Synthesis of lamellarine series compounds and analogues

FIELD: organic synthesis.

SUBSTANCE: invention provides methods for preparing lamellarine compounds of general formula II: (II) via intramolecular cyclization of compounds having general formula I: (I), in which formulas moiety RA1RA2C-CRA3RA4 forms optionally monosubstituted aryl group or optionally monosubstituted aromatic 3-6-membered heteromonocyclic group with one nitrogen atom; Y represents hydrogen atom, optionally monosubstituted C1-C20-alkyl, optionally monosubstituted C2-C20-alkenyl, optionally monosubstituted C2-C20-alkynyl, hydroxy, optionally monosubstituted amino, optionally monosubstituted C1-C20-alkoxy, optionally monosubstituted C1-C20-alkenoxy, optionally monosubstituted C1-C20-alkynoxy, optionally monosubstituted aryl, optionally monosubstituted saturated or unsaturated 3-6-membered heteromonocyclic group with one nitrogen atom, carboxy, carboxyester, carboxamide, C1-C20-acyl, C1-C20-acyloxy, mercapto, optionally monosubstituted C1-C20-alkylthio, halogen, nitro, sulfate, phosphate, or cyano; W and X, together with nitrogen and carbon atoms to which they are linked, form group selected from quinoline, isoquinoline, dehydroquinoline, and pyridyl groups all optionally monosubstituted, dihydro- or tetrahydro-derivatives of indicated groups, and optionally monosubstituted phenantridine; wherein optional substituent is selected from C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, aryl, halogen, halo-C1-C20-alkyl, halo-C2-C20-alkenyl, halo-C2-C20-alkynyl, haloaryl, hydroxy, C1-C20-alkoxy, C2-C20-alkenyloxy, aryloxy, benzyloxy, halo-C1-C20-alkoxy, halo-C1-C20-alkenyloxy, haloaryloxy, nitro, nitro-C1-C20-alkyl, nitro-C2-C20-alkenyl, nitro-C2-C20-alkynyl, nitroaryl, nitro-substituted 3-6-membered heteromonocyclic group with one nitrogen atom, amino, C1-C20-alkylamino, di-C1-C20-alkylamino, C2-C20-alkenylamino, C2-C20-alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino, C1-C20-acyl, C2-C20-alkenylacyl, C2-C20-alkynylacyl, arylamino, diarylamino, benzylamino, dibenzylamino, C1-C20-acyl, C2-C20-alkenylacyl, C2-C20-alkynylacyl, arylacyl, C1-C20-acylamino, di-C1-C20-acylamino, C1-C20-acyloxy, C1-C20-alkylsulfonyloxy, arylsulfenyloxy, 3-6-membered heteromonocyclic group with one nitrogen atom, oxy-, amino-, and halogen-derivatives of the latter, C1-C20-alkylsulfenyl, arylsulfenyl, carbo-C1-C20-alkyloxy, carbo-C6-C24-aryloxy, mercapto, C1-C20-alkylthio, benzylthio, C1-C20-acylthio, cyano, sulfate, and phosphate; V represents halogen, hydrogen, or oxygen atom; and intermediates having general formulas Ia and Ib:

EFFECT: expanded synthetic possibilities in lamellarine series.

28 cl, 1 dwg, 2 tbl

 

The technical field

The present invention is directed, mainly, to intermediate compounds useful for obtaining the compounds are useful in therapy. More specifically, the present invention relates to intermediate compounds useful in obtaining class condensed polycyclic alkaloids. The invention relates also to methods for condensed polycyclic alkaloids and their analogues and derivatives.

Prior art

Existing in the nature of a molecule exhibiting potentially curative pharmacological properties, can be distinguished from environmental objects, such as marine, plant or microbial sources. One example of such molecules is the General class of compounds known as lamellarin. These polyaromatic alkaloids are allocated from marine sources and they have a condensed structure. It was shown that lamellarin C and D cause inhibition of cell division in the sample fertilized sea urchin, while lamellarin I, K and L all show comparable and significant cytotoxicity against cell lines R and A in culture. Recently it was shown that lamellarin N are active in cell lines of lung cancer, acting as a microtubule poison type IV. Moreover, it was also shown that those with the organisations possess cytotoxic activity against cells resistant to a large number of medicines, as well as effective non-toxic modulators phenotype that is resistant to a large number of drugs, and therefore provide an attractive potential source of chemotherapeutic agents.

However, the possible clinical usefulness lamellarins much limited to modest amounts received in the nature of, and difficulties associated with their selection.

Accordingly, considerable activity has been directed to the development sinteticheskogo path for this class of molecules and approaches to these molecules included consecutive double cyclization of 1,3,4-Triaryl-2,5-dicarboxylate pyrrole rings (Steglich et al., Angew. Chem., Int. Ed. Ing., 1997, 36, 155) and flowing through the N-ylides education pyrrole rings for introduction into the molecule of pyrrole and lactone parts (Banwell et al., Chem. Commun., 1997, 2259; Ishibashi et al., Tetrahedron, 1997, 53, 5951).

At the moment the present invention provides an alternative way through synthetic intermediate compound, which allows for the introduction of a number of models of substitution and potentially opens the access to a large number lamellarins compounds and analogues containing condensed polycyclic-pyrrole core.

Description of the invention

Accordingly, in the first aspect of izopet the tion relates to a method for obtaining compounds of formula (II):

including the stage of carrying out intramolecular cyclization of compounds of formula (I):

where:

RA1-A4each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted quinil, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted, alkenone, optionally substituted, alkyloxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, complex carboxyester, carboxamido, acyl, acyloxy, mercapto, optionally substituted, alkylthio, halogen, nitro, sulphate, phosphate and cyano; or

RA2and RA3can optionally together form a bond, a RA1and RA4are defined above, or together with the carbon atom to which they are bound, form an optionally substituted carbocyclic or heterocyclic group; or

RA2and RA3together with the carbon atom to which they are bound, form an optionally substituted saturated or unsaturated carbocyclic or heterocyclic group; or

RA1RA2C-CRA3RA4form an optionally substituted aryl group or aromatica is such a heterocyclic group;

Y is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted quinil, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted, alkenone, optionally substituted, alkyloxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, complex carboxyester, carboxamide, acyl, acyloxy, mercapto, optionally substituted, alkylthio, halogen, nitro, sulphate, phosphate and cyano;

W and X are such as defined for Y, or together with the nitrogen atoms and the carbon to which they are linked, form a saturated or unsaturated nitrogen-containing heterocyclic group which optionally may be locked or optionally condensed with a saturated or unsaturated carbocyclic group, aryl group or heterocyclic group;

V is a halogen atom or a hydrogen atom;

Z represents -(CH2)n-U-(CH2)about-where U is chosen from CH2, NH or heteroatoms, and n and o are independently 0, 1, 2, or 3.

In a second aspect the present invention provides an intermediate compound useful in obtaining compounds of formula (II)where the above-mentioned intermediate compound has the formula (I):

where:

RA1-A4each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted quinil, optionally protected hydroxyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted, Alcoxy, optionally substituted, alkyloxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, complex carboxyester, carboxamido, acyl, acyloxy, mercapto, optionally substituted, alkylthio, halogen, nitro, sulphate, phosphate and cyano; or

RA2and RA3can optionally together form a bond, and RA1and RA4are defined above, or together with the carbon atoms to which they are linked, form an optionally zameshannuu carbocyclic or heterocyclic group; or

RA2and RA3together with the carbon atom to which they are bound, form an optionally substituted saturated or unsaturated carbocyclic or heterocyclic group; or

RA1RA2C-CRA3RA4form an optionally substituted aryl group or aromatic heterocyclic group;

Y is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, but not necessarily the replacement of the seal quinil, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted, alkenone, optionally substituted, alkyloxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, complex carboxyester, carboxamide, acyl, acyloxy, mercapto, optionally substituted, alkylthio, halogen, nitro, sulphate, phosphate and cyano;

W and X are such as defined for Y, or together with the nitrogen atoms and the carbon to which they are linked, form a saturated or unsaturated nitrogen-containing heterocyclic group, which optionally can be substituted or optionally condensed with a saturated or unsaturated carbocyclic group, aryl group or heterocyclic group;

V represents a halogen atom or a hydrogen atom;

Z is -(CH2)n-U-(CH2)about-where U is chosen from CH2, NH or heteroatoms, and n and o are independently 0, 1, 2, or 3.

Another aspect of the present invention relates to compounds of the formula (II), as defined above, obtained by the methods described here.

Used here, the term “alkyl” denotes fully saturated, unbranched, branched or cyclic hydrocarbon residues. If the number of carbon atoms is not specified, this term is predpochtitelno applies to C 1-20the alkyl or cycloalkyl. Examples of unbranched and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terbutyl, tertbutyl, amyl, isoamyl, veramil, 1,2-dimethylpropyl, 1,1-dimethylpropyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methoxyphenyl, 1-etylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3-trimethylbutane, 1,1,2-trimethylbutane, 1,1,3-trimethylbutane, octyl, 6-methylheptan, 1-methylheptan, 1,1,3,3-TETRAMETHYLBUTYL, nonyl, 1-, 2-, 3-, 4-, 5-, 6 - or 7-metrotel, 1-, 2-, 3-, 4 - or 5-atergatis, 1 -, 2 - or 3-propyloxy, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7 - or 8-methylnon, 1-, 2-, 3-, 4-, 5 - or 6-etilosti, 1-, 2-,3 - or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8 - or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6 - or 7-atenonol, 1-, 2-, 3-, 4 - or 5-prophylactic, 1-, 2 - or 3-butylate, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9 - or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7 - or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5 - or 6-propylene, 1-, 2-, 3 - or 4-butyloctyl, 1-2-intergates etc. are Examples of cyclic alkyl include mono-or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentamine, tsiklogeksilnogo, cycloheptyl, qi is loackilla, cicloserina, cicadellinae etc.

Used herein, the term “alkenyl” denotes groups formed from an unbranched, branched or cyclic hydrocarbon residues containing at least one double carbon-carbon bond, including ethanobotany mono-, di - or polyunsaturated alkyl or cycloalkyl groups defined above. If the number of volumes of carbon is not specified, this term refers to the C1-20alkenyl. Examples alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, Isobutanol, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methylcyclopentanol, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctene, 1 nonenal, 2-nonanol, 3-nonanol, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1,4-pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadiene, 1,3,5-cycloheptatriene and 1,3,5,7-cyclooctatetraene.

Used here, the term “quinil” denotes a group derived from an unbranched, branched or cyclic hydrocarbon residues containing at least one triple carbon-carbon bond, including ethnobotany mono-, di - or polyunsaturated alkyl or cycloalkyl groups defined above. If the number of carbon atoms is not specified, the term relative is seeking to C 1-20the quinil. Examples include ethinyl, 1-PROPYNYL, 2-PROPYNYL, and the isomers of butenyl, and isomers of pentenyl.

The terms “alkoxy”, “alkenone and alkyloxy” mean respectively an alkyl, alkenylphenol and alkylamino group, as defined above, in the case of bonding through the oxygen.

The term “halogen” means fluorine, chlorine, bromine or iodine.

The term “aryl” denotes single, polynuclear, conjugated and condensed residues of aromatic hydrocarbon cyclic systems. Examples of aryl include phenyl, diphenyl, triphenyl, tetraphenyl, naphthyl, tetrahydronaphthyl, anthracene, dihydroanthracene, benzanthracenes, dibenzanthracene, phenanthrene, fluorene, pyrenyl, adenyl, azulene, Christel.

The term “heterocyclic” means a mono - or polycarbocyclic group, including aryl in which at least one carbon atom is replaced by a heteroatom, preferably selected from nitrogen, sulfur or oxygen. When mono - or polycarbocyclic group, in which at least one carbon atom replaced by a heteroatom, represents an aryl group, it is called an aromatic heterocyclic group.

