Pyridyl-substituted heterocycles, suitable for treatment or prevention of infections, caused by hepatitis c virus

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to compounds with formula (I), their pharmaceutical salts or N-oxide used as an inhibitor to replication and/or proliferation of HCV, to the method of inhibiting replication or proliferation of hepatitis C virion using formula (I) compounds, as well as to pharmaceutical compositions based on them. The compounds can be used for treating or preventing infections, caused by hepatitis C virus. In general formula (I) cycle B is an aromatic or non-aromatic ring, which contains two heteroatoms, where X and Y, each is independently chosen from C, CH, N or O, under the condition that, both X and Y are not O and that, both X and Y are not N; U and T represent C; Z represents -CH-; A represents N or -CR2-; B represents -CR3-; D represents N or -CR4-; E represents N or -CR5-; G represents N or -CR6-; J represents N or -CR14-; K represents -CR8-; L represents N or -CR9-; M represents N or -CR10-; R2 and R6, each is independently chosen from a group, consisting of hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C1-C6alkoxy, C1-C6substituted alkoxy, C1-C6alkoxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, -O-carbamoil, substituted -O-carbamoil, halogen C1-C6alkyl, diC1-C6alkylamino, substituted diC1-C6alkylamino and sylye ethers, where cycloheteroalkyl is a 3-7-member ring, containing 1-2 heteroatoms, chosen from N and O, under the condition that, one of R2 and R6 is not hydrogen; R3 and R5, each is independently chosen from a group, consisting of hydrogen, halogen; R4 represents hydrogen; R7 represents - NR11C(O)R12; R8, R9, R10 and R14, each is independently represents hydrogen; R11 represents hydrogen, C1-C6alkyl; and R12 is chosen from a group, consisting of halogen C1-C6alkyl; where each substituted group is substituted with one or more groups, chosen from -Q, -R40, -OR40, -C(O)R40, -C(O)OR40, where each Q independently represents halogen, R40 and R41 are independently chosen from a group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, under the condition that: (i) at least one of A, D, E, G, J, L or M represents N; (ii) not more than one of A, D, E or G represents N; and (iii) not more than one of J, L or M represents N.

EFFECT: obtaining pyridyl-substituted heterocycles for treating and preventing infections, caused by hepatitis C virus.

33 cl, 85 dwg, 101 ex

 

1.The technical field

On this request in accordance with Section 35, United States Code § 119(e) multiple priority is claimed on the basis of the application 60/405467, filed August 23, 2002, application 60/417837, filed October 11, 2002, and claims 60/471373, filed may 15, 2003, the contents of which are incorporated into this description by reference.

2.The technical field

This invention relates to pyridylamine the compounds and compositions useful for the treatment or prevention of infectious disease caused by the hepatitis C virus (HCV) (hereinafter HCV infection). In particular, this invention relates to pyridylamine the heterocycles and related gidrirovanny isomers, compositions on their basis and application of these compounds and compositions for inhibition of replication and/or proliferation of HCV as a therapeutic approach to the treatment and/or prevention of HCV infections in humans and animals.

3.Prior art

Infectious disease caused by the hepatitis C virus (HCV)is a global health problem man, with approximately 150,000 new registered each year cases only in the United States. HCV is a virus containing single-stranded RNA, which is the etiologic agent identified in most cases p is transfusional and posttransplantation hepatitis, caused by an infectious agent, antigen different from hepatitis a and b, and which is well-known cause of acute sporadic hepatitis (Choo et al., Science 244:359, 1989; Kuo et al., Science 244:362, 1989; and Alter et al., in Current Perspective in Hepatology, p. 83, 1989). It is shown that more than 50% of patients infected with HCV become chronically infected and 20% of them will develop liver cirrhosis within 20 years (Davis et al., New Engl. J. Med. 321:1501, 1989; Alter et al., in Current Perspective in Hepatology, p. 83, 1989; Alter et al., New Engl. J. Med. 327:1899, 1992; and Tuesday Gastroenterology 85:430, 1983). In addition, the only therapy is generally available for treatment of HCV infection is interferon-α. (INTRON®A, PEG-INTRON®A, Schering-Plough; ROFERON-A®, Roche). The majority of patients are unresponsive to treatment with interferon-αhowever, among patients reacting to it, there is a high rate of relapse within 6-12 months after stopping treatment (Liang et al., J. Med. Virol. 40:69, 1993). Ribavirin, an analogue of guanosine with a wide spectrum of activity against many RNA and DNA viruses, as has been shown in clinical trials, is effective against chronic HCV infection when used in combination with interferon-α (see, for example, Poynard et al., Lancet 352:1426-1432, 1998; Reichard et al., Lancet 351:83-87, 1998), and this combination therapy has recently been approved (REBETRON, Schering-Plough). However, the extent of the Council, still, significantly below 50%. Therefore, there is a need for additional compounds for the treatment and prevention of infectious diseases caused by HCV.

4.Brief description of the invention

In one aspect, the invention provides pyridylamine heterocycles, which are potent inhibitors of replication and/or proliferation of hepatitis C virus ("HCV"). In one embodiment, compounds are pyridylamine heterocycles and their hydrogenated isomers cycle In accordance with the structural formula (I)having the following "skeleton" with accepted order numbering:

where the cycle represents an aromatic or non-aromatic ring which contains one to four heteroatoms. X, Y, Z, each independently from each other selected from C, CH, N, NR16, NR18, S or O, and U and T each, independently of one another, selected from C, CH or N, provided that X and Y both are not O. One of the cycles "A" or "C" represents peregrinae ring, and the other represents a phenyl ring or peregrinae ring. When "A" and/or "C" represents a pyridyl, a loop can be attached to the illustrated cycle "B" through any available carbon atom. Thus, the loops "A" and/or "C" can represent pyrid-2-ILN is e, pyrid-3-ilen or pyrid-4-ilen rings.

Loop "A" includes a Deputy located in anthopology to the place of connection (2'- or 6'-position), and may optionally include from 1 to 4 optional substituents. The nature of the substituents can vary widely. A typical group-Vice, used to override the cycle "A", include halogen, fluorine, chlorine, alkyl, alkylthio, alkoxy, alkoxycarbonyl, arylalkylamine, aryloxyalkyl, cycloheptadiene, carbamoyl, halogenoalkane, dialkylamino or sulfamoyl group, and their substituted versions. In one embodiment, the loop A is disubstituted at the 2'- and 6'-positions and unsubstituted in all other positions.

Cycle "C" is substituted in the meta(3" or 5")-the position of Deputy of the formula-NR11C(O)R12where R11represents hydrogen, alkyl or methyl and R12is substituted alkyl, halogenated, dehalogenation, dichloromethyl, cyclogeranyl or substituted cyclogeranyl. In one embodiment, R12represents halogenation or dichloromethylene group. Cycle "C" may also be optionally substituted in one or more of 2"-, 4"-, 5"- and/or 6-positions are the same or different groups of halogen.

As should be obvious by qualified specialists who Stam in this area, the actual distribution of electrons or the arrangement of double bonds in the loop "B" will depend on the nature of the substituents X, Y, Z, T and/or u. In particular, mean that the above structural formula (I) includes at least the following six structures:

where A, B, D, E, G, J, K, L, M, R11and R12such as defined below.

In particular, mean that the above structural formula (I) includes, for example, at least the following isomers of hydrogenated cycle:

where A, B, D, E, G, j, K, L, M11, R12, R16and R18such as defined below.

In another aspect, the present invention provides compositions comprising the compounds of this invention. The compositions typically include a pyridyl-substituted heterocycle or hydrogenated isomer (discussed throughout the description of this invention or its salt, hydrate, MES or N-oxide and a suitable excipient, carrier or diluent. The composition may be formulated for veterinary use or for use for people.

The compounds of this invention are potent inhibitors of replication and/or proliferation of HCV. Accordingly, in this aspect, the present invention is offering ways to inhibit replication and/or proliferation of HCV, including the contacting of hepatitis C virion with a compound or composition of this invention in amounts effective to inhibit replication and/or proliferation of HCV. The methods can be implemented in practice in vitro or in vivo, and can be used as a therapeutic approach to the treatment and/or prevention of infectious diseases caused by HCV.

In a final aspect, the present invention provides methods for treatment and/or prevention of HCV infections. The methods typically include an introduction to the subject, which has HCV infection, or a subject with an increased risk of HCV infection, the compounds or compositions of the present invention in amounts effective for the treatment or prevention of HCV infection. This method can be applied in practice for animals in veterinary situations or people.

5.Brief description of drawings

Figure 1 is illustrative of the compounds of this invention: and

Fig. 2-63 present illustrative synthesis scheme for producing compounds of the present invention.

6.A detailed description of the preferred optionsimplementation

6.1Definitions

Referring to that used in the present description, the following terms have the following meanings:

"Alkyl"separately or as part of another substituent, refers to a feast upon nomu or unsaturated, branched, straight chain or cyclic monovalent hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of the original alkane, alkene or alkyne. Typical alkyl groups include, but are not limited to, methyl; ethyl groups, such as atenil, ethynyl, ethinyl; various groups, such as propan-1-yl, propan-2-yl, cyclopropane-1-yl, prop-1-EN-1-yl, prop-1-EN-2-yl, prop-2-EN-1-yl (allyl), cycloprop-1-EN-1-yl, cycloprop-2-EN-1-yl, prop-1-in-1-yl, prop-2-in-1-yl, etc.; butylene groups, such as butane-1-yl, butane-2-yl, 2-methylpropan-1-yl, 2-methylpropan-2-yl, cyclobuta-1-yl, but-1-EN-1-yl, but-1-EN-2-yl, 2-methylprop-1-EN-1-yl, but-2-EN-1-yl, but-2-EN-2-yl, buta-1,3-Dien-1-yl, buta-1,3-Dien-2-yl, cyclobuta-1-EN-1-yl, cyclobuta-1-EN-3-yl, cyclobuta-1,3-Dien-1-yl, but-1-in-1-yl, but-1-in-3-yl, but-3-in-1-yl and so on; and so on

In particular, mean that the term "alkyl" includes groups having any degree or level of saturation, i.e, groups having exclusively simple carbon-carbon links, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. In those cases, when referring to a certain saturation level, use the expression "lceil", "alkenyl" and "quinil". Preferably, the alkyl group contains from 1 to 15 carbon atoms (C1-C15alkyl), more preferably from 1 to 10 carbon atoms (C1-C10alkyl), and even more preferably from 1 to 6 atoms of carbon (C1-C6alkyl or lower alkyl).

"Alkenyl"separately or as part of another substituent, refers to a saturated branched, straight chain or cyclic alkyl, the radical obtained by removing one hydrogen atom from a single carbon atom of the alkane source. Typical alkaline groups include, but are not limited to, methanol; etenil; propylene groups such as propan-1-yl, propan-2-yl (isopropyl), cyclopropane-1-yl, etc.; butylene groups, such as butane-1-yl, butane-2-yl (sec-butyl), 2-methylpropan-1-yl (isobutyl), 2-methylpropan-2-yl (tert-butyl), CYCLOBUTANE-1-yl and so on; and so on

"Alkenyl"separately or as part of another substituent refers to an unsaturated branched, straight chain or cyclic alkyl, the radical, having at least one carbon-carbon double bond derived by removing one hydrogen atom from a single carbon atom of the original alkene. The group may be in either the CIS-or transforms relative to the double bond(s). Typical alkeneamine groups include, but are they the e limited ethynyl; propylene groups, such as prop-1-EN-1-yl, prop-1-EN-2-yl, prop-2-EN-1-yl (allyl), prop-2-EN-2-yl, cycloprop-1-EN-1-yl, cycloprop-2-EN-1-yl; butenolide groups, such as but-1-EN-1-yl, but-1-EN-2-yl, 2-methylprop-1-EN-1-yl, but-2-EN-1-yl, but-2-EN-1-yl, but-2-EN-2-yl, buta-1,3-Dien-1-yl, buta-1,3-Dien-2-yl, cyclobuta-1-EN-1-yl, cyclobuta-1-EN-3-yl, cyclobuta-1,3-Dien-1-yl and so on; and so on

"Quinil"separately or as part of another substituent refers to an unsaturated branched, straight chain or cyclic alkyl, the radical, having at least one carbon-carbon triple bond derived by removing one hydrogen atom from a single carbon atom source alkyne. Typical alkyline groups include, but are not confined, ethinyl; propiverine groups, such as prop-1-Jn-1-yl, prop-2-in-1-yl, etc.; butonline groups, such as but-1-in-1-yl, but-1-in-3-yl, but-3-in-1-yl and so on; and so on

"Alkoxy"separately or as part of another substituent refers to a radical of the formula-OR30where R30represents an alkyl or cycloalkyl group that is defined in this description. Typical examples of alkoxygroup include, but are not confined, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, cyclopropylamine, cyclopentyloxy, cyclohexyloxy etc.

"Alkoxycarbonyl"separately or is it part of another substituent, refers to a radical of the formula-C(O)-alkoxy, where alkoxygroup such as defined above.

"Alkylthio"separately or as part of another substituent refers to a radical of the formula-SR31where R31represents an alkyl or cycloalkyl group that is defined above. Typical examples include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, cyclopropylethyl, cyclopentyl, cyclohexylthio etc.

"Aryl"separately or as part of another substituent refers to a monovalent aromatic hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of a particular in this description of the original aromatic cyclic system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, Exacta, hexagen, hexylene, Asim-indacene, SIMM-indacene, indane, indene, naphthalene, octazen, octavina, octalene, evalena, Penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pesantren, rubiana, triphenylene, Trenitalia etc. Preferably, the aryl group includes from 6 to 20 carbon atoms (C6-C20the Rila), more preferably from 6 to 15 carbon atoms (C6-C15aryl), and even more preferably from 6 to 10 carbon atoms (C6-C10aryl).

"Arylalkyl"separately or as part of another substituent refers to an acyclic alkyl group in which one of the hydrogen atoms associated with carbon atom, typically a terminal or sp3-hybridized carbon atom, defined above, substituted aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-Penilaian-1-yl, 2-Penilaian-1-yl, naphthylmethyl, 2-Nettleton-1-yl, 2-naphthalate-1-yl, naphthalenyl, 2-naphthenate-1-yl, etc. In those cases, when we have in mind certain alkyl part, use the terminology arylalkyl, arylalkyl and/or arylalkyl. Preferably, arylalkyl group represents a (C6-C30)arylalkyl, for example, alkaneella, Alchemilla or Alchemilla part arylalkyl group represents a (C1-C10)alkyl and the aryl part is a (C6-C20)aryl, more preferably, arylalkyl group represents a (C6-C20)arylalkyl, for example, alkaneella, Alchemilla or Alchemilla part arylalkyl group represents a (C1-C8)alkyl and the aryl part is a (C6-C12 )aryl, and more preferably, arylalkyl group represents a (C6-C15)arylalkyl, for example, alkaneella, Alchemilla or Alchemilla part arylalkyl group represents a (C1-C5)alkyl and the aryl part is a (C6-C10)aryl.

"Aryloxy"separately or as part of another substituent refers to a radical of the formula-O-aryl, where aryl is as defined above.

"Arylalkylamine"separately or as part of another substituent refers to a radical of the formula-O-arylalkyl where arylalkyl is the same as defined above.

"Aryloxyalkyl"separately or as part of another substituent refers to a radical of the formula-C(O)-O-aryl, where aryl is as defined above.

"Carbarnoyl"separately or as part of another substituent refers to a radical of the formula-C(O)NR32R33where R32and R33each, independently of one another selected from the group consisting of hydrogen, as defined above, alkyl and cycloalkyl, or, alternatively, R32and R33taken together with the nitrogen atom to which they are bound, form specified in this description cyclogeranyl a cyclic structure.

The term "The compounds of this invention" refers to compounds, various generalized descriptions and General f is salami, disclosed in this description. The compounds of this invention can be identified or according to their chemical structure and/or chemical name. In cases where the chemical structure and chemical name conflict, the chemical structure is the determining factor, describing the data connection. The compounds of this invention can contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as isomers on double bond (i.e., geometric isomers), rotamer, enantiomers or diastereoisomers. Accordingly, in cases where the stereochemistry at the chiral centers are not specifically mentioned, the chemical structures depicted herein encompass all possible configurations in these chiral centers, including stereoisomers pure form (e.g., geometrically pure, enantiomerically pure or diastereomers pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be separated into their components, enantiomers or stereometry, using well-known experts in this field separation methods or methods of chiral synthesis. The compounds of this invention may also exist in several tautomeric forms including the enol form, ketoform and MESI. Accordingly, depicted in this description of chemical structures cover all possible tautomeric forms of the illustrated compounds. The compounds of this invention may also include isotope-labeled compounds where one or more atoms have an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include, but are not limited to,2H,3H,13C,14C,15N18O,17O,31P,32P,35S18F and36Cl. The compounds of this invention can be in resolutiony forms as well as solvated forms, including forms, hydrates and N-oxides. In General, hydrated, solvated, and N-oxide forms, all included in the scope of the present invention. Some compounds of the present invention may exist in different crystalline or amorphous forms. In General, all physical forms of the compounds are equivalent to the assumed according to the present invention uses, and you have in mind that all of these forms are within the scope of the present invention.

"Cycloalkyl"separately or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl, RA is ikulu, determined above. In those cases, when referring to a certain level of unsaturation, use the terminology "cycloalkenyl" or "cycloalkenyl". Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane and the like, Preferably, cycloalkyl group contains from 3 to 10 ring atoms (C3-C10cycloalkyl) and more preferably from 3 to 7 ring atoms (C3-C7cycloalkyl).

"Cyclogeranyl"separately or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl, the radical, in which one or more carbon atoms (and optionally any associated hydrogen atoms) are independently replaced with the same or different heteroatoms. Typical heteroatoms to replace the atom(s) of carbon include, but are not limited to, N, P, O, S, Si, etc. In those cases, when referring to a certain saturation level, use the terminology "cyclogeranyl" or "cyclogeranyl". Typical cyclogeranyl groups include, but are not limited to, groups derived from epoxides, azirines, tyranov, imidazolidine, research, piperazine, piperidine, pyrazolidine, pyrrolidone, hinoklidina etc. Preferably, cyclogeranyl GRU the PA includes from 3 to 10 ring atoms ((3-10)-membered cyclogeranyl)) and more preferably from 3 to 7 ring atoms ((3-7)-membered cyclogeranyl)).

"Dialkylamino"separately or as part of another substituent refers to a radical of the formula-NR34R35where R34and R35each, independently of one another selected from the group consisting of alkyl and cycloalkyl defined above. Typical examples of dialkylamino include, but are not limited to, dimethylamino, methylethylamine, di(1-methylethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino etc.

"Halogen" or "Alo"by themselves or as part of another substituent, refers to a radical of fluorine, chlorine, bromine and/or iodine.

"Halogenated"separately or as part of another substituent, refers to a higher alkyl group in which one or more hydrogen atoms replaced by a group of halogen. In particular, mean that the term "halogenated" includes monohalogenated, dihalogenoalkane, trihalogen etc. until perhalogenated. Halogen group, replacing halogenating group can be the same or different. For example, the expression(C1-C2)halogenated" includes 1-vermeil, 1-fluoro-2-chloroethyl, deformity, trifluoromethyl, 1-foretel, 1,1-dottorati, 1,2-dottorati, 1,1,1-triptorelin, perforated etc.

"Heteroaryl"separately or as part of another substituent, refers to monovalent is the heteroaromatic radical, obtained by removing one hydrogen atom from a single atom of the original heteroaromatic cyclic systems defined in this specification. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsehole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochroman, isoindole, isoindoline, isoquinoline, isothiazole, isoxazol, naphthiridine, oxadiazole, oxazole, pyrimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, Piran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, heatline, quinoline, hemolysin, cinoxacin, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like, Preferably, the heteroaryl group contains from 5 to 20 ring atoms (5-20-membered heteroaryl), more preferably from 5 to 10 ring atoms (5-10-membered heteroaryl). Preferred heteroaryl groups include groups derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.

"A heterocycle" refers to compounds within the scope of the invention defined by the characteristic "cycle B", which is depicted in this description. Such compounds can be aromati the institutions or non-aromatic (hydrogenated isomers). The cycle has the General formula:

which includes from one to four heteroatoms, where X, Y, Z, each independently from each other represents C, CH, N, NR16, NR18, S, or O; and U and T, each independently from each other represents C, CH or N. R16and R18each, independently of one another selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, lower heteroalkyl, substituted lower heteroalkyl, cycloalkyl, substituted cycloalkyl, cyclogeranyl, substituted cyclogeranyl, lower halogenoalkane, monohalogenated, dehalogenating, trihalomethyl, trifloromethyl, lower alkylthio, substituted lower alkylthio, lower alkoxy, substituted lower alkoxy, methoxy, substituted methoxy, lower heteroatomic, substituted lower heteroatomic, cycloalkane, replaced cycloalkane, cyclohexaneacetic, replaced cyclohexaneacetic, lower halogenoalkane, monohalogenated, dehalogenate, trihalomethane, triptoreline, lower di or monoalkylamines, substituted lower di - or monoalkylamines, aryl, substituted aryl, aryloxy, replaced aryloxy, phenoxy, replaced phenoxy, arylalkyl, substituted arylalkyl, arylalkyl, replaced arylalkyl, benzyl, benzyloxy, heteroaryl, Zam the seal heteroaryl, heteroaromatic, replaced heteroaromatic, heteroaromatic, substituted heteroaromatic, heteroarylboronic, replaced heteroarylboronic, carboxyl, lower alkoxycarbonyl, substituted lower alkoxycarbonyl, aryloxyalkyl, substituted aryloxyalkyl, arylalkylamine, substituted arylalkylamine, carbamate, substituted carbamate, carbamoyl, replaced carbamoyl, sulfamoyl, substituted sulfamoyl and groups of the formula-L-R17where "L" is a linker and R17is cycloalkyl, substituted cycloalkyl, cyclogeranyl or substituted cyclogeranyl. The linker can be any group of atoms that are suitable for joining the parts R17to the nitrogen atom. Suitable linkers include, but are not limited to, pieces, selected from the group consisting of -(CH2)1-6-, S, -C(O)-, -SO2-, -NH-, -C(O)-SO2NH -, and combinations thereof.

