Method for producing macrocyclic compounds

FIELD: medicine, pharmaceutics.

SUBSTANCE: present patent claim discloses sulphonyl-substituted compounds of formula QUIN which are used for the purpose of a method for producing a macrocyclic compound of formula (I)

EFFECT: compounds of formula (I) are effective active agents for treating Hepatitis C viral (HCV) infection.

8 cl, 1 ex

 

This application claims the benefit of provisional patent application U.S. No. 60/659,696, registered March 8, 2005

Background of invention

1. The technical field to which the invention relates.

The present invention relates to an improved process for the preparation of macrocyclic compounds applicable as agents for the treatment of viral infections hepatitis C (HCV).

2. Supporting information

Macrocyclic compounds of the following formulas (I) and methods for their production are known from Tsantrizos, and others, U.S. patent No. 6,608,027 B1, Llinas Brunet and others, application for U.S. patent No. 2003/0224977 A1, Llinas Brunet and others, application for U.S. patent No. 2005/0075279 A1, Llinas Brunet and others, application for U.S. patent No. 2005/0080005 A1, Brandenburg and others, application for U.S. patent No. 2005/0049187 A1 and Samstag, etc., U.S. patent application U.S. No. 2004/0248779 A1:

in which

W is CH or nitrogen,

L0is hydrogen, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen(C1-C6)alkyl, (C1-C6)alkoxygroup, (C3-C6)cycloalexie, hydroxy-group or N(R23)2where each of R23independently is H, (C1-C6)alkyl or (C3-C6)cycloalkyl,

L1L2independently of one another are hydrogen, halogen, (C1- 4)alkyl, -O-(C1-C4)alkyl or-S-(C1-C4)alkyl (sulfur is in any oxidized form), or

L0and L1or L0and L2can be covalently linked, forming together with the two carbon atoms to which they are attached, a 4-, 5 - or 6-membered carbocycle, where one or two (in the case of 5 - or 6-membered cycle) -CH2groups that are not associated directly with each other, can be independently replaced by-O - or-NRawhere Rais hydrogen or (C1-C4)- alkyl and where the above-mentioned cycle is optionally mono - or Disaese (C1-C4)alkyl,

R2is hydrogen, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen(C1-C6)alkyl, (C1-C6)thioalkyl, (C1-C6)alkoxygroup, (C3-C6)cycloalexie, (C2-C7)alkoxy(C1-C6)alkyl, (C6)or (C10)aryl or Het, where Het is a five-, six - or semiclean saturated or unsaturated heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur, and mentioned cycloalkyl, aryl or Het substituted R6where R6is hydrogen, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxygroup is Oh, (C3-C6)cycloalexie, NO2N(R7)2, NH-C(O)-R7or NH-C(O)-NH-R7where each of R7independently is hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, or R6is NH-C(O)-OR8where R8is (C1-C6)alkyl or (C3-C6)cycloalkyl,

R3is a hydroxy-group, NH2or a group of the formula-NH-R9where R9is (C6)or (C10)aryl, heteroaryl, -C(O)-R10, -C(O)-other10or-C(O)-OR10where R10is (C1-C6)alkyl or (C3-C6)cycloalkyl,

D is unsaturated alkalinous chain comprising from 5 to 10 atoms

R4is hydrogen or one, two or three substituents at any carbon atoms in the specified chain D, which Deputy independently selected from (C1-C6)alkyl, halogen(C1-C6)alkyl, (C1-C6)alkoxygroup, hydroxy-group, halogen, an amino group, carbonyl group, tigraphy and (C1-C6)thioalkyl, and

And is amidol formula-C(O)-NH-R11where R11selected from (C1-C8)alkyl, (C3-C6)cycloalkyl, (C6)or (C10)aryl, (C7-C16)arylalkyl and SO2R11Awhere R11Ais (C1-C8)alkyl, (C 3-C7)cycloalkyl or (C1-C6)alkyl(C3-C7)cycloalkyl,

or

A is a carboxylic acid or its pharmaceutically acceptable salt or a complex ester.

The compounds of formula (I) disclosed in the above patent documents as active agents for the treatment of viral infections hepatitis C (HCV). Disclosed methods of obtaining these compounds include a large number of stages of the synthesis. The problem to be solved by the present invention is directed, is to develop a practical and economical process for efficient production of these compounds with the minimum number of stages of synthesis and with sufficient final output product.

Brief description of the invention

It was found that the compounds of formula (I)described above can be obtained in a more efficient manner, if the synthesis is carried out using the following process substitution as a key step in the synthesis consists in the fact that the macrocyclic compound of the formula (3) interacts with sulfanilamidnam compound of formula QUIN

and, in those cases when a is a protected carboxyl group, the compound of formula (I) optional carry out the removal of the protective group under appropriate conditions in order to obtain compounds which ia of the formula (I), in which a is a carboxyl group, and in those cases when a is a carboxyl group in the final compound of formula (I), optional carry out the reaction mix this connection with a sulphonamide of the formula R11ASO2NH2in the presence of a suitable agent for combinations, such as carbodiimide reagents, tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea (TBTU) and hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (GATA), with the aim of obtaining the compounds of formula (I)in which a is-C(O)-NH-SO2R11A.

In this way also does not occur inversion of configuration at the hydroxyl group prolinnova fragment, which further simplifies this way and minimizes the problem of stereocontrol, and quinoline structural element is introduced into the molecule by the end of the process, thus minimizing the loss of expensive intermediate connection.

Detailed description of the invention

The definition of used terms and agreements.

Terms which are not specifically defined in the context, should be attributed to such values that would be assigned to a specialist in the relevant field in light of the present disclosure and context. Unless otherwise indicated, in the present description of the invention the following terms are adopted in the t values specified and adhered to the following agreement.

In groups, radicals or residues, as defined below, the designation of the number of carbon atoms is often preceded by the group. For example, (C1-C6)alkyl means alkyl group or moiety containing from 1 to 6 carbon atoms. Generally, for groups comprising two or more subgroups, the group, called the last, contains a provision according to which the radical forms of communication, for example, "thioalkyl" means a monovalent radical of the formula HS-alkyl-. Except as specifically stated below, have the force of generally accepted definitions of terms and are assumed and achieved the standard stable valence of the atoms in all the formulas and groups.

The term "(1-C6)alkyl"as used in the context by itself or in combination with another Deputy, means acyclic, unbranched or branched alkyl substituents containing from 1 to 6 carbon atoms, and includes, for example, methyl, ethyl, propyl, butyl, hexyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl.