Suitable heterocyclic groups include N-containing heterocyclic group such as unsaturated 3-6 membered heterogenities group is s, containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolidyl, imidazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl;

saturated 3-6 membered heterogenities group containing 1 to 4 nitrogen atoms, for example, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidine or piperazinil;

condensed saturated or unsaturated heterocyclic group containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolinyl, isoindolyl, indolizinyl, isoindolyl, benzimidazolyl, hinely, ethanolic, indazoles, benzotriazolyl, purinol, hintline, honokalani, phenanthridines, phenanthrolines, phthalazine, naphthyridine, cinnoline, pteridine, pyrimidinyl, or tetrachloropyridine;

saturated 3-6 membered heterogenities group containing from 1 to 3 oxygen atoms, such as tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyranyl;

unsaturated 3-6 membered heterogenities group containing an oxygen atom, such as pyranyl, dioxines or furyl;

condensed saturated or unsaturated heterocyclic group containing from 1 to 3 oxygen atoms, such as benzofuranyl, chromanol or xantener;

unsaturated 3-6 membered heterogenities group containing from 1 to 2 atoms of ser is, such as thienyl or ditolyl;

unsaturated 3-6 membered heterogenities group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, oxazolyl, isoxazolyl, furutani or oxadiazolyl;

saturated 3-6 membered heterogenities group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morpholinyl;

unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxazolyl or benzoxadiazole;

unsaturated 3-6 membered heterogenities group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiazolyl or thiadiazolyl;

saturated 3-6 membered heterogenities group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as diazolidinyl; and

unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl or benzothiadiazole.

The term “acyl” refers to the residue of a carboxylic acid, in which HE replaced by a group such as defined for W, X and Y, and may, in particular, to mean carbarnoyl, aliphatic acyl group or acyl group containing an aromatic ring, called aromatic acyl, or heterocyclic number of the TSO, called heterocyclic acyl, preferably, C1-20the acyl. Examples of suitable acyl include carbarnoyl; unbranched or branched alkanoyl, such as formyl, acetyl, propanol, butanol, 2-methylpropanol, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanol, deletion, pentadecanol, hexadecanol, heptadecanol, octadecanol, nonadecanoic and emosanal; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, tertbutoxycarbonyl, treatmentelectrical and heptyloxybiphenyl; cycloalkylcarbonyl, such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl and cyclohexylcarbonyl; alkylsulfonyl such as methylsulphonyl and ethylsulfonyl; alkoxycarbonyl, such as methoxycarbonyl and ethoxycarbonyl; aroyl, such as benzoyl, toluoyl and naphtol; arkanoid, such as phenylalkanoic (for example, phenylacetyl, phenylpropanol, phenylmethanol, phenylethanol, phenylmethanol and phenylhexanoic) and naphthalenol (for example, naphthylacetyl, afterrepair and afterburner); arukenai, such as phenylalkanoic (for example, phenylpropenoyl, phenylmethanol, phenylmethanol, phenylmethanol and phenylhexanoic), and naphthalenol (for example, afterproperties, afterburner and afterpotential) arelaxation, such as generalconditions (for example, benzyloxycarbonyl); aryloxyalkyl, such as phenoxycarbonyl and naphthalocyanines; aryloxyalkanoic, such as phenoxyacetyl and phenoxypropionyl; arylcarbamoyl, such as phenylcarbamoyl; aristochromis, such as phenylthiocarbamoyl; acilglycerol, such as phenylglyoxylic and afterpotential; arylsulfonyl, such as phenylsulfonyl and naphthylmethyl; heterocyclicamines; heterocyclochain, such as titilate, tanypodinae, thienylmethyl, thienylmethyl, tinyhexer, thiazoleacetic, thiadiazolyl and tetrazolyl; heterocyclochain, such as heterocyclization, heterocyclization, heterocyclization and heterocyclisation; and heterosynaptically, such as triazolylmethyl and tanygrisiau.

The term “acyloxy” refers to acyl as defined here above, in the case when it is linked through oxygen.

In this specification “optionally substituted” is used to indicate that the group may or may not be further substituted or condensed for the formation of a condensed polycyclic group of one or more groups selected from alkyl, alkenyl, quinil, aryl, halogen, halogenoalkane, halogenoalkane, halogenoalkane, halogenfree, hydroxy, alkoxy, and is keylocks, aryloxy, benzyloxy, halogenoalkane, halogenations, halogenations, nitro, nitroalkyl, nitroalkane, nitroalkyl, nitrourea, nitroheterocyclic, amino, alkylamino, dialkylamino, alkenylamine, alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino, acyl, alkenylacyl, alkenylacyl, Ariella, acylamino, diarylamino, aryloxy, alkylsulfonate, arylsulfonate, heterocyclyl, heterocyclic, heterocycles, halogenmethyl, alkylsulfanyl, arylsulfenyl, carbalkoxy, barbarians, mercapto, alkylthio, benzylthio, atillio, cyano, nitro, sulfate and fosfato. The term “optionally protected” is used to denote that a group such as a hydroxy-group, may or may not be protected by a protective group. Suitable protective groups are known and examples are described in Protective Groups in Organic Synthesis, by T.W. Greene (1981), John Wiley & Son.

Used here “heteroatom” refers to any atom other than carbon atom, which may be a member of the cyclic organic compounds. Examples of suitable heteroatoms include nitrogen, oxygen, sulfur, phosphorus, boron, silicon, arsenic, selenium and tellurium, especially nitrogen, oxygen and sulphur.

A preferred variant embodiment are compounds of formulas (I) and (II), where U, is defined in Z are selected from CH2, NH oxygen and sulfur. More preferably, U is NH or oxygen. Most preferably, U is oxygen. For another preferred values of Z, n+o=0, 1, 2, 3 or 4. Suitable examples of Z include-O-CH2-, -CH2-N-, -O-CH2-O-, -(CH2)3-, -CH2-NH-CH2- or-CH2-O-CH2-. In the following preferred variant of embodiment, and n and o are both equal to zero.

In the following preferred embodiment, V is hydrogen, iodine or bromine.

Other forms of embodiment are compounds of formulas (I) and (II)when W and X together with the nitrogen atoms and the carbon to which they are linked, form a saturated or unsaturated heterocyclic group, and this group preferably represents optionally substituted chinoline, optionally substituted ethenolysis, optionally substituted dihydroquinoline, optionally substituted dihydroisoquinolyl, optionally substituted pyridyl or dihydro or tetrahydro analogs, or optionally substituted phenanthridine. Preferably, W and X together with the nitrogen atoms and the carbon to which they are linked, form an optionally substituted athinodorou or optionally substituted dihydroisoquinolyl group of General formula (i):

where R1-R4and R14such as defined above for the, andrepresents an optional double bond.

Preferably, R1-R4formula (i) is hydrogen; hydroxy; optionally substituted alkyl; optionally substituted, alkyloxy; acyloxy; carboxy; complex carboxylation, in which the ester is preferably methyl, ethyl, propyl or butyl ether complex; optionally substituted amino; carboxamido, in which the nitrogen atom optionally substituted by one or two alkyl groups, independently selected from methyl, ethyl, propyl or butyl; or a sulfate. Most preferably they are hydrogen, hydroxy, methoxy, ethoxy, ISO-propoxy, stands, ethyl, propylene, acetoxy or sulfate. Preferably, R14is hydrogen or hydroxy.

The following variant of the embodiment are compounds of formulas (I) and (II)when RA1RA2C-CRA3RA4forms the aryl group or aromatic heterocyclic group, it may be optionally substituted benzene or naphthalene ring or an optionally substituted aromatic heterocyclic group such as pyridine, furan, pyrrole or thiophene, and their analogs, condensed with benzene, for example, quinoline, indole, benzofuran and benzothiophene.

The accession Bicycle eskay heterocyclic group may be through a benzene or heterocyclic ring. Preferably, RA1RA2C-CRA3RA4forms an optionally substituted benzene group. Preferably, the substituents are hydrogen; hydroxy; optionally substituted alkyl; optionally substituted, alkyloxy; acyloxy; carboxy; complex carboxyethyl, in which the ester is preferably methyl, ethyl, propyl or butyl ether complex; optionally substituted amino; carboxamido in which its atoms optionally substituted by one or two alkyl groups, independently selected from methyl, ethyl, sawn or butilkoi; or sulfate. Most preferably, they were hydrogen, hydroxy, methoxy, ethoxy, ISO-propoxy, stands, ethyl, propylene, acetoxy or sulfate.

In the next version of embodiment RA1-A4preferably independently selected from hydrogen, optionally substituted alkyl, optionally protected hydroxy, optionally substituted alkoxy, optionally substituted phenyl or acyloxy. In one of the preferred variants of the embodiment, at least one of RA1or RA3can be hydrogen. In another variant embodiment as RA1and RA3are hydrogen. In the next version of embodiment three or four of RA1-A4are hydrogen.

The following vari is NTE embodiment, when RA2and RA3together form a bond so as to form a group RA1C=CRA4each of RA1and RA4can be independently selected from hydrogen; hydroxy; optionally substituted alkyl; optionally substituted, alkyloxy; acyloxy; carboxy; complex carboxyester, in which the ester is preferably methyl, ethyl, propyl or butyl ether complex; optionally substituted amino or carboxamido, in which the nitrogen atom optionally substituted by one or two alkyl groups, independently selected from methyl, ethyl, propyl or butyl. In particularly preferred embodiments, one or both of RA1and RA4are hydrogen.

When RA2and RA3together with the carbon to which they are linked, form a carbocyclic or heterocyclic group, as defined above, preferably, they form a 3-8-membered cyclic group, preferably 5-6-membered cyclic group. Preferably, they form a cyclopentane, cyclohexanone, cyclopentenone, cyclohexenone, cyclopentadienyl, cyclohexadienyl, tertrahydrofuran ring, dihydrofuran, pyrolidine, pyrrolinone, pornowww, dihydropyrrole, tetrahydropyranyl or piperidinyl group. Preferably, RA1and RA4are hydrogen.

In one of the following variant of the embodiment Has preferably a is optionally substituted phenyl group of formula (ii):

where R9-R13such as defined for R1-R4, a R14defined above.

More preferably, R9-R13are hydrogen; hydroxyl; optionally substituted alkyl; optionally substituted, alkyloxy; acyloxy; carboxy; complex carboxylation, in which the ester is preferably methyl, ethyl, propyl or butyl ether complex; optionally substituted amino; carboxamido, in which the nitrogen atom optionally substituted by one or two alkyl groups, independently selected from methyl, ethyl, propyl or butyl; or a sulfate. Most preferably, R9-R13selected from hydrogen, hydroxy, methoxy, ethoxy, ISO-propoxy, methyl, ethyl, n-propyl, ISO-propyl, acetoxy or sulfate.

The following preferred embodiments are the compounds of formula (I)representing the compound of formula (Ia)where X is hydrogen, and W is a group of formula (iii):

where V is hydrogen or halogen; RB1-B4respectively as defined for RA1-A4above; and

m is 1, 2, 3, or 4.

Thus in a preferred variant embodiment, the present invention relates to a method for obtaining compounds of formula (IIA):

including the state of the two intramolecular cyclization of compounds of formula (Ia):

where:

RA1-A4, V, Y, Z have the meanings defined above;

RB1-B4each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted quinil, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted, alkenone, optionally substituted, alkyloxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, complex carboxyester, carboxamido, acyl, acyloxy, mercapto, optionally substituted, alkylthio, halogen, nitro, sulphate, phosphate and cyano; or

RB2and RB3optional may together form a bond, a RA1and RA4such as defined above, or together with the carbon atoms to which they are linked, form an optionally substituted carbocyclic or heterocyclic group; or

RB2and RB3together with the carbon atoms to which they are linked, form a optionally substituted saturated or unsaturated carbocycles heterocyclic group; or

RB1RB2C-CRB3RB4form an optionally substituted aryl group or aromatic heterocyclic group; and

m is 1, 2, 3, or 4.