Suitable heterocycles include, for example, isoxazoles, pyrazoles, oxadiazoles, oksazolov, thiazole, imidazoles, triazoles, thiadiazoles and their hydrogenated isomers. Suitable hydrogenated isomers of the above heterocyclic compounds include, for example, digidrirovannye isomers, as well as tetrahydrofurane isomers. Such hydrogenated isomers include, for example, 2-isoxazoline, 3-isoxazol is h, 4-isoxazolines, isoxazolidine,

1,2-pyrazoline, 1,2-pyrazolidine,

(3H)-dihydro-1,2,4-oxadiazole,

(5H)-dihydro-1,2,4-oxadiazole, oxazoline, oxazolidine,

(3H)-dihydrothiazolo, (5H)-dihydrothiazolo, thiazolidine

(tetrahydrothieno), (3H)-dihydrotriazine, (5H)-dihydrotriazine,

thiazolidine (tetrahydrocarbazole), dihydroimidazole,

tetrahydroindazole, (3H)-dihydro-1,2,4-thiadiazole,

(5H)-dihydro-1,2,4-thiadiazole,

1,2,4-thiadiazolidine (tetrahydroindazole),

(3H)-dihydroimidazole, (5H)-dihydroimidazole and

tetrahydroimidazo.

"The original aromatic cyclic system" refers to an unsaturated cyclic or polycyclic system with close-coupled system π-electrons. In particular, the term "original aromatic cyclic system" includes condensed cyclic system in which one or more cycles are aromatic and one or more cycles are saturated or unsaturated, such as, for example, fluorene, indan, inden, finale etc. Typical source of aromatic cyclic system include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysin, corona, fluoranthene, fluorene, exact, hexagen, hexalen, Asim-indocin, SIMM-indocin, indan, inden, naphthalene, octazen, octave, Oct is Yong, oval, Penta-2,4-diene, pentacene, pentalene, Pentagon, fixed, finale, phenanthrene, pizen, Pleiades, pyrene, pesantren, Rubicon, triphenylene, triathalon etc.

"Source heteroaromatic cyclic system" refers to the original aromatic cyclic system, in which one or more carbon atoms (and optionally any associated hydrogen atoms)are each independently replaced with the same or different heteroatoms. Typical heteroatoms to replace the carbon atoms include, but are not limited to, N, P, O, S, Si, etc. In particular, the term "source heteroaromatic cyclic system" includes condensed cyclic structures in which one or more cycles are aromatic and one or more cycles are saturated or unsaturated, such as, for example, Arendal, benzodioxan, benzofuran, chroman, chrome, indole, indoline, Xanten, etc. Typical source heteroaromatic cyclic systems include, but are not limited to, Arendal, carbazole, β-carbolin, chroman, chrome, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochroman, isoindole, isoindoline, isoquinoline, isothiazol, isoxazol, naphthiridine, oxadiazol, oxazol, pyrimidin, phenanthridine, phenanthroline, fenesin, phthalazine, pteridine, purine, Piran, pyrazin, Piras is l, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, hinzelin, quinoline, hemolysin, cinoxacin, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like,

"Pharmaceutically acceptable salt" refers to salts of the compounds of this invention, which is formed with counterions, which are generally known in the field as acceptable for pharmaceutical applications, and which possesses the desired pharmacological activity of the parent compound. Such salts include: (1) additive salt of the acid formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, 1,2-ethicality acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonate the acid, 4-toluensulfonate acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-Oct-2-ene-1-carboxylic acid, glucoheptonate acid, 3-phenylpropionate acid, trimethylhexane acid, tert-Butylochka acid, louisanna acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova acid and the like; or (2) salts formed in the case, when an acidic proton present in the original compound is replaced by a metal ion, for example, alkali metal ion, alkali earth metal ion or ion aluminum; or coordinates with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine etc. also Included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic (galactunoric) acids and the like (see, for example, Berge et al., 1977, J. Pharm. Sci. 66:1-19).

"Pharmaceutically acceptable filler" refers to a diluent, adjuvant (auxiliary substance), excipient or media, which administered the compound of the present invention.

"Protective group" it belongs to the group, which when attached to a reactive functional group in a molecule masks functional group reduces or ven is tstuat the manifestation of its reactivity. Typically, the protective group can be selectively removed, if required, during the synthesis. Examples of protective groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rdEd., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Typical amino-protective groups include, but are not limited to, formyl, acetyl, TRIFLUOROACETYL, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilylethynyl ("SES"), trityl and substituted triteleia group, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl ("FMOC"), nitroferricyanide ("NVOC") and other Typical hydroxyl-protective groups include, but are not limited to, groups, where the hydroxyl group or allerban (for example, methyl and ethyl esters, acetate or propionate group or glycol esters), or alkylated such as benzyl and trifilova ethers, and alkalemia ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups) and allyl ethers.

"The prodrug" refers to a derivative of the active compound (drug)that undergoes transformation in the conditions of use, such as in the body, releasing the active drug. Prodrugs of I which are often but not necessarily, pharmacologically inactive until then, until we are transformed into the active drug. Prodrugs are typically obtained by masking functional groups in medicine, which is believed to be in part required for activity of proletarienne group (defined below) with the formation of the precursor, which undergoes a transformation, such as splitting, in particular conditions of use, releasing this functional group and, therefore, the drug. Cleavage of the precursor can occur spontaneously, for example, by hydrolysis, or it may be catalyzed or be called by another agent, such as, for example, an enzyme, a source of light, acid, or change or impact on the physical or environmental parameter, such as temperature change. The agent may be endogenous to the conditions of use, such as an enzyme present in the cells, which impose a prodrug, or acid environment of the stomach, or it can be introduced exogenously. In a specific embodiment, the term prodrug includes hydrogenated isomers of the compounds of the invention. Such hydrogenated isomers included in the scope of the present invention, can be oxidized in fisiologicas what their conditions to the corresponding aromatic cyclic system.

A large variety proletarienne groups, as well as the resulting precursors suitable for masking functional groups in the active compounds, to produce prodrugs, known in this area. For example, hydroxyl functional groups can be masked in the form of sulfate, ester or carbonate precursor, which can be hydrolyzed in vitro with getting a hydroxyl group. Functional amino group can be masked in the form of an amide, imine, pospisilova, fostering, phosphoryl predecessor, which can be hydrolyzed in vivo to obtain an amino group. The carboxyl group can be masked in the form of an ester (including Silovye esters and thioesters), amide or hydrazide precursor, which can be hydrolyzed in vivo to obtain carboxyl group. Specialists in this field is obvious and other specific examples of suitable proletarienne groups and their respective predecessors.

"Proletarienne group" refers to the type of the protective group, which, when used to mask a functional group within drug education predecessor, converts the drug into a prodrug. Proletarienne group usually recognize Aut to the functional group of drugs through links, which can be broken down into specific conditions of use. Thus, proletarienne group is that part of the precursor, which is cleaved, releasing functional group in a particular application. As a concrete example, amide precursor of the formula-NH-C(O)CH3contains Palekastro group-C(O)CH3.

"Silloway simple ether" refers to the type of the protective group, which, when used for masking the hydroxyl groups within drug education predecessor, converts the drug into a prodrug. Silovye ethers known in this area and belong to the deleted group, which prevents the participation of the hydroxy-group in the reaction carried out in the molecule. Such groups are discussed by T. W. Greene in chapters 2 and 7 "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, 1981; and J.W. Barton in Chapter 2, "Protective Groups in Organic Chemistry", J.F.W. McOmie, ed., Plenum Press, New York, which are included in the present description in its entirety by reference. Silovye ethers include, for example, trimethylsilyloxy, triethylsilyl, tert-butyldimethylsilyl and methyldiisopropanolamine group.

The term "replaced", when used to modify a specified group or radical, means that one or more hydrogen atoms ODA is divided group or radical, each, independently of one another, replaced by identical or different substituents. Typical substituents include, but are not confined, -M, -R40, -O-, =O, -OR40, -SR40-S-, =S, -NR40R41, =NR40, -CM3, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2O-, -S(O)2OH, -S(O)2R40, -OS(O2)O-, -OS(O)2R40, -P(O)(O-)2, -P(O)(OR40)(O-), -OP(O)(OR40))(OR41), -C(O)R40, -C(S)R40, -C(O)OR40, -C(O)NR40R41, -C(O)O-, -C(S)OR40, -NR42C(O)NR40N41, -NR42C(S)NR40R41, -NR42C(NR43)NR40R41and-C(NR42)NR40N41where each M is independently a halogen; R40, R41, R42, R43and R44each, independently of one another selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cyclogeranyl, substituted cyclogeranyl, -NR45R46, -C(O)R45and-S(O)2R45or, alternatively, R40and R41and/or R45and R46taken together with the respective nitrogen atoms to which they are linked, form cyclogeranyl or substituted cyclogeranyl cycle, as defined above.

"Sulfamoyl", otdeljnoye as part of another substituent, refers to a radical of the formula-S(O)2NR36R37where R36and R37each, independently of one another represents hydrogen, as defined above, alkyl or cycloalkyl, or, alternatively, R36and R37taken together with the nitrogen atom to which they are bound, form a, as defined above, cyclogeranyl or substituted cyclogeranyl cycles.

7.Connections

In one embodiment, the compounds of this invention are pyridylamine heterocycles and hydrogenated isomers cycle according to structural formula (I):

or their pharmaceutically acceptable salt, hydrate, solvate or N-oxides, where:

cycle B is an aromatic or nonaromatic ring which contains one to four heteroatoms, where

X, Y, Z, each independently from each other selected from C, CH, N, NR16, NR18, S or O, provided that X and Y both are not O;

U and T each, independently of one another, selected from C, CH or N;

Z is N or-CH-;

A represents N or CR2-;

B is N or CR3-;

D represents N or CR4-;

E is N or CR5-;

G is N or CR6-;

J is N or CR14-;

K is N or CR8-;

L is N or CR9;

M is N or CR10-;

R2and R6each, independently of one another selected from the group consisting from the group consisting of hydrogen, halogen, Torah, chlorine, alkyl, methyl, substituted alkyl, alkylthio, replaced alkylthio, alkoxy, methoxy, isopropoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkylamine, substituted arylalkylamine, aryloxyalkyl, substituted aryloxyalkyl, cyclogeranyl, substituted cyclogeranyl, carbamoyl, replaced carbamoyl, halogenoalkane, trifloromethyl, sulfamoyl, substituted sulfamoyl and salelologa simple ester, provided that one of R2and R6is other than hydrogen;

R3and R5each, independently of one another selected from the group consisting of hydrogen, halogen, chlorine, alkyl, substituted alkyl, alkylthio, replaced alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkylamine, substituted arylalkylamine, aryloxyalkyl, substituted aryloxyalkyl, cyclogeranyl, substituted cyclogeranyl, carbamoyl, replaced carbamoyl, halogenoalkane, sulfamoyl and substituted sulfamoyl;

R4selected from the group consisting of hydrogen, halogen, alkyl, Sames the frame of alkyl, alkylthio, replaced alkylthio, carbamoyl, replaced carbamoyl, aloxi, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkylamine, substituted arylalkylamine, aryloxyalkyl, substituted aryloxyalkyl, dialkylamino, replaced dialkylamino, halogenoalkane, sulfamoyl and substituted sulfamoyl;

R7is-NR11C(O)R12;

R8, R9, R10and R14each, independently of one another selected from the group consisting of hydrogen, halogen and fluorine;

R11represents hydrogen, alkyl or methyl; and

R12is substituted alkyl, halogenated, halogenmethyl, dehalogenation, dichloromethyl, cyclogeranyl or substituted cyclogeranyl;

R16and R18each, independently of one another selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, lower heteroalkyl, substituted lower heteroalkyl, cycloalkyl, substituted cycloalkyl, cyclogeranyl, substituted cyclogeranyl, lower halogenoalkane, monohalogenated, dehalogenating, trihalomethyl, trifloromethyl, lower alkylthio, substituted lower alkylthio, lower alkoxy, substituted lower alkoxy, methoxy, substituted methoxy, lower heteroatomic, substituted lower gets the realacci, cycloalkane, replaced cycloalkane, cyclohexaneacetic, replaced cyclohexaneacetic, lower halogenoalkane, monohalogenated, dehalogenate, trihalomethane, triptoreline, lower di - or monoalkylamines, substituted lower di - or monoalkylamines, aryl, substituted aryl, aryloxy, replaced aryloxy, phenoxy, replaced phenoxy, arylalkyl, substituted arylalkyl, arylalkyl, replaced arylalkyl, benzyl, benzyloxy, heteroaryl, substituted heteroaryl, heteroaromatic, replaced heteroaromatic, heteroaromatic, substituted heteroaromatic, heteroarylboronic, replaced heteroarylboronic, carboxyl, lower alkoxycarbonyl, substituted lower alkoxycarbonyl, aryloxyalkyl, substituted aryloxyalkyl, arylalkylamine, substituted arylalkylamine, carbamate, substituted carbamate, carbamoyl, replaced carbamoyl, sulfamoyl, substituted sulfamoyl and groups of the formula-L-R17where "L" is a linker and R17is cycloalkyl, substituted cycloalkyl, cyclogeranyl or substituted cyclogeranyl.

provided that

(i) at least one of A, B, D, E, G, J, K, L or M is N;

(ii) not more than one of A, B, D, E, or G represents N; and

(iii) not more than one of J,K, L or M is n

In another embodiment, the compounds of this invention are pyridylamine thiazole and hydrogenated isomers cycle In accordance with the structural formula (II):

or their pharmaceutically acceptable salt, hydrate, solvate or N-oxides, where A, B, D, E, G, J, K, L, M, and R7are as defined above for structural formula (I), and subordinate to the same conditions, and ---- means either an aromatic or non-aromatic (hydrogenated isomer) heterocyclic ring.

In one embodiment, compounds of structural formula (I), Z represents-CH-, so that connections are isoxazoles or pyrazoles. In another embodiment, compounds of structural formula (I), Z represents N, so that connections are oxadiazole or azoles. In another embodiment, compounds of structural formula (I) are isoxazoles. In a specific embodiment, isoxazole, X represents N and Y represents O. In the following embodiment, compounds of structural formula (I) are oxadiazole.

In one embodiment, compounds of structural formulas (I) and (II), A, B, D, E or G is N and one of J, K, L or M is N. In another embodiment, the Dean of A, B, D, E or G is N and none of the J, K, L or M is n In the following embodiment, none of A, B, D, E or G is N and one of J, K, L or M is N. Preferably, in any of the above embodiments of compounds of formula (I) and/or (II), R7is-NR11C(O)R12where R11represents hydrogen or methyl and R12is-CHCl2.

In another embodiment, compounds of structural formulas (I) and (II), A represents-CR2-, G represents-CR6and R7is-NR11C(O)R12where R11represents hydrogen or methyl and R12is-CHCl2. In another specific embodiment, B represents-CR3-, D is N, E is-CR5-, J is-CR14-, K is-CR8-, L is-CR9-, M represents-CR10-, and R3, R5, R9, R10and R14each represents hydrogen. In the following another specific embodiment, B represents-CR3-, D is-CR4-, E is-CR5-, J is-CR14-, K is-CR8-, L is-CR9-, M is N, and R3, R4, R5, R8, R9and R14each represents hydrogen. Once another specific embodiment, B before the hat-CR 3-, D is-CR4-, E is-CR5-, J is-CR14-, K is-CR8-L is N, M is-CR10-, and R3, R4, R5, R8, R10and R14each represents hydrogen. Preferably, in the above embodiment, R2and R6each, independently of one another selected from the group consisting of chlorine, fluorine, methyl, trifloromethyl, thiomethyl, methoxy, isopropoxy, N-morpholino and N-morpholinomethyl. More preferably, R2and R6each, independently of one another selected from the group consisting of chlorine, fluorine, methyl, trifloromethyl, methoxy, isopropoxy. In another embodiment, R2and R6each represents the same or different Halogens. Preferably, in the above embodiments, implementation, X is N, Y is O and Z is-CH-.

In the following embodiment, compounds of structural formulas (I) and (II) A is-CR2-, G represents-CR6and R7is-NR11C(O)R12where R11represents hydrogen or methyl and R12represents-CH2I. Preferably, R2and R6each, independently of one another selected from the group consisting of chlorine, fluorine, methyl, trifloromethyl, thiomethyl, methoxy, isopropoxy, N-morpho is Ino and N-morpholinomethyl. More preferably, R2and R6each, independently of one another selected from the group consisting of chlorine, fluorine, methyl, trifloromethyl, methoxy, isopropoxy. In another embodiment, R2and R6each is identical or different halogen. Preferably, in the above embodiments, implementation, X is N, Y is O and Z is-CH-.

In the following embodiment, compounds of structural formulas (I) and (II) A is-CR2-, B is-CR3-, R7is-NR11C(O)R12where R11represents hydrogen or methyl and R12is-CHCl2. In another specific embodiment, D is-CR4-, G represents-CR6-, E is-CR5-, J is-CR14-, K is-CR8-, L is-CR9-, M is N, and R4, R5, R6, R8, R9and R14each represents hydrogen. In the following another specific embodiment, D is-CR4-, G represents-CR6-, E is-CR5-, J is-CR14-, K is-CR8-L is N, M is-CR10-, and R4, R5, R6, R8, R10and R14each represents hydrogen. Preferably, R2and R6each, independently researched the mo from each other, selected from the group consisting of chlorine, fluorine, methyl, trifloromethyl, thiomethyl, methoxy, isopropoxy, N-morpholino and N-morpholinomethyl. More preferably, R2and R6each, independently of one another selected from the group consisting of additional chlorine, fluorine, methyl, trifloromethyl, methoxy, isopropoxy. In another embodiment, R2and R6each is identical or different halogen. Preferably, in the above embodiments, implementation, X is N, Y is O and Z is-CH-.

In the following embodiment, compounds of structural formulas (I) and (II) A is-CR2-, G represents-CR6and R2and R6are identical, provided that they are not hydrogen. In another embodiment A is-CR2-, B is-CR3and R2and R3are identical, provided that they are not hydrogen. In the following embodiment, B represents-CR3-, E is-CR5and R3and R5are identical, provided that they are not hydrogen. In the following embodiment, B represents-CR3-, D is-CR4-, E is-CR5-, J is-CR14-, K is-CR8-, and R3, R4, R5, R8and R14to whom jdy, represents hydrogen. In the following embodiment, D represents-CR4-, E is-CR5-, G is CR6J represents-CR14-, K is-CR8-, and R4, R5, R6, R8and R14each represents hydrogen.

In other embodiments, implementation of the compounds of structural formula (I) and their hydrogenated isomers cycle To include a loop that represents pyrid-3-yl.

In the following embodiments, the implementation of the compounds of structural formula (I) and their hydrogenated isomers cycle To include a loop, which represents pyrid-4-yl.

In another embodiments, the implementation of the compounds of structural formula (I) are compounds of isoxazol according to structural formula (Ia), (Ib), (Ic), (Id) or (Ie):

or their pharmaceutically acceptable salt, hydrate or solvate, where X, Y, R2, R6, R11and R12are as defined above for structural formula (I), and ---- means or unsaturated bond (aromatic heterocycle), or a rich communication (the non-aromatic heterocycle, for example, hydrogenated isomer) cycle Century

In one embodiment, the compounds of structural formulae (Ia), (Ib), (Ic), (Id) and (Ie) are, independently from each other, one or more characteristics is selected from the group consisting of:

X is O and Y is N;

X represents N and Y represents O;

R11represents hydrogen;

R12is dichloromethyl;

R2and R6each, independently of one another selected from the group consisting of methyl, halogen, fluorine, chlorine, trifloromethyl and methoxy; and

R2and R6each, independently of one another selected from the group consisting of halogen, fluorine and chlorine.

In another aspect of this invention, X is N, Y is O, Z is CH, T and U are C (isoxazoline ring), A is-CR2-, G represents-CR6-.