The term "(3-C6)cycloalkyl"as used in the context by itself or in combination with another Deputy, means cycloalkenyl Deputy containing from three to six carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "unsaturated, alkylene the th chain." as used in the context, means the divalent alkanniny Deputy obtained by removing one hydrogen atom from each end of the mono - or polyunsaturated unbranched or branched aliphatic hydrocarbon, and includes, for example,- CH2-CH2-CH2-CH2-CH2-CH=CH - and-CH2-CH2-CH2-CH2-CH=CH-CH2-.

The term "(1-C6)alkoxygroup"as used in the context by itself or in combination with another Deputy, means the Deputy (C1-C6)alkyl-O-, in which alkyl is responsible as defined above containing up to six carbon atoms. Alkoxygroup includes a methoxy group, ethoxypropan, propoxylate, 1-methylethoxy, butoxypropyl and 1,1-dimethylaminopropyl. The last Deputy commonly known as tert-butoxypropan.

The term "(3-C6)cycloalkanes"as used in the context by itself or in combination with another Deputy, means the Deputy (C3-C6)cycloalkyl-About-containing 3 to 6 carbon atoms.

The term "(2-C7)alkoxy(C1-C6)alkyl"as used in the context, means the Deputy (C2-C7)alkyl-O-(C1-C6)alkyl, in which alkyl meets the above definition, with the containing a series of up to six carbon atoms.

The term "haloalkyl"as used in the context by itself or in combination with another Deputy, means acyclic, unbranched or branched alkyl substituents in which one or more hydrogen atoms substituted by halogen selected from bromine, chlorine, fluorine or iodine.

The term "thioalkyl"as used in the context by itself or in combination with another Deputy, means acyclic, branched or unbranched alkyl substituents containing Tilney (HS) group as a substituent. Example thioalkyl group is thiopropyl, for example, HS-CH2-CH2-CH2-.

The term "(6)or (C10)aryl", as used in the context by itself or in combination with another Deputy, means either an aromatic monocyclic system containing 6 carbon atoms, or aromatic bicyclic system containing 10 carbon atoms. For example, aryl includes phenyl or naftalina system cycles.

The term "(7-C16)arylalkyl"as used in the context by itself or in combination with another Deputy, means aryl, as defined above, linked through alkyl group, and alkyl meets the above definition and contains from 1 to 6 carbon atoms. Arylalkyl includes, for example, benzyl and butyle the mud.

The term "Het"as used in the context by itself or in combination with another Deputy, means monovalent Deputy derived by removing a hydrogen atom from a five-, six - or semichasnoho saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and from one to four ring heteroatoms selected from nitrogen, oxygen and sulfur. Examples of suitable heterocycles include tetrahydrofuran, thiophene, diazepine, isoxazol, piperidine, dioxane, morpholine, pyrimidine or

.

The term "Het" includes a heterocycle, as defined above, is condensed with one or more other cycles, if they are heterocycles or carbocycle, each of which may be saturated or unsaturated. One of these examples includes thiazolo[4,5-b]pyridine. The term "heteroaryl"as used in the context, although included in the scope of the term "Het", means exactly that, unsaturated heterocycle, in which the double bond to form an aromatic system. A suitable example of a heteroaromatic system includes quinoline, indole, pyridine,

,,,,,

, or.

The term "oxoprop" means a group (=O) with a double bond attached as Deputy.

The term "tighrope" means a group (=S) with a double bond attached as Deputy.

As a rule, includes all tautomeric forms, and all isomeric forms and mixtures chemical structure or compound, whether an individual geometric isomers or optical isomers or racemic or nerezisca mixture of isomers, unless the specific stereochemistry or isomeric form is not stated specifically in the connection name or in the structure.

The term "pharmaceutically acceptable ester"as used in the context by itself or in combination with another Deputy, means esters of compounds of formula I in which any carboxyl group of the molecule, but preferably terminal carboxyl group is replaced by alkoxycarbonyl group

,

in which the residue R of ester selected from alkyl (e.g. methyl, ethyl, n-propyl, tert-butyl), alkoxyalkyl (for example, methoxymethyl), alkoxyalkyl (for example, acetoxymethyl), arylalkyl (e.g., benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (e.g. phenyl), optionally substituted with halogen, (C1-C4)alkyl or (C -C4)alkoxygroup. Other suitable esters that may act as prodrugs described in the monograph "Design of Prodrugs", edited by H. Bundgaard, Elsevier (1985). Such pharmaceutically acceptable esters are usually hydrolyzed in vivo when administered to a mammal and is converted to the acid form of the compounds of formula I.

In the above-described esters, any alkyl residue mainly includes, unless otherwise specified, from 1 to 16 carbon atoms, particularly from 1 to 6 carbon atoms. Any present in such esters, aryl residue mainly contains a phenyl group.

In particular, the esters may be (C1-C16)alkylbis complex ester, unsubstituted benzyl complex ether or benzyl ether complex, substituted by at least one halogen, (C1-C6)alkyl, (C1-C6)alkoxygroup, the nitro-group or trifluoromethyl.

The term "pharmaceutically acceptable salt"as used in the context, include salts derived from pharmaceutically acceptable bases. Examples of suitable bases include choline, ethanolamine and Ethylenediamine. Salts of Na+, K+and Ca+also considered as included in the scope of the present invention (see also "Pharmaceutical Salts", Birge S.M. and others, J. Pharm. Sci. (1977), 66, 1-19).

the Following chemicals can be denoted by the following abbreviations:

AbbreviationThe name of the chemical compound
MeCNacetonitrile
Boctert-butoxycarbonyl
DABCO1,4-diazabicyclo[2.2.2]octane
DBU1,8-diazabicyclo[5.4.0]undec-7-EN
DC1,3-dicyclohexylcarbodiimide
DCHAdicyclohexylamine
MeCl2methylene chloride
DIPEAdiisopropylethylamine or base Hunga
DMAPdimethylaminopyridine
DMFN,N-dimethylformamide
DMSOthe sulfoxide
DMTMchloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine
The EDChydrochloride of 1-(3-dimethylaminopropyl)-3-tilcara is himeda
GATAhexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea
Gbtuhexaphosphate O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea
GOAT1-hydroxy-7-asobancaria
HOBT1-hydroxybenzotriazole
i-Disopropyl alcohol
DMOC3,7-dimethyl-3-octant potassium
MCGmethylcyclohexane
MP4-methyl-2-pentanon
NRM1-methyl-2-pyrrolidinone
EGN2-ethylhexanoate, sodium
TBTUtetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea
THFtetrahydrofuran
TGMPTris(hydroxymethyl)phosphine
GMFHchloride tetrakis(hydroxymethyl)phosphonium

Embodiments of the inventions

Unless otherwise specified, the following synthesis schemes all replacement groups in the chemical formulas should be attributed the same meaning as in formula (I). The reagents used in the following synthesis schemes, or can be obtained outlined in this application form, or, if they are not described in this application, are either commercially available or can be obtained from commercially available materials using known in the relevant field methods. Some original substance, for example, can be obtained using the methods described in international patent applications WO 00/59929, WO 00/09543 and WO 00/09558, in U.S. patent US 6323180 B1 and in U.S. patent US 6608027 B1.