The following preferred embodiment of the invention provides an intermediate compound of formula (Ia):

where:

RA1-A4, RB1-B4, V, Y, Z and m have the meanings defined above, and, optionally, one or more (CH2group group (CH2)mdefined in the formula (iii)may be optionally substituted by a group R14defined above.

In a preferred embodiment, m is 1 or 2.

More preferably, when m is 2.

The following variants of the embodiment are compounds of formulas (Ia) and (IIA), when RB1RB2C-CRB3RB4forms the aryl group or aromatic heterocyclic group, it may be optionally substituted benzene or naphthalene ring, or an optionally substituted aromatic heterocyclic group such as pyridine, furan, pyrrole or thiophene, and their condensed with benzene analogues, for example, quinoline, indole, benzofuran and benzothiophene. Join bicyclic heterocyclic group may be through a benzene or heterocyclic ring. Preferably, RB1RB2 C-CRB3RB4forms an optionally substituted benzene group. When RB1RB2C-CRB3RB4forms a substituted benzene group (containing Deputy V), cyclization can lead to a group of the formula (i)as described here above. Preferably, the substituents are hydrogen, hydroxy, optionally substituted alkyl, optionally substituted, alkyloxy, acyloxy, carboxy, complex carboxyethyl, in which the ester is preferably methyl, ethyl, propyl or butyl ether complex; optionally substituted amino, carboxamido, in which the nitrogen atom optionally substituted by one or two alkyl groups, independently selected from methyl, ethyl, propyl or butyl; or a sulfate. The most preferred substituents are hydrogen, hydroxy, methoxy, ethoxy, ISO-propoxy, methyl, ethyl, propyl, acetoxy or sulfate.

In other variant embodiments, RB1-B4preferably independently selected from hydrogen, optionally substituted alkyl, optionally protected hydroxy, optionally substituted alkoxy, optionally substituted phenyl or acyloxy. In one of the preferred variants of the embodiment, at least one of RB1or RB3can be hydrogen. In another embodiment, embodiment and RB1and RB3both JW is Auda hydrogen. In yet another variant embodiment three or four of RB1-B4are hydrogen.

In the following variant embodiment, when RB2and RB3together form a bond so as to form a group RB1C=(CRB4each of RB1and RB4can be independently selected from hydrogen; hydroxy; optionally substituted alkyl; optionally substituted, alkyloxy; acyloxy; carboxy; complex carboxyester, in which the ester is preferably methyl, ethyl, propyl or butyl ether complex; optionally substituted amino or carboxamido, in which the nitrogen atom optionally substituted by one or two alkyl groups, independently selected from methyl, ethyl, propyl or butyl. In particularly preferred embodiments, one or both of RA1and RA4are hydrogen.

When RB2and RB3together with the carbon to which they are linked, form a carbocyclic or heterocyclic group as defined above, they preferably form a 3-8-membered cyclic group, preferably 5-6-membered cyclic group. Preferably, they form a cyclopentane, cyclohexane, cyclopentenone, cyclohexenone, cyclopentadienyl, cyclohexadienyl, tertrahydrofuran ring, dihydrofuran, pyrolidine, pyrrolinone, lisanova, digitrapper the new, tetrahydropyranol or piperidino group. Preferably, RB1and RB4are hydrogen.

Especially preferred compounds of formula (I) have a structure of the following formula (Ib):

where R1-R14independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted quinil, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted, alkenone, optionally substituted, alkyloxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, complex carboxyester, carboxamido, acyl, acyloxy, mercapto, optionally substituted, alkylthio, halogen, nitro, sulphate, phosphate and cyano. Preferred R1-R14selected from hydrogen; hydroxy; optionally substituted alkyl; optionally substituted, alkyloxy; acyloxy; carboxy; complex carboxyester, in which the ester is preferably methyl, ethyl, propyl or butyl; optionally substituted amino, such as mono - or dialkylamino; carboxamido, in which the nitrogen atom optionally substituted by one or two alkyl groups, independently selected from methyl, ethyl propyl or butyl; or sulfate. More preferably R1-R13selected from hydrogen; hydroxy; optionally substituted alkyl, such as methyl, ethyl or propyl; optionally substituted, alkyloxy, such as methoxy, ethoxy, n-propoxy, ISO-propoxy; acyloxy, such as acetoxy; or sulfate, a R14preferably is hydrogen or hydroxy. V is as defined above, preferably hydrogen, iodine or bromine.

Thus, in a preferred embodiment, the invention provides a method of obtaining a condensed polycyclic errorcodehex the compounds of formula (IIb):

including the state of the two intramolecular ciclisti the compounds of formula (Ib).

Intramolecular cyclization of compounds of formula (I), preferably formula (Ia) or (Ib), with the formation of the condensed polycyclic compounds of the formula (II), preferably of formula (IIA) or (IIb), can be accomplished in any suitable manner known to specialists in this field of technology. Suitable methods are described below, but any other method by which you can make the desired cyclization, also forms part of the present invention. It is clear that the groups V, W, X, Y, Z, RA1-A4, RB1-B4and R1-14are such as not to interfere with the proceedings of the CEC is Itachi.

In the case when V is a hydrogen atom, for the implementation of the cyclization you can use the method of oxidative intramolecular cyclization, as described in Black et al., Tetrahedron Lett., 1989, 30, 5807, and Kita et al., Chem. Someapp., 1996, 1481.

Alternatively, if V is a halogen atom, an intramolecular cyclization may occur through the generation of a suitable radical in a manner analogous to the method described Antonio et al., Can. J. Chem., 1994, 72, 15, and Moody et al, Tetrahedron Lett., 1995, 36, 9501.

Another way intramolecular cyclization of compounds of formula (I) in the case when V is halogen, includes cyclization involving Pd[0]. Intramolecular Pd[0]-catalysed rafinirovaniyu organic halide (intramolecular reaction Hake) known to specialists in this field and can be implemented using any combination of reagents that will provide palladium in a neutral state (Pd[0]).

Suitable combination of reagents for carrying out Pd[0])-catalyzed cyclization described, for example, Burwood et

al, Tetrahedron Lett., 1995, 36, 9053; Desarbe et al, Heterocycles, 1995, 41, 1987; Harayoma et al, Chem. Pharm. Bull., 1997, 45, 1723; and Grigg et al. Tetrahedron, 1995, 50, 359.

Thus, in one variation of the embodiment of the invention Pd[0]-catalyzed cyclization of compounds of formula (I) can be done by generating Pd[0] in situ by the combination of Pd(II) reagent and “ligand”and then ensure the sustainable base for the generation of Pd[0]-catalyst.

Suitable examples of Pd(II)/Pd(0) reagent include, but are not limited to: Pd(OAc)2, PdCl2(CH3SP)2, PdCl2(PPh3)2Pd(C6H5CN)2Cl2Pd (dibenzylideneacetone)3.

Suitable examples of “ligand” providing reagents include, but are not limited to: h3, P(o-tolyl)3, 1,3-bis[diphenylphosphino]propane and 1,3-bis[diphenyl-phosphino]ethane.

Suitable bases for generating Pd[0] Pd[II], which is formed when Pd[0]-catalyzed cyclization include, but are not limited to: bonds alkylamines, such as triethylamine and diisopropylethylamine; acetates such as sodium acetate and potassium acetate; carbonates such as potassium carbonate, sodium carbonate, silver carbonate; hydroxides such as sodium hydroxide and potassium.

When processing the compounds of formula (Ia) or (Ib) with the purpose of double cyclization to obtain the compounds of formula (IIA) or (IIb) the cyclization can be performed radical or oxidative Pd-catalyzed methods, as described above, and each cyclization you can spend the same, similar, or otherwise.

Thus, in one variant of embodiment two cyclization can be performed sequentially, in any order, and, optionally, you can use a variety of reagents and conditions, for example, as described above. obazatelno, after spending one cyclization monocytopenia product can be distinguished before it is treated in suitable conditions for carrying out the second intramolecular cyclization. In another embodiment, a “double cyclization” can be done “in one bottle, preferably, only when the selection of the reaction conditions.

In a more preferred embodiment, the compound of formula (Ia), preferably, (Ib), is subjected to “double cyclization to obtain the compounds of formula (IIA), preferably, (IIb), in the conditions of the catalysis of Pd[0].

In an even more preferred form both cyclization carried out in one flask”, when the only selection of the reaction conditions.

The compounds of formula (I), (Ia) and (Ib) can be derived from pyrrole nucleus, known in the art standard methods, which are aimed at carrying out the substitution of carbon atoms of the pyrrole nucleus, for example, by electrophilic aromatic substitution or by halogenation of the pyrrole nucleus and holding substitution reactions of cross-combination of Calm, Suzuki or of Njegusi using stannane, Bronevoy acid or compounds of zinc, such as aristanemi, arylboronic acid and arizonasee connection. Replacement of the N-atom can be performed by standard methods.

One of the suitable approaches, although in no way limits the speaker, consider as an illustration of suitable methods of substitution of the pyrrole nucleus, the following scheme 1.

It will be clear that when using the appropriate reagents in the stages used to introduce a substitution at positions 1-, 2-, 4 - pyrrole nucleus, for example, forsteriana reagents used in stages (d), (e) and (f), in which the phenyl fragment further substituted, as described here above, to obtain the intermediate compounds amenable to process cyclization and formation of the corresponding cyclic compounds, you can enter a number of models of substitution and deputies.

SCHEME I

Scheme 1: Reagents and conditions: (a) CL3l (1 mol. equiv.) Et2O, 35°C, 1 h (80%); (b) I2(1 mol. equiv.) q2F3(1 mol. copies), l3on 18°C, 1 h (82%); (C) To2CO3(2 M in H2O), DMSO, 18°S, 32 h (92%); (d) (i) (COCl)2(1,1 mol. equiv.) DMF (cat.), CH2CL2on 18°s, 2 h; (ii) o-bromophenol (1 mol. equiv.) DMAP (cat.), CH2CL2on 18°C, 1 h (92%); (e) To2CO3, (1,14 mol. equiv.) VI4l (0,1 mol. equiv.) DMF, 80°C, 2 h (90%); (f) PhZnCl (1,3 mol. equiv.) PdCl2(PPh3)2(0,05 mol. EQ)/ TAMPA, 1 h (95%); (g) Pd(OAC)2(0,5 mol. equiv.) PPh3, (1 EQ.), NaOAc (4 equiv.) DMF, 130°S, 6 h (16%); (h) TsCl (2,4 mol. equiv.) KOHN (2,4 mol. equiv.) Et2O 0® 18°C, 2 h (98%).

If there is obezatelnoe double bond, as in the compounds of formula (II), which contain part of the formula (I), such as compounds of formula (IIb), you can enter any dehydrogenative cyclization product or, alternatively, the introduction of the corresponding double bond in its predecessor. Appropriate methods are known in the art (see, for example, Advanced Organic Chemistry, Reactions, Mechanisms and Structure, Jerry March, 3rd edition, Wiley Interscience). One such suitable method includes processing collisuem the compounds of formula (IIb) DH (2,3-dichloro-5,6-dicyano-1,4-benzoquinone). For example, diisopropyl ether lamellarin T (compound 37 in table 2) can be translated in diisopropyl ether lamellarin W (compound 11 in table 1) processing DDH in dry chloroform at 60-65°With (see example 11 in WO 98/50365).

In WO 97/01336 (the full content of which is taken to include here by reference) connection class lamellarins described as possessing inhibitory and cytotoxic activity against tumors that are resistant to a large number of drugs.