The following aspect of this invention, X is N, Y is O, Z is CH, T and U are C (isoxazoline ring), A is-CR2-, G represents-CR6-where R6is piperazine or substituted piperazine. Suitable substituted piperazines include, for example,

In another aspect of this invention, X is N, Y is O, Z is CH2, T, and U are C (isoxazoline ring), A is-CR2-, G is-C-O-R6-so that R6forms an ester, a simple ester or silloway simple ether. Suitable groups R6that form when you esters, ethers or Silovye ethers include, for example, alkyl, methyl, substituted alkyl, alkylthio, replaced alkylthio, alkoxy, methoxy, isopropoxy, replaced aloxi, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkylamines, substituted arylalkylamines, aryloxyalkyl, substituted aryloxyalkyl, cyclogeranyl, substituted cyclogeranyl, carbarnoyl, substituted carbarnoyl, halogenated, trifluoromethyl and silloway simple ether.

Illustrative compounds of this invention are presented in figure 1 and in Table 1.

For specialists in this area it is obvious that the described compounds of this invention may include functional groups that can be masked proletarienne groups to create prodrugs. Such prodrugs are typically, but not necessarily, pharmacologically inactive until converted into their active pharmaceutical form. In the prodrugs of the present invention, any available functional part can be masked proletarienne group with obtaining prodrugs. In this area known significant number proletarienne groups, suitable for masking such functional groups, to obtain a precursor, which is easily cleaved at the desired conditions of use.

7.1How the Intesa

The compounds of this invention can be obtained by synthetic methods illustrated in Fig. 2-7. It should be borne in mind that in Fig. 2-7, A, B, D, E, G, J, K, L, M, and R7are as defined above for structural formula (I), and contain the same restrictions.

The source materials used to produce compounds of the present invention and their intermediates are commercially available or can be obtained by known synthetic methods (see, for example, Harrison et al., "Compendium of Synthetic Organic Methods", Vols. 1-8, John Wiley and Sons, 1971-1996; "Beilstein Handbook of Organic Chemistry," Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al., "Reagents for Organic Synthesis," Volumes 1-17, Wiley Interscience; Trost et al., "Comprehensive Organic Synthesis," Pergamon Press, 1991; "Theilheimer''s Synthetic Methods of Organic Chemistry," Volumes 1-45, Karger, 1991; March, "Advanced Organic Chemistry," Wiley Interscience, 1991; Larock "Comprehensive Organic Transformations," VCH Publishers, 1989; Paquette, "Encyclopedia of Reagents for Organic Synthesis," John Wiley & Sons, 1995). Other methods of synthesis described compounds and/or source of the products or described in this area, or they are obvious to a person skilled in this field. Alternative reagents and/or protective groups, illustrated in figure 2-7 the above links and other short guides, well-known specialists in this field. Recommendations for selection of suitable protective groups can be found, for example, in Greene &Wuts, "Protective Groups in Organic Synthesis," Wiley Interscience,1999. Accordingly, presented in this description of the methods and strategy of synthesis of compounds are illustrative rather than exhaustive.

One method of synthesis of substituted isoxazoles in accordance with structural formula (I) (when Z is-CH-), presented at Figo. Referring to Figa, andolina condensation of ketone 201 with benzaldehyde 203 in alkaline conditions, followed by dehydration in situ, gives α-β unsaturated northward 205, which can be easily converted into a isoxazol 207 treatment with hydroxylamine. Recovery 207 gives aminoethoxy 209, which can be converted into the final product 211 in a variety of ways, known to specialists in this field. A specific illustrative example of the synthesis method Figa is getting isoxazol 9 presented on Figv.

Another method of synthesis of substituted isoxazoles structural formula (I) (when Z is-CH-) presented on Figa. Condensation on Clausena of ketone 201 with a complex ester 223 in alkaline conditions gives the 1,3-diketone 229, which can be converted into a mixture of isoxazoles 207 and 231 by treatment with hydroxylamine. As above, the recovery 207 gives aminoethoxy 209, which can be turned into isoxazol 211 known synthetic methods. It should be noted that isoxazol 231 can be turned in for whom the tender regioisomer of isoxazol 211 the same synthetic means. A specific illustrative example of the synthesis method Figa is getting isoxazol 9 presented on Figv.

In an alternative embodiment, the synthesis is illustrated in Figa, ester 225 condensed with ketone 227, getting a 1,3-diketone 229, which is then carried through the rest of the above synthetic route.

The following method of synthesis of substituted isoxazoles structural formula (I) (where Z denotes-CH-) presented on Figa. Nucleophilic attach of hydroxylamine to benzaldehyde 245 gives the intermediate oxime, which can be converted by treatment with N-chlorosuccinimide (NCS) α-chlorosis 247. Dehydrohalogenating α-chloroxine 247 gives unstable ylides, which is subjected to the reaction of 1,3-dipolar cycloaddition to the acetylene 249 with obtaining the desired isoxazol 211. Acetylene 249 can be easily obtained from commercially available precursors known synthetic methods.

A specific illustrative example of the synthesis method Figa is getting isoxazol 9 presented on Figv. Figs illustrates the production of acetylene 255, presented at Figv. Similar methods can be used to obtain other compounds of pyridylacetate.

The following method of synthesis of substituted isoxazoles structural formula (I) (when the and Z signifies-CH-) presented on Figa. Nucleophilic attach of hydroxylamine to benzaldehyde 245 gives the intermediate oxime, which can be directly converted into ylides 257 with NaOCl. 1,3-Dipolar cycloaddition ilide 257 to the ketone 259 gives the desired isoxazol 211. The ketone 259 can be easily obtained from commercially available precursors known synthetic methods. A specific illustrative example of the synthesis method Figa is getting isoxazol 9 presented on Figv.

The ways presented on Figure 2-5 above, can be easily adapted for the synthesis of pyrazoles by the substitution in the sequence of reactions of hydroxylamine with hydrazine. In addition, for specialists in this area it is obvious that the regioisomers of isoxazoles, depicted in the above Figure 2-5 can be synthesized by a simple exchange of the reactive functional groups of two different aromatic rings. An example of this approach is depicted in Fig.4D for "converted" isoxazol 262. As you can see in Fig.4D, the interchange of functional groups chloroxine and alkyne two different aromatic rings (i.e. cycle A and C) gives regioisomeric isoxazol 262 (cf 253 and 255 254 and 256). In addition, some schemes of synthesis can directly provide both regioisomer of isoxazol (for example, Figa and 3B), which can be separated from each other using the conventional separation methods.

One method of synthesis of substituted oxadiazoles structural formula (I) (when Z is-N-) presented on Figa. Referring to Figa, nucleophilic attach of hydroxylamine to vinylcyanide 265 gives α-aminooxy 267, which may be condensed with the acid chloride of acetic acid 269 of obtaining oxadiazole 271 after cyclodehydration and recovery. Aminoimidazole 271 can be transformed in various ways known to specialists in this field in the final product 273. A specific illustrative example of the synthesis method Figa is getting oxadiazole 283 presented on Figv.

Another method of synthesis of substituted oxadiazoles structural formula (I) (where Z denotes-N-), which represent the regioisomers obtained above oxadiazole presented on Figa. Referring to Figa, α-aminooxy 287 (obtained by the condensation of hydroxylamine with vinylcyanide) can be condensed with the acid chloride of acetic acid 285 with getting oxadiazole 289 after cyclodehydration and recovery. Aminoimidazole 289 can be transformed into the final product 291 in a variety of ways, known to specialists in this field. A specific illustrative example of the synthesis method Figa is getting oxadiazole 301 presented on Figv.

It should be noted that the ways PR is dostavlennya on 6 and 7 above, can be easily adapted for the synthesis of triazoles replacement depicted in the sequence of reactions of hydroxylamine with hydrazine. Triazole structural formula (II) can be obtained by standard methods of adaptation of the methods described in figure 2-7, or by other known methods.

7.2Tests on the modulation of HCV

The compounds of this invention are potent inhibitors of replication and/or proliferation of HCV. The activity of compounds of this invention can be demonstrated in vitro, suitable for measuring inhibition of replication or proliferation of a virus or retrovirus. Such tests are known in this field. A specific example of analysis of replicon that is appropriate to confirm the activity of certain compounds, is discussed in the "Examples"section. Alternatively, the active compounds can be confirmed using quantitative method Western blotting using labeled antibodies specific for proteins of HCV. Another analysis that can be used to confirm the activity of various compounds of this invention against HCV, described in Fournier et al., 1998; J. Gen. Virol. 79(10):2367-2374, the content of which is incorporated into this description by reference. According to this method, the hepatocytes can be investigated in the presence and absence of specific ispite the CSO connections and defined IC 50connection.

Typically, the active compounds are compounds that demonstrate specific test IC50(for example, concentration of a compound that gives the decrease in replication by 50% or decrease by 50% the number of measured protein HCV) within about 1 mm or less. Compounds that demonstrate IC50for example, within about 100 μm, 10 μm, 1 μm, 100 nm, 10 nm, 1 nm or even lower, are particularly useful as therapeutic agents or prophylactic agents for the treatment or prevention of infectious diseases caused by HCV. Alternatively, the active compounds are compounds that demonstrate LD50(i.e. the concentration that kills 50% of the virus) in the range of about 1 mm or less. Compounds that exhibit lower LD50for example, within about 100 μm, 10 μm, 1 μm, 100 nm, 10 nm, 1 nm or even lower, are particularly useful as therapeutic agents or prophylactic agents for the treatment or prevention of infectious diseases caused by HCV.

7.3Application and introduction

Due to its ability to inhibit replication and/or proliferation of HCV, the compounds of this invention and/or compositions on their basis can have a number of applications. For example, the compounds of this invention can be COI is used as a control in assays in vitro to identify additional more or less active against HCV compounds. As another example, the compounds of this invention and/or compositions can be used as preservatives or disinfectants in clinical settings to protect medical instruments from infection by HCV virus. When used in this case, the compound of this invention and/or compositions can be applied to the instrument to be disinfected, at a concentration, which is a multiple of, for example, 1X, 2X, 3X, 4X, 5X, or even above, the measured IC50for the connection.

The compounds of this invention and/or compositions find particular application in the treatment and/or prevention of infectious diseases caused by HCV, animals and people. When used in this context, the compounds can be administered by themselves, however, as a rule, they are included in the pharmaceutical composition is administered in this form. The exact composition of the song that you want, usually depends, among other factors, from the way of introduction and is obvious to a person skilled in this field. A large variety of suitable pharmaceutical compositions are described, for example, in Remington''s Pharmaceutical Sciences, 17thed., 1989.

Preparations suitable for oral administration can consist of (a) liquid solutions, namely, in the form of an effective amount of an active compound, suspended in diluents, is aka as water, saline or PEG 400; (b) capsules, sachets or tablets, each dosage form contains a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin; (c) suspensions in an appropriate liquid; and (d) suitable emulsions. The dosage form in tablet form can include one or more excipients selected from lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, callitroga silicon dioxide, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffer funds, humectants, preservatives, fragrances, dyes, dezintegriruetsja tools, and pharmaceutically compatible carriers. Dosage forms in the form of candy may include an active component in corriente, for example, sucrose, and tablets containing the active ingredient in an inert basis such as gelatin and glycerin, or emulsions, gels or sucrose Arabian gum, and the like containing, in addition to the active ingredient, carriers known in this field.

The selected connection, by itself or in combination with other suitable components, can be included in the compositions of the aerosol (i.e., they can be the ü sprayed), which is administered by inhalation. Aerosol formulations can be placed into pressurized acceptable propellants such as DICHLORODIFLUOROMETHANE, propane, nitrogen, etc.

Suitable preparations for rectal injection include, for example, suppositories, which consist of nucleic acid combined with a base of the suppository. Suitable bases for suppositories include natural or synthetic triglycerides or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the selected connection basis, including, for example, liquid triglyceride, glycols, and paraffin hydrocarbons.

Preparations suitable for parenteral administration, for example, by such ways as intraarticular, intravenous, intramuscular, nutritionally, intraperitoneal, and subcutaneous, include aqueous and non-aqueous, isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostatic factors and dissolved substances, which make the composition isotonic to the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspendresume funds solubilisate, thickeners, stabilizers and preservatives. In the practice of this invention comp the flies can enter, for example, intravenous infusion, orally, topically administered intraperitoneally, intravesical or vnutriobolochechnoe. Parenteral administration, oral administration and intravenous administration are the preferred methods of administration. Preparations of the compounds may be presented in sealed containers containing the dose by one dose or multiple dose, such as ampoules or vials. Solutions and suspensions for injection can be obtained from sterile powders, granules and tablets of the type indicated above.

The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into uniform doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, with each pack contains discrete quantities of preparation, such as tablets, capsules, packaging and powders in vials and ampoules. In addition, the unit dosage form can be a capsule, tablet, sachet or a Lollipop, by itself, or it may represent the appropriate number of any of the above forms in the package. The composition can, if desired, also contain other compatible therapeutic agents.

In therapeutic use for the treatment of HCV-and the burden, the compounds used in the pharmaceutical method of the invention is administered to patients with a diagnosis of HCV infection at dose levels that are suitable for therapeutic use. Under therapeutic benefit is meant that the introduction of compounds will have a beneficial effect on the patient after some time. For example, therapeutic benefit is achieved when the title or the load of HCV in a patient or decreases, or when it stops increasing. therapeutic benefit is also achieved if the introduction of the connection slows down or stops, in General, the beginning of organ damage or any other adverse symptoms that usually accompany the course of infectious diseases caused by HCV, regardless of title or load of HCV in a patient.

The compounds of this invention and/or compositions based on them can also be used prophylactically for patients with increased risk for HCV infection, or who have been exposed to HCV, to prevent the development of HCV-infection. For example, the compounds of this invention and/or compositions on their basis it is possible to enter the hospital, accidentally tear yourself needles when working with patients, HCV, to reduce the risk or to avoid in General, the development of infectious diseases caused by HC.

The initial dose suitable for administration to humans, can be determined based on in vitro or animal models. For example, the initial dose can be formulated as the dose that achieved serum concentrations, which includes the IC50specific connection, be inserted defined in the test in vitro. Alternatively, the initial dose for humans can be based on doses that, as installed, are effective in animal models of HCV infection, as is well known in this field. Illustrative suitable system models described in Muchmore, 2001, Immumol. Rev. 183:86-93 and Lanford & Bigger, 2002. Virology 293(i):1-9 and the references cited therein, the contents of which are incorporated into this description by reference. As one example, the initial dose may be in the range from about 0.001 mg/kg to about 1000 mg/kg, daily. You can also use a range of daily dose from about 0.01 mg/kg to about 500 mg/kg, or from about 0.1 mg/kg to about 200 mg/kg, or from about 1 mg/kg to about 100 mg/kg, or from about 10 mg/kg to about 50 mg/kg Dose, however, may vary depending on the needs of the patient, the severity of the condition to be treated, and a connection that will be used. The size of the dose also will be determined by the existence, nature and degree of manifestation of any adverse side effects that soprovoditelnie individual patient specific connection. Determination of the proper dosage for a particular situation is within the skill of the practicing physician. Typically, treatment begins with smaller doses that are less than the optimum dose of the compound. Subsequently, the dose is increased in small increments until then, until you reach the optimum effect under the circumstances. For convenience, if desired, the total daily dose may be divided into parts and put on parts during the day.

7.4Combination therapy

In some embodiments, implementation of the present invention compounds of this invention and/or compositions based on them can be used in combination therapy with at least one other therapeutic agent. The compound of the invention and/or composition based on it and a therapeutic agent can act more or, more preferably, synergistically. In a preferred embodiment, the compound of the invention and/or a composition based on it is injected simultaneously with the introduction of another therapeutic agent. In another embodiment, the compound of the invention and/or a composition based on it being before or after administration of another therapeutic agent.

In one embodiment, compounds of the invention and/or compositions on their basis b is to be used in combination therapy with other antiviral agents. In one embodiment of the invention the compounds of the invention and/or compositions based on them can be used in combination therapy with interferon-α. In another embodiment, compounds of the invention and/or compositions based on them can be used in combination therapy with ribavirin and interferon-α.

8.Examples

The following example is only an illustration and not limitation. For specialists in this area obviously a number of minor settings that you can change or modify to get essentially the same results.

8.1Illustrative compounds of this invention which inhibit translation or replication of HCV

Inhibitory activity of some illustrative compounds of this invention was confirmed using analysis of the HCV replicon. The HCV replicon may include such features as HCV IRES, noncoding region of HCV 3', individual HCV genes, encoding the HCV polypeptides, breeding markers and reporter gene such as luciferase, GFP, etc. In the analysis of actively dividing 5-2Luc the replicon-containing cells were seeded at a density of about 5000 to 7500 cells/well in 96-well plates (about 90 ál of cells per well) and incubated at 37°C and 5% CO2within 24 hours. Then to each well add ulali test compound (in a volume of about 10 μl) at various concentrations and the cells were incubated for an additional 24 hours prior to analysis for luciferase. The cells were collected and replication or HCV transmission was controlled by analysis of reporter gene, for example, analysis of the reporter is luciferase. The medium was removed from each of the cells by aspiration and each well was added reagents Bright-Glo (Pharmacia, Peapack, NJ) for analysis of luciferase in accordance with the manufacturer's instructions. This analysis determined the amount of test compound which gives an emission reduction of luciferase by 50% (IC50).

Some illustrative compounds of this invention were also tested for their ability to inhibit the replication of HCV by using quantitative method Western blotting using antibodies specific for certain proteins of HCV. This analysis determined the amount of test compound that results from the reduction of the amount of a protein of HCV by 50% compared with the control sample (IC50).

The results of the analysis of the replicon and the method of Western blotting are shown in Table 1, below. The structures of these compounds are presented in figure 1. In Table 1, the value "+" means IC5010 μm or less for a particular analysis; the value "-" means IC50more than 10 μm for a particular analysis. A series of compounds was demonstrated in the analysis of the replicon IC50in the nanomolar concentration range.

To identify non-specific inhibitors of reporter gene used screening. In screening to identify compounds that inhibit reporter gene, but not HCV, used a cell line, the load-bearing structure, such as CMV-activated gene luciferase. In the analysis of inhibition luciferase screening method for many compounds the values of the IC50was more than 10 μm. To determine the cytotoxicity of the compounds of this invention used standard methods of cell proliferation. The measured values LD50for many compounds was greater than 10 microns, which confirmed that the results reflect a decrease in the production of the virus, and not cell death.

TaqMan RT-PCR assay (Roche Molecular Systems, Pleasanton, CA) was used to study the number of copies of HCV RNA, which confirmed that the virus genome is not replicated. Actively dividing 9-13 the replicon-containing cells were sown at a density of 3×104cells/well in a volume of 1 ml/well in 24-well plates. Then cells were incubated at 37°C and 5% CO2within 24 hours. 24 hours after seeding the cells in each well was added with the unity at various concentrations (volume of 10 μl). Cells were incubated with compounds for 24 hours, the medium was removed by aspiration and each well received sample RNA. One-step TaqMan RT-PCR was carried out using their sample RNA according to the manufacturer's instructions. The ratio of HCV RNA to cellular RNA GAPDH was used as an indicator of the specificity of inhibition of HCV and to confirm that the virus genome is not replicated.

8.2The compounds are non-toxic at the cellular and animal models

8.2.1Cytotoxicity

Connection 1, 3, 7, 9, 11, 13, 17, 19, 21, 27, 29, 31, 33, 35, 37, 39, 47, 49, 51, 57 and 69 were tested in the analysis of cytotoxicity in the cells of the liver, including the HCV replicon (5-2 Luc cells, 9-13 cells or Huh-7 cells). In this assay, cells were seeded in 96-well plates (approximately 7500 cells/well in a volume of 90 μl) and were cultured for 24 hours at 37°C. On day 2 in the wells was added with different concentrations of the test compounds (10 μl) and cells were cultured for additional 48 h at 37°C. On day 4 was carried out by analysis of ATP-dependent R-Luciferase (definition of cell titer on Glo)to determine the number of viable cells. Except for compounds 13, 19 and 57, all compound showed IC50more than or equal to 10 μm, confirming that the compounds are non-toxic. Of the remaining connection of the clusters all except the connection 13, which showed IC503 μm, had IC50more than 5 μm, demonstrating that these compounds to the same well tolerated.

8.3The synthesis of compounds

8.3.1Compound 3 (R909794) and 9 (R909921)

Stage A

In accordance with Figs connection 230 (25 g, 98,1 mmol) are added to 96% H2SO4(50 ml) at 0°C followed by the addition of 96% HNO3(17.5 ml) and the resulting mixture is heated at 130°C for 3 hours. The reaction mixture is cooled, then poured into ice, add sodium carbonate to cause the formation of sludge (pH>7). The product distinguish by filtration, washed with water and dried, obtaining a yellow solid 232 (17.0 g, 79%).

Stage

Connection 232 (17 g, 78 mmol) in CHCl3(200 ml) add PBr3(7,4 ml) and the resulting mixture is refluxed for about 1 hour or until completion of the reaction, the speed of which is controlled by thin layer chromatography. The reaction mixture is cooled, bóthe greater part of the solvent is removed under reduced pressure and the residue was poured on ice, getting a yellow solid. The product distinguish by filtration, getting 234 (14.5 g, 92%).