The optimal conditions of interaction and the time of interaction can vary depending on the specific reagents. Unless otherwise stated, solvents, temperature, pressure and other conditions interactions for optimal results in a given reaction can be easily picked up by someone with a standard knowledge in the relevant field. As a rule, the course of the reaction can be tracked, if necessary, using high-performance liquid chromatography (HPLC), and intermediate compounds the Oia and the products can be purified using chromatography on silica gel and/or by recrystallization.

I. General multistage method of synthesis

In one of the embodiments of the present invention it is a General object of the multistage method of synthesis for the preparation of compounds of formula (I). More specifically, an object of the present invention in this embodiment, its implementation is a method for obtaining compounds of the following formula (I)

in which

W is CH or nitrogen,

L0is hydrogen, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen(C1-C6)alkyl, (C1-C6)alkoxygroup, (C3-C6)cycloalexie, hydroxy-group or N(R23)2where each of R23independently is hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl,

L1L2independently of one another are hydrogen, halogen, (C1-C4)alkyl, -O-(C1-C4)alkyl or-S-(C1-C4)alkyl (sulfur is in any oxidized state), or

L0and L1or L0and L2can be covalently linked, forming together with the two carbon atoms to which they are attached, a 4-, 5 - or 6-membered carbocycle, where one or two (in the case of 5 - or 6-membered cycle) -CH2groups that are not associated directly with each other, can b the th independently of each other replaced by-O - or-NR awhere Rais hydrogen or (C1-C4)alkyl, and the above cycle optionally containing one or two (C1-C4)alkyl substituent.

R2is hydrogen, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen(C1-C6)alkyl, (C1-C6)thioalkyl, (C1-C6)alkoxygroup, (C3-C6)cycloalexie, (C2-C7)alkoxy(C1-C6)alkyl, (C6)or (C10)aryl or Het, where Het is a five-, six - or semiclean saturated or unsaturated heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur, and mentioned cycloalkyl, aryl or Het substituted R6where R6is hydrogen, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxygroup, (C3-C6)cycloalexie, NO2N(R7)2, NH-C(O)-R7or NH-C(O)-NH-R7where each R7independently is hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, or R6is NH-C(O)-OR8where R8is (C1-C6)alkyl or (C3-C6)cycloalkyl,

R3is a hydroxy-group, NH2or a group of the formula-NH-R9where R9/sup> is (C6)or (C10)aryl, heteroaryl, -C(O)-R10, -C(O)-other10or-C(O)-OR10where R10is (C1-C6)alkyl or (C3-C6)cycloalkyl,

D is unsaturated alkalinous chain containing from 5 to 10 atoms

R4is hydrogen or one, two or three substituents at any carbon atoms in the specified chain D, which Deputy independently selected from (C1-C6)alkyl, halogen(C1-C6)alkyl, (C1-C6)alkoxygroup, hydroxy-group, halogen, an amino group, carbonyl group, tigraphy and (C1-C6)thioalkyl, and

And is amidol formula-C(O)-NH-R11where R11selected from (C1-C8)alkyl (C3-C6)cycloalkyl, (C6)or (C10)aryl, (C7-C16)arylalkyl and SO2R11Awhere R11Ais (C1-C8)alkyl, (C3-C7)cycloalkyl or (C1-C6)alkyl(C3-C7)cycloalkyl,

or

A is a carboxylic acid or its pharmaceutically acceptable salt or a complex ester.

This method includes the following stages:

(i) in the case when R=PG, where PG is a protecting group, the method comprises the cyclization of diene compounds of formula (1) in the presence of a suitable catalyst in order to obtain joint is of the formula (2) and further removing the protective group under appropriate conditions in order to obtain the compounds of formula (3) or, in those cases where R=H, the cyclization of diene compounds of formula (1) in the presence of a suitable catalyst in order to obtain the compounds of formula (3)

,

where A, D, R3and R4take these to the above formula (I) values, R is hydrogen or PG, where PG is a protecting group, n is an integer from 0 to 2, and D1=D-(n+2),

(ii) in the case when a is a protected carboxyl group in the formula (3), the method optionally includes removing the protective group from compounds of formula (3) under appropriate conditions in order to obtain the compounds of formula (3), where a is a carboxyl group, and

(iii) the interaction of the compounds of formula (3) with a compound of formula QUIN, where R3, R4, D, A, L0L1L2, W, and R2take these to the above formula (I) values, R is a (C1-C6)alkyl, (C6)or (C10)aryl or heteroaryl, with the aim of obtaining the compounds of formula (I)

and, in those cases when a is a protected carboxyl group in the formula (I), the method optionally includes removing the protective group from compounds of formula (I) in appropriate circumstances, with the aim of obtaining the compounds of formula (I), where a is a carboxyl group, and in those cases, And when t is aetsa carboxyl group in the final compound of formula (I), the method optionally includes the reaction of a combination of this compound with a sulphonamide of the formula R11ASO2NH2in the presence of a suitable agent for combinations, such as carbodiimide agents, TBTU and GATA, with the aim of obtaining the compounds of formula (I), where a is-C(O)-NH-SO2R11A

II. Individual phase synthesis

In additional embodiments, the implementation of the present invention its objects are the individual phases of the above General multi-stage method of synthesis, as well as individual intermediate compounds used in these stages. These individual stages and intermediate compounds of the present invention are described in detail below. All replacement group in the following stages consistent with the definitions given in the above description of the General multistage method.

Stage (i)

This stage focused on the cyclization of diene compounds of formula (1) in the presence of a suitable catalyst in order to obtain the compounds of formula (2), where R = protective group, and subsequently removing the protective group from compounds of formula (2) under appropriate conditions in order to obtain the compounds of formula (3), or, in cases where R=H, the cyclization of diene compounds of formula (1) in the presence of a suitable catalyst that leads directly to the soy is inniu formula (3)

Suitable catalysts for the cyclization stage include catalysts based on ruthenium, as well as widely used catalysts based on molybdenum (Schrock catalysts and modified Schrock catalysts), and catalysts based on tungsten. For example, any of the well known catalysts based on ruthenium used in the metathesis reactions of olefins, such as catalyst verification (first and second generation), Hoveyda catalyst (first and second generation) and the catalyst Nolan, can be used with appropriate adjustment of reaction conditions, as it may be necessary to implement the response of the closed loop depending on the particular catalyst selected.

Suitable ruthenium catalysts for the cyclization stage include, for example, compounds of formulas a, B, C, G or D.