Accordingly, in this aspect of the present invention is described treatment, including the introduction of effective treatment amount of compound of General formula (II)obtained by the methods described here, as an active ingredient, an animal, including man, in need of this.

the AK used here the term “effective amount” refers to that amount of compound that, when introduced in accordance with the desired dosing regime provides the desired therapeutic activity. This dose will depend on the age, weight and condition of the subject, and determining the appropriate dosage is the responsibility of the attending physician. Dosage (prescription drug specific dose) may occur in intervals of minutes, hours, days, weeks, months, or years, or permanently during any of these periods. Suitable dosages are in the range of from about 0.1 ng per kg of body weight to 1 g per kg body weight per dose. Preferably, the dosage is in the range from about 1 μg to 1 g per kg body weight per dose. More preferably, the dosage is in the range from about 1 mg to 1 g per kg of body weight. Convenient to dosage was in the range of from about 1 mg to 500 mg per kg of body weight, for example, between 1 mg and 250 mg, or 1 mg and 100 mg.

In a preferred variant embodiment of the method of treatment refers to the treatment of tumors that are resistant to a large number of drugs.

In the following variant embodiment of the method of treatment involves improving antitumor chemotherapeutic effect of drugs causing resistance to a large number of drugs.

In the trail of the future preferred variant embodiment of the method of treatment is a method of inducing apoptosis. More preferably, the treatment method is a method induzione of apoptosis in the cell resistant to bodomo number of drugs.

In the following variant embodiment of the method of treatment considers the modulation of immunological functions.

The active ingredient can be entered in one dose or in divided doses. Although the active ingredient can be entered by itself, it is preferable that he was in the compositions, preferably pharmaceutical compositions.

The following aspect of the invention discussed the composition containing the compound of General formula (II)obtained according to the present invention, together with a pharmaceutically acceptable carrier, excipient or diluent.

The carrier must be pharmaceutically acceptable in the sense of compatibility with other ingredients of the composition and in the absence of harm to the subject. The compositions include compositions for oral, rectal, nasal, local (including transbukkalno and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The composition may suitably be in the form of standard dosage forms and may be obtained by any known in the field of pharmacy techniques. Such methods include phase associations actively what about the ingredient with the carrier, which comprises one or more additional ingredients. Typically, these compositions are prepared by uniformly and thin combining the active ingredient with liquid carriers or finely ground solid carriers, or both, and then, if necessary, shaping the product.

Compositions of the present invention suitable for oral administration may be in the form of separate units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or suspension in an aqueous or nonaqueous liquid; or in the form of a liquid emulsion oil in water, or a liquid emulsion of water in oil. The active ingredient can also be in the form of a bolus, electuary or paste.

The tablet can be manufactured by extrusion or molding, optionally with one or more additional ingredients. Molded tablets can be made by pressing in a suitable device is the active ingredient in free-flowing form such as powder or granules, optionally mixed with a binder (for example, inert diluent, preservative baking powder (glycolate, starch sodium, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose)), surface-active sludge is dispersing agent. Molded tablets can be made by molding in a suitable device is a mixture of the powdered compound moistened inert liquid diluent. The tablets may optionally be coated or ledge, and you can compose them in such a way as to ensure rapid or controlled release of the active ingredients using, for example, hydroxypropylmethylcellulose in different proportions to provide the desired release profile. The tablets may optionally be covered enteric coated to provide release in parts of the intestines, not the stomach.

Compositions suitable for local insertion through the mouth include pellet, containing the active ingredient in a flavor, usually sucrose and the Arabian or tragacanth gum; mints containing the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and Arabian gum; and liquid mouth rinse containing the active ingredient in a suitable liquid carrier.

Compositions for rectal injection can be a suppositories (candles) with a suitable base comprising, for example, cocoa butter.

Compositions suitable for vaginal administration, can be represented as pessaries, tampons, creams, gel, paste, foam or spray containing in addition to the active ingredient such carriers, which, as is known from the art are suitable for this purpose.

Compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bactericides and dissolved substances, making this composition is isotonic with the blood of the expected recipient; and aqueous and non-aqueous sterile suspensions that can include suspendresume agents and thickeners. These compositions can be a single dose or mnogorazovye sealed containers, such as ampoules or vials and may be stored in dried by the method of freezing (liofilizirovannom) condition requiring only the addition of sterile liquid carrier, for example water for injections, immediately prior to use. Improvised solutions for injection suspensions can be obtained from sterile powders, granules and tablets of the type indicated above.

Preferred compositions with standard dose are compositions containing a daily dose or unit, daily curioso, as described here above, or its corresponding fraction of the active ingredient.

It should be understood that in addition to the active ingredients particularly mentioned above, the compositions of this invention may include other conventional in the art agents,related to the type of considered composition, for example, compositions suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavorings, loosening agents, covering agents, preservatives, lubricants and/or delaying agents. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar-agar. Suitable flavoring agents include peppermint oil, oil of Grushenka, cherry, orange or raspberry the odorant. Suitable covering agents include polymers or copolymers of acrylic acid and/or methacrylic acid, and/or their esters, waxes, fatty alcohols, Zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride, or talc. Suitable inhibiting agents include glycerylmonostearate or glycerylmonostearate.

The present invention is also the use of compounds of General formula (I), obtained according to the present invention, in the manufacture of a medicinal product for the treatment of the animal or human, in need thereof.

In another aspect of the invention considered the agent for treating an animal or human, in need thereof containing the compound of General formula (II)obtained according to the present invention.

In the first variant embodiment, the agent is designed to treat tumors that are resistant to a large number of drugs.

In the following variant embodiment, the agent is intended to induce apoptose in the cell resistant to a large number of drugs.

In the following variant embodiment, the agent is designed to enhance the antitumor chemotherapeutic effect of drugs causing resistance to a large number of drugs.

The following variant of embodiment is the agent for modulation of immunological functions.

Appropriate, but in no way limiting, examples of compounds which can be obtained through the intermediate compounds of this invention are described below in tables 1 and 2:

Now the invention will be described with reference to the following examples. However, you must p is to understand they do not supersede the generality of the preceding description.

Examples

Example 1

2-(Trichloroacetyl)pyrrol

2-(Trichloroacetyl)pyrrole derived from pyrrole (12.5 g, 186 mmol) and trichloroacetamide (36.5 g, 200 mmol) according to the method of Bailey et al., Orq. Synth., 1971, 100. Thus, the target compound (31,3 g, 80%) are obtained in the form of a cream solid color, TPL 73-74°With (more precisely TPL 73-75°). NMR1H δ of 9.30, Shir. C. 1 N; 7,39 m, 1 H; 7,17, m, 1 N; 6,40 dt, J 3.9 and 2.4 Hz, 1 H (see also J. Org. Chem., 1972, 37, 3618; 1993, 58, 7245).

4-Iodine-2-(Trichloroacetyl)pyrrol

The target compound is obtained from 2-(Trichloroacetyl) pyrrole by way Belanger, Tetrahedron Lett., 1979, 2505. So, to stir on a magnetic stirrer mix trifenatate silver (11,0 g of 49.8 mmol) and 2-(trichloroacetyl)pyrrole (10.0 g, or 47.1 mmol) in dry chloroform (70 ml), maintained at 0°C (ice bath), was added iodine (12.0 g, to 47.2 mmol) in portions (about 1 g per serving) for 0,17 hours Upon completion of addition, the reaction mixture is allowed to warm to 18°C and stirred at this temperature for 2 hours. The resulting suspension was filtered through a funnel with glass solder (porosity No. 3), and the filtrate washed with Na2S2O5(1×80 ml of 5%wt./about. aqueous solution) and water (2×80 ml), dried (MgSOq), filtered and concentrated under reduced pressure. Receiving a solid education is anywayt a mixture of hexane/ether (50 ml of a mixture of 4:1 vol./about.) and the resulting suspension stirred at 18° C for 5 hours, then the solid is filtered off, obtaining the target compound (13.1 g, 82%) as a cream solid color, TPL 129-130°With (more precisely TPL 128-130° (C) NMR1H δ 9,45, broad s, 1 H; 7,44, DD, J 2.6 and 1.3 Hz, 1 H; 7,19, DD, J 2.6 and 1.3 Hz, 1 H.

4-Iterra-Kurbanova acid

To a solution of 4-iodine-2-(trichloroacetyl)pyrrole (8.5 g, 2.5 mmol) in DMSO (30 ml) was added To a2CO3(100 ml of 2M aqueous solution) and stirred the mixture at 18°3 hours, then diluted with H2O (200 ml). Resulting solution washed with ethyl acetate (2×100 ml), then acidified to pH 3 by adding dropwise Hcl (2 M aqueous solution). The resulting suspension is extracted with ethyl acetate (3×100 ml)and the combined organic fractions are dried (MgSO4), filtered and concentrated under reduced pressure, obtaining the target compound (8) (5,51 g, 92%) as a white solid, TPL 200° (Found: M+- 236,9285. For C5H4INO2calculated M+- 236,9287). nmax(CVG) 3287, 3129, 3035, 1703, 1544, 1430, 1300, 1212, 1122cm-1. NMR1H [300 MHz, 3:1 (CD3)2SO/Dl3] δ 11,98 broad s, 1 H; 6,98, t, J 1.5 Hz, 1 H; 6,76 broadened s, 1 N (resonance due to unobserved N-H). NMR13[75.5 MHz, 3:1 (CD3)2SO/Dl3] δ 159,0 (C), 126,0 (CH), 123,3 (C)of 118.8 (CH), 59,0 (C). Mass spectrum m/z 237 (100%) (M+); 219 (87) [(M-H2 O)+].

2-Bromophenyl 4-iterra-2-carboxylate

To a suspension of 4-iterra-2-carboxylic acid (8) (500 mg, 2,11 mmol) in dry CH2Cl2(15.0 ml)containing DMF (dimethylformamide) (1 drop), add oxalicacid (203 ml, 2.32 mmol) under stirring on a magnetic stirrer. After stirring the resulting solution at 18°C for 2 h, added to stir on a magnetic stirrer a solution of o-bromophenol (363 mg, 2,11 mmol), triethylamine (660 ml, to 4.73 mmol) and 4-(N,N-dimethylamino)pyridine (DMAP, a few crystals) in CH2CL3(10 ml). After 1 h the reaction mixture was concentrated on silica gel (5 g) and throw the rest flash chromatography (silica gel, elution with hexane/ether 3:1). When the concentration of the relevant fractions (Rf0,2) obtain the target compound (761 mg, 92%) as a white crystalline substance, TPL 126-127° (Found: C, 33,9; N, 1,7; VG, 20,4; I, 32,4; N, 4,0. For C11H7rINO2calculated, Or 33.7; H, 1,8; VG, 20,4; I, 32,4; N, 3.6 per cent). nmax3383, 2969, 1709, 1580, 1541, 1472, 1444, 1377, 1312, 1218, 1169, 1133, 1043 cm-1. NMR1H δ to 9.57 broad S, 1 H; 7,65, DD, J 8.1 and 1.5 Hz, 1 H; 7,37 dt, J 8.1 and 1.5 Hz, 1 H; 7,27 m, 2 H; 7,18, dt, J 8.1 and 1.5 Hz, 1H; 7,08 m, 1 h NMR13With δ to 158.0 (C), 148,3 (C), 134,0 (CH), 129,8 (CH), 129,1 (CH), 128,1 (SN), to 124.4 (CH), 124,3 (CH), 123,6, 116,9 (C)62,9 (C). Mass spectrum m/z 393 (24%) 391 (22) (M+); 220 (100) [(M-C6H4BrO)+].