Stage

To a mixture of 234 (6 g, 0,029 mol), PdCl2(Ph3)2(620 mg, 3 mol.%), CuI (338 mg, 6 mol.%) in nitrogen atmosphere add diisopropylethylamine (100 ml). The mixture of paramashiva the t at ambient temperature for several minutes until the introduction of TMS-acetylene (6.3 ml, 1.5 EQ.). Then the contents are heated at 60°C within 24 hours. The solvent is removed under reduced pressure and the crude product is filtered through a column of silica gel (a mixture of hexane:EtOAc 10:1)getting 236 in the form of a yellow solid, 4.9 g (76%).

Stage D

A mixture of compound 236 (1.4 g), Fe powder (3.55 g, 10 equiv.) concentrated HCl (1 ml) and methanol (100 ml) is refluxed for 3 hours. After cooling, the reaction mixture is filtered, the solution concentrated and the residue diluted with NaHCO3and extracted with EtOAc (several times). The combined EtOAc extracts are dried, filtered and concentrated, obtaining the crude product (1.0 g) in a mixture of 238 and desilusionado (not containing TMS-group) product 240. The oily mixture was dissolved in methanol (100 ml) and treated with K2CO3(about 2 EQ.). After stirring at room temperature for 1 hour, the reaction mixture was concentrated in vacuo. The residue is dissolved in EtOAc, washed with water, dried, filtered and concentrated in vacuo. Get product 240 (513 mg) as a dark purple oil.

Stage E

Connection 240 (513 mg) was dissolved in dry dichloromethane (50 ml) and added dropwise under nitrogen atmosphere Et3N (of 0.786 ml, 1.3 EQ.). The mixture is cooled in a bath with ice and added dropwise a solution of acid chloride of dichloracetic acid (0,483 ml, 1,1 is square) in dry dichloromethane (5 ml). The reaction mixture allow to warm to room temperature for 6 hours and then diluted with EtOAc, washed with saturated sodium bicarbonate, dried, filtered and concentrated in vacuo. The crude product is passed through a layer of silica gel, elute with a mixture of hexane/EtOAc, 1:1. Fraction concentrate, receiving a purple oil which was aterials under high vacuum, giving the compound 255 (658 mg).

Stage F

Chlorosis 2-fluoro-6-triftormetilfullerenov (645 mg, 1.1 EQ.) and the connection 255 (658 mg) dissolved in dry THF (30 ml) and add Et3N (0,521 ml, 1.3 EQ.). The mixture is stirred at room temperature for 1 hour and then refluxed for 5 hours to complete the reaction. The solvent is removed in vacuum, the residue is dissolved in EtOAc, washed with water, washed with saturated sodium chloride, dried, filtered and concentrated. The crude product is purified by chromatography (mixture of 3:2 hexane:EtOAc)to give compound 3 (800 mg). Connection 9 have a similar way of chloroxine 2,6-dichlorobenzaldehyde and 255.

8.3.2Synthesis of compound 49 (R905952)

Obtaining 3-(2-methoxy-6-triptoreline)-5-(4-aminopyridin)isoxazol

To a solution of N-hydroxy-(2-methoxy-6-triptoreline)carboxymethylated (1 g, of 3.94 mmol) and 4-amino-2-ethynylpyridine (310 mg, 2,63 mmol) in THF added treat the Lamin (550 ml, of 3.94 mmol). The reaction mixture was stirred at room temperature for one hour and then refluxed for three hours. The mixture is cooled to room temperature, add ethyl acetate and water. The organic layer is separated, dried over sodium sulfate, filtered and concentrated in vacuo, obtaining the crude product. The final product, 3-(2-methoxy-6-triptoreline)-5-(4-aminopyridin)isoxazol (609 mg), obtained by purification with flash chromatography using a mixture of hexane:ethyl acetate (4:1).

MM=335,28 confirmed by LC-MS, tr=scored 8.38 min (Method Y) M+=335,28. NMR (300 MHz, CDCl3): 8,24 (m, 1H), of 7.48 (m, 1H), and 7.4 (m, 1H), 7,26 (m, 1H), 7,2 (m, 1H), 7,0 (s, 1H), 6,6 (m, 1H), 4,8 (CL, 2H), and 3.8 (s, 3H).

Getting 2,2-Dichloro-N-[2-[3-(2-methoxy-6-triptoreline)-5-isoxazolyl]-(4-pyridyl)ndimethylacetamide

A mixture of 3-(2-methoxy-6-triptoreline)-5-(4-aminopyridin)isoxazol (609 mg, 1.82 mmol) and triethylamine (1.8 ml, 12.9 mmol) in dichloromethane cooled in a bath with ice. Add dropwise a solution of acid chloride of dichloracetic acid (1.3 ml, 12.9 mmol) in dichloromethane. After stirring for a further one hour, add water and ethyl acetate. The organic layer is separated, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The final product, 2,2-dichloro-N-[2-[3-(2-methoxy-6-trifloromethyl the Nile)-5-isoxazolyl]-(4-pyridyl)ndimethylacetamide (300 mg), get flash chromatography using a mixture of hexane:ethyl acetate (4:1).

MM=446, confirmed by LC-MS, tr=9,84 min (Method Y) MH+=447,21. NMR (300 MHz, CDCl3): 9,84 (s, 1H), 8,63 (m, 1H), 7,9 (m, 1H), 7.62mm (m, 1H), 7,41 (m, 1H), 7,22 (m, 1H), 5,64 (s, 1H), and 3.8 (s, 3H).

(Activity: replicon ++)

8.3.3Synthesis of compound 57 (R905948)

Obtaining 3-(2,2-dichloroacetamide)-5-ethynylpyridine

A mixture of 3-amino-5-ethynylpyridine (2,73 g of 23.1 mmol) and triethylamine (3.54 in ml, 25,42 mmol) in dichloromethane cooled in a bath with ice. Add dropwise a solution of acid chloride of dichloracetic acid (to 2.57 ml, 25,42 mmol) in dichloromethane. After stirring for a further one hour, add water and ethyl acetate. The organic layer is separated, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, obtaining 3-(2,2-dichloroacetamide)-5-ethynylpyridine (3.5 g).

MM=229,31 confirmed by LC-MS, tr=9,76 min (Method Y) MH+=230,3. NMR (300 MHz, CDCl3): 8,7 (s, 1H), charged 8.52 (s, 1H), and 8.2 (m, 2H), between 6.08 (s, 1H), 3,21 (s, 1H).

Getting 2,2-dichloro-N-[3-[3-(2-methoxy-6-triptoreline)-5-isoxazolyl]-(5-pyridyl)ndimethylacetamide

To a solution of N-hydroxy-(2-methoxy-6-triptoreline)carboxymethylated (111 mg, 0.44 mmol) and 3-(2,2-dichloroacetamide)-5-ethynylpyridine (100 mg, 0.44 mmol) in THF added triethylamine (0,91 ml of 0.65 mmol). The reaction mixture is stirred at room temperature for one hour and then refluxed for three hours. The mixture is cooled to room temperature, add ethyl acetate and water. The organic layer is separated, dried over sodium sulfate, filtered and concentrated in vacuo, obtaining the crude product. The final product, 2,2-dichloro-N-[3-[3-(2-methoxy-6-triptoreline)-5-isoxazolyl]-(5-pyridyl)ndimethylacetamide (103 mg), obtained by purification with flash chromatography using a mixture of hexane:ethyl acetate (4:1).

MM=446,31 confirmed by LC-MS, tr=13,45 min (Method Y) MH+=7,31. NMR (300 MHz, CDCl3): 9,4 (SHS, 1H), and 9.0 (s, 1H), 8,9 (s, 2H), 7,58 (m, 1H), and 7.4 (m, 1H), 7,24 (m, 1H), 6,8 (s, 1H), 6,2 (s, 1H), and 3.8 (s, 3H).

(Activity: replicon ++)

8.3.4Total syntheses of the compounds of the invention

In addition, the compounds of this invention can be obtained by methods generally described in Fig. 8-63. The person skilled in the art can easily obtain the compounds included in the scope of the present invention on the basis of this description of the recommendations and illustrations presented in Fig. 1-63, references cited in the figures, and taking into account the experimental method proposed in the provisional patent application U.S. 60/467650, filed may 2, 2003. (registration number in the Affairs of attorney P-71847-2), the contents of which are incorporated into this description by reference. For example, see sections 5.3 and 6.1 and later, concerning the General synthesis of isomers containing no nitrogen cycle "C" Pyrid-2-yl, pyrid-3-yl or pyrid-4-yl can be used in the loop "C" as a substitute for not containing heteroatoms in aromatic rings represented there. In addition, it should be borne in mind that for convenience, all 1-63 use isomers provisions of the series "C". It should be borne in mind that peregrinae ring may be either of pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl. In addition, it should be borne in mind that many of the syntheses affect cycle "A", which is 2,6-dichlorophenyl. The latter is illustrative in nature, and, as expected, is by no means the limit.

The source materials used to produce compounds of the present invention and their intermediates are commercially available or they can get well-known synthetic methods (see, for example, Harrison et al; "Compendium of Synthetic Organic Methods", Vols. 1-8 (John Wiley and Sons, 1971-1996); "Beilstein Handbook of Organic Chemistry," Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al., "Reagents for Organic Synthesis," Volumes 1-21, Wiley Interscience; Trost et al., "Comprehensive Organic Synthesis," Pergamon Press, 1991; "Theilheimer''s Synthetic Methods of Organic Chemistry," Volumes 1-45, Karger, 1991; March, "Advanced Organic Chemistry," Wiley Interscience, 1991; Larock "Comprehensive Organic Transformations," VCH Publishers, 1989; Paquette, "Encyclopedia of Reagents for Organic Synthesis,3d Edition, John Wiley & Sons, 1995). Other methods of synthesis described compounds and/or original materials or described in this area, or they are obvious for skilled professionals in D. the authorized area. Alternative reagents and/or protective groups, illustrated in Figure 1-63, can be found in the above reference materials and other short guides, known qualified specialists in this field. Recommendations for the selection of suitable protective groups can be found, for example, in Greene &Wuts, "Protective Groups in Organic Synthesis," Wiley Interscience, 1999. Accordingly, presented in this description of the methods and strategy of synthesis of compounds are illustrative rather than exhaustive.

In particular, the methods of synthesis of substituted diphenyl-containing isoxazole according to structural formula (I) (where Z denotes-CH-) is shown in Fig. 2A-7b and 12C-12E.

Figs, 4D and 15-18, which describe the obtaining of acetylene compounds, are discussed in the "Examples"section.

It should be borne in mind that figure 1-63 and over a large part of the description, meta isomers cycle "C" is shown only as an example. The methodology to obtain ortho-, meta - or para-position isomers cycle "C" can be selected by qualified specialists in this field. Therefore, if 1-63 the attention is focused on getting meta-isomers cycle "C", the same methodology can be used to obtain the ortho - or para-isomers cycle "C." Meta-isomer selected in Fig. 1-63 for convenience and consistency of the presentation is Oia, to demonstrate the possibility of obtaining interest compounds.

Figure 1-63, the substituents R2, R3, R4, R5, R6, R8, R9, R10and R14may contain reactive functional groups that require protection during synthesis. The choice of suitable protective groups usually depends on the nature of functional groups and the applicable method of synthesis, and this choice is obvious for specialists in this field. Recommendations for selection of suitable protective groups can be found in Greene &Wuts, see above, and various other reference materials cited in this description.

For more information on the implementation of the reactions of 1,3-dipolar cycloaddition, also known reactions of 1,3-dipolar accession, [3+2] cyclization or [3+2] cycloaddition can be found in "Cycloaddition Reactions in Organic Synthesis", (Kobayashi, S. and Jorgensen, K.A., Editors), 2002, Wiley-VCH Publishers, pp. 1-332 pages (specifically, Chapters 6 and 7 on [3+2] cycloadditions and 1,3-dipolar additions, pp. 211-248 and 249-300); "1,3-Dipolar Cycloaddition", Chemistry of Heterocyclic Compounds, Vol. 59, (Padwa, A. and Pearson, W., Editors), 2002, John Wiley, New York. pp.1-940; "suffix Oxides, Nitrones, and Nitronates in Organic Synthesis: Novel Strategies in Synthesis", Torssel, K. B. G., 1988, VCH Publishers, New York, pp. 1-332; Barnes & Spriggs, 1945, J. Am. Chem Soc. 67:134; Anjaneyulu et al., 1995, Indian J. Chem., Sect. 5 34(11):933-938); and T.L. Gilchrist, Pitman Publishing Ltd, 1985 ISBNO-273-02237-7; Strategies for Organic Drug Synthesis and Design, Lednicer, D., John Wiley and Sons, 1998.