,,

,,

in which

X1and X2independently from each other represent an anionic ligand,

L1represents a neutral electron donor ligand, which is associated with the ruthenium atom and optionally linked to the phenyl group, and

L2represents a neutral electron-up to the priori ligand, associated with the ruthenium atom, and

R5selected from one or more of the substituents in the benzene cycle, each Deputy is independently selected from hydrogen, (C1-C6)alkyl, halogen(C1-C6)alkyl, HS-(C1-C6)alkyl, BUT-(C1-C6)alkyl, PERFLUORO(C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxygroup, hydroxyl, halogen, nitro, aminogroup, carbonyl group, tigroup or aryl,

and in which X2and L2together may not necessarily form a chelat forming bidentate ligand.

In a more specific embodiment of the present invention the ruthenium catalyst is a compound of formula (a-1) or (a-2):

,

in which

L1is tizamidine phosphine group of the formula PR3in which R is selected from (C1-C6)alkyl and (C3-C8)cycloalkyl,

L2is tizamidine phosphine group of the formula PR3in which R is selected from (C1-C6)alkyl and (C3-C8)cycloalkyl, or L2is a group of formula a or B

where

R7and R8independently from each other represent a hydrogen atom or (C1-the 6)alkyl, (C2-C6)alkenyl, (C6-C12)aryl and (C6-C12)aryl(C1-C6)alkyl, and

R9and R10independently from each other represent a hydrogen atom or (C1-C6)alkyl, (C2-C6)alkenyl, (C6-C12)aryl and (C6-C12)aryl(C1-C6)alkyl, each of which is optionally substituted with one, two or three groups selected from hydrogen, (C1-C6)alkyl, halogen(C1-C6)alkyl, HS-(C1-C6)alkyl, BUT-(C1-C6)alkyl, PERFLUORO(C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxygroup, hydroxyl, halogen, nitro, aminogroup, carbonyl group, tigroup or aryl,

X1and X2independently from each other represent a halogen atom,

R5represents hydrogen or a nitro-group, and

R6is a (C1-C6)alkyl group.

In another specific embodiment, the present invention ruthenium catalyst selected from the

,

where Ph is phenyl and Mes is 2,4,6-trimetilfenil.

The catalyst is based ruthenium suitable for stage metathesis with the closing of the cycle, such as the above, are well-known catalysts that can be obtained by well known synthetic methods. For example, see the following links contain examples of suitable catalysts based on ruthenium:

Organometallics 2002, 21, 671; 1999, 18, 5416; 1998, 17, 2758,

J. Am. Chem. Soc. 2001, 123, 6543; 1999, 121, 791; 1999, 121, 2674; 2002, 124, 4954; 1998, 120, 2484; 1997, 119, 3887; 1996, 118, 100; 1996, 118, 9606,

J. Org. Chem. 1998, 63, 9904; 1999, 64, 7202,

Angew. Chem. Int. Ed. Engl. 1998, 37, 2685; 1995, 34, 2038; 2000, 39, 3012; 2002, 41, 4038,

U.S. patents 5811515, 6306987 B1, and 6608027 B1.

In another specific embodiment of the present invention the reaction of the closing cycle is carried out in a solvent at a temperature in the range from approximately 20°to approximately 120°C. May be used any solvent that is suitable for the metathesis reaction with the closing of the cycle. Examples of suitable solvents include alkanes, such as n-pentane, n-hexane or n-heptane, aromatic hydrocarbons such as benzene, toluene or xylene, chlorinated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, cyclopentylmethyl ether, tert-butyl methyl ether, dimethyl ether, methyl alcohol, dioxane, ethyl acetate and tert-butyl acetate.

In another specific embodiment, the present izaberete the Oia response of the closed loop is carried out in the conditions, when the molar ratio of diene compounds (1) and the catalyst is in the range from 1000:1 to 100:1, preferably from 500:1 to 110:1, in particular from 250:1 to 150:1.

In another specific embodiment of the present invention the reaction of the closing cycle is carried out in conditions where the ratio of diene compounds (1) and solvent is in the range from 1:400 by weight to 1:25 by weight, preferably from 1:200 by weight to 1:50 by weight, in particular from 1:150 by weight to 1:75 by weight.

In another specific embodiment of the present invention the reaction of the closing cycle performed by adding the catalyst portions in an amount of from 2 to 6, preferably 3-5 servings.

Specialist in the relevant field can easily optimize phase cyclization by selection and control of relevant conditions suitable for a particular catalyst reaction of the closing cycle. For example, depending on the selected catalyst may be preferred implementation of the cyclization stage at high temperature, for example, higher than 90°C, although it is also possible engagement at lower temperatures when adding an activator such as copper halide (CuX, where X is a halogen)in the reaction mixture.

In a specific embodiment, this stage Conn the General formula (1) is dissolved in obezvojennom organic solvent (such as toluene or dichloromethane) to concentrations below approximately 0.02 M, then treated with a catalyst based on ruthenium, such as Hoveyda catalyst, at a temperature from approximately 40°to approximately 110°C until the end of the interaction. Part of the metallic ruthenium or all of ruthenium can be removed from the reaction mixture by treatment with a suitable absorber heavy metals, such as CGMP or other agents capable of capturing heavy metals. The reaction mixture was then washed with water, the organic layer is separated and washed. The resulting organic solution may be discolored, for example, the addition of activated charcoal, followed by filtration.

In one embodiment, the implementation of this stage polynomy ring oxygen atom in the formula (1) protect protecting group (where R=PG) at any time prior to the cyclization stage, using conventional techniques. Can be used with any suitable for oxygen protective group, including, for example, acetate, benzoate, para-nitrobenzoate, naphthoate, haloganated, methoxyacetate, phenylacetate, phenoxyacetate, pivalate, crotonate, methylcarbonate, methoxyethylamine, ethylcarbonate, halogencarbonic, para-nitrophenylarsonic, triisopropylsilyl, triethylsilyl, dimethylethanol, diatrizoate, dimethylacrylic, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, t is et-butoxyethoxyethanol, tert-butoxyphenyl etc. After the cyclization stage protective group PG in the compound (2) is removed using conventional conditions unprotect suitable for removing this particular protective group, as can be easily understood by any person skilled in the art, to obtain compound (3).

In another embodiment, this stage may be desirable cleaning solution of diene compounds of formula (1) first stage metathesis with the closing of the cycle in order to remove any possible contaminants that could inhibit cyclization reaction, from the reaction mixture. Can be applied to conventional cleaning methods, well known to the specialist in the relevant field. In one of the preferred embodiments of this stage, the solution of diene compounds purified by treatment with alumina, for example, activated alumina before it is used in the cyclization stage.