2-(2-Bromphen the l)ethyl 4-methylbenzenesulfonate (13)

Stir on a magnetic stirrer a solution of 2-bromophenethylamine alcohol (5,00 g, 24,9 mmol, ALDRICH) and 4-methylbenzenesulfonamide (11,20 g, 59,7 mmol) in diethyl ether (50 ml) cooled to 0°C (ice bath), then treated with powdered KOH (3.2 g, 2,4 molar equivalent). Resulting reaction mixture allowed to warm to 18°C, stirred at this temperature for 2.0 hours, then diluted with water (100 ml). The separated organic phase is washed with water (1×100 ml), then dried (gSO4), filtered and concentrated under reduced pressure, obtaining a white solid. Because this substance contains residual 4-methylbenzenesulfonate it is dissolved in pyridine (75 ml) and the resulting solution was stirred at 18°within 0,16 h, then diluted with water (500 ml) and extracted with diethyl ether (1×500 ml). The separated organic phase before drying (MgSO4) washed model HC1 (1×250 ml of 5M aqueous), then with sodium bicarbonate (1×250 ml of 0.5m aqueous solution), filtered and concentrated under reduced pressure, obtaining the target compound (8,66 g, 98%) as a white crystalline mass, TPL 39-39,5° (Found: C, Up 50.9; H, 4,2; VG, 22,6; S, 8,8. For C15H15BrO3's calculated, At 50.7; H, 4,3; VG, 22,5; S, 9.0 per cent). nmax(CVG) 1356, 1177, 1021, 980, 962, 895, 812, 769, 752, 665, 557 cm-1The NMR1H δ 7,68, the, J 8,3 Hz, 2 H; 7,45, d, J 7.7 Hz, 1 H; 7,27, d, J 8,3 Hz, 2 H; 7,17 m, 2 H; 7,07, m, 1 N; 4,25, t, J 7.0 Hz, 2 H; 3,09, t, J 7.0 Hz, 2 H; 2,43, C, 3 H. NMR13With δ 144,5 (C), 135,3 (C), 132,7 (SN), to 132.8 (C), 131,3 (CH), 129,7 (CH), 128,5 (CH), uniforms, 127.6 (CH), 127,4 (CH), 124,2 (C), only 68.6 (CH2), 35,5 (CH2), 21,5 (CH3). Mass spectrum m/z 356 (0,7%) 354 (0,7) (M+); 184 (98) 182(100) [(M-H3CC6H4SO3H)+]; 171 (49) 169 (51); 155 (45); 103 (32); 91 (80) (With7H

+
7
).

2-Bromophenyl 1-[2’-(2’-bromophenyl)ethyl]-4-iterra-2-carboxylate

To a solution of compound (11) (700 mg, to 1.79 mmol) in dry DMF (30 ml) was added the compound (13) (700 mg, 1.97 mmol), tetraethylammonium (30 mg, 0.18 mmol) and K2CO3(278 mg, 2.0 mmol) and stir the resulting suspension at 80°C for 2 hours. The cooled reaction mixture is diluted with ethyl acetate (150 ml) and washed with water (3×150 ml). Then the separated organic phase is dried (MgSO4), filtered and concentrated under reduced pressure. Resulting solid is subjected to flash chromatography (silica gel, elution with hexane/ether 4:1) and concentration of the appropriate fractions (Rf0,5, elution with a mixture of hexane/ether 3:1) to obtain the target compound (14) (920 mg,89%) as a white crystalline solid, TPL 122-123&#HWS (Found: C, To 39.5; H, 2,1; VG, 27,6; I, 22,1; N, 2,3. For C19H14Br2INO2calculated, And 39.7; H, 2,5; Br, 27,8; I, 22,1; N, 2.4 per cent). nmax(KBr) 2949, 1716, 1517, 1468, 1438, 1411, 1374, 1326, 1232, 1216, 1191, 1055, 1028 cm-1. NMR1H δ 7,65, DD, J 7.8 and 1.8 Hz, 1 H; 7,55, DD, J 7.8 and 1.8 Hz, 1 H; 7,37 m, 2 H; 7,28? 7.04 baby mortality, m, 5 H; 6,70, d, J 2.1 Hz, 1 H; 4,55, t, J 7.5 Hz, 2 H; 3,20, t, J 7.5 Hz, 2 H. NMR13With δ 157,0 (C), 147,8 (C), 136,9 (C), 134,5 (CH), 133,3 (CH), 132,7 (CH), 131,2 (SN), of 128.6 (CH), 128,4 (CH), uniforms, 127.6 (CH), RUB 127.3 (CH), a 126.7 (CH), to 124.4 (C), 124,0 (CH), 122,0 (C), 116,6 (C)59,6 (C)49,0 (CH2), 38,0 (CH2). Mass spectrum m/z 577 (1%) 575 (2) 573 (1) (M+); 496 (10) 494 (11) [(M-Br)+]; 404 (98) 402 (100) [(M-C6H4Ged)+].

2-Bromophenyl 1-[2’-(2’-bromophenyl)ethyl]-4-phenylpyrrole-2-carboxylate (4)

To stir on a magnetic stirrer to a solution of compound (14) (1.75 g, 3.04 from mmol) and Pd (h3)2Cl2(106 mg, 0,152 mmol) in DMF (15 ml), added dropwise over 2 min chloride phenelzine [obtained by addition of anhydrous zinc chloride (540 mg, of 3.96 mmol) to a solution of finelite (2.0 ml, 1.8 M solution in a mixture of cyclohexane/ether, 3.6 mmol) in THF (4.0 ml)]. Stirring is continued at 18°C for 1 h, then the reaction mixture was transferred into a separating funnel, diluted with ethyl acetate (100 ml) and washed with NH4Cl (100 ml saturated aqueous solution), then H2O (2×100 ml). The separated organic phase is dried (gSO4), filtered and concentrated under reduced is the first pressure, receiving light yellow oil, which was subjected to flash chromatography (silica, elution with a mixture of 2:1 hexane/CH2CL2). When the concentration of the relevant fractions (Rf0,5) obtain the target compound (1.52 g, 95%) as a microcrystalline solid, TPL 90-92° (found: C, 57,1; N, 3,4; VG, 30,7; N, 2,5. For C25H19VG2NO2calculated, 57,2; N, 3,7; VG, 30,4; N, 2.7 per cent). nmax(CVG) 2958, 2930, 1718, 1603, 1580, 1562, 1472, 1397, 1215, 1196, 1066, 1024 cm-1. NMR1H δ 7,70, DD, J 8.0 and 1.5 Hz, 1 H; 7,60-7,00, m, 14 H; 4,63, t, J 6.9 Hz, 2 H; 3,32, t, J 6.9 Hz, 2 H. NMR13(75.5 MHz, CDCl3) δ to 158.4 (C), 148,3 (C), 137,5 (C), 134,2 (C), to 133.5 (CH), 132,9 (C), 131, 5mm (CH), 128,9 (SN), of 128.6(3) (SN), of 128.6(1) (CH), 127,8 (CH), 127,4 (CH), RUB 127.3 (CH), 126,5 (SN), and 125.4 (CH), of 124.8 (C), Of 124.6 (C), to 124.4 (CH), 120,9 (C)117,5 (CH), 116,9 (C)49,3 (CH2), 38,2 (CH2). Mass spectrum m/z 527 (3%) 525 (6) 523 (3) (M+); 446 (12) 444 (11) [(M-Br)+]; 354 (100) 352 (96) [(M-C6H4BrO)+].

14-Phenyl-8,9-dihydro-6N-[1]benzopyrano[4’,3’:4,5] pyrrolo[2,1-a]isoquinoline-6-he

To stir on a magnetic stirrer to a solution of compound (4) (148 MT, 0,292 mmol), NaOAc (of 92.7 mg, 1.13 mmol) and h3(74,0 mg, 0,282 mmol) in DMF (2 ml)contained in a tube of Slanka, add Pd(OAc)2(32 mg, 0,143 mmol). The resulting mixture is pumped gas (1/0 mm Hg) and re-fill N2(gaseous) three times to remove dissolved oxygen), and then heated is in a nitrogen atmosphere at 135° C for 6 h the Cooled reaction mixture is diluted with ether (25 ml) before drying (gSO4) washed with brine (2×20 ml) and then water (20 ml), filtered and concentrated onto silica (2 g). The residue is subjected to flash chromatography (silica, elution with a mixture of CH2CL2-g/hexane 1:2, 1:1, then 2:1) and concentration of the appropriate fractions (Rf0,3, elution with a mixture of 2:1 CH2Cl2/hexane) under reduced pressure to obtain the target compound (16 mg, 16%) in the form of microcrystals cream color, TPL 259-260° (found: M+, 363,1257. For C25H17NO2calculated M+, 363,1259). nmax(CVG) 2925, 2853, 1708, 1449, 1420, 1396, 1339, 1281, 1241, 1198, 1151, 1133, 1106, 1085, 1047 cm-1. NMR1H δ 7,58-7,55 m, 2 H; 7,51-7,50 m, 3 H; 7,40, DD, and 7.5 and 0.9 Hz, 1 H; 7,32-7,18 m, 4 H; 7,10, DD, J 7.8 and 1.2 Hz, 1 H; 7,01-6,97 m, 3 H; 4,88, t, J 6.9 Hz, 2 H; 3,21, t, J 6.9 Hz, 2 H. NMR13With δ was 155.3 (S), 151,2 (C)135,6 (C), 135,3 (C), 133,8 (C), 130,7 (CH), 129,4 (CH), 128,3 (CH), 128,1 (CH), 127,5 (C), 127,4 (CH), 126,9 (CH), 125,7 (CH), 123,7 (CH), 123,3 (CH), 118,2 (C)117,5 (C), 117,1 (CH), 42,3 (CH2), 29,3 (CH2) (three staggered or overlapping peak). Mass spectrum m/z 363 (100%) (M+).

2’-Bromophenyl 5,6-dihydro-1-phenylpyrrole[2,1-a]Sochi-nolin-3-carboxylate (16) and bromine{2’-(5’,6’-dihydro-1’-phenylpyrrole[2’,1’-a]isoquinoline-3’-carboxy)phenyl}bis(triphenylphosphine)palladium (17)

To a solution of compound (4) (230 mg ,438 mmol), NaOAc (80 mg, 0,975 mmol) and h3(460 mg, about 1.75 mmol) in DMF (20 ml) was added Pd(OAc)2(197 mg, 0.88 mmol). From the resulting solution pumped gas (1.0 mm Hg) and re-fill N2(gaseous) three times to remove dissolved oxygen and then heated in nitrogen atmosphere at 110°C for 19 h the Cooled reaction mixture is diluted with ethyl acetate (25 ml), then washed with brine (2×20 ml) and water (20 ml). Then the separated organic phase is dried (gSO4), filtered and concentrated under reduced pressure over silica (2 g). When cleaning the obtained substances flash chromatography (silica, elution with a mixture of 1:2, then 1:1 CH2Cl2/hexane, then 4:1 CH2CL2/ethyl acetate) to obtain two fractions, a and B.

When the concentration of fraction A (Rf0.6 elution with a mixture of 2:1 CH2Cl2/hexane) to obtain compound (16) (34 mg, 17%) as off-white crystalline mass, so pl. 130-131° (Found: M+, 443,0529. For C25H2879BrNO2calculated M+, 443,0521). nmax(CVG) 2950, 1710, 1471, 1439, 1418, 1240, 1212, 1176, 1046 cm-1. NMR1N δ EUR 7.57, DD, J 8.1 and 1.5 Hz, 1 H; 7,45-7,05, m, 12 H; 6,95, Shir. t, J 8.1 Hz, 1 H; 4,57, t, J 6.3 Hz, 2 H; 3,05, t, J 6.3 Hz, 2 H. NMR13With δ 158,5 (C), 148,1 (C), 136,1 (C), 133,4 (C), 133,3 (SK), 132,9 (C), 129,1 (SN), of 128.6 (C), 128,4 (CH), 128,1 (C), to 127.9 (CH), of 127.7 (CH), 127,1 (CH), 126,9 (SN), a 126.7 (CH), output reached 125.5 (CH),to 124.2 (CH), to 123.5 (C), 121,3 (CH), 119,4 (C)Of 116.7 (C)42,4 (CH2)and 29.5 (CH2). Mass spectrum m/z 445(10%) 443 (9) (M+); 272 (100) [(M-C6H4BrO)+].