For more information on this issue, the synthesis of isoxazoles and their hydrogenated isomers can be found in M. Sutharchanadevi, R. Murugan in Comprehensive Heterocyclic Chemistry II, A.R. Katritzky, C.W. Rees, E.F.V. Scriven, Eds.; Pergamon Press, Oxford, Vol. 3, p. 221; R Grünager, P, Vita-Finzi in Heterocyclic Compounds, Vol. 49, Isoxazoles, Part one, John Wiley and Sons, New York, 1991; K.B. G. Torssell, suffix Oxides, Nitrones, and Nitronates in Organic Synthesis, VCH Publishers, New York, 1988; Y-Y. Ku, T. Grieme, P. Sharma, Y.-M. Pu, P. Raje, H. Morton, S. King Organic Letters, 2001, 3, 4185; V.G. Desai, S.G. Tilve Synth. Comm., 1999, 29, 3017; X. Wei, J. Fang, Y. Hu, H. Hu, Synthesis, 1992, 1205; C. Kashima, N. Yoshihara, S. Shirai Heterocycles, 1981, 16, 145; A.S.R. Anjaneyulu, G.S. Rani, K.G. Annapurna, U.V. Mallavadhani, Y.L.N. Murthy Indian J. Chem. Sect B, 1995, 34, 933; R.P. Barnes, A.S. Spriggs, J. Am. Chem. Soc., 1945, 67, 134; A. Alberola, L. Calvo, A.G. Ortega, M.L. Subada, M.C. Sacudo, S.G. Granda, E.G. Rodriguez Heterocycles, 1999, 51, 2675; X. Wang, J. Tan, K. Grozinger Tetrahedron Lett. 2000, 41, 4713; A.R. Katritzky, M. Wang, S. Zhang, M.V. Voronkov J. Org. Chem., 2001, 66, 6787; J. Bohrisch, M. Pätzel, C. Mügge, J. Liebscher Synthesis, 1991, 1153; SHANKAR, B.B.; Yang, D.Y.; Girton, S.; Ganguly, A.K.; Tetrahedron Lett (TELEAY) 1998, 39(17), 2447-2448. CHENG, W.C.; Wong, M.; Olmstead, M.M.; Kurth, M.J.; Org Lett (ORLEF7) 2002, 4(5), 741-744. KHAN, M.S.Y.; Bawa, S.; Indian J. Chem, Sect B: Org Chem Incl Med Chem (USBDB) 2001, 40(12), 1207-1214. SIMONI, D.; et al; J Med Chem (JMCMAR) 2001, 44(14) 2308-2318. NUGIEL, D.A.; Tetrahedron Lett (TELEAY) 2001, 42(21), 3545-3547. ARAI N.; Iwakoshi, M.; Tanabe, K.; Narasaka, K.; Bull Chem Soc Jpn (BCSJA8) 1999, 72(10), 2277-2285. SAGINOVA, L.G.; Grigorev, E.V.; Chem Heterocyd Compd (NY) (CHCCAL) 1999, 35(2), 244-247. MURI, D.; Bode, J.W.; Carreira, E.M.; Org Lett (ORLEF7) 2000, 2(4), 539-541. KANEMASA, S.; Matsuda, H.; Kamimura, A.; Kakinami, T.; Tetrahedron (TETRAB) 2000, 56(8), 1057-1064. MOCHALOV, S.S.; Kuzmin, Y.I.; Fedotov, A.N.; Trofmova, E.V.; Gazzaeva, R.A.; Shabarov, Y.S.; Zefirov, N.S.; Zh Org Khim (ZORKAE) 1998, 34(9), 1379-1387. DAVIES, C.D.; Marsden, S.P.; Stokes, ESE; Tetrahedron Lett (TELEAY) 1998, 39(46), 8513-8516. KANEMASA, S.; Matsuda, H.; Kamimura, A.: Kakinami, T.; Tetrahedron (TETRAB) 2000, 56(8), 1057-1064. WEIDNER WELLS, M.A.; Fraga Spano, S.A.; Turchi, I.J; J Org Chem (JOCEAH) 1998, 63(18), 6319-6328. PADMAVATHI, V.; Bhaskar Reddy, A.V.; Sumathi, R.P.; Padmaja, A.; Bhaskar Reddy, D.; Indian J Chem, Sect B: Org Chem Incl Med Chem (IJSBDB) 1998, 37(12), 1286-1289. WILLIAMS, A.R.; Angel, A.J.; French, K.L.; Hurst, D.R.; Beckman, D.D.; Beam, C.F.; Synth Commun (SYNCAV) 1999, 29(11), between 1977 and 1988. CARAMELLA, P.; Reami, D.; Falzoni, M.; Quadrelli, P.; Tetrahedron (TETRAB) 1999, 55(22), 7027-7044. KIDWAJ, M.; Misra, P.; Synth Commun (SYNCAV) 1999, 29 (18), 3237-3250. SYASSI. B.; El Bakkali, B.; Benabdellah, G.A.; Hassikou, A.; Dinia, M.N.; Rivere, M.; Bougrin, K.; Soufiaoui, M.; Tetrahedron Lett (TELEAY) 1999, 40(40), 7205-7209. SYASSI, B.; Bougrin. K.; Soufiaoui. M.; Tetrahedron Lett (TELEAY) 1997, 38(51), 8855-8858. LI, P.; Gi, H.J.; Sun, L.; Zhao, K.; J Org Chem (JOCEAH) 1998, 63(2), 366-369. BOUGRIN, K.; Lamri, M.; Soufiaoui, M.; Tetrahedron Lett (TELEAY) 1998, 39(25), 4455-4458. SRIVASTAVA, Y.K.; Sukhwai, S.; Ashawa, A.; Verma, B.L.; J Indian Chem Soc (JICSAH) 1997, 74(7) 573-574. CORSARO, A.; Buemi, G.; Chiacchio, U.; Pistara, V.; Rescifina, A.; Heterocycles (HTCYAM) 1998, 48(5) 905-918. CORSARO. A.; Librando, V.; Chiacchio, U.; Pistara, V.; Rescifna, A.; Tetrahedron (TETRAB) 1998, 54(31), 9187-9194. CORSARO, A.; Librando, V.; Chiacchio, U.; Pistara, V.; Tetrahedron (TETRAB) 1996, 52(40), 13027-13034. BELENKII, L.I.; Gromova, G.; Lichitshii, B.V.; Krayushkin, M.M.; Izv Akad Nauk Ser Khim (IASKEA) 1997, (1), 106-109. KASHIMA, C.; Takahashi, K.; Fukuchi, I.; Fukusaka, K.; Heterocycles (HTCYAM) 1997, 44(1) 289-304. BASEL, Y.; Hassner, A.; Synthesis (SYNTBF) 1997, (3), 309 to 312. BANNIKOV, G.F.; Ershov, V.V.; Nikiforov, G.A.; Izv Akad Nauk. Ser Khim (IASKEA) 1996 (2), 426-429. TOKUNAGA, Y.; lhara, M.; Fukumoto, K.; Heterocycles (HTCYAM) 1996, 43(8), 1771-1775. AHMED, G.A.; J Indian Chem Soc (JICSAH) 1995, 72(3) 181-183. LU, T.J.; Yang, J.F.; Sheu, L.J.; J Org Chem (JOCEAH) 1995, 60(23) 7701-7705. EASTON, C.J.; Hughes, C.M.M.; Tiekink, E.R.T.; Savage, G.P.; Simpson, G.W.; Tetrahedron Lett (TELEAY) 1995, 36(4) 629-632. WALLACE, R.H.; Liu, J.; Tetrahedron Lett (TELEAY) 1994, 35(41) 7493-7496. BALDOLI, C.; Gioffreda, F.; Zecchi, G.; J Heterocycl Chem (JHTCAD) 1994, 31(1), 251-253. WEIDNER WELLS, M.A.; Fraga, S.A.; Demers, J.P.; Tetrahedron Lett (TELEAY) 1994, 35(35), 6473-6476. HANSEN, J.F.; Georgiou, P.J.; J Heterocycl Chm (JHTCAD) 1994, 31(6), 1487-1491. ANKHIWALA, M.D.; Hathi, M.V.; J Indian Chem Soc (JICSAH) 1994, 71(9) 587-589. KAMIMURA, A.; Hori. K.; Tetrahedron (TETRAB) 1994, 50(27) 7969-7980. ABBADY, M.A.; Hebbachy, R.; Indian J Chem, Sect B (IJSBDB) 1993, 32(11), 1119-1124. MORIYA, O.; Takenaka, H.; Iyoda, M.; Urata, Y.; Endo, T.; J Chem Soc, Perkin Trans 1 (JCPRB4) 1994 (4), 413-417. TANAKA, S.; Kohmoto, S.; Yamamoto, M.; Yamada, K.; Nippon Called Kaishi (NKAKB8) 1992 (4), 420-422. NAGARAJAN, A.; Pillay, M.K.; Indian J Chem, Sect B (IJSBDB) 1993, 32(4), 471-474. STOYANOVICH, F.M.; Bulgakova, V.N.; Krayushkin, M.M.; Lzv Akad Nauk SSSR, Ser Khim (IASKA6) 1991 (11), 2606-2611. BALDOLI, C.; Del Buttero, P.; Manorana, S.; Zecchi, G.; Moret, M.; Tetrahedron Lett (TELEAY) 1993, 34(15), 2529-2532. MIZUNO, K.; Ichinose, N.; Tamai, T.; Otsuji, Y.; J Org Chem (JOCEAH) 1992, 57(17), 4669-4675. HUANG, Z.T.; Wang, M.X.; Synth Commun (SYNCAV) 1991, 21, 1167-1176. MOHAMED, T.A.; Kandeel, M.M.; Awad, I.M.A.; Youssef, M.S.K.; Collect Czech Chem Commun (CCCCAK) 1991, 56(12), 2999-3005. MORIYA, O.; Urata, Y.; Endo, T.; J Chem Soc. Chem Commun (JCCCAT) 1991 (13), 884-885. HUANG, Z.T.; Wang, M.X.; Synth Commun (SYNCAV) 1991, 21, 1167-1176. MORIYA. O.; Takenaka, H.; Urata, Y.; Endo, T.; J Chem Soc, Chem Commun (JCCCAT) 1991 (23), 1671-1672. SOUFIAOUI, M.; Syassi, B.; Daou, B.; Baba, N.; Tetrahedron Lett (TELEAY) 1991, 32(30), 3699-3700. SAGINOVA, L.G.; Kukhareva, I.L.; Lebedev, A.T.; Shabarov, YU, S.; Zh Org Khim (ZORKAE) 1991, 27 (9) 1852-1860. KANEMASA, S.; Nishiuchi, M.; WADA, E.; Tetrahedron Lett (TELEAY) 1992, 33(10), 1357-1360. MAMAEVA, O.O.; Krayushkin, M.M.; Stoyanovich, F.M.; Izv Akad Nauk SSSR, Ser Khim (IASKAG) 1990 (4), 913-916. BRTOKHOVETSKII, D.B.; Belenkii, L.I.; Krayushkin, M.M.; Izv Akad Nauk SSSR, Ser Khim (IASKAG) 1990 (7), 1692-1693. ITO, S.; Sato, M.; Bull Chem Soc Jpn (BCSJA8) 1990, 63(9), 2739-2741. MORIYA, O.; Urata, Y.; Endo, T.; J Chem Soc, Chem Commun (JCCCAT) 1991 (1), 17-18. ALMTORP, G.T.; Bachmann, T.L.; Torssell, K.B.G.; Acta Chem Scand (ACHSE7) 1991, 45(2), 212-215. KHAN, M.S.Y.; Khan, M.H.; Kumar, M.; Javed, K.; J Indian Chem Soc (JICSAH) 1990, 67(8), 689-691. KHALIL, Z.H.; Yanni, A.S.; Abdel-Hafez, A.A.; Khalaf, A.A.; J Indian Chem Soc (JICSAH) 1990, 67(10), 821-823. SHIMIZU, T.; Hayashi, Y.; Furukawa, N.; Teramura, K.; Bull Chem Soc Jpn (BCSJA8) 1991, 64(1), 318-320. FADA, A.A.; Indian J Chem, Sect B (IJSBDB) 1991, 30(8), 749-753, RAMA RAO, K.; Bhanumathi, N.; Srinivasan, T.N.; Sattur, P.B.; Tetrahedron Lett (TELEAY) 1990, 31, 899. ICHINOSE, N.; Mizuno, K.; Yoshida, K.; Otsuji, Y.; Chem Lett (CMLTAG) 1988, 723. SINISTERRA, J.V.; Marinas, J.M.; Bull Soc Chim Belg (BSCBAG) 1987, 96(4), 293. BALABAN, A.T.; Zugravescu, L; Avramovici, S.; Silhan, W.; Monatsh Chem (MOCMB7) 1970, 101, 704. LITINAS, K.E.; Nicolaides, D.N.; Varelia, E.A.; J Heterocycl Chem (JHTCAD) 1990, 27, 769. ICHINOSE. N.; Mizuno, K.; Tamai, T.; Otsuji, Y.; Chem Lett (CMLTAG) 1988, 233. THOSEN, I.; Torsseli, K.B.G.; Acta Chem Scand, Ser B (ACBOCV) 1988, 42, 303. ROCHE; Synthesis (SYNTBF) 1984 (12), 1083. CURRAN, D.P.; J Am Chem Soc (JACSAT) 1983, 105(18), 5826. JAGER, V.; et al.; Bull Soc Chim Belg (BSCBAG) 1983, 92, 1039. RAO, C.J.; Reddy, C.M.; Murthy, A.K.; Indian J Chem, Sect B (IJSBDB) 1981, 20, 282. EIKASABY, M.A.; Salem, M.A.I.; Indian J Chem (IJOCAP) 1950, 19, 571. CHINCHOLKAR, M.M.; Jamoda, V.S.; Indian J Chem (IJOCAP) 1979, 17 610. SHABAROV, Y.S.; Saginova, L.G.; Gazzaeva. R.A.; J Org Chem USSR (Engl Transl) (JOCYA9) 1982, 18, 2319. SHIMIZU, T.; Hayashi, Y.; Yamada, K.; Nishlo, T.; Teramura, K.; Bull Chem Soc Jpn (BCSJA8) 1981, 54, 217. WTTZCAK, Z.; Heterocycles (HTCYAM) 1980, 14, 1319. DEMINA, L.A.; et al.; Zh Org Khim (ZORKAE)1979, 15, 735. CHEM ABSTRA (CHABA8), 91 (74512). ARCHIBALD, A. T.; Nielsen, T.G.; Tetrahedron Lett (TELEAY) 1968, 3375. KOHLER, E.P.; Barrett, G.R.; J Am Chem Soc (JACSAT) 1924, 46, 2105. DEMINA, L.A.; Khismutdinov, G.K.; Tkachev, S.V.; Fainzilberg, A.A.; J Org Chem USSR (Engl Transl) (JOCYA9) 1979, 15, 654. BAAVA, L.N.; Demina, L.A.; Trusova, T.V.; Furin, G.G.; Khisamutdinov, G.K.; J Org Chem USSR (Engl Transl) (JOCYA9) 1979, 15, 2179. CARAMELLA, P.; Cellerino, G.; Houk, K.N.; Albini, F.M.; Santiago, C.; J Org Chem (JOCEAH) 1978, 43, 3007. CARAMELLA, P.; Cellerino, G.; Houk, K.; Albini, F.M.; Santiago, C.; J Org Chem (JOCEAH) 1978, 43, 3006. SAUTER, F.; Buyuk, G.; Monatsh Chem (MOCMB7) 1974, 105, 254. ELKASABY, M.A.; Salem, M.A.I; Indian J Chm (IJOCAP) 1980, 19, 571. BAEVA, L.N.; Demina, L.A.; Trusova, T.V.; Furin, G.G.; Khisamutdinov, G.K.; J Org Chem USSR (Engl Transl) (JOCYA9) 1979, 15, 2179. MAKSOUD, A.A.; Hosnig, G.; Hassan, O.; Shafik, S.; Rev Roum Chim (RRCHAX) 1978, 23, 1541. FUKUNAGA, K.; Synthesis (SYNTBF) 1978, 55. FARAGER, R.; Gilchrist, T.L.; J Chem Soc, Perkin Trans 1 (JCPRB4) 1977, 1196. BIANCHI, G.; De Micheli, C.; Gandolfi, R.; J Chem Soc, Perkin Trans 1 (JCPRB4) 1976, 1518. LO VECCHIO, G.; Atti Accad Peloritana Periocolanti, CI Sci Fis Mat Nat (AAPFAO) 1972, 52, 207. JURD, L.; Chem Ind (London) (CHINAG) 1970, 2, 624. BELTRAME, P.L.; Cattania, M.G.; Redaelli, V.; Zecchi, G.; J Chem Soc, Perkin Trans 2 (JCPKBH) 1977, 706. PARK, C.A.; Beam, C.F.; Kaiser, E.M.; Hauser, C.R.; et al.; J Heterocycl Chem (JHTCAD) 1976, 13, 449. LO VECCHIO, G.; Atti Accad Peloritana Pericolanti, CI Sci Fis Mat Nat (AAPFAO) 1972, 52, 217. BORKHADE, K.T.; Marathey, M.G.; Indian J Chem (IJOCAP) 1970, 8, 796. WAKEFIELD, B.J.; Wright, D.J.; J Chem Soc C (JSOOAX) 1970,1165. UNTERHALT, B.; Pham Zentralhalle (PHZEBE) 1968, 107, 356. NIELSEN, A.T.; Archibald, T.G.; Tetrahedron Lett (TELEAY) 1968, 3375. KIRTZ, D.W.; Shechter, H.; J Chem Soc, Chem Commun (JCCCAT) 1965, 689. JOSHI, K.C.; Jauhar, A.K.; J Indian Chem Soc (JICSAH) 1965, 42, 733. NIELSEN, A.T.; Archibald, T.G.; J Org Chem (JOCEAH) 1969, 34, 984. BATTAGLIA, A.; Dondoni, A.; Rio Sci (RISCAZ) 1968, 38, 201. MONIORTE, F.; Lo Vecchio, G.; Atti Accad Peloritana Periocolanti, CI Sci Fis Mat Nat (AAPFAO) 1966, 49, 169. ARBASINO, M.; Finzi, P.V.; Rio Sci (RISCAZ) 1966, 36, 1339. ROTH, H.J.; Schwartz, M.; Arch Pharm Ber Dtsch Pharm Ges (APBDAJ) 1961, 294, 769. ROTH, H.J.; Schwarz, M.; Arch Pharm Ber Dtsch Pharm Ges (APBDAJ) 1961, 294, 761. GRUNANGER, P.; Gandini, C.; Quilico, A.; Rend - 1st Lomb Accad Sci Lett, A: Sci Mat, Fis, Chim Geol (RLMAAK) 1959, 93, 467. RUPE, H.; Schneider, F.; Chem Ber (CHBEAM) 1895, 28, 957. BARLUENGA, J.; Aznar, F.; Palomero, M.A.; Chem Eur J (CEUJED) 2001, 7(24), 5318-5324. ASCHWANDEN, P.; Frantz, D.E.; Carreira, E.M.; Org Lett (ORLEF7) 2000, 2(15), 2331-2333. BALASUNDARAM, B.; Veluchamy, T.P.; Velmurugan, D.; Perumal, P.T.; Indian J Chem, Sect B (IJSBDB) 1995, 34 (5), 367-371. CHAN, for K.S.; Yeung, M.L.; Chan, W.; Wang, R.-J.; Mak, T.C.W.; J Org Chem (JOCEAH) 1995, 60(6), 1741-1747. CHIACCHIO, U.; Casuscelli, F.; Liguori, A.; Rescifina, A.; Romeo, G.; Sindona, G.; Uccella, N.; Heterocycles (HTCYAM) 1993, 36(3), 585-600. CHAN, for K.S.; J Chem Soc, Perkin Trans 1 (JCPRB4) 1991 (10), 2602-2603. LIGUORI, A.; Ottana, R.; Romeo, G.; Sindona, G.; Uccelia, N.; Heterocycles (HTCYAM) 1988, 27, 1365. STAMM, H.; Staudie, H.; Arch Pharm (Weiheim, Ger) (ARPMAS) 1976, 309, 1014. TASZ, M.K.; Plenat, F.; Christau, H.-J.; Skowronski, R.; Phosphorus, Sulfur Silicon Relat Elem (PSSLEC) 1991, 57, 143-146. ALBEROIA, A.; Gonzalez, M.; Laguna, M.A.; Pulido, F.J.; Synthesis (SYNTBF) 1982, 1067. JACOB K.C.; Jadhar, G.V.; Vakharia, M.N.; Pesticides (PSTDAN) 1972, 6, 94. CLERICI, F.; Gelmi, M.L; Pini, E.; Valle, M.; Tetrahedron [TETRAB] 2001, 57(25), 5455-5459. JURD, L.; Chem Ind (London) [CHINAG] 1970, 2, 624. JURD, L.; Tetrahedron [TETRAB] 1975, 31, 2884.

For more information on the synthesis of pyrazoles can be found in J. Elguero in Comprehensive Heterocyclic Chemistry II, A.R. Katritzky, C.W. Reees, E.F.V. Scriven., Eds.; Pergamon Press, Oxford, 1996; Vol. 3, p.1.

A guide for the synthesis of compounds described in Figa and 8B, can be found at LHOTAK, P.; Kurfuerst, A.; Collect Czech Chem Commun [CCCCAK] 1993, 58 (11), 2720-2728. BRAIN, C.T.; Paul, J.M.; Synlett [SYNLES] 1999, (10), 1642-1644. VARMA, R. S.; Kumar, D.; J Heterocycl Chem [JHTCAD] 1998, 35(6), 1533-1534. FEDYUNYAEVA, I.A.; Yushko, E.G.; Bondarenko, V.E.; Khim Geterotsiki Soedin [KGSSAQ] 1996 (3), 333-337. DOROSHENKO, A.O.; Patsenker, L.D.; Baumer, V.N.; Chepeleva, L.V.; Vankevich, A.V.; Shilo, O.P.; Yarmolenko, S.N.; Shershukov, V.M.; Mitina, V.G.; Ponomarev, O.A.; Zh Obshch Khim [ZOKHA4] 1994, 64(4), 646-652. FEDYUNYAEVA, I.A.; Shershukov, V.M.; Khim Geterotsiki Soedin [KGSSAQ] 1993 (2), 234-237. KLEIN, R.F.X.; Horak, V.; Baker. G.A.S.; Collect Czech Chem Commun [CCCCAK] 1993, 58 (7), 1631-1635. KERR, V.N.; Hayes, F.N.; Ott, D.G.; Lier, R.; Hansbury, E., J Org Chem (JOCEAH] 1959, 24, 1864. NISHIO. T.; Ori, M.; Helv Chim Acta [HCACAV] 2001, 84(8), 2347-2354. LHOTAK, P.; Kurfuerst, A.; Collect Czech Chem Commun [CCCCAK] 1993, 58(11), 2720-2728. SIEGREST, A.E.; Helv Chim Acta [HCACAV] 1967, 50, 906; and GABRIEL, S.; Chem Ber [CHBEAM] 1910, 43, 134.

A guide for the synthesis of compounds described in Figa and 9B, can be found in ZHANG, P.-F.; Chen, Z.-C; Synthesis (SYNTBF) 2001, (14), 2075-2077. BUTLER, R.N.; Cloonan, M.O.; McMahon. J.M.; Burke, L.A.; J Chem Soc, Perkin Trans 1 (JCPRB4) 1999, (12), 1709-1712. NAKAWISHI, S.; Otsuji, Y.; Nantaku, J.; Chem Lett (CMLTAG) 1983, 341. POAR, D.; Stradi, R.; Tetrahedron Lett (TELEAY) 1976, 1839. POPILIN, O.N.; Tishchenko, V.G.; Khim Geterotsiki Soedin (KGSSAQ) 1972, 1264; and KUNCKELL, F.; Chem Ber (CHBEAM) 1901, 34, 637.

A guide for the synthesis of compounds described in Figa and 10B, can be found at VARLAMOV, A.V.; Turchin, K.F.; Chernyshev, A.I.; Zubkov, F.I.; Borisova, T.N.; Chem Heterocycl Compd (N Y) [CHCCAL] 2000, 36 (5), 621-622. CASUSCELLI, F.; Chiacchio, U.; Rescifina, A.; Romeo, R.; Romeo, G.; Tommasini, S.; Uccella, N.; Tetrahedron (TETRAB) 1995, 51 (10), 2979-2990. CHIACCHIO, U.; Casuscelli, F.; Corsaro, A.; Rescifina, A.; Romeo, G.; Uccella, N.; Tetrahedron (TETRAB) 1994, 50 (22), 6671-6680. MUKAI, C.; Kim, I.J.; Cho, W.J.; Kido, M.; Hanaoka, M.; J Chem Soc, Perkin Trans 1 (JCPRB4) 1993 (20), 2495-2503. MINAMI, T.; Isonaka. T.; Okada, Y.; Ichikawa, J.; J Org Chem (JOCEAH) 1993, 58 (25), 7009-7015. TANAKA, K.; Mori, T; Mitsuhashi, K.; Bull Chem Soc Jpn (BCSJA8) 1993, 66 (1), 263-268. HUISGEN, R.; et al.; Tetrahedron Lett (TELEAY) 1960, 12, 5. CHEM BER (CHBEAM) 1968, 101, 2043. CHEM BER (CHBEAM) 1968, 101, 2568. CHEM BER (CHBEAM) 1969, 102, 117. SASAKI, T.; Bull Soc Chim Fr (BSCFAS) 1968, 41, 2960; and SASAKI, T.; Bull Chem Soc Jpn (BCSJA8) 1968, 41, 2964.

A guide for the synthesis of compounds described in Figa and 11B, can be found at KATRIZKY, A.R.; Qi, M.; Feng, D.; Zhang, G.; Griffith, M.C.; Watson, K.; Org Lett (ORLEF7) 1999, 1 (8), 1189-1191. FRANCIS, J.E.; Cash, W.D.; Barbaz, B.S.; Bernard, P.S.; Lovell, R.A.; Mazzenga, G.C.; Friedmann, R.C.; Hyun, J.L.; Braunwalder, A.F.; Loo, P.S.; Bennett, D.A.; J Med Chem (JMCMAR) 1991, 34 (1), 281-290. POTTS, K.T.; J Chem Soc (JCSOA9) 1954, 3461. EDMHORN, A.; Justus Liebigs Ann Chem (JLACBF) 1905, 343, 207. SHBA, S.A.; El-Khamry, A.A.; Shaban, M.E.; Atia. For K.S.; Pharmazie (PHARAT) 1997, 52 (3), 189-194; and MOLINA, P.; Tarranga, A.; Espinosa, A.; Lidon, M.J.; Synthesis (SYNTBF) 1987 (2), 128.

A guide for the synthesis of compounds described in Figa and 12B, can be found in ASCHWANDEN, P.; Frantz, D.E.; Carreira, E.M.; Org Lett (ORLEF7) 2000, 2 (15), 2331-2333. BALASUNDARAM, B.; Veluchamy, T.P.; Velmurugan, D.; Perumal, P.T.; Indian J Chem, Sect B (IJSBDB) 199, 34 (5), 367-371. CHAN, for K.S.; Yeung, M.L,; Chan, W.; Wang, R.-J.; Mak, T.C.W.; J Org Chem (JOCEAH) 1995, 60(6), 1741 -1747. ALBEROLA, A.; Gonzalez, M.; Laguna, M.A.; Pulido, F.J.; Synthesis (SYNTBF) 1982, 1067; and JACOB, K.C.; Jadhar, G.V.; Vakharia, M.N.; Pesticides (PSTDAN) 1972, 6, 94.

The following compounds are typical examples of the present invention. Identified below compounds produced by the methods described in General terms throughout the description.

Methods for determining the melting temperature

The melting temperature is determined on electrothermal digital device for determining the melting point of the series IA9100. All melting points are not corrected.

Elemental analysis

Elemental analysis was performed on the instrument Desert Analytics, Tucson, AZ.

Methods NMR

NMR spectra were obtained on a Varian instrument Mercury with a frequency of 300 MHz.

Methods LC-MS

General

Analysis by LC-MS was performed on a Waters instrument Micromass ZQ with electrospray ionization. The HPLC system consisted of a separation module (Waters Model 2690, coupled with a photodiode array detector.

Methodology W

According to this method used 2,1×250 mm column (Alltech) with reversed phase C-18 Altima with a particle size of 5 μm with a volumetric flow rate of 0.25 ml/min and the gradient 5-85% acetonitrile in water, containing 0.1% triperoxonane acid for 36 minutes, Then a linear gradient was changed to 100% acetonitrile at protag the research Institute for 0.5 min, and these conditions were maintained (100% acetonitrile) over 3,5 hours

Method X

According to this method used 2,1×250 mm column (Alltech) with reversed phase C-18 Altima with a particle size of 5 μm with a volumetric flow rate of 0.25 ml/min and the gradient 5-85% acetonitrile in water, containing 0.1% triperoxonane acid for 15 min and Then a linear gradient was changed to 100% acetonitrile for 0.5 min, and these conditions were maintained (100% acetonitrile) for 25 minutes

Method Y

According to this method used 2,1×150 mm column with reversed phase C-18 Agilent Bond with a particle size of 5 μm with a volumetric flow of 0.3 ml/min and a gradient of 10-100% acetonitrile in water, containing 0.1% triperoxonane acid for 16 min, then continued for 2 min with 100% acetonitrile.