Stage (ii)

In those cases, when a is a protected carboxyl group in the formula (3), for example, carboxylic ester group, before moving to the next stage, the compound of formula (3) may be optionally subjected to removal of the protective group (hydrolysis) to obtain the corresponding carboxylic acid in free form. The hydrolysis can be carried out in normal conditions the x hydrolysis, known in the relevant field. In a particular embodiment, for example, esterified compound of the formula (3) is dissolved in an organic solvent, such as THF, and add suitable gidrolizuemye agent, such as a monohydrate of lithium hydroxide (LiOH·H2O) or sodium hydroxide (NaOH), followed by the addition of water. Thus obtained solution is stirred at a temperature of from about 35°to about 50°C. At the end of the reaction the solution is cooled and selected organic layer. Suitable solvent, such as ethanol, is added to the organic layer and set the pH range from about pH 5 to about pH 6. The mixture is then heated to a temperature from about 40°to about 50°C. upon reaching this temperature, add water and mix the solution, resulting in the compound of the formula (3) begins to precipitate. After complete precipitation, the solution is cooled to room temperature and the compound of formula (3) is collected by filtration, washed and dried.

Stage (iii)

This stage consists in the method of obtaining the compounds of formula (I), including the interaction of the compounds of formula (3) with a compound of formula QUIN order to obtain the compounds of formula (I)

and, in those cases when a is protected carb is Xylenol group, optional removal of the protective group from compounds of formula (I) in appropriate circumstances, to obtain the compounds of formula (I)in which a is a carboxyl group, and in those cases when a is a carboxyl group in the final compound of formula (I), the optional combination of this compound with a sulphonamide of the formula R11ASO2NH2in the presence of an appropriate agent for a combination, such as a carbodiimide agents, TBTU or GATE, with the aim of obtaining the compounds of formula (I)in which a is-C(O)-NH-SO2R11A.

The group R in sulfonyloxy group in QUIN include, for example, (C1-C6)alkyl, (C6)or (C10)aryl or heteroaryl. A preferred group R is phenyl.

The reaction mix between the compounds of the formula (3) and QUIN are usually carried out in the presence of a base in a suitable solvent or mixture of solvents. Examples of suitable bases for this reaction include t-BuOK, t-BuONa, t-BuOCs, bis(trimethylsilyl)amide, sodium and DMOC, and preferred bases are t-BuOK and DMOC. Examples of suitable solvents for this reaction include polar aprotic solvents such as DMSO, DMF, NRM or other common polar aprotic solvents and THF and other moderately polar ethers, or a suitable mixture of these rest is ritala. The preferred solvent is DMSO.

The preferred temperature is in the range between 0°C and 50°C (depending on the freezing temperature of the solvent), most preferably, between 10°C and 25°C.

In another preferred embodiment, this stage you can use the following set of reaction conditions: in the flask macrocycle (3) and quinoline QUIN, rinsed with nitrogen (3 times), then add DMSO via syringe. The mixture was again washed with nitrogen (3 times) and bring the temperature to 20°C. To the suspension is added via syringe pump over one hour 50% of DMAC in heptane. The resultant mixture was stirred in nitrogen atmosphere at a temperature of ~20°C for 2 hours. Then decompose the remains of reagents, adding drops of glacial acetic acid, and stirred the mixture. After that, the reaction mixture is slowly poured into the water, resulting in precipitation of the product. After that, the suspension is stirred, filtered, washed precipitate on the filter with water and then with hexane and dried solid.

In those cases, when a is a protected carboxyl group in the formula (I), for example, carboxylic ester group, the compound of formula (I) can optionally be subjected to removal of the protective group (hydrolysis) under appropriate conditions in order to obtain consistent is her carboxylic acid in free form. The hydrolysis can be carried out using conventional hydrolysis conditions, known in the relevant field. Suitable conditions are the same as discussed previously for stage (ii). In addition, in those cases when a is a carboxyl group in the final compound of formula (I)can be implemented on a combination of this compound with a sulphonamide of the formula R11ASO2NH2in the presence of an appropriate agent for a combination, such as a carbodiimide agents, TBTU or GATE, with the aim of obtaining the compounds of formula (I)in which a is-C(O)-NH-SO2R11A.

III. Obtaining peptide diene source connection.

Peptide diene original connection (1)used in the above schemes, can be synthesized from known compounds using methods that are described below in schemes I, II and III.

Scheme I - obtain P1-P2

Peptide condensation with the formation of the P2-P1-PG, where PG is a protective group for the amino group, in scheme I can be carried out using any conventional reagents peptide condensation techniques, known in the relevant field, the protective group PG to an amino group may be any suitable protecting group for an amino group, well known in the relevant field. For example, see sub is face-to-face connection and combination techniques, disclosed in international patent applications WO 00/09543, WO 00/09558 and U.S. patent 6608027 B1. Peptide condensation compounds P2-PG and P1 may be implemented, for example, in a variety of conditions known in the relevant field, using conventional reagents peptide condensation, such as DCC, EDC, TBTU, hbtu, GATA, DMTM, the acid chloride cyanuric acid (the churches of Christ), Teilhard (TsCl), methylchloride (MsCl), isobutyl ether of Harborview acid (IBC), HOBT or HOAT, in aprotic solvents such as dichloromethane, chloroform, THF, DMF, NRM, DMSO.

The next stage of cleavage of the protective group for the amino group in the compound of formula P2-P1-PG may also be made of well known ways, for example as described in international patent applications WO 00/095543, WO 00/09558 and U.S. patent 6608027 B1. In specific embodiments, the implementation of this method involves acid hydrolysis of compounds of formula P2-P1-PG involving organic or inorganic acid, such as HCl, H2SO4, triperoxonane acid, acetic acid, MeSO3H, in a variety of proton or polar aprotic solvents, such as alcohols, ethers, MeCN or MeCl2.

The compounds of formula P2-PG, used as starting material, or are commercially available as, for example, Boc-4(R) - hydroxyproline, or can be is Holocene from known compounds using conventional methods. In one of the examples of the compounds of formula P2-PG, where R is hydrogen, a PG is a protective group for the amino group, can be obtained by protecting the amino group in 4-hydroxyprolin:

.

In the first stage, a suitable protective group for the amino group introduced on the ring nitrogen atom of the 4-hydroxyproline, using conventional methods. For example, the compound may be dissolved in a suitable solvent and introduced into an interaction with an appropriate reagent, introducing a protective group for amino group. As an example, but without implying a limitation of the framework itself, in those cases, when Boc (tert-butoxycarbonyl) is the desired protective group, the compound is administered in cooperation with Boc anhydride2O (or Boc-HE) in a mixture of solvents, such as acetone/water, MP/water or THF/water, to which is added a base, such as NaOH, KOH, LiOH, triethylamine, diisopropylethylamine or N-methylpyrrolidine, and the interaction is carried out at a temperature of between 20-60°C.