When the concentration of fraction B (Rf0,1, elution CH2Cl2) get the connection (17) (40 mg, 8,5%) as off-white crystalline mass, TPL 159-162°C. nmax(CVG) 3052, 2923, 1705, 1481, 1435, 1416, 1238, 1172, 1095, 1058, 1024 cm-1. NMR1H δ the 7.65 7,40, m, 18 H; 7,30-7,05, m, 22 H; 6,58 m, 1 H; 6,52, t, J 6.6 Hz, 1 H; 6,39 m, 1 H; 6,07, kV, J 6.6 Hz, 1 H; 4,73, m, 2H; 3,05 m, 2 H. NMR13With δ 159,2 (C), To 151.8 (S), 138,3 (SN), to 136.5 (C), 134,8 (CH), 133,2 (C), 131,8 (C), 131, 5mm (C), 131,0 (C), 129, 9mm (CH), 129,8 (SN), of 129.5 (CH), 129,0 (CH), 128,7 (C), 127,8 (SN), of 127.5 (CH), to 127.2 (CH), 127,0 (CH), 125,7 (CH), 125,0 (SN), of 123.2 (C), 123,0 (CH), 121,9 (CH), 121, 1million (C)of 120.5 (CH), 42,2 (CH2), and 29.7 (CH2). Mass spectrum m/z 365 (6) [(M-Pd(PPh3)2Br+H)+]; 277 (26); 272 (32) {[M-C6H4Od(h3)2VG]+}; 262 (100) (Ph3P+).

1-Phenylpyrrole[2,1-a]isoquinoline (18) and 1-[2’-(2’-bromophenyl)ethyl]-4-phenylpyrrole (19)

A solution of dibromide (4) (13 mg, 25 mmol), TRANS-di(m-acetato)-bis[o-(di-o-tolylphosphino)benzyl]diplegia (11) Chem. Eur. J. 1997, 3, 1357, (2.5 mg, 2.5 mmol) and anhydrous sodium acetate (6.2 mg, 75 mmol) in degassed N,N-dimethylacetamide (0.25 ml) is heated in a nitrogen atmosphere at 140°C for 72 hours, then cooled reaction mixture is diluted with diethyl ether (5 ml) and the resulting solution was washed with a mixture of RA the Sol/water (3× 5 ml of a mixture 1:1 V/V). Then the organic phase is dried (gSO4), filtered and concentrated under reduced pressure, obtaining a light yellow oil. After purification of this substance flash chromatography (silica, elution with a mixture of 3:7, then 7:3 CH2CL2/hexane) receive, after concentration of appropriate fractions (Rf0,7, elution with a mixture of 3:7 CH2Cl2/hexane), a mixture of 1:3 compounds (18) and (19) (4 mg, total yield 52%) as a light yellow and volatile oils. nmax(CVG) 1705, 41,2, 1555, 1500, 1471, 1441, 1359, 1202, 1071, 1027, 751, 694, 655 cm-1. NMR1H δ [compound (18)] 7,60-6,95, complex m, 9 H; 6,92, t, J 2.0 Hz, 1 H, H-2; 6,63, t, J 1.6 Hz, 1 H, H-5; to 6.43, broadened t, J 2.3 Hz, 1 H, H-4; 4,14, t, J 7.7 Hz, 2 H; [compound (19)] 7,60-6,95, complex m, 9 H; of 6.73, d, J 2,7 Hz, 1 H, H-3; 6,23, d, J 2.7 Hz, 1 H, H-2; 4,08, t, J 7.7 Hz, 2 H; 3,10, t, J 7.7 Hz, 2 H. GH/MS [compound (18)] (Rfto 4.52 min) 245 (100) (M+.), 167 (21), 149 (28), 120 (6); [the compound (19)] (Rfto 5.85 min) 327 (12) 325 (12) (M+.), 246 (100) [(M-Br.)+].

Throughout this description and the subsequent claims, if the context does not imply the other, the word “include” and variations such as “comprises” and “comprising”should be understood to mean the inclusion of a stated integer or a stage, or group of integers or steps, but not as excluding any other integer or stage, or group of integers or steps.

Experts in this field will be clear, what is described here, the invention allows changes and modifications other than those specifically described. You must understand that the invention includes all such changes and modifications. In addition, this invention includes all stages, features, compositions and compounds referred to or indicated herein, individually or collectively, and any and all combinations of any two or more of these stages or features.

1. The method of obtaining the compounds of formula (II)

including the stage of carrying out intramolecular cyclization of compounds of formula (I):

in which RA1RA2C-CRA3RA4form an aryl group, optional

substituted by the Deputy, or an aromatic 3-6-membered heterogenities group with one nitrogen atom, optionally substituted Deputy;

Y is selected from hydrogen; C1-20the alkyl, optionally substituted by Deputy; C2-20alkenyl, optionally substituted Deputy; C2-20the quinil, optionally substituted Deputy; hydroxy; amino, optionally substituted Deputy; C1-20alkoxy, optionally substituted Deputy; C2-20alkenone, neoba is consequently replaced by Deputy; With2-20alkyloxy, optionally substituted Deputy; aryl, optionally substituted Deputy; a saturated or unsaturated 3-6 membered heterophilically group with one nitrogen atom, optionally substituted Deputy; carboxy; complex carboxyamide; carboxamide; C1-20acyl; C1-20acyloxy; mercapto; C1-20alkylthio, optionally substituted Deputy; halogen; nitro; sulfate; phosphate and cyano; W and X together with the nitrogen atoms and the carbon to which they are linked, form a group selected from hyalinella group, optionally substituted by Deputy; ethanolamines group, optionally substituted by Deputy; dihydroquinoline group, optionally substituted by Deputy; dihydroisoquinolyl group, optionally substituted by Deputy; peredelnoj group, optionally substituted by a Deputy, or dihydro or tetrahydropyrimidine of these structures, or phenanthridine, optionally substituted Deputy;

where specified not necessarily present Deputy selected from C1-20of alkyl, C2-20alkenyl,2-20the quinil, aryl, halogen, halogen1-20of alkyl, Halogens2-20alkenyl, Halogens1-20the quinil, halogenfree, hydroxy, C1-20alkoxy, C2-20alkenylacyl, aryloxy, benzyloxy, who Halogens 1-20alkoxy, Halogens1-20alkenylacyl, halogenations, nitro, nitros1-20of alkyl, nitros2-20alkenyl, nitros2-20the quinil, nitrourea, nitro(3-6-membered getelementstyle with one nitrogen atom), amino, C1-20alkylamino, dis1-20alkylamino,2-20alkenylamine,2-20alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino,1-20acyl, C2-20alkenylacyl,2-20alkenylacyl, Ariella,1-20acylamino, dis1-20acylamino,1-20acyloxy,1-20alkylsulfonate, arylsulfonate, 3-6-membered getelementstyle with one nitrogen atom, (3-6-membered heterogenity with one nitrogen atom)hydroxy, (3-6-membered heterogenity with one nitrogen atom), amino, halogen(3-6-membered getelementstyle with one nitrogen atom)1-20alkylsulfanyl, arylsulfenyl, carbos1-20alkyloxy, barbarians, mercapto, C1-20alkylthio, benzylthio,1-20atillio, cyano, sulfate and phosphate;

V is a halogen atom or a hydrogen atom;

Z is selected from NH or O.

2. The method according to claim 1, in which W and X together with the nitrogen atoms and the carbon to which they are linked, form athinodorou or dihydroisoquinolyl group of General formula (i):

where R1- R4and R14defined is for Y in claim 1, andrepresents an optional double bond.

3. The method according to claim 2, in which R1- R4independently selected from the group consisting of hydrogen; hydroxy; C1-20the alkyl, optionally substituted by Deputy; C1-20alkyloxy, optionally substituted Deputy; C1-20acyloxy; carboxy; complex carboxyamide; amino, optionally substituted Deputy; carboxamido or sulfate; and R14is hydrogen or hydroxy,

where specified not necessarily present Deputy selected from C1-20of alkyl, C2-20alkenyl,2-20the quinil, aryl, halogen, halogen1-20of alkyl, Halogens2-20alkenyl, Halogens1-20the quinil, halogenfree, hydroxy, C1-20alkoxy, C2-20alkenylacyl, aryloxy, benzyloxy, halogen1-20alkoxy, Halogens1-20alkenylacyl, halogenations, nitro, nitros1-20of alkyl, nitros2-20alkenyl, nitros2-20the quinil, nitrourea, nitro(3-6-membered getelementstyle with one nitrogen atom), amino, C1-20alkylamino, dis1-20alkylamino,2-20alkenylamine,2-20alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino,1-20acyl, C2-20alkenylacyl,2-20alkenylacyl, Ariella,1-20acylamino, dis1-20the atilov is but With1-20acyloxy,1-20alkylsulfonate, arylsulfonate, 3-6-membered getelementstyle with one nitrogen atom, (3-6-membered heterogenity with one nitrogen atom)hydroxy, (3-6-membered heterogenity with one nitrogen atom), amino, halogen(3-6-membered getelementstyle with one nitrogen atom)1-20alkylsulfanyl, arylsulfenyl, carbos1-20alkyloxy, barbarians, mercapto, C1-20alkylthio, benzylthio,1-20atillio, cyano, sulfate and phosphate.

4. The method of obtaining the compounds of formula (IIA):

including the state of the two intramolecular ciclisti in the compound of formula (Ia):

where

RA1- RA4, V, Y, Z are defined in claim 1;

RB1RB2C-CRB3RB4form an aryl group optionally substituted by the Deputy, or an aromatic 3-6-membered heterogenities group with one nitrogen atom, optionally substituted Deputy

where specified not necessarily present Deputy selected from C1-20of alkyl, C2-20alkenyl,2-20the quinil, aryl, halogen, halogen1-20of alkyl, Halogens2-20alkenyl, Halogens1-20the quinil, halogenfree, hydroxy, C1-20alkoxy, C2-20alkenylacyl, aryloxy, Benz is lexi, Halogens1-20alkoxy, Halogens1-20alkenylacyl, halogenations, nitro, nitros1-20of alkyl, nitros2-20alkenyl, nitros2-20the quinil, nitrourea, nitro(3-6-membered getelementstyle with one nitrogen atom), amino, C1-20alkylamino, dis1-20alkylamino,2-20alkenylamine,2-20alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino,1-20acyl, C2-20alkenylacyl,2-20alkenylacyl, Ariella,1-20acylamino, dis1-20acylamino,1-20acyloxy,1-20alkylsulfonate, arylsulfonate, 3-6-membered getelementstyle with one nitrogen atom, (3-6-membered heterogenity with one nitrogen atom)hydroxy, (3-6-membered heterogenity with one nitrogen atom), amino, halogen(3-6-membered getelementstyle with one nitrogen atom)1-20alkylsulfanyl, arylsulfenyl, carbos1-20alkyloxy, barbarians, mercapto, C1-20alkylthio, benzylthio,1-20atillio, cyano, sulfate and phosphate, and

m is 2.