Methodology Z

When this technique is used 2,1×5 mm column with reversed phase C-18 Agilent Bond with a particle size of 5 μm with a volumetric flow rate of 0.5 ml/min and a gradient of 5-100% acetonitrile in water, containing 0.1% triperoxonane acid for 8 min, then continued for 2 min with 100% acetonitrile.

Connection 1. (R909850) 2,2-Dichloro-N-[2-[3-(2-chloro-6-forfinal)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=401 confirmed by LC-MS, tr=32,63 min (Method W) MH+=399-403

The connection 3. (R909794) 2,2-Dichloro-N-[2-[3-(2-fluoro-6-triptoreline)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=434 confirmed by LC-MS, t r=34,01 min (Method W) MH+=432-436

The connection 5. (R911427) 2,2-Dichloro-N-[2-[3-(2-fluoro-6-methoxyphenyl)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=396 confirmed by LC-MS, tr=31,28 min (Method W) MH+=394-398

The connection 7. (R911418) 2,2-Dichloro-N-[5-[3-(2,6-dichlorophenyl)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide

MM=417 confirmed by LC-MS, tr=33,10 min (Method W) MH+=415-419

The connection 9. (R909921) 2,2-Dichloro-N-[2-[3-(2,6-dichlorophenyl)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=417 confirmed by LC-MS, tr=34,25 min (Method W) MH+=415-419

TPL=187-188°C

The connection 11. (R909833) 2,2-Dichloro-N-[3-[3-[(2,6-dichloro)-4-pyridyl]-5-isoxazolyl]phenyl]ndimethylacetamide

MM=417 confirmed by LC-MS, tr=34,13 min (Method W) MH+=415-419

The connection 13. (R909845) 2,2-Dichloro-N-[5-[3-(2-chloro-6-forfinal)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide

MM=401 confirmed by LC-MS, tr=worth 32.55 min (Method W) MH+=399-403

The connection 17. (R911424) 2,2-Dichloro-N-[5-[3-(2-fluoro-6-methoxyphenyl)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide

MM=396 confirmed by LC-MS, tr=30,47 min (Method W) MH+=394-398

Connection 19. (R909851) 2,2-Dichloro-N-[2-[3-(2,6-dimetilfenil)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=376 confirmed by LC-MS, tr=34,63 min (Method W) MH+=374-378

Connection 21. (R909846) 2,2-Dichloro-N-[5-[3-(2,6-dimetilfenil)-5-isoxazolyl]-(3-pyridyl)]acetone is

MM=376 confirmed by LC-MS, tr=29,69 min (Method W) MH+=374-378

The connection 27. (R911422) 2,2-Dichloro-N-[5-[3-(2,6-deformity)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide

MM=384 confirmed by LC-MS, tr=31,64 min (Method W) MH+=382-386

The connection 29. (R911423) 2,2-Dichloro-N-[5-[3-(2,3-dichlorophenyl)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide

MM=417 confirmed by LC-MS, tr=34,99 min (Method W) MH+=415-419

The connection 31. (R909864) 2,2-Dichloro-N-[2-[3-(2-morpholino-6-triptoreline])-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=501 confirmed by LC-MS, tr=6,97 min (Method Z) MH+=499-503

The connection 33. (R904855) 2,2-Dichloro-N-[3-[3-(3-methyl-2-pyridyl)-5-isoxazolyl]phenyl]ndimethylacetamide

MM=362 confirmed by LC-MS, tr=30,89 min (Method W) MH+=360-364

The connection 35. (R904800) 2,2-Dichloro-N-[6-[3-(2,6-dichlorophenyl)-5-isoxazolyl]-(2-pyridyl)]ndimethylacetamide

MM=417 confirmed by LC-MS, tr=20,74 min (Method X) MH+=415-419

The connection 37. (R909793) 2,2-Dichloro-N-[5-[3-(2-fluoro-6-triptoreline)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide

MM=434 confirmed by LC-MS, tr=32,79 min (Method W) MH+=432-436

The connection 43. (R909873) 2,2-Dichloro-N-[2-[3-(2,6-dichlorophenyl)-5-isoxazolyl]-[4-(1-oxypyridine)]ndimethylacetamide

MM=433 confirmed by LC-MS, tr=6,44 min (Method Z) MH+=431-435

The connection 45. (R909878) 2,2-Dichloro-N-[3-[3-[(3-adoxical is of IMT-2-pyridyl]-5-isoxazolyl]phenyl]ndimethylacetamide

MM=420 confirmed by LC-MS, tr=6,65 min (Method Z) MH+=418-422

The connection 47. (R909884) 2,2-Dichloro-N-[2-[3-(2-fluoro-6-morpholinosydnonimine)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=515 confirmed by LC-MS, tr=6,32 min (Method Z) MH+=513-517

The connection 49. (R905952) 2,2-Dichloro-N-[2-[3-(2-methoxy-6-triptoreline)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=446 confirmed by LC-MS, tr=14,41 min (Method Y) MH+=444-448

The connection 51. (R909909) 2,2-Dichloro-N-[2-[3-(2,6-dichlorophenyl)-5-isoxazolyl]-(4-pyridyl)]-N-methylacetamide

MM=431 confirmed by LC-MS, tr=14,99 min (Method Y) MH+=429-433

The connection 53. (R905954) 2,2-Dichloro-N-[2-[3-[2-chloro-6-[4-(N-2-pyridyl)piperazine derivatives]phenyl])-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=544 confirmed by LC-MS, tr=11,81 min (Method Y) MH+=542-546

The connection 57. (R905948) 2,2-Dichloro-N-[5-[3-(2-methoxy-6-triptoreline)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide

MM=446 confirmed by LC-MS, tr=13,45 min (Method Y) MH+=444-448

The connection 61. (R905961) 2,2-Dichloro-N-[5-[3-[2-chloro-6-[4-(N-acetyl)piperazine derivatives]phenyl])-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide

MM=509 confirmed by LC-MS, tr=12,11 min (Method Y) MH+=507-511

Connection 63. (R905962) 2,2-Dichloro-N-[5-[3-[2-chloro-6-[4-(N-ethyl)piperazine derivatives]phenyl])-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide

MM=495 confirmed by LC-MS, t =9,48 min (Method Y) MH+=493-497

The connection 65. (R904857) 2,2-Dichloro-N-[5-[3-(2,6-dichlorophenyl)-5-isoxazolyl]-(2-pyridyl)]ndimethylacetamide

MM=417 confirmed by LC-MS, tr=35,19 min (Method W) MH+=415-419

The connection 67. (R905451) 2,2-Dichloro-N-[5-[3-(2-triptoreline)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide

MM=416 confirmed by LC-MS, tr=13,81 min (Method Y) MH+=414-418

Connection 69. (R905949) 2,2-Dichloro-N-[5-[3-[2-chloro-6-[4-(N-2-pyridyl)piperazine derivatives]phenyl])-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide

MM=544 confirmed by LC-MS, tr=11,29 min (Method Y) MH+=542-546

The connection 71. (R905965) 2,2-Dichloro-N-[5-[3-[2-chloro-6-[4-(N-tert-butoxycarbonyl)piperazine derivatives]phenyl])-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide

MM=567 confirmed by LC-MS, tr=15,91 min (Method Y) MH+=565-569

Connection 73. (R905966) 2,2-Dichloro-N-[5-[3-(2-chloro-6-piperidinophenyl)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide

MM=467 confirmed by LC-MS, tr=9,51 min (Method Y) MH+=465-469

Connection 75. (R905967) 2,2-Dichloro-N-[5-[3-(2-chloro-6-tert-butyldimethylsilyloxy)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide

MM=513 confirmed by LC-MS, tr=17,49 min (Method Y) MH+=511-515

Connection 77. (R905968) 2,2-Dichloro-N-[5-[3-(2-chloro-6-hydroxyphenyl)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide

MM=399 confirmed by LC-MS, tr=12,51 min (Method Y) MH+=397-401

Connection 79. R905969) 2,2-Dichloro-N-[5-[3-(2-chloro-6-N-ethylcarbamate)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide

MM=470 confirmed by LC-MS, tr=12,85 min (Method Y) MH+=468-472

Connection 81. (R905970) 2,2-Dichloro-N-[5-[3-[2-chloro-6-[4-(N-ethylcarbodiimide)piperazine derivatives]phenyl])-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide

MM=538 confirmed by LC-MS, tr=12,77 min (Method Y) MH+=536-540

Connection 83. (R905971) 2,2-Dichloro-N-[2-[3-(2-chloro-6-tert-butyldimethylsilyloxy)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=513 confirmed by LC-MS, tr=17,96 min (Method Y) MH+=511-515

Connection 85. (R905973) 2,2-Dichloro-N-[2-[3-(2-chloro-6-N-profilerviewer)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=484 confirmed by LC-MS, tr=made 13.36 min (Method Y) MH+=482-486

Connection 87. (R905982) 2,2-Dichloro-N-[2-[3-(2-chloro-6-methoxyethoxymethyl)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=443 confirmed by LC-MS, tr=14,65 min (Method Y) MH+=441-445

Connection 89. (R905983) 2,2-Dichloro-N-[2-[3-(2-chloro-6-hydroxyphenyl)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=399 confirmed by LC-MS, tr=13,53 min (Method Y) MH+=397-401

Connection 91. (R905984) 2,2-Dichloro-N-[3-[3-[(4-chloro-2-dimethylamino)-3-pyridyl]-5-isoxazolyl]phenyl]ndimethylacetamide

MM=426 confirmed by LC-MS, tr=13,33 min (Method Y) MH+=424 to 428

Connection 93. (R905985) 2,2-Dichloro-N-[3-[3-[(2,4-dichloro)-3-pyridyl]-5-isoxazolyl]phenyl]ndimethylacetamide

MM=417 confirmed by LC-MS, tr=15,7 min (Method Y) MH +=4l5-4l9

Connection 95. (R905987) 2,2-Dichloro-N-[3-[3-[(2-chloro-4-morpholino)-3-pyridyl]-5-isoxazolyl]phenyl]ndimethylacetamide

MM=468 confirmed by LC-MS, tr=13,73 min (Method Y) MH+=466-470

Connection 97. (R909874) 2,2-Dichloro-N-[3-[3-[(6-bromo)-2-pyridyl]-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=427 confirmed by LC-MS, tr=36,03 min (Method W) MH+=425-429

(R904871) cleaners containing hydrochloride salt of 2,2-Dichloro-N-[2-[3-(2,6-dichlorophenyl)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=453

MP=240-241°

Elemental analysis: C16H10Cl5N2O2calculated: C, 42,37; H, 2,22; Cl, 39,09; N, 9,27; found: C, 42,51; H, 2,18; Cl, 39,06; N, 9,05

(R909919) Toluensulfonate salt of 2,2-Dichloro-N-[2-[3-(2,6-dichlorophenyl)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=589

TPL=246-247°C

Elemental analysis: C23H17Cl4N3O5S calculated: C, 46,88; H, 2.91 in; N, 7,13; S, 5,44; found: C, 47,05; H, a 3.06; N, 7,00; S, 5,30

(R909920) Econsultancy salt of 2,2-Dichloro-N-[2-[3-(2,6-dichlorophenyl)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=527

TPL=210-211°C

Elemental analysis: C18H15Cl4N3O5S calculated: C, 41,01; H, 2,87; N, 7,97; S, between 6.08; found: C, 41,00; H, 2,77; N, 7,72; S 5,80

(R909923) Mononitratee salt of 2,2-dichloro-N-[2-[3-(2,6-dichlorophenyl)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide

MM=480

TPL=175-176°C

Elemental analysis: C16H10Cl4N4O5calculated: C 40,03; H, 2,10; N, 11,67; found: C, 40,33; H, 1,94; N, 11,25

The following is a more experimental methods of synthesis used to obtain some of the compounds of this invention.

Method F(See Fig)

Stage 1.Reaction cross-acetylene combination

Appropriately substituted o-pantropical or substituted o-initroot dissolved in a suitable solvent, such as p-dioxane or THF, and then treated at least five molar equivalents of a suitable amine base, which may be triethylamine, diethylamine or diisopropylethylamine. Alternatively, the amine base, in itself, can be used as solvent. Then through the solution for several minutes bubbled gas stream of argon, followed by addition of dichlorobis(triphenylphosphine)palladium (II) (3-4 mol%), CuI (6-8 mol%) and, finally, trimethylsilylacetamide (1.2 to 1.5 molar equivalents). Then the reaction mixture is heated at 50-80°C as long, until the end of the reaction, the speed of which is controlled TLC or LC-MS. In those cases, when using the more reactive substituted o-ignitability, the above reaction mix can be carried out at room temperature. If the reaction proceeds slowly, we use the t more trimethylsilylacetamide. This General method is known in the literature as linking by Sonogashira (K. Sonogashira et.al., Tetrahedron Lett., 1975, 4467). Then the reaction mixture was diluted with ethyl acetate and the resulting solution was washed several times with saturated salt solution. Alternatively, the crude reaction mixture was filtered through a layer of celite, then diluted with ethyl acetate and washed with a saturated solution of salt. Thus obtained organic layer is dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is purified column chromatography on silica gel, elwira mixtures of ethyl acetate and hexanol, to obtain the desired substituted o-(trimethylsilylethynyl)nitrobenzol.

Stage 2.Recovery of nitro group to amine.

Substituted o-(trimethylsilylethynyl)nitrobenzene obtained in stage 1, dissolved in a mixture of 10-15 volume percent of concentrated hydrochloric acid in methanol. Then add iron powder (Aldrich Chemical Co.) (5-10 molar equivalents) and the mixture is heated at 70-80°C for 3-4 hours This reaction can be highly exothermic when conducting it on a large scale. After cooling to room temperature the reaction mixture was filtered through celite and the filtrate concentrated under reduced pressure. The residue is dissolved in ethyl acetate and then gently washed Lieb is aqueous sodium hydroxide, or an aqueous solution of sodium bicarbonate. The aqueous layer was discarded and the organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. If necessary, the crude product can be purified column chromatography on silica gel, elwira mixtures of hexanol and ethyl acetate, to obtain the desired substituted o-(trimethylsilylethynyl)anilines.

Stage 3.Remove trimethylsilyloxy group of acetylenes

Substituted o-(trimethylsilylethynyl)aniline obtained in stage 2, is dissolved in methanol containing 2-5% water. If the solubility of aniline in methanol insufficient, use an appropriate amount of tetrahydrofuran (THF) as co-solvent. Then added anhydrous potassium carbonate (1 molar equivalent) and the mixture is stirred at room temperature for 1-24 h to complete the reaction according to TLC analysis. The reaction mixture was concentrated under reduced pressure, the residue is dissolved in ethyl acetate and washed with a saturated solution of salt. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Substituted o-aminophenylacetylene, if necessary, can be purified column chromatography on silica gel, elwira mixtures of hexanol and atilas the same.

Stage 4.Introduction halogenating or dehalogenating side chains

Substituted o-aminophenylacetylene, obtained in stage 3, is dissolved in dichloromethane. Add triethylamine (to 1.3 molar equivalents) and the solution is cooled in a bath with ice in a nitrogen atmosphere. Then added dropwise a solution of acid chloride halogenases acid or acid chloride dehalogenase acid (1.0 in molar equivalents) in dichloromethane. After complete addition, the reaction mixture is allowed the opportunity to mix 0.5-1 h at 0°C and then provide an opportunity to warm to room temperature. After 1-4 hours. the total time course of the reaction, the reaction mixture was diluted with water. The organic layer was separated and further washed with saturated aqueous sodium bicarbonate and saturated salt solution. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, obtaining the substituted 2-halogen - or 2,2-dihalogen-N-(2-ethynylphenyl)ndimethylacetamide. Alternatively, the original product, substituted o-aminophenylacetylene, dissolved in dichloromethane and successively treated with the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1 molar equivalent), halogen - or dehalogenases acid (1 molar equivalent) and finally triethylamine (1 molar equivalent is UNT). Then the reaction mixture was stirred at room temperature until until used the original product, substituted o-aminophenylacetylene as determined by TLC analysis. The mixture is washed with water and the organic layer is dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure, obtaining or substituted 2-halogen-, or 2,2-dihalogen-N-(2-ethynylphenyl)acetamide.

Method G(See Fig)

The original product, appropriately substituted o-iodoaniline or o-bromaniline, associated with trimethylsilylacetamide, as described in stage 1 of the Method of F. Then the resulting substituted o-(trimethylsilylethynyl)aniline remove protection using the procedure described in stage 3 of Method F, to obtain the substituted o-aminophenylacetylene, which is then converted into the desired 2-halogen - or 2,2-dihalogen-N-(2-ethynylphenyl)ndimethylacetamide, as described in stage 4 of Method F.

General method for obtaining 2-halogen - or 2,2-dihalogen-N-(4-ethynylphenyl)acetamide.

Method H(See Fig)

Introduction halogenating or dehalogenating side chains

p-Aminophenylacetylene purchased from Aldrich Chemical Co., dissolved in dichloromethane. Add triethylamine (to 1.3 molar equivalents) and the solution is cooled in a bath with ice in a nitrogen atmosphere. Then added dropwise a solution of acid chloride of g is loginaccount acid or acid chloride dehalogenase acid (1.0 in molar equivalents) in dichloromethane. After complete addition, the reaction mixture is allowed the opportunity to mix 0.5-1 hour at 0°C and then allow to warm to room temperature. After 1-4 hours total reaction time the reaction mixture is diluted with water. The organic layer was separated and further washed with saturated aqueous sodium bicarbonate and saturated salt solution. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, obtaining the substituted 2-halogen - or 2,2-dihalogen-N-(4-ethynylphenyl)ndimethylacetamide. Alternatively, the original substance, substituted p-aminophenylacetylene, dissolved in dichloromethane and successively treated with the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1 molar equivalent), halogen - or dehalogenases acid (1 molar equivalent) and finally triethylamine (1 molar equivalent). Then the reaction mixture was stirred at room temperature until until used starting material, substituted p-aminophenylacetylene as determined by TLC analysis. The mixture is washed with water and the organic layer is dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure, obtaining or substituted 2-halogen-, or 2,2-dihalogen-N-(4-ethynylphenyl)acetamide.

All cited publications, patents and atentie applications included in the present description by reference, as if meant that each individual publication, patent or patent application was specifically and individually incorporated into this description by reference.

Although the above invention is described in detail by means of illustration and example for purpose of clarity of understanding, to the average person skilled in the art it will be obvious from the disclosure of the present invention that may be subject to some changes and modifications, without departing from the substance or scope of the following claims.

1. The compound corresponding to the structural formula (I):

or its pharmaceutically acceptable salt or N-oxide,

where the cycle represents an aromatic or non-aromatic ring which includes two heteroatoms,

where X and Y each, independently of one another, selected from C, CH, N or O, provided that X and Y both are not On and that X and Y both are not N;

U and T are C;

Z represents a-CH-;

And represents N or CR2-;

Represents a-CR3-;

D represents N or CR4-;

E represents N or CR5-;

G represents N or CR6-;

J represents N or CR14 -;

It is a-CR8-;

L represents N or CR9-;

M represents N or CR10-;

R2and R6each, independently of one another selected from the group consisting of hydrogen, halogen, C1-C6of alkyl, substituted C1-C6of alkyl, C1-C6alkoxy, C1-C6substituted alkoxy, C1-C6alkoxycarbonyl, cyclogeranyl, substituted cyclogeranyl, -O-carbamoyl, substituted-O-carbamoyl, halogen, C1-C6of alkyl, dis1-C6alkylamino, substituted dis1-C6alkylamino and cyrilovich ethers, where cyclogeranyl represents a 3-7-membered ring comprising 1-2 of heteroatom selected from N and O, provided that one of R2and R6different from hydrogen;

R3and R5each, independently of one another selected from the group consisting of hydrogen, halogen;

R4represents hydrogen;

R7is-NR11C(O)R12;

R8, R9, R10and R14each, independently of one another, represents hydrogen;

R11represents hydrogen, C1-C6alkyl; and

R12selected from the group consisting of halogen With1-C6of alkyl;

where each sameena is a group substituted by one or more groups, selected from-Q-R40, -OR40, -C(O)R40, -C(O)OR40where each Q independently represents a halogen, R40and R41independently selected from the group consisting of hydrogen, C1-C6of alkyl, C1-C6alkoxy;

provided that:

(i) at least one of A, D, E, G, J, L or M represents N;

(ii) not more than one of a, D, E, or G represents N; and

(iii) not more than one of J, L and M represents N.

2. The connection of claim 1, wherein one of a, D, E, or G represents N, and one of J, L and M represents N.

3. The connection of claim 1, wherein one of a, D, E, or G represents N, and none of J, K, L or M is not n

4. The compound according to claim 1, in which none of a, b, D, E or G is not N, and one of J, L and M represents N.

5. The compound according to claim 1, in which the cycle is a isoxazol.

6. The compound according to any one of claims 1 to 5, in which R7is-NR11C(O)R12where R11represents hydrogen or methyl and R12represents-CHCl2.

7. The connection according to claim 6, in which X represents N, Y is O and Z represents-CH-.

8. The connection according to claim 6, in which a represents a-CR2-, G represents-CR6-, R7represents-NR11C(O)R12where R1 represents hydrogen or methyl and R12represents-CHCl2.