The compounds of formula P1 is known from international patent applications WO 00/09543, WO 00/09558 and U.S. patent 6608027 B1 and can be obtained as described in methods.

Scheme II - getting P3-P2

Peptide condensation, leading to P3-P2-IU in scheme II can be carried out and the use of any standard reagents peptide condensation techniques, known in the relevant field. Examples of suitable reagents and conditions described above in part related peptide condensation in scheme I.

Subsequent hydrolysis, leading to P3-P2 in scheme II can be carried out in an aqueous basic solution, optionally containing a co-solvent that is miscible with water, such as THF, dioxane, alcohols or 1,2-dimethoxyethane (DME), or combinations of these co-solvents. The preferred mixture of solvents can be aqueous solution of a base containing THF as co-solvent. Can be used any water-soluble base, such as LiOH, NaOH, KOH, Na2CO3, K2CO3etc. the Preferred base is LiOH. The number can vary from 1 to 100 equivalents, preferably 1 to 10 equivalents. The concentration can vary from 0.25 M to 12 M, preferably, 1-4 PM, the reaction Temperature can range from -40°C to 100°C, preferably from -20°C. to 50°C.

All stages of the peptide condensation P3 with P2-IU can be carried out in the same reactor with the use of the churches of Christ or acid chloride alkane - or arenesulfonyl (for example, TsCl, MsCl) suitable for condensing conditions that lead to P3-P2-IU, with subsequent hydrolysis of the product by adding an aqueous basic solution with the aim of obtaining the soedineniya P3-P2 scheme II, which can then be crystallized. In this dorectory sequence connection P3 can also be applied in the form of its salt with sterically difficult secondary amine, such as its salt with DCHA.

Substituted acid compound of the formula R3 used as starting substances are known from U.S. patent 6608027 B1 and can be obtained from commercially available materials using the techniques described in this application.

Scheme III - obtaining (1)

The reaction of the peptide condensation, leading to the compound (1) in scheme III can be carried out using any standard reagents peptide condensation techniques, known in the relevant field. Examples of suitable reagents and conditions described above in part related peptide condensation in scheme I. the IBC is the preferred reagent peptide condensation scheme III.

IV. Obtaining source materials - sulfonated quinoline.

The original substance - sulfonated quinoline - QUIN can be obtained from known compounds according to the method shown in the following scheme IV:

Scheme IV

Such replacement of the quinoline II can be converted into sulfonanilide QUIN by initial conversion to the halide is hinolinova compound III (where X is a halogen), following the well-known methods of halogenation using various halogenation agents such as widely used ROCH3and PX5where X=F, Cl, Br or I, and these reagents can be used in some cases as solvents or in combination with polar aprotic solvents such as DMF or acetonitrile, and subsequent conversion of the halogenated compound III in the search sulforhodamine QUIN via interaction with sulfinate RSO2M, such as PhSO2Na, where M is an alkaline metal.

Alternatively, II can be converted to sulforhodamine dorectory way in the initial formation of an intermediate sulfonate by reaction with the acid chloride of arenesulfonyl RASO2Cl, where RAis neutral or rich in electrons Arroway group, such as benzosulphochloride or tailhold, in the presence of a suitable base in a suitable solvent. Appropriate for this stage of the base include tertiary amines, such as N-methylpyrrolidine and diisopropylethylamine, and suitable solvents include aprotic solvents such as acetonitrile, THF, toluene and DMF, preferably acetonitrile. Thus obtained compound is then injected into the interaction in situ acid in the conditions (for example, in the presence of acetic acid, triperoxonane acid, hydrochloric acid or the like, preferably acetic acid) with sulfinate RSO2M (where M is an alkaline metal), such as PhSO2Na, PhSO2K or PhSO2Cs, suitable temperature conditions, for example, in the range from 0 to 100°C., preferably from 25 to 50°C. Sulfonanilide product can be isolated from the reaction mixture using conventional methods, well known to the specialist in the relevant field. In one embodiment, the implementation of sulforhodamine can be crystallized by cooling the solution to room temperature and adding water. Crystallized product can then be filtered, washed and washed using standard methods.

Replacement quinoline compounds of the formula (II) can be synthesized from commercially available materials using the techniques described, for example, in international patent applications WO 00/59929, WO 00/09543 and WO 00/09558, U.S. patents 6323180 B1, 6608027 B1 and in the application for U.S. patent No. 2005/0020503 A1.

An alternative way of getting some replacement quinoline compounds of the formula (II) and their halogenation to the compounds of formula (III) below in scheme V (in which the connection 7 is an example of compound (II)and compound 8 is an example of compound (III)).

Scheme V

img src="https://img.russianpatents.com/1113/11132090-s.jpg" height="163" width="172" />

In this diagram, each independently is alkyl (C1-C6)alkyl group, X is a halogen atom, Z is tert-bootrom or tert-butoxypropyl, R6and Het correspond to the definitions given for formula I.

In the first stage, the compound of formula 1 is treated with a base and brainwashin agent to obtain compound 2. General requirements for this stage is the use of a base of sufficient strength for the formation of the desired dianion. This can be any alkyllithium connection, metal amide, such as diisopropylamide lithium (LDA), tetramethylpiperidine lithium hexamethyldisilazide metal, such as hexamethyldisilazide potassium (KHMDS), organozinc, the anion of the metal in the cation-salvatorem a solvent such as DMSO, and the like. The preferred bases are n-utility and LDA. Can be applied to any organic solvents that do not affect the formation of dianion, such as THF, alkyl derivatives THF, dioxane, alkanes, cycloalkanes, dialkyl ethers such as methyl tert-butyl ether, cyclopentylmethyl ether, disutility ether and the like. Preferred solvents are THF, alkyl-THF and alkanes. The temperature for the reaction of formation of dianion may be in the range between -100°C and 25°C, is preferred in erval between -30°C and 25°C. Brainwashin agent can be any compound containing a movable bromine atom, such as Br2N-bromosuccinimide (NBS), bromhidrosis, N-bromophthalimide, bromeloideae, such as 1,2-dibromotetrachloroethane and performancebased, and the like. Preferred romirowsky agents are bromeloideae. As soon as dianion is formed in a suitable solvent, may be added pomeroyi agent in pure form or in solution or, alternatively, dianion can be added to romirowsky agent in pure form and in solution. The preferred method is slow adding dianion to romirowsky agent in solution. The temperature of the synthesized may be in the range between -100°C and 25°C, and the preferred interval lies between -30°C and 25°C.

