group of the formula: n = 0; each R4, R5, R6 and R7 represents independently hydrogen atom (H), (C1-C6)-alkyl either R4, R5, R6 and R7 represent in common (C1-C4)-alkylene chain joining two carbon atoms to which they are bound to form 4-7-membered saturated carbon ring, either each R5, R6 and R7 represents hydrogen atom, and R4 and R8 in common with carbon atoms to which they are bound form 5-6-membered saturated carbon ring; R8 represents hydrogen atom (H), (C1-C6)-alkyl or it is bound with R4 as determined above; each R9 and R10 represents independently hydrogen atom (H), (C1-C6)-alkyl; R15 represents (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, adamantyl, phenyl or saturated or unsaturated 5-10-membered heterocyclic ring system comprising at least one heteroatom taken among nitrogen, oxygen and sulfur atoms wherein each group can be substituted with one or more substitute taken independently among nitro-group, hydroxyl, oxo-group, halogen atom, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, phenyl and -NHC(O)-R17 under condition that R15 doesn't represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group; t = 0, 1, 2 or 3; each R16 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C)-halogenalkoxy-group, -NR18R19, (C1-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group, (C1-C6)-alkyl; R17 means (C1-C6)-alkykl, amino-group, phenyl; each R18 and R19 means independently hydrogen atom (H), (C1-C6)-alkyl, or its pharmaceutically acceptable salt or solvate. Compounds of the formula (I) elicit activity of a modulating agent with respect to activity of chemokine MIP-1α receptors that allows their using in pharmaceutical composition in treatment of inflammatory diseases.

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazine of the general formula (I):

wherein R1 means hydrogen (H) or halogen atom; R2, R3 and R5 mean hydrogen atom (H); R4 and R6 mean hydroxy-group optionally protected with acetyl or benzoyl group; A means oxygen atom (O); n = 0; Y means oxygen atom (O), or their salts. Compounds show the excellent anti-viral activity and useful as a therapeutic agent in treatment of viral infections. Also, invention describes a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 2 tbl, 15 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new stable crystalline forms of derivative of pyrimidine nucleoside of the formula (I) eliciting the excellent anti-tumor activity. Also, invention relates to pharmaceutical composition eliciting an anti-tumor effect, applying crystalline form for preparing medicinal agent and to a method for prophylaxis or treatment of tumor diseases.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of derivative.

10 cl, 2 tbl, 4 dwg, 9 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: 5-aryl-1H-1,2,4-triazole derivatives of general formula I

, pharmaceutically acceptable salts thereof or pharmaceutical composition containing the same are described. In formula R1 is C1-C6-alkyl, C1-C6-haloalkyl or phenyl; R2 is C3-C8-cycloalkyl; phenyl optionally substituted with one or more substituents selected from C1-C4-alkyl; halogen, hydroxyl, C1-C4-alkoxy, nitro, di-(C1-C4)-alkylamino, C1-C4-alkylsulphonyl, C1-C4- alkylsulphonylamino, and methylenedioxy; phenyl-(C1-C4)-alkyl, wherein phenyl is substituted with C1-C4-alkoxy; or pyridil. New compounds are effective and selective cyclooxygenase-2 (COX-2) inhibitors and useful in treatment of inflammations.

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: color-forming compositions and recording material.

SUBSTANCE: claimed composition includes developer containing urea-urethane compound and colorless or light colored leuco dye. Recording material based on this composition also is proposed.

EFFECT: color-forming compositions with improved image conservation ability and increased image intensity.

21 cl, 14 tbl, 153 ex

The invention relates to a method for producing a condensed 2-getreleasedate General formula

using the diamine of General formula

where A=

R=2-furyl, 2-thienyl, 2-(1-methyl)pyrrolyl, 3-(1-methyl)indolyl, and aldehydes in the presence of acetate or copper sulfate, characterized in that the interaction takes place by boiling in 50% acetic acid, followed by decomposition of the copper salt, the effect on its suspension in 50% acetic acid sodium thiosulfate in 100With

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

The invention relates to 1-methyl-5-alkylsulfonyl-, 1-methyl-5-alkylsulfonyl - 1-methyl-5-alkylthiomethyl pyrazolylborate and herbicide tool based on them

The invention relates to tricyclic condensed heterocyclic compounds of the formula I, X is, for example, CH, CH2, СНR (where R means a lower alkyl group or a substituted lower alkyl group) or CRR' (where R and R' have the values specified above for R); Y means, for example, CH, CH2or C=O; z means, for example, S, S=O=; U denotes C; R1-R4independent means, for example, a hydrogen atom, SR (where R has the above values), phenyl group, substituted phenyl group, follow group, thienyl group, benzofuran or benzothiazyl at least one element of R5and R8means, for example, HE and the rest of the elements of R5and R8independent means, for example, a hydrogen atom; and their optical isomers, conjugates, and pharmaceutically acceptable salts

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

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