9. The connection of claim 8, in which a represents-CR3-, D is N, E is-CR5-, J is-CR14- ,- CR8-, L is-CR9-, M represents-CR10-, and R3, R5, R9, R10and R14each represents hydrogen.

10. The connection of claim 8, in which a represents-CR3-, D is-CR4-, E is-CR5-, J is-CR14- ,- CR8-, L is-CR9-, M is N, and R3, R4, R5, R8, R9and R14each represents hydrogen.

11. The connection of claim 8, in which a represents-CR3-, D is-CR4-, E is-CR5-, J is-CR14- ,- CR8-L is N, M is-CR10-, and R3, R4, R5, R8, R10and R14each represents hydrogen.

12. The connection of claim 8, in which R2and R6each, independently of one another selected from the group consisting of chlorine, fluorine, methyl, trifloromethyl, methoxy, isopropoxy, N-morpholino.

13. The connection of claim 8, in which R2and R6each, independently of one another selected from the group consisting of chlorine, fluorine, methyl, trifloromethyl, labels and or isopropoxy.

14. The connection of claim 8, in which R2and R6each is identical or different halogen.

15. The connection of claim 8, in which X is N, Y is O and Z is-CH-.

16. The compound according to claim 1, in which a represents-CR2- ,- CR3-, R7is-NR11C(O)R12where R11represents hydrogen or methyl and R12is-CHCl2.

17. The connection clause 16, in which D represents-CR4-, G represents-CR6-, E is-CR5-, J is-CR14- ,- CR8-, L is-CR9-, M is N, and R4, R5, R8, R9and R14each represents hydrogen.

18. The connection clause 16, in which D represents-CR4-, G represents-CR6-, E is-CR5-, J is-CR14- ,- CR8-L is N, M is-CR10-, and R4, R5, R8, R10and R14each represents hydrogen.

19. The compound according to any one of p-18, in which R2represents chlorine, fluorine, methyl, trifluoromethyl, methoxy, isopropoxy, N-morpholino and R3represents chlorine, fluorine, methyl, trifluoromethyl or methoxy.

20. The compound according to any one of p-18, in which R2represents chlorine, fluorine, methyl, trifluoromethyl and R3the stand is made by chlorine.

21. The compound according to any one of p-18, in which R2and R3each is identical or different halogen.

22. The compound according to any one of p-18, in which X is N, Y is O and Z is-CH-.

23. The compound according to claim 1, in which a represents-CR2-, G represents-CR6and R and R6are identical, provided that R2and R6are not hydrogen.

24. The compound according to claim 1, in which a represents-CR2- ,- CR3and R2and R3are identical, provided that R2and R3are not hydrogen.

25. The compound according to claim 1, in which a represents-CR3-, D is-CR4-, E is-CR5-, J is-CR14- ,- CR8-, and R3, R4, R5, R8and R14each represents hydrogen.

26. The compound according to claim 1, in which D represents-CR4-, E is-CR5-, G is CR6J represents-CR14- ,- CR8-, and R4, R5, R6, R8and R14each represents hydrogen.

27. The compound according to claim 1, which has the structural formula (Ia), (Ib), (Ic), (Id) or (1E):

or its pharmaceutically acceptable salts, where X, Y, R2, R6, R11and R12are as defined above for claim 1 and a-indicates a double bond.

28. The connection 34, in which R11is hydrogen, R12is dichloromethyl and R2and R6each, independently of one another selected from the group consisting of fluorine, chlorine, trifloromethyl and methoxy.

29. The compound according to claim 1, which has the structural formula (If):

or its pharmaceutically acceptable salts, where R2, R3, R4, R5, R6, R8, R9, R11, R12and R14such as defined for claim 1 and subordinate to the same conditions, and ---- means of the double bond.

30. Compound that inhibits the replication and/or proliferation of HCV, as measured in in vitro assays, selected from the following groups:

2,2-Dichloro-N-[2-[3-(2-chloro-6-forfinal)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide (Compound 1),

2,2-Dichloro-N-[2-[3-(2-fluoro-6-triptoreline)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide (Compound 3),

2,2-Dichloro-N-[2-[3-(2-fluoro-6-methoxyphenyl)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide (Compound 5),

2,2-Dichloro-N-[5-[3-(2,6-dichlorophenyl)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 7),

2,2-Dichloro-N-[2-[3-(26-dichlorophenyl)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide (Compound 9),

2,2-Dichloro-N-[3-[3-[(2,6-dichloro)-4-pyridyl]-5-isoxazolyl]phenyl]ndimethylacetamide (Compound 11),

2,2-Dichloro-N-[5-[3-(2-chloro-6-forfinal)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 13),

2,2-Dichloro-N-[5-[3-(2-fluoro-6-methoxyphenyl)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 17),

2,2-Dichloro-N-[2-[3-(2,6-dimetilfenil)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide (Compound 19),

2,2-Dichloro-N-[5-[3-(2,6-dimetilfenil)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 21),

2,2-Dichloro-N-[5-[3-(2,6-differenl)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 27),

2,2-Dichloro-N-[5-[3-(2,3-dichlorophenyl)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 29),

2,2-Dichloro-N-[2-[3-(2-morpholino-6-triptoreline])-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide (Compound 31),

2,2-Dichloro-N-[3-[3-(3-methyl-2-pyridyl)-5-isoxazolyl]phenyl]ndimethylacetamide (Compound 33),

2,2-Dichloro-N-[6-[3-(2,6-dichlorophenyl)-5-isoxazolyl]-(2-pyridyl)]ndimethylacetamide (Compound 35),

2,2-Dichloro-N-[5-[3-(2-fluoro-6-triptoreline)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 37),

2,2-Dichloro-N-[2-[3-(2-methoxy-6-forfinal)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide (Compound 39),

2,2-Dichloro-N-[2-[3-(2,6-dichlorophenyl)-5-isoxazolyl]-[4-(1-oxypyridine)]ndimethylacetamide (Compound 43),

2,2-Dichloro-N-[3-[3-[(3-etoxycarbonyl)-2-pyridyl]-5-isoxazolyl]phenyl]ndimethylacetamide (Compound 45),

2,2-Dichloro-N-[2-[3-(2-what Thor-6-morpholinosydnonimine)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide (Compound 47),

2,2-Dichloro-N-[2-[3-(2-methoxy-6-triptoreline)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide (Compound 49),

2,2-Dichloro-N-[2-[3-(2,6-dichlorophenyl)-5-isoxazolyl]-(4-pyridyl)]-N-methylacetamide (Compound 51),

2,2-Dichloro-N-[2-[3-[2-chloro-6-[4-(N-2-pyridyl)piperazine derivatives]phenyl])-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide (Compound 53),

2,2-Dichloro-N-[5-[3-(2-methoxy-6-triptoreline)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 57),

2,2-Dichloro-N-[5-[3-(2-chloro-6-[4-(N-2-pyridyl)piperazine derivatives]phenyl])-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 59),

2,2-Dichloro-N-[5-[3-[2-chloro-6-[4-(N-acetyl)piperazine derivatives]phenyl])-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 61),

2,2-Dichloro-N-[5-[3-[2-chloro-6-[4-(N-ethyl)piperazine derivatives]phenyl])-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 63),

2,2-Dichloro-N-[5-[3-(2,6-dichlorophenyl)-5-isoxazolyl]-(2-pyridyl)]ndimethylacetamide (Compound 65),

2,2-Dichloro-N-[5-[3-(2-triptoreline)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 67),

2,2-Dichloro-N-[5-[3-[2-chloro-6-[4-(N-2-pyridyl)piperazine derivatives]phenyl])-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 69),

2,2-Dichloro-N-[5-[3-[2-chloro-6-[4-(N-tert-butoxycarbonyl)piperazine derivatives]phenyl])-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 71),

2,2-Dichloro-N-[5-[3-(2-chloro-6-piperidinophenyl)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 73),

2,2-Dichloro-N-[5-[3-(2-chloro-6-tert-butyldimethylsilyloxy the l)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 75),

2,2-Dichloro-N-[5-[3-(2-chloro-6-hydroxyphenyl)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 77),

2,2-Dichloro-N-[5-[3-(2-chloro-6-N-ethylcarbamate)-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 79),

2,2-Dichloro-N-[5-[3-[2-chloro-6-[4-(N-ethylcarbodiimide)piperazine derivatives]phenyl])-5-isoxazolyl]-(3-pyridyl)]ndimethylacetamide (Compound 81),

2,2-Dichloro-N-[2-[3-(2-chloro-6-tert-butyldimethylsilyloxy)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide (Compound 83),

2,2-Dichloro-N-[2-[3-(2-chloro-6-N-profilerviewer)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide (Compound 85),

2,2-Dichloro-N-[2-[3-(2-chloro-6-methoxyethoxymethyl)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide (Compound 87),

2,2-Dichloro-N-[2-[3-(2-chloro-6-hydroxyphenyl)-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide (Compound 89),

2,2-Dichloro-N-[3-[3-[(4-chloro-2-dimethylamino)-3-pyridyl]-5-isoxazolyl]phenyl]ndimethylacetamide (Compound 91),

2,2-Dichloro-N-[3-[3-[(2,4-dichloro)-3-pyridyl]-5-isoxazolyl]phenyl]ndimethylacetamide (Compound 93),

2,2-Dichloro-N-[3-[3-[(2-chloro-4-morpholino)-3-pyridyl]-5-isoxazolyl]phenyl]ndimethylacetamide (Compound 95),

2,2-Dichloro-N-[3-[3-[(6-bromo)-2-pyridyl]-5-isoxazolyl]-(4-pyridyl)]ndimethylacetamide (Compound 97), ...

and their pharmaceutically acceptable salts.

31. Method of inhibiting replication or proliferation of hepatitis C virion ("NA"), including the state of contact of the virion NS connection with any of the at one of claims 1 to 4 in number, effective for inhibiting replication of the virion to the national Assembly.

32. The method according to p, which is carried out in practice in vitro.

33. Pharmaceutical composition having the property of inhibiting the replication and/or proliferation of HCV-containing compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

Priority signs and items:

23.08.2002 and 11.10.2002 apply equally to claims 1 to 29, 31-33, except for compounds of formula (I), which is a non-aromatic ring, a U and T are CH;

15.05.2003 and 22.08.2003 apply equally to claims 1 to 29, 31-33 for compounds of formula (I), which is a non-aromatic ring, and U and T are CH.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to the bonds of the formula (I) and their pharmaceutically acceptable salts in the capacity of modulators of receptors CB1 and to the pharmacological composition on their basis. Bonds can be used for treatment and prophylaxis of diseases, which are associated with the modulation of receptor CB1, for example, obesity and diabetes of type II. In the general formula (I) R1 means hydrogen or the lowest alkyl; R2 means hydrogen, the lowest alkyl, the lowest alkenyl, the lowest alkoxy-lowest alkyl, the lowest alkoxycarbonilamino-group or - (CH2)m-R2a; or R1 and R2 form together with atom of nitrogen to which they are attached, a 5-or 6-member saturated heterocyclic ring; R2a means cycloalkyl, which is not necessarily mono- or tetra-substituted independently by hydroxy-group, the lowest alkyl; C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen; 5- or 6-member monovalent heteroaromatic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heteroaromatic ring is not necessarily mono-substituted independently with the lowest alkyl; or phenyl which is not necessarily mono- or di-substituted independently with the lowest of the alkoxy group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy group or nitro-group; R3 means the lowest alkyl, the lowest alkoxy-lowest alkyl, diphenyl-lowest alkyl or - (CH2)n-R3a; R3a means C3-6cycloalkyl which can be not necessarily condensed with the phenol ring; or C3-6cycloalkyl, which can be not necessarily mono-, di- or trisubstituted independently hydroxy-group, the lowest alkyl, C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heterocyclic rings are not necessarily mono-substituted independently by the lowest alkyl, 5- or 6-member monovalent heteroaromatic ring containing one heteroatom, independently selected from oxygen and sulfur, the aforesaid heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, or the phenyl, which can be not necessarily mono-, di- or trisubstituted independently by the hydroxy-group, lowest alkyl, lowest alkoxy-group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; R4 means the lowest alkyl the lowest alkoxycarbonyl; C3-6 cycloalkyl, 5- or 6-member monovalent heteroaromatic ring, which contains one or two heteroatoms, independently selected from nitrogen, the said heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, lowest alkoxy-group; phenoxy-lowest alkyl, in which the phenyl part is not necessarily mono-, di- or trisubstituted independently by the lowest alkoxy-group; or the phenyl, which not necessarily can be mono-, di- or trisubstituted independently, by the lowest alkyl, by the lowest alkoxy-group, by halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; or two adjusted substitutes of the said phenyl remainder indicate together -O-(CH2)p-O- or -(CH2)2-O-; R5 and R6 each indicates a substitute independently selected from hydrogen of lowest alkyl; R7 indicates hydrogen; m indicates 0,1 or 2; n indicates 1.

EFFECT: new bonds possess useful biological properties.

28 cl, 4 dwg, 380 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new bonds in the formula (I-0): or its pharmaceutically acceptable salts, where X represents a carbon atom or nitrogen atom; X1, X2, X3 and X4, each independently, represents a carbon atom or a nitrogen atom; ring A of the formula (II): represents tiazolil, imidazolil, izotiazolil, tiadiazolil, triazolil, oxazolil, oxadiazolil, izoxazolil, pirazinil, piridil, piridazinil, pirazolil or pirimidinil; R¹ represents aryl or represents a 4-10- membered monocyclic or bicyclic heteroring, which has in the ring from 1 to 4 heteroatoms, selected from the group, consisting of a nitrogen atom, sulphur atom and an oxygen atom, and R¹ can be independently substituted with 1-3 R4, and, when the specified heteroring is an aliphatic heteroring, then it can have 1 or 2 double bonds; R² independently represents hydroxy, formyl, -CH3-aFa, -OCH3-aFa, amino, CN, halogen, C1-6 alkyl or -(CH2)1-4OH; R3 represents -C1-6 alkyl, -(CH2)1-6-OH, -C(O)-OC1-6 alkyl, -C(O)-OC1-6 alkyl, -(CH2)1-6-NH2, cyano, -C(O)-C1-6 alkyl, halogen, -C2-6 alkenyl, -OC1-6 alkyl, -COOH, -OH or oxo; R4 independently represents -C1-6 alkyl, and the alkyl can be substituted with identical or different 1-3 hydroxyls, halogens, -OC(O)-C1-6 alkyls, and the alkyl can be substituted with 1-3 halogens or -OC1-6 alkyls, -C3-7 cycloalkyl, -C2-6 alkenyl, -C(O)-N(R51)R52, -S(O)2-N(R51)R52,-O-C1-6 alkyl, and C1-6 alkylcan be substituted with a halogen or N(R51)R52, -S(O)0-2-C1-6 alkyl, -C(O)-C1-6 alkyl, and C1-6 alkyl can be substituted with a halogen, amino, CN, hydroxy, -O-C1-6 alkyl, -CH3-aFa, -OC(O)-C1-6 alkyl, -N(C1-6 alkyl)C(O)O-C1-6 alkyl, -NH-C(O)O-C1-6 alkyl, phenyl, -N(R51)R52, -NH-C(O)-C1-6 alkyl, -N(C1-6 alkyl)-C(O)-C1-6 alkyl or -NH-S(O)0-2-C1-6 alkyl, -C(S)-C3-7 cycloalkyl, -C(S)- C1-6 alkyl, -C(O)-O- C1-6 alkyl, -(CH2)0-4-N(R53)-C(O)-R54, -N(R53)-C(O)-O-R54,-C(O)-aryl, it is optional to substitute the halogen, -C(O)-aromatic heteroring, -C(O)-aliphatic heteroring, heteroring, and the heteroring can be substituted with C1-6 alkyl, optionally substituting the halogen or -O-C1-6 alkyl, phenyl, optionally substituting the halogen, -C1-6 alkyl, -O-C1-6 alkyl, halogen, CN, formyl, COOH, amino, oxo, hydroxy, hydroxyamidine or nitro; R51 and R52, each independently, represents a hydrogen atom, C1-6 alkyl or a nitrogen atom, R51 and R52 together form 4-7-member heteroring; R53 represents a hydrogen atom or C1-6 alkyl, R54 represents -C1-6 alkyl or alkyls for R53 and R54 and -N-C(O)- together form 4-7-member hydrogen containing heteroring, or alkyls for R53 and R54 and -N-C(O)-O- together form 4-7-member hydrogen containing aliphatic heteroring and an aliphatic heteroring can be substituted with oxo, or an aliphatic heteroring can have 1 or 2 double bonds in the ring; X5 represents -O-, -S-, -S(O)-, -S(O)2-, a single bond or -O-C1-6 alkyl; a independently denotes a whole number 1, 2 or 3; q denotes a whole number from 0 till 2; m denotes a whole number from 0 till 2, except in the case when one of the X5 represents -O-, -S-, -S(O)- or -S(O)2-, and the other from X5 represents a single bond, and R1 represents aryl, optionally substituted with 1-3 R4, or a hydrogen containing aromatic heteroring, consisting of from 1 to 4 heteroatoms, selected from the group, comprising of a hydrogen atom, sulphur atom and an oxygen atom, in the case, when X5, both represent single bonds or in cases, when R1, both represent aliphatic heteroring. The invention also relates to the bonding in the formula (I-12), and also to the bonding in the formula (I-0), to the pharmaceutical composition, to the glucokinase activator and to the medication.

EFFECT: getting new bioactive compounds which can be used for treatment and/or prophylaxis of diabetes or obesity.

23 cl, 603 ex

FIELD: chemistry; obtaining of medicinal preparations.

SUBSTANCE: description is given of a compound with general formula where R1 represents a halogen, C1-C6alkyl, CF3, CF2H or cyano, R2 represents C1-C6alkyl, R3 represents 5- or 6 - member hetero-aryl, optionally substituted with one, two or three substitutes, chosen from a group, consisting of a halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylhalogen, C1-C6alkoxy, NR'R", or substituted with a 1-morpholinyl group or substituted with thiomorpholinyl groups, 1-oxothiomorpholinyl or 1,1-dioxothiomorpholinyl; R', R" independently represent hydrogen, C1-C6alkyl, (CH2)0,1-(C3-C6)cycloalkyl, R represents hydrogen as well as its pharmaceutical salts and the method of obtaining them. The invention also relates to use of the given amidazole derivatives for obtaining medicinal preparations and to medicinal preparations containing them, meant for prevention or treatment of damages, through the mGluR5 receptor, such as acute and/or chronic neurologic damages, primarily shock pain, or for treatment of chronic and sharp pain.

EFFECT: obtaining of new compounds, with useful biological properties.

40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzimidazol of the general formula I R1 designates phenyl group which unessentially contains up to three substitutors independently chosen of the group including F, Cl, Br, J, R4; R2 designates monocyclic or bicyclic 5-10-terms heteroaryl group which contains 1-2 heteroatoms, chosen of N, S and O; R3 designates H; R4 designatesC1-6alkyl; A designates C2-6 alkylene group; B designates group COOH, CONH2, CONHR5 or CONR5R5, in each case attached to atom of carbon of group A; R5 and R5 ' independently designate the residue chosen from group includingC1-6 alkyl where one C-atom can be replaced by O, and(C0-3 alkandiil-C3-7 cycloalkyl); and to their pharmaceutically acceptable salts, except for following compounds: 6 [[1-phenyl-2 (pyridine-4-il)-1H-benzimidazol-6-il] oxi] hexanic acid and 6 [[1-phenyl-2 (benzothien-2-il)-1H-benzimidazol-6-il] oxi] hexanic acid. The invention relates also to pharmaceuticals and to application of compounds of general formula I.

EFFECT: new biologically active compounds possess inhibiting effect on activation of microglia.