The next phase connection 2 hydrolized by treatment with a mixture of acids in water to obtain compound 3. Can be applied to any mixture of acids in water, such as water [triperoxonane acid, Chloroacetic acid, such as trichloroacetic acid, acid, such as methanesulfonate, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, strongly acidic ion exchange resin such as DOWEX 50], and other similar. Preferred acids are hydrochloric and sulfuric acid is you at a concentration of 2-12 M, preferably, at least 6 Meters can Also be used co-solvents, miscible with water, such as alcohols such as ethanol, isopropanol, or ethers such as dimethyl ether, diglyme and the like. The hydrolysis can be carried out at temperatures between 0°C and 200°C, and the preferred temperature is between 0°C and 100°C.

At the next stage, the compound 3 is treated with alkyllithium (alkyl-CN) and a Lewis acid to obtain compound 4. To convert 3 to 4 can be applied Lewis acid alone, or in combination, such as AlCl3, BCl3, GaCl3, PeCl3and mixtures thereof, and the like. The preferred method is the use of BCl3with AlCl3. Can be used any solvent which allroots with difficulty, such as halogenated hydrocarbons, haloidbenzenes, alkyl benzenes, such as toluene, and alternately, such as acetonitrile, and the preferred solvents are 1,2-dichloroethane, chlorobenzene and toluene. The reaction temperature may be between 0°C and 150°C, preferably between 25°C and 75°C.

The next phase connection 4 acelerou using compound 5 to obtain compound 6. To convert 4 6 acylation can be carried out, or by first converting the carboxylic acid 5 in Akti the new form, such as the acid chloride of the acid, or by using standard techniques of peptide condensation. The preferred method is the formation of carboxylic acid compound 5 using acid chloride oxalic acid or thionyl chloride. Data activated compounds can then be introduced into the reaction mix with aniline 4 in any organic solvent or in water, with or without added base. Preferred solvents are met and THF, and the preferred basis (if used) is triethylamine. The reaction temperature is between -30°C and 150°C, preferably between -20°C and 50°C.

At the next stage, the connection 6 cyclist in the presence of a base to obtain compound 7. Compound 6 can be isolated and purified, or, alternatively, the crude product 6 in an organic solvent, such as NRM, just may be subjected to cyclization with the purpose of immediate receipt of quinoline 7 that converts two stages in dorectory process. To convert 6 in 7 in scheme V can be used any base capable of forming enolate, such as t-BuOK, DMOC, LDA and the like, and preferred are t-BuOK and DMOC. Can be used any of organic solvents, not reacts with Enola the Ohm, such derivatives as THF, dioxane, DMSO, NRM, DME and the like, and preferable are met, DME and DMSO. The cyclization can be carried out at any temperature between 25°C and 150°C, preferably between 50°C. and 100°C.

At the last stage hydroxyquinolinato connection 7 process of halogenation agent to obtain compound 8. To convert 7 in 8 in scheme V can be used many halogenation agents such as acid chloride of methansulfonate, SOCl2, POCl3, PCl3, PCl5, POBr3, HF and the like, and preferable are POCl3and SOCl2. Halogenoalkane can be carried out in a clean halogenation agent or any organic solvent which does not react with a halogenation agent is dimethyl ether, diglyme, THF derivatives, halogenated hydrocarbons and the like, and preferred are dimethyl ether and tetrahydrofurane. The reaction temperature can be between -20°C and 150°C, preferably between 25°C. and 100°C.

V. Preferred options for implementation of the compounds of formula (I).

Preferred embodiments of the compounds of formula (I), which can be by using the method according to the present invention includes the embodiments set forth below.

Preferred options for implementation include connected the I of the formula (I), as described above, in which cyclopropyl balance on the right side selected from two different stereoisomers, and carbon centre cyclopropyl in position 1 is R-configuration, as exemplified by structures (i) and (ii):

.

In one specific implementation variants of compounds of formula (I), the linker D is in the SYN-configuration relative to group a, as represented by the above structure (ii)

W is nitrogen,

L0selected from hydrogen, -OH, -och3, -OC2H5, -Och(CH3)2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -N(CH3)2, -N(CH3)2H5, -N(CH3)3H7and-N(CH3)CH(CH3)2.

L1and L2independently from each other selected from hydrogen, fluorine, chlorine, bromine, -CH3- 2H5- 3H7, -CH(CH3)2, -Och3, -OS2H5, -OS3H7and-och(CH3)2,

R2is hydrogen, (C1-C6)thioalkyl, (C1-C6)alkoxygroup, phenyl or Het selected from the following list:

,,,

,, ,,,

,,,

or,

where R6is hydrogen, (C1-C6)alkyl, NH-R7, NH-C(O)-R7, NH-C(O)NH-R7where each R7independently is hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, or R6is NH-C(O)-OR8where R8is (C1-C6)alkyl,

R3is NH-C(O)-R10, NH-C(O)-OR10or NH-C(O)-NR10where in each case R10is (C1-C6)alkyl or (C3-C6)cycloalkyl,

D is unsaturated alkalinous chain comprising from 6 to 8 atoms

R4is hydrogen or (C1-C6)alkyl, and

A is a carboxylic acid or its pharmaceutically acceptable salt or a complex ester.

In another specific implementation of the compounds of formula (I), the linker D is in the SYN-configuration relative to group a, as presented above structure (ii)

W is nitrogen,

L0selected from hydrogen, -OH, -och3and-M(CH3)2,

one of the substituents L1and L2is-CH3, fluorine, chlorine or bromine, then to the other of the substituents L 1and L2is hydrogen, or L1and L2both are hydrogen,

R2is,or,

where R6is NH-R7or NH-C(O)-R7where R7independently is a (C1-C6)alkyl or (C3-C6)cycloalkyl,

R3is NH-C(O)-OR10where R10is (C1-C6)alkyl or (C3-C6)cycloalkyl,

R4is hydrogen or (C1-C6)alkyl,

D is semitonal unsaturated alkalinous chain containing one double bond, and

A is a carboxylic acid or its pharmaceutically acceptable salt or a complex ester.

In another specific embodiment, the implementation of the compounds of formula (I) meet the following formula (I'),

L0is-och3,

L1is-CH3, fluorine, chlorine or bromine, and L2is hydrogen, or L1and L2both are hydrogen,

R6is NH-R7or NH-C(O)-R7where R7independently is a (C1-C6)alkyl or (C3-C6)cycloalkyl,

R10is bootrom, cyclobutyl or cyclopentyl,

A is a carboxylic acid or its pharmaceutically p is yimlamai salt or a complex ester.