5. The method according to claim 4, in which RB1RB2C-CRB3RB4form an aryl group or an aromatic 3-6-membered heterogenities a single nitrogen atom, and the specified group chosen from benzene or naphthalene ring optionally substituted by a Deputy, or pyridine, optionally Zam the seal Deputy; or pyrrole, optionally substituted Deputy, and their condensed with benzene analogues,

where specified not necessarily present Deputy selected from C1-20of alkyl, C2-20alkenyl,2-20the quinil, aryl, halogen, halogen1-20of alkyl, Halogens2-20alkenyl, Halogens1-20the quinil, halogenfree, hydroxy, C1-20alkoxy, C2-20alkenylacyl, aryloxy, benzyloxy, halogen1-20alkoxy, Halogens1-20alkenylacyl, halogenations, nitro, nitros1-20of alkyl, nitros2-20alkenyl, nitros2-20the quinil, nitrourea, nitro(3-6-membered getelementstyle with one nitrogen atom), amino, C1-20alkylamino, dis1-20alkylamino,2-20alkenylamine,2-20alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino,1-20acyl, C2-20alkenylacyl,2-20alkenylacyl, Ariella. With1-20acylamino, dis1-20acylamino,1-20acyloxy,1-20alkylsulfonate, arylsulfonate, 3-6-membered getelementstyle with one nitrogen atom, (3-6-membered heterogenity with one nitrogen atom)hydroxy, (3-6-membered heterogenity with one nitrogen atom), amino, halogen(3-6-membered getelementstyle with one nitrogen atom)1-20alkylsulfanyl, arylsulfenyl, carbos1-20alkyloxy, barbarians, markup is about, With1-20alkylthio, benzylthio,1-20atillio, cyano, sulfate and phosphate.

6. The method according to claim 5, in which RB1RB2C-CRB3RB4form a benzene group, optionally substituted Deputy, selected from C1-20of alkyl, C2-20alkenyl,2-20the quinil, aryl, halogen, halogen1-20of alkyl, Halogens2-20alkenyl, Halogens1-20the quinil, halogenfree, hydroxy, C1-20alkoxy, C2-20alkenylacyl, aryloxy, benzyloxy, halogen1-20alkoxy, Halogens1-20alkenylacyl, halogenations, nitro, nitros1-20of alkyl, nitros2-20alkenyl, nitros2-20the quinil, nitrourea, nitro(3-6-membered getelementstyle with one nitrogen atom), amino, C1-20alkylamino, dis1-20alkylamino,2-20alkenylamine,2-20alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino,1-20acyl, C2-20alkenylacyl,2-20alkenylacyl, Ariella,1-20acylamino, dis1-20acylamino,1-20acyloxy,1-20alkylsulfonate, arylsulfonate, 3-6-membered getelementstyle with one nitrogen atom, (3-6-membered heterogenity with one nitrogen atom)hydroxy, (3-6-membered heterogenity with one nitrogen atom), amino, halogen(3-6-membered heterogenity with one nitrogen atom)1-20alkyls of lifesyle, arylsulfenyl, who arbos 1-20alkyloxy, barbarians, mercapto, C1-20alkylthio, benzylthio,1-20atillio, cyano, sulfate and phosphate.

7. The method according to claim 6, in which the substituents are selected from hydrogen; hydroxy; C1-20the alkyl, optionally substituted by Deputy; C1-20alkyloxy, optionally substituted Deputy; C1-20acyloxy; carboxy; complex carboxyamide; amino, optionally substituted Deputy; carboxamido; or sulfate,

where specified not necessarily present Deputy selected from C1-20of alkyl, C2-20alkenyl,2-20the quinil, aryl, halogen, halogen1-20of alkyl, Halogens2-20alkenyl, Halogens1-20the quinil, halogenfree, hydroxy, C1-20alkoxy, C2-20alkenylacyl, aryloxy, benzyloxy, halogen1-20alkoxy, Halogens1-20alkenylacyl, halogenations, nitro, nitros1-20of alkyl, nitros2-20alkenyl, nitros2-20the quinil, nitrourea, nitro(3-6-membered getelementstyle with one nitrogen atom), amino, C1-20alkylamino, dis1-20alkylamino,2-20alkenylamine,2-20alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino,1-20acyl, C2-20alkenylacyl,2-20alkenylacyl, Ariella,1-20acylamino, dis1-20acylamino,1-20acyloxy,1-20alcalali is aryloxy, arylsulfonate, 3-6-membered getelementstyle with one nitrogen atom, (3-6-membered heterogenity with one nitrogen atom)hydroxy, (3-6-membered heterogenity with one nitrogen atom), amino, halogen(3-6-membered getelementstyle with one nitrogen atom)1-20alkylsulfanyl, arylsulfenyl, carbos1-20alkyloxy, barbarians, mercapto, C1-20alkylthio, benzylthio,1-20atillio, cyano, sulfate and phosphate.

8. The method according to claim 1, in which Y is a phenyl group of formula (II):

where R9- R13defined as R1- R4item 2.

9. The method according to claim 1, in which Y is a phenyl group of formula (II):

where R9- R13defined as R1- R4in item 4.

10. The method according to claim 8, in which R9- R13independently selected from hydrogen; hydroxy; C1-20the alkyl, optionally substituted by Deputy; C1-20alkoxy, optionally substituted Deputy; C1-20acyloxy; carboxy; complex carboxyamide; amino, optionally substituted Deputy; carboxamido or sulfate,

where specified not necessarily present Deputy selected from C1-20of alkyl, C2-20alkenyl,2-20the quinil, aryl, halogen, halogen1-20of alkyl,Halogens 2-20alkenyl, Halogens1-20the quinil, halogenfree, hydroxy, C1-20alkoxy, C2-20alkenylacyl, aryloxy, benzyloxy, halogen1-20alkoxy, Halogens1-20alkenylacyl, halogenations, nitro, nitros1-20of alkyl, nitros2-20alkenyl, nitros2-20the quinil, nitrourea, nitro(3-6-membered getelementstyle with one nitrogen atom), amino, C1-20alkylamino, dis1-20alkylamino,2-20alkenylamine,2-20alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino,1-20acyl, C2-20alkenylacyl,2-20alkenylacyl, Ariella,1-20acylamino, dis1-20acylamino,1-20acyloxy,1-20alkylsulfonate, arylsulfonate, 3-6-membered getelementstyle with one nitrogen atom, (3-6-membered heterogenity with one nitrogen atom)hydroxy, (3-6-membered heterogenity with one nitrogen atom), amino, halogen(3-6-membered getelementstyle with one nitrogen atom)1-20alkylsulfanyl, arylsulfenyl, carbos1-20alkyloxy, barbarians, mercapto, C1-20alkylthio, benzylthio,1-20atillio, cyano, sulfate and phosphate.

11. The method according to claim 10, in which R12- R13independently selected from hydrogen, hydroxy, methoxy, ethoxy, isopropoxy, methyl, ethyl, n-propyl, isopropyl, acetoxy or sulfate.

12. The way of getting to generowania polycyclic errorcodehex the compounds of formula (IIb):

including the state of the two intramolecular ciclisti in the compound of formula (Ib):

where V is halogen or hydrogen, and R1-R14independently selected from hydrogen, C1-20the alkyl, optionally substituted by Deputy; C2-20alkenyl, optionally substituted Deputy; C2-20the quinil, optionally substituted Deputy; hydroxy; amino, optionally substituted Deputy; C1-20alkoxy, optionally substituted Deputy; C2-20alkenone, optionally substituted Deputy; C2-20alkyloxy, optionally substituted Deputy; aryl, optionally substituted Deputy; a saturated or unsaturated 3-6 membered heterophilically group with one nitrogen atom, optionally substituted Deputy; carboxy; complex carboxyamide; carboxamido; C1-20acyl; C1-20acyloxy; mercapto, C1-20alkylthio, optionally substituted Deputy; halogen, nitro, sulphate, phosphate and cyano,

where specified not necessarily present Deputy selected from C1-20of alkyl, C2-20alkenyl,2-20the quinil, aryl, halogen, halogen1-20of alkyl, Halogens2-20alkenyl, Halogens1-20 the quinil, halogenfree, hydroxy, C1-20alkoxy, C2-20alkenylacyl, aryloxy, benzyloxy, halogen1-20alkoxy, Halogens1-20alkenylacyl, halogenations, nitro, nitros1-20of alkyl, nitros2-20alkenyl, nitros2-20the quinil, nitrourea, nitro(3-6-membered getelementstyle with one nitrogen atom), amino, C1-20alkylamino, dis1-20alkylamino,2-20alkenylamine,2-20alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino, C1-20acyl, C2-20alkenylacyl,2-20alkenylacyl, Ariella, C1-20acylamino, dis1-20acylamino,1-20acyloxy,1-20alkylsulfonate, arylsulfonate, 3-6-membered getelementstyle with one nitrogen atom, (3-6-membered heterogenity with one nitrogen atom)hydroxy, (3-6-membered heterogenity with one nitrogen atom), amino, halogen(3-6-membered getelementstyle with one nitrogen atom)1-20alkylsulfanyl, arylsulfenyl, carbos1-20alkyloxy, barbarians, mercapto, C1-20alkylthio, benzylthio,1-20atillio, cyano, sulfate and phosphate, and

optional dehydrogenization product cyclization with the formation of the compounds of formula (Ib), in which there is an optional double bond.

13. The method according to item 12 in which R1-R14regardless you who eraut from hydrogen; hydroxy; C1-20the alkyl, optionally substituted by Deputy; C1-20alkyloxy, optionally substituted Deputy; C1-20acyloxy; carboxy; complex carboxyamide; amino, optionally substituted Deputy; carboxamide or sulfate, preferably, R1-R13independently selected from hydrogen; hydroxy; C1-20of alkyl, such as methyl, ethyl or propyl, optionally substituted by Deputy; C1-20alkyloxy, such as methoxy, ethoxy, n-propoxy, ISO-propoxy, optionally substituted Deputy; C1-20acyloxy, such as acetoxy; or sulfate, and R14preferably is hydrogen or hydroxy, and V is bromine, iodine or hydrogen

where specified not necessarily present Deputy selected from C1-20of alkyl, C2-20alkenyl,2-20the quinil, aryl, halogen, halogen1-20of alkyl, Halogens2-20alkenyl, Halogens1-20the quinil, halogenfree, hydroxy, C1-20alkoxy, C2-20alkenylacyl, aryloxy, benzyloxy, halogen1-20alkoxy, Halogens1-20alkenylacyl, halogenations, nitro, nitros1-20of alkyl, nitros2-20alkenyl, nitros2-20the quinil, nitrourea, nitro(3-6-membered getelementstyle with one nitrogen atom), amino, C1-20alkylamino, dis1-20alkylamino, 2-20alkenylamine,2-20alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino,1-20acyl, C2-20alkenylacyl,2-20alkenylacyl, Ariella,1-20acylamino, dis1-20acylamino,1-20acyloxy,1-20alkylsulfonate, arylsulfonate, 3-6-membered getelementstyle with one nitrogen atom, (3-6-membered heterogenity with one nitrogen atom)hydroxy, (3-6-membered heterogenity with one nitrogen atom), amino, halogen(3-6-membered getelementstyle with one nitrogen atom)1-20alkylsulfanyl, arylsulfenyl, carbos1-20alkyloxy, barbarians, mercapto, C1-20alkylthio, benzylthio,1-20atillio, cyano, sulfate and phosphate.

14. The method according to claim 1, in which Z is oxygen.

15. The method according to claim 4, in which Z is oxygen.

16. The method according to claim 1, wherein each V is independently hydrogen, bromine or iodine.

17. The method according to claim 4, in which each V independently is hydrogen, bromine or iodine.

18. The method according to item 12, wherein each V is independently hydrogen, bromine or iodine.

19. The method according to claim 1, in which V is hydrogen, and the cyclization is carried out in oxidizing conditions.

20. The method according to claim 1, in which V is a halogen atom, preferably bromine or iodine, and the cyclization is carried out through the generation of a radical of the formula (I).