10 cl, 34 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts and esters wherein R1 means phenyl, naphthyl, 5-6-membered heterocyclyl comprising oxygen (O), nitrogen (N) or sulfur atom (S) as heteroatoms and wherein phenyl, naphthyl and heterocyclyl are optionally substituted with 1-3 substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy, nitro; di-(C1-C6)-alkylamino or (C1-C6)-alkoxy groups; R2 means hydrogen atom; R3 means (C1-C6)-alkyl or trifluoromethyl; A1 means C-R3 or nitrogen atom; A2 means piperidine or pyrrolidine wherein nitrogen atom in piperidine or pyrrolidine ring is added to A3 wherein A3 means -S(O)2- or -C(O)-; n = 0, 1 or 2. Also, invention relates to a pharmaceutical composition based on compounds proposed by the invention. Proposed compounds possess properties of NPY receptors antagonists and can be used in treatment arthritis, diabetes mellitus, nutrition disorders, obesity and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 1 tbl, 1 dwg, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I) possessing inhibitory effect on production of interleukin-12 (IL-12) wherein R1 represents group of the formula , aryl or heteroaryl; each among R2 and R4 represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy group; R3 represents Rc, alkenyl, -ORc, -OC(O)Rc, -SRc, -NRcCORd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcSO2Rd, -CORc, -C(O)ORc or -C(O)NRcRd; R5 represents hydrogen atom (H); n = 0, 1, 2, 3, 4, 5 or 6; X represents oxygen atom (O) or -NRc; Y represents a covalent bond. -CH2, O or -NRc; Z represents nitrogen atom (N); one of values U and V represents N and another represents -CRc; W represents O, sulfur atom (S) or -S(O)2 wherein each radical among Ra and Rb represents independently H, (C1-C6)-alkyl, aryl or heteroaryl; each radical among Rc and Rd represents independently H, (C1-C6)-alkyl, phenyl, heteroaryl, cyclyl, heterocyclyl or (C1-C6)-alkylcarbonyl wherein term "aryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring; term "heteroaryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring that comprises at least one heteroatom, such as O, N or S as a part of cyclic system and wherein other atoms mean carbon; term "cyclyl" and "heterocyclyl" relate to partially or completely saturated monocyclic or bicyclic system comprising from 4 to 14 carbons in rings wherein heterocyclic ring comprises one or some heteroatoms (for example, O, N or S) as part of cyclic system and wherein other atoms mean carbon, and under condition that when X represents -NH, Y represents a covalent bond, n = 0, and R3 represents H or CH3 then R1 doesn't mean thiazolyl or pyrimidinyl. Also, invention relates to a pharmaceutical composition and a method for treatment of disorder associated with hyperproduction of interleukin-12.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

49 cl, 43 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrrolidinium of the general formula (I): possessing antagonistic effect with respect to muscarinic receptors M3 wherein B means phenyl or thienyl group; each radical among R1, R2 and R means independently hydrogen, fluorine, chlorine atom or hydroxyl; n means a whole number from 0 to 1; A means group chosen from groups -CH2 and -O-; m means a whole number from 0 to 6; R means (C1-C8)-alkyl; X- represents a pharmaceutically acceptable anion of mono- or multibasic acid, and involving all separate stereoisomers and their mixtures. Also, invention relates to methods for synthesis of such compounds, pharmaceutical compositions containing such compounds and to their using in therapy as antagonists of muscarinic receptors M3.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

17 cl, 51 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I) or their pharmaceutically acceptable salts wherein R1 and R2 are similar or different and chosen independently from group comprising aryl and heteroaryl. Each of them as a substitute comprises optionally from one to sic groups chosen from group comprising the following groups: (a) halogen atom; (b) -OCF3 or -OCHF2; (c) -CF3; (d) -CN; (e) alkyl; (f) R18-heteroaljyl; (k) hydroxyl; (l) alkoxyl comprising cyclopropylmethoxyl, and (s) trifluoroalkoxyl; R3 means hydrogen atom (H); R4, R5, R7 and R8 are similar or different and chosen independently from group comprising H, -OH, alkyl, heteroalkyl and

under condition that if Z and/or X means nitrogen atom (N) then all radicals R4, R5, R7 and R8 don't mean -OH; R6 means -C(O)R15; R9 and R10 mean H; R11 is chosen from group comprising H and alkyl; R12 is chosen from group comprising H and alkyl; R13 is chosen from group comprising alkyl and alkoxyl; R14 means H; R15 is chosen from group comprising -NR16R17, -OR16 and alkyl wherein R16 and R17 are similar or different and chosen independently from group comprising H and alkyl; R18 means a substitute chosen from group comprising lower alkyl, halogen alkyl, halogenalkyl, alkoxycarbonyl, dialkylamino-group and piperidinyl; X and Z are similar or different and chosen independently from carbon atom (C) and N. Proposed compounds possess properties of inhibitor of 17β-hydroxysteroid dehydrogenase of type 3. Also, invention describes a pharmaceutical composition based on compound of the formula (I).

EFFECT: valuable medicinal and biochemical properties of compound and pharmaceutical composition.

16 cl, 23 tbl, 651 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines represented by the formula (I): wherein n means 2, 3 or 4; R1 means hydrogen atom or alkyl with 1-4 carbon atoms; R2 means pyridyl or thiazolyl that can be substituted with alkyl with 1-4 carbon atoms, halogen atom, amino-, dimethylamino-, acetylamino-, guanidino-, pyridylamino-group, thienyl, pyridyl, morpholinyl and thiazolyl substituted if necessary with alkyl with 1-4 carbon atoms or phenyl comprising if necessary up to three substitutes as halogen atom, alkyl with 1-4 carbon atoms or alkoxy-group with 1-4 carbon atoms, and to their salts, hydrates, salt hydrates and solvates, and also to substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridine of the formula (I) possessing properties of agonist of A1-adenosine receptors. Also, invention describes a medicinal agent possessing properties of agonist of A1-adenosine receptors. Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal and pharmacological properties of compounds and drug.

7 cl, 3 tbl, 27 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel nitrogen-containing aromatic derivatives of the general formula (I): wherein X1 means nitrogen atom (N) or group -CR10= wherein R10 means hydrogen atom (H), halogen atom or -CN; X2 means N or group -CR11= but X1 and X2 can't mean N simultaneously; Y means oxygen atom (O) or group -NRY- wherein RY means hydrogen atom or (C1-C6)-alkyl group; R1 means phenoxy-group, group -NR12aR12b, group , group and other values; each radical among R3, R4, R5, R6 and R11 means hydrogen atom; R7 means hydrogen atom or (C1-C6)-alkyl group; R8 means hydrogen atom or (C1-C6)-alkyl group; R10 means hydrogen atom, halogen atom or cyano-group; R9 means group -NR16aR16b or group of the formula: wherein T2 means pyrrolidine, piperazine ring possibly substituted with (C1-C6)-alkyl group, or morpholine ring; R12a and R12b mean independently hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; R2 means hydrogen atom or (C1-C6)-alkyl; R16a means hydrogen atom or (C1-C6)-alkyl, and R16b means (C1-C6)-alkyl possibly substituted with phenyl, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or di-(C1-C6)-alkylamino-group, (C3-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl possibly substituted with halogen atom, thiazolyl or piperidinyl possibly substituted with (C1-C6)-alkyl, and their salts or hydrates. Also, invention describes a pharmaceutical composition, method for treatment or prophylaxis of tumor diseases and using the novel compounds for preparing an agent useful in treatment abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method for treatment.

26 cl, 17 tbl, 221 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the bonds of the formula (I) and their pharmaceutically acceptable salts in the capacity of modulators of receptors CB1 and to the pharmacological composition on their basis. Bonds can be used for treatment and prophylaxis of diseases, which are associated with the modulation of receptor CB1, for example, obesity and diabetes of type II. In the general formula (I) R1 means hydrogen or the lowest alkyl; R2 means hydrogen, the lowest alkyl, the lowest alkenyl, the lowest alkoxy-lowest alkyl, the lowest alkoxycarbonilamino-group or - (CH2)m-R2a; or R1 and R2 form together with atom of nitrogen to which they are attached, a 5-or 6-member saturated heterocyclic ring; R2a means cycloalkyl, which is not necessarily mono- or tetra-substituted independently by hydroxy-group, the lowest alkyl; C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen; 5- or 6-member monovalent heteroaromatic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heteroaromatic ring is not necessarily mono-substituted independently with the lowest alkyl; or phenyl which is not necessarily mono- or di-substituted independently with the lowest of the alkoxy group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy group or nitro-group; R3 means the lowest alkyl, the lowest alkoxy-lowest alkyl, diphenyl-lowest alkyl or - (CH2)n-R3a; R3a means C3-6cycloalkyl which can be not necessarily condensed with the phenol ring; or C3-6cycloalkyl, which can be not necessarily mono-, di- or trisubstituted independently hydroxy-group, the lowest alkyl, C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heterocyclic rings are not necessarily mono-substituted independently by the lowest alkyl, 5- or 6-member monovalent heteroaromatic ring containing one heteroatom, independently selected from oxygen and sulfur, the aforesaid heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, or the phenyl, which can be not necessarily mono-, di- or trisubstituted independently by the hydroxy-group, lowest alkyl, lowest alkoxy-group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; R4 means the lowest alkyl the lowest alkoxycarbonyl; C3-6 cycloalkyl, 5- or 6-member monovalent heteroaromatic ring, which contains one or two heteroatoms, independently selected from nitrogen, the said heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, lowest alkoxy-group; phenoxy-lowest alkyl, in which the phenyl part is not necessarily mono-, di- or trisubstituted independently by the lowest alkoxy-group; or the phenyl, which not necessarily can be mono-, di- or trisubstituted independently, by the lowest alkyl, by the lowest alkoxy-group, by halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; or two adjusted substitutes of the said phenyl remainder indicate together -O-(CH2)p-O- or -(CH2)2-O-; R5 and R6 each indicates a substitute independently selected from hydrogen of lowest alkyl; R7 indicates hydrogen; m indicates 0,1 or 2; n indicates 1.

EFFECT: new bonds possess useful biological properties.

28 cl, 4 dwg, 380 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new bonds in the formula (I-0): or its pharmaceutically acceptable salts, where X represents a carbon atom or nitrogen atom; X1, X2, X3 and X4, each independently, represents a carbon atom or a nitrogen atom; ring A of the formula (II): represents tiazolil, imidazolil, izotiazolil, tiadiazolil, triazolil, oxazolil, oxadiazolil, izoxazolil, pirazinil, piridil, piridazinil, pirazolil or pirimidinil; R¹ represents aryl or represents a 4-10- membered monocyclic or bicyclic heteroring, which has in the ring from 1 to 4 heteroatoms, selected from the group, consisting of a nitrogen atom, sulphur atom and an oxygen atom, and R¹ can be independently substituted with 1-3 R4, and, when the specified heteroring is an aliphatic heteroring, then it can have 1 or 2 double bonds; R² independently represents hydroxy, formyl, -CH3-aFa, -OCH3-aFa, amino, CN, halogen, C1-6 alkyl or -(CH2)1-4OH; R3 represents -C1-6 alkyl, -(CH2)1-6-OH, -C(O)-OC1-6 alkyl, -C(O)-OC1-6 alkyl, -(CH2)1-6-NH2, cyano, -C(O)-C1-6 alkyl, halogen, -C2-6 alkenyl, -OC1-6 alkyl, -COOH, -OH or oxo; R4 independently represents -C1-6 alkyl, and the alkyl can be substituted with identical or different 1-3 hydroxyls, halogens, -OC(O)-C1-6 alkyls, and the alkyl can be substituted with 1-3 halogens or -OC1-6 alkyls, -C3-7 cycloalkyl, -C2-6 alkenyl, -C(O)-N(R51)R52, -S(O)2-N(R51)R52,-O-C1-6 alkyl, and C1-6 alkylcan be substituted with a halogen or N(R51)R52, -S(O)0-2-C1-6 alkyl, -C(O)-C1-6 alkyl, and C1-6 alkyl can be substituted with a halogen, amino, CN, hydroxy, -O-C1-6 alkyl, -CH3-aFa, -OC(O)-C1-6 alkyl, -N(C1-6 alkyl)C(O)O-C1-6 alkyl, -NH-C(O)O-C1-6 alkyl, phenyl, -N(R51)R52, -NH-C(O)-C1-6 alkyl, -N(C1-6 alkyl)-C(O)-C1-6 alkyl or -NH-S(O)0-2-C1-6 alkyl, -C(S)-C3-7 cycloalkyl, -C(S)- C1-6 alkyl, -C(O)-O- C1-6 alkyl, -(CH2)0-4-N(R53)-C(O)-R54, -N(R53)-C(O)-O-R54,-C(O)-aryl, it is optional to substitute the halogen, -C(O)-aromatic heteroring, -C(O)-aliphatic heteroring, heteroring, and the heteroring can be substituted with C1-6 alkyl, optionally substituting the halogen or -O-C1-6 alkyl, phenyl, optionally substituting the halogen, -C1-6 alkyl, -O-C1-6 alkyl, halogen, CN, formyl, COOH, amino, oxo, hydroxy, hydroxyamidine or nitro; R51 and R52, each independently, represents a hydrogen atom, C1-6 alkyl or a nitrogen atom, R51 and R52 together form 4-7-member heteroring; R53 represents a hydrogen atom or C1-6 alkyl, R54 represents -C1-6 alkyl or alkyls for R53 and R54 and -N-C(O)- together form 4-7-member hydrogen containing heteroring, or alkyls for R53 and R54 and -N-C(O)-O- together form 4-7-member hydrogen containing aliphatic heteroring and an aliphatic heteroring can be substituted with oxo, or an aliphatic heteroring can have 1 or 2 double bonds in the ring; X5 represents -O-, -S-, -S(O)-, -S(O)2-, a single bond or -O-C1-6 alkyl; a independently denotes a whole number 1, 2 or 3; q denotes a whole number from 0 till 2; m denotes a whole number from 0 till 2, except in the case when one of the X5 represents -O-, -S-, -S(O)- or -S(O)2-, and the other from X5 represents a single bond, and R1 represents aryl, optionally substituted with 1-3 R4, or a hydrogen containing aromatic heteroring, consisting of from 1 to 4 heteroatoms, selected from the group, comprising of a hydrogen atom, sulphur atom and an oxygen atom, in the case, when X5, both represent single bonds or in cases, when R1, both represent aliphatic heteroring. The invention also relates to the bonding in the formula (I-12), and also to the bonding in the formula (I-0), to the pharmaceutical composition, to the glucokinase activator and to the medication.

EFFECT: getting new bioactive compounds which can be used for treatment and/or prophylaxis of diabetes or obesity.

23 cl, 603 ex

FIELD: chemistry; oxa-and thiazole derivatives.

SUBSTANCE: oxa- and thiazole derivatives have general formula . Their stereoisomers and pharmaceutical salts have PPARα and PPARγ activity. The compounds can be used for treating diseases, eg. diabetes and anomaly of lipoproteins through PPARα and PPARγ activity. In the general formula, x has value of 1, 2, 3 or 4; m has value of 1 or 2; n has value of 1 or 2; Q represents C or N; A represents O or S; Z represents O or a bond; R1 represents H or C1-8alkyl; X represents CH; R2 represents H; R2a, R2b and R2c can be the same or different and they are chosen from H, alkoxy, halogen; R3 represents aryloxycarbonyl, alkyloxycarbonyl, alkyl(halogen)aryloxycarbonyl, cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, arylcarbonylamino, alkylsulphonyl, cycloheteroalkyloxycarbonyl, heteroarylalkenyl, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, halogenalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenylsulphonyl, heteroarylsulphonyl, arylsulphonyl, arylalkenylarylalkyl, arylalkoxycarbonyl-heteroarylalkyl, heteroaryloxyarylalkyl, where alkyl is in form of C1-8alkyl; Y represents CO2R4, where R4 represents H or C1-8alkyl; including all their stereoisomers and pharmaceutical salts, under the condition that, if A is O, then R3 is not aryloxycarbonyl or alkoxyaryloxycarbonyl.

EFFECT: the compounds can be used in curing such diseases as diabetes and lipoprotein anomalies.

10 cl, 30 dwg, 12 tbl, 584 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel derivatives of 1,2,4-triazole of the general formula (I): wherein A and b can be taken separately or in common being when they are taken separately then A means (C1-C6)-alkyl or phenyl, and B means (C1-C6)-alkyl; A and B taken in common mean (C2-C5)-alkanediyl, and they form with C-atoms 3-6-membered cycle optionally substituted with (C1-C4)-alkylene, oxo, ethylenedioxy group, (C1-C4)-alkyl, 1-2 halogen atoms, (C1-C3)-alkoxy-(C1-C3)-alkoxy or hydroxy group; each R1 means independently hydrogen atom, -OH, halogen atom, (C3-C6)-cycloalkyl, (C1-C6)-alkyl optionally substituted with 1-3 halogen atoms; or two R1 groups near adjacent carbon atoms form 6-membered aryl cycle; R2 and R3 can be taken in common or separately, and when they are taken in common then they represent (C3-C8)-alkanediyl that forms condensed 5-10-membered nonaromatic cycle; when R2 and R3 are taken separately then R2 means (C1-C6)-alkyl possibly substituted with 1-3 halogen atoms or cyclopropyl, and R3 means cyclopropyl possibly substituted with (C1-C4)-alkyl, naphthyl, phenyl possibly substituted with halogen atom, -OH, (C1-C6)-alkyl wherein indicated (C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, -O-(C1-C6)-alkyl wherein indicated -O-(C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, phenyl or benzyloxy group, dihydrobenzofuranyl, benzothiadiazolyl or benzoimidazolyl possibly substituted with (C1-C6)-alkyl, their pharmaceutically acceptable salts or solvates, and pharmaceutical composition based on thereof. Proposed compounds are inhibitor of 11β-hydroxysteroid dehydrogenase I, and can be used in medicine in treatment of diabetes mellitus, obesity and dyslipidemia.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

19 cl, 17 tbl, 4 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and/or stereomer form of compound of the formula (I), and/or physiologically compatible salt of compound of the formula (I) wherein X and M are similar or different and mean independently of one another nitrogen atom (N) or -CH; R1 and R11 are similar or different and mean independently of one another: (1.) hydrogen atom; (2.) fluorine (F), chlorine (Cl), iodine (J) or bromine (Br) atom; R2 means: (1.) heteroaryl residue of group comprising 1,3,4-oxadiazole, oxadiazolylidinedione, oxadiazolone, thiazole, and heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another: (1.1.) keto-group; (2) -C(O)-R5 wherein R5 means hydrogen atom or -(C1-C4)-alkyl, or (3.) -C(O)-N(R7)-R8 wherein R7 and R8 mean independently of one another hydrogen atom, -(C1-C4)-alkyl-OH, -O-(C1-C4)-alkyl or -(C1-C4)-alkyl; R3 means hydrogen atom or -(C1-C4)-alkyl; R4 means: (1.) heteroaryl residue of group comprising thiazole, isothiazole, pyridine, pyrazine, pyrimidine wherein heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another with -(C1-C5)-alkyl, halogen atom, trifluoromethyl, or (2.) aryl residue of group comprising phenyl. Also, invention relates to a method for preparing a medicinal agent and to using compounds based on the formula (I) possessing activity with respect to IkB kinase. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical agent.

6 cl, 67 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of carboxylic acid represented by the general formula (I): , their pharmaceutically acceptable salts or esters wherein values Y, L, X, T, Z, M, R1, W and are given in the invention claim. Proposed compounds possess insulin-sensitizing effect and they are double agonists with respect to PPARα and γ, and triple agonists with respect to PPARα, β(δ) and γ. Except for, the invention relates to a medicinal agent and pharmaceutical compositions based on the claimed derivatives of carboxylic acid, to methods for prophylaxis or treatment of diseases, and to using derivatives carboxylic acid for preparing a medicinal agent.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

56 cl, 2 tbl, 609 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to using compounds of the general formula (I): and their pharmaceutically acceptable acid-additive salts. Compounds are used for preparing medicinal agents used in treatment diseases and state associated with system of adenosine receptors A2A, such as Alzheimer's disease, Parkinson's diseases, Huntington's syndrome, schizophrenia, anxiety state, pain, depression, narcomania to such substances as amphetamine, cocaine, opioides, ethyl alcohol, nicotine, cannabinoids, or in treatment of hypoxia, ischemia, epileptic attack. Also, proposed compounds exert neuroprotective effect and can be used as sedative, antipsychotic or anti-epileptic agents.

EFFECT: valuable medicinal properties of compounds.

18 cl, 1 tbl, 49 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new compounds of general formula I , wherein one from V or X is N and another is CRa or both V and X are CRa (each CRa is independently hydrogen atom); Y is O, S; Z is N(R2)(R3); R1 is hydrogen, C1-C10-alkyl, C3-C7-cycloalkyl, etc.; R4 is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl, etc.; A is hydrogen, C1-C10-alkyl, halo-C1-C6-alkyl, etc.; B is optionally substituted 5-membered aromatic ring containing at least one nitrogen atom and 0-3 additional heteroatoms; U is -NR5; meanings of the rest substituents are as defined in specification, and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical composition and intermediates of formula I.

EFFECT: new biologically active compounds and pharmaceutical compositions based on the same having inhibition activity in relates to IKK-β enzyme.

26 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the general formula: , where R1 is an inferior alkyl, -(CH2)n-aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluormethyl, or pyridine; R2 is an inferior alkyl, -(CH2)n- aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluoromethyl, nitro-, cyano-, -NR'R", hydroxy-, or heteroaryl group that is a monovalent heterocyclic 5- or 6-membered aromatic radical with N atoms, either R2 is a heteroaryl that is monovalent heterocyclic 5- or 6-membered aromatic radical where heteroatoms are chosen from N, O or S group, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl or halogen; R3 is pyridine or aryl, unsubstituted or substituted by a halogen or inferior alkyl; R4 is hydrogen or hydroxy-. A is -S(O)2- or -C(O)-; X, Y are -CH2- or -O- independently from each other, though both X and Y should not be -O- at the same time; R'R" are hydrogen or inferior alkyl independently from each other; n is 0, 1 or 2. Also the invention concerns pharmaceutically acceptable additive salts and acids of the compounds, and a medicine based on it.

EFFECT: new biologically active compounds show inhibition effect in glycine absorption.

21 cl, 214 ex, 1 tbl

Up!