21. The way p is 1, where V is a halogen atom, preferably bromine or iodine, and the cyclization is carried out through the Pd[0]-catalyzed process.

22. The method according to claim 4, in which both V is halogen, preferably bromine or iodine, and two cyclization is carried out in one flask.

23. The method according to item 12, in which both V is halogen, preferably bromine or iodine, and two cyclization is carried out in one flask.

24. The method according to p, which is held in one flask double cyclization is Pd[0]-catalyzed.

25. The compound of formula (Ia):

where RA1- RA4, RB1- RB4, V, Y and m are defined in claim 4, a Z is O.

26. Connection A.25, in which RA1RA2C-CRA3RA4form a benzene ring group optionally substituted by the Deputy, is selected from C1-20of alkyl, C2-20alkenyl,2-20the quinil, aryl, halogen, halogen1-20of alkyl, Halogens2-20alkenyl, Halogens1-20the quinil, halogenfree, hydroxy, C1-20alkoxy, C2-20alkenylacyl, aryloxy, benzyloxy, halogen1-20alkoxy, Halogens1-20alkenylacyl, halogenations, nitro, nitros1-20of alkyl, nitros2-20alkenyl, nitros2-20the quinil, nitrourea, nitro(3-6-membered getelementstyle with one nitrogen atom), amino, C1-20alkylamino, dis 1-20alkylamino,2-20alkenylamine,2-20alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino,1-20acyl, C2-20alkenylacyl,2-20alkenylacyl, Ariella,1-20acylamino, dis1-20acylamino,1-20acyloxy,1-20alkylsulfonate, arylsulfonate, 3-6-membered getelementstyle with one nitrogen atom, (3-6-membered heterogenity with one nitrogen atom)hydroxy, (3-6-membered heterogenity with one nitrogen atom), amino, halogen(3-6-membered getelementstyle with one nitrogen atom)1-20alkylsulfanyl, arylsulfenyl, carbos1-20alkyloxy, barbarians, mercapto, C1-20alkylthio, benzylthio,1-20atillio, cyano, sulfate and phosphate.

27. The compound of formula (Ib):

where

R1- R14independently selected from hydrogen; C1-20the alkyl, optionally substituted by Deputy; optionally substituted C2-20alkenyl, optionally substituted Deputy; C2-20the quinil, optionally substituted Deputy; hydroxy; amino, optionally substituted Deputy; C1-20alkoxy, optionally substituted Deputy; C2-20alkenone, optionally substituted Deputy; C2-20alkyloxy, optionally substituted by Deputy; and the sludge, optionally substituted by a Deputy; a saturated or unsaturated 3-6 membered heterophilically group with one nitrogen atom, optionally substituted Deputy; carboxy; complex carboxyamide; carboxamido; C1-20acyl, C1-20acyloxy, mercapto, C1-20alkylthio, optionally substituted Deputy; halogen, nitro, sulphate, phosphate and cyano;

where specified not necessarily present Deputy selected from C1-20of alkyl, C2-20alkenyl,2-20the quinil, aryl, halogen, halogen1-20of alkyl, Halogens2-20alkenyl, Halogens1-20the quinil, halogenfree, hydroxy, C1-20alkoxy, C2-20alkenylacyl, aryloxy, benzyloxy, halogen1-20alkoxy, Halogens1-20alkenylacyl, halogenations, nitro, nitros1-20of alkyl, nitros2-20alkenyl, nitros2-20the quinil, nitrourea, nitro(3-6-membered getelementstyle with one nitrogen atom), amino, C1-20alkylamino, dis1-20alkylamino,2-20alkenylamine,2-20alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino,1-20acyl, C2-20alkenylacyl,2-20alkenylacyl, Ariella,1-20acylamino, dis1-20acylamino,1-20acyloxy, C1-20alkylsulfonate, arylsulfonate, 3-6-membered getelementstyle with one ATO is ω nitrogen, (3-6-membered heterogenity with one nitrogen atom)hydroxy, (3-6-membered heterogenity with one nitrogen atom), amino, halogen(3-6-membered getelementstyle with one nitrogen atom), C1-20alkylsulfanyl, arylsulfenyl, carbos1-20alkyloxy, barbarians, mercapto, C1-20alkylthio, benzylthio, C1-20atillio, cyano, sulfate and phosphate, and V is halogen or hydrogen,

28. Connection item 27, in which R1- R14independently selected from hydrogen; hydroxyl; C1-20the alkyl, optionally substituted by Deputy; C1-20alkyloxy, optionally substituted Deputy; C1-20acyloxy; carboxy; complex carboxyamide; amino, optionally substituted Deputy; carboxamido or sulfate, preferably, R1- R13independently selected from hydrogen; hydroxyl; C1-20of alkyl, such as methyl, ethyl or propyl, optionally substituted by Deputy; C1-20alkyloxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, optionally substituted; With1-20acyloxy, such as acetoxy; or sulfate, a R preferably is hydrogen or hydroxy; and V is bromine, iodine or hydrogen.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new substance eliciting an antiviral and antibacterial activity that is based on derivatives of 2,8-dithioxo-1H-pyrano[2,3-d;6,5-d']dipyrimidine and their 10-aza-analogues. This substance comprises derivative of indicated group of the general formula: A1*M: wherein X is taken among the group: oxygen atom (O), NH, N-alkyl; R1 is taken among the group: hydrogen atom (H), OH, chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, NH-Ar, N-(alkyl)2, SH, S-alkyl; R2 is taken among the group: unsubstituted or substituted phenyl, naphthyl, thienyl; R3 is taken among the group: hydrogen atom (H), chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, S-dihydroxypyrimidinyl; M is absent or taken among the group: cation Na, K, Li, ammonium or any other pharmacologically acceptable cation; or complex of pharmacologically acceptable cation (see above) with anion of one of derivatives of A1 (variants R1-R3 are given above). Invention provides preparing new compounds eliciting an antiviral and antibacterial activity.

EFFECT: valuable medicinal properties of substance.

17 cl, 7 tbl, 16 ex

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The invention relates to the field of macrolides

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compound of the formula (I): wherein cycle A represents imidazo[1,2-a]pyrid-3-yl or pyrazole[2,3-a]pyrid-3-yl; R2 is joined to cyclic carbon atom and taken among halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkyl-S(O)a wherein a = 0, phenyl, phenylthio- or (heterocyclic group)-thio-group wherein any (C1-C6)-alkyl, phenyl or heterocyclic group can be substituted optionally by carbon atom with one or some G wherein heterocyclic group represents saturated, partially saturate or unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least atom is taken among nitrogen, sulfur or oxygen atom that can be bound if another variants are not specified with unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least one atom is taken among nitrogen, sulfur or oxygen atoms that can be bound if another variants are not specified with carbon or nitrogen atom wherein group -CH2- can be substituted optionally with -C(O)- and cyclic atom can carry optionally (C1-C6)-alkyl group and to form quaternary compound, or cyclic atom of nitrogen and/or sulfur can be oxidized to form N-oxide and/or S-oxides; m = 0-2 and R2 values can be similar or different; R1 means halogen atom, (C1-C3)-alkyl-S(O)a wherein a = 0 wherein any (C1-C3)-alkyl can be substituted optionally by carbon atom with one or some J; n = 0-1; cycle B represents phenyl or phenyl condensed with (C5-C7)-cycloalkyl cycle; R3 means halogen atom or sulfamoyl; p = 0-2 and R3 values can be similar or different; R4 means group A-E- wherein A is taken among (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heterocyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl wherein (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heteroccyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl can be substituted optionally by carbon atom with one or some D and wherein above mentioned heterocyclic group comprises fragment -NH- then nitrogen atom can be substituted optionally with group taken among R; E means a simple bond or -O-, -C(O)-, -N(Ra)C(O)- or -N(Ra)SO2-, -S(O)r wherein Ra means hydrogen atom or (C1-C6)-alkyl and r = 0-2; D is taken independently among hydroxy-, amino- (C1-C6)-alkoxy-, N-(C1-C6-alkyl)-amino-, N,N-(C1-C6-alkyl)-amino-, (C1-C6)-alkoxycarbonylamino- and benzyloxycarbonylamino-group wherein any (C1-C6)-alkyl or phenyl can be substituted optionally by carbon atom with one or some K; q = 0-1; G, J and K are taken independently among hydroxy-, dimethylamino-, diethylamino-group; R is taken among (C1-C4)-alkyl; or its pharmaceutically acceptable salt. Invention proposes applying pyrimidine compounds for inhibition of activity of kinases CDK2, CDK4 and CDK6 in cellular cycle eliciting anti-proliferative properties. Indicated properties have value in treatment of cancer diseases (solid tumors and leukemia), fibroproliferative and differential disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial repeated stenosis, osseous and ophthalmic diseases with proliferation of cellular tissue in vessels.

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22 cl, 99 ex

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23 cl, 10 tbl, 231 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes 8-cyclo-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I):

in crystalline modification D and a medicinal agent based on thereof eliciting effect against pathogenic microorganisms. The prepared crystalline form of compound of the formula (I) shows low hygroscopicity and can be processed to galenic preparations easily and it has the highest filled density and satisfied fluidity.

EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 ex

FIELD: organic chemistry, medicine pharmacy.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid in the crystalline modification C of the formula (I):

and a medicinal agent eliciting effect against pathogenic microorganisms. This crystalline modification of compound of the formula (I) elicits low hygroscopicity, satisfied friability and can be processed easily to galenic preparations.

EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 tbl, 1 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I):

in the crystalline modification B and a medicinal agent based on thereof that elicits effect against pathogenic microorganisms. Indicated modification of compound of the formula (I) shows stability and insignificant absorption of air moisture ant doesn't convert to another crystalline modification or amorphous form being even in the prolonged storage.

EFFECT: valuable properties of agent.

4 cl, 4 dwg, 6 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S)-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I): with the crystalline modification A and a drug eliciting effect against pathogenic microorganisms. The prepared crystalline modification shows stability and doesn't transform to another crystalline modification or amorphous form being even at prolonged storage.

EFFECT: improved and valuable properties of compound.

4 cl, 4 dwg, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new substance eliciting an antiviral and antibacterial activity that is based on derivatives of 2,8-dithioxo-1H-pyrano[2,3-d;6,5-d']dipyrimidine and their 10-aza-analogues. This substance comprises derivative of indicated group of the general formula: A1*M: wherein X is taken among the group: oxygen atom (O), NH, N-alkyl; R1 is taken among the group: hydrogen atom (H), OH, chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, NH-Ar, N-(alkyl)2, SH, S-alkyl; R2 is taken among the group: unsubstituted or substituted phenyl, naphthyl, thienyl; R3 is taken among the group: hydrogen atom (H), chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, S-dihydroxypyrimidinyl; M is absent or taken among the group: cation Na, K, Li, ammonium or any other pharmacologically acceptable cation; or complex of pharmacologically acceptable cation (see above) with anion of one of derivatives of A1 (variants R1-R3 are given above). Invention provides preparing new compounds eliciting an antiviral and antibacterial activity.

EFFECT: valuable medicinal properties of substance.

17 cl, 7 tbl, 16 ex

The invention relates to (DL)-1-hydroxy-3,7,7,9,9-pentamethyl-1,4,8-diazaspiro[4.5]decane-2-ONU formula (1)

The invention relates to crystalline polyhydroxylated 8-cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid of formula (VI)

The invention relates to a method for the synthesis of nitrogen-containing heterocyclic compounds, in particular the production of substituted pyrido[1,2-][1,3] benzimidazole of General formula

where 1 R=NO2, R1=H;

2 R=CF3, R1=H;

3 R=CN, R1=H;

4 R=R1=CN

FIELD: organic synthesis.

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EFFECT: expanded atorvastatine synthesis possibilities.

16 cl, 2 dwg, 5 ex

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