The following table lists typical examples of the compounds of formula (I). The compound of the following formula

,

in which L0L1L2and R2take the following values:

The connection numberL2L0L1R2
101N-OMeMe
102N-OMeMe
103N-OMeMe
104N-OMeMe
105N-OMeBr
106N-OMeBr
107N-OMeCl
108N-OMeCl
109Me-OMeMe
110Me-OMeMe
111N-OMeF
112N-OMeF
113 N-OMeCl
114N-OMeBr
115H-OMeBr
116H-OMeBr

The following table presents additional compounds, which are typical examples of compounds of formula (I). The compound of the following formula

,

in which the relationship between position 14 and cyclopropene group is in the SYN-configuration relative to COOH, and the mentioned substituents at the double bond 13, 14 are in the CIS-configuration, and R13, R4and R2take the following values:

The connection numberRl3:R4:R2:
201H
202H
203H
204NOEt
205NOEt
206N
207N
208N
209N
210N
211N
212N
213N
214N
215N
216 H
217H
218H
219H
22010-(R) MeOEt,
221H
222H
223H
224 H

Additional specific compounds, which are typical examples of compounds of formula (I), can be found in U.S. patent 6608027 B1.

VI. Preferred implementations of the compounds of formula QUIN.

Preferred embodiments of the compounds of formula QUIN, which can be applied in the method according to the present invention includes the embodiments presented below, for example, those that correspond to the preferred options for the implementation of the compounds of formula (I)described above.

In one implementation options of the compounds of formula QUIN

W is nitrogen,

L0selected from hydrogen, -OH, -och3. -OS2H5, -OS3H7, -Och(CH3)2. -NHCH3, -NHC2H5, -MTL3H7, -NSN(CH3)2, -N(CH3)2, -N(CH3)2H5, -N(CH3)3H7and-N(CH3)CH(CH3)2.

L1and L2independently from each other selected from hydrogen, fluorine, chlorine, bromine, -CH3. -C2H5- 3H7, -CH(CH3)2, -Och3, -OS2H5, -OS3H7and-och(CH3)2,

R2is (C1-C6)thioalkyl, (C1-C6)alkoxygroup and the and Het, selected from the following:

,,,

,,,,,

,,,

or,

where R6is hydrogen, (C1-C6)alkyl, NH-R7, NH-C(O)-R7, NH-C(O)-NH-R7where each R7independently is hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, or R6is NH-C(O)-OR8where R8is (C1-C6)alkyl, and

R is a (C6)or (C10)aryl.

In another specific implementation of the compounds of formula QUIN

W is nitrogen,

L0selected from hydrogen, -OH, -och3and-N(CH3)2one of the substituents L1and L2is-CH3, fluorine, chlorine or bromine, and the other of the substituents L1and L2is hydrogen, or L1and L2both are hydrogen,

R2is,or,

where R6is NH-R7or NH-C(O)-R7where 7independently is a (C1-C6)alkyl or (C3-C6)cycloalkyl, and

R is a (C6)or (C10)aryl.

In another specific embodiment, the implementation of the compounds of formula QUIN respond to the following formula:

L0is-och3,

L1is-CH3, fluorine, chlorine or bromine, and L2is hydrogen, or L1and L2both are hydrogen,

R6is NH-R7or NH-C(O)-R7where R7independently is a (C1-C6)alkyl or (C3-C6)cycloalkyl, and

R is a (C6)or (C10)aryl.

The following table lists compounds that are typical examples of compounds of formula QUIN. The compound of the following formula

in which Ph is a phenyl, a-L0L1L2and R2take the following values:

The connection numberL2L0L1R2
301N-OMeMe
302N-OMeMe
303N-OMeMe
304N-OMeMe
305N-OMeBr
306N-OMeBr
307N-OMeCl
308N-OMeCl
309 Me-OMeMe
310Me-OMeMe
311N-OMeF
312N-OMeF
313N-OMeCl
314N-OMeBr
315N-OMeBr
316N-OMeBr

The following table lists additional compounds, which are typical examples of compounds of formula QUIN. The compound of the following formula

,

in which Ph is phenyl, and R2accepts the following values:

The connection numberR2
401
402
403
404OEt,
405OEt,
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420OEt,
421
422
423
424

1. The compound of the following formula QUIN

in which W is nitrogen, L0 is-och3,
L1is-CH3, fluorine, chlorine or bromine, a L2is hydrogen, or L1and L2both are hydrogen,
R6is NH-R7or NH-C(O)-R7where R7independently is a (C1-C6)alkyl or (C3-C6)cycloalkyl, and
R is a (C6)or (C10)aryl.

2. The method of obtaining the compounds of formula QUIN according to claim 1, which method includes

the interaction of the compound (II) with a halogenation agent to obtain compounds of formula III in which X is a halogen atom, followed by the interaction of the compounds of formula III with sulfinate RSO2M, in which M is an alkaline metal, with the aim of obtaining compounds of QUIN, and L0L1L2, W, R6and R meet the definitions according to claim 1,
and R2is

3. The method according to claim 2, in which the halogenation agent is selected from the POX3and PX5where X=F, Cl, Br or I, and in which sulfinate RSO2M is PhSO2Na.

4. The method for obtaining the compounds of formula QUIN according to claim 1, which method includes

the interaction of the compound (II) with the acid chloride of arenesulfonyl RASO2Cl, where RAis neutral or rich in electrons Arroway group presets is under the appropriate base in a suitable solvent, followed by the interaction of the compounds obtained in the presence of acid with sulfinate RSO2M, in which M is an alkaline metal, with the aim of obtaining compounds of QUIN, and L0L1L2, W, R6and R meet the definitions according to claim 1, and R2is

5. The method according to claim 4, in which in the first stage, the acid chloride of arenesulfonyl RASO2Cl is benzosulphochloride or mozillateam, the substrate is N-methylpyrrolidine or diisopropylethylamine, and the solvent is selected from acetonitrile, THF, toluene and DMF, and in the second stage, the acid is acetic acid, triperoxonane acid or hydrochloric acid, and sulfinic RSO2M is PhSO2Na, PhSO2K or PhSO2Cs.

6. The compound according to claim 1, which is selected from compounds of the following formula

in which Ph is a phenyl, a-L, L1L2and R2take the following values:

The connection numberL2L0L1R2
301N-OMeMe
302N-OMeMe
303N-OMeMe
304N-OMeMe
305N-OMeBr
306N-OMeBr
307N-OMeCl
308N-OMe Cl
309Me-OMeMe
310Me-OMeMe
311N-OMeF
312N-OMeF
The connection numberL2L0L1R2
313N-OMeCl
314 N-OMeBr
315N-OMeBr

7. The compound according to claim 1, which is selected from compounds of the following formula

in which Ph is a phenyl, a R2accepts the following values:

The connection numberR2
401
402
406
407
408
412
The connection numberR2
416
418
421
422
423
424

8. The compound according to claim 1, which is a



 

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SUBSTANCE: invention relates to peptide-based compounds containing three-member rings containing a heteroatom, which efficiently and selectively inhibit specific activity of N-terminal nucleophilic (Ntn) hydrolase, bonded with a proteasome. The peptide-based compounds contain epoxide and are functionalised at the N-end.

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FIELD: chemistry.

SUBSTANCE: invention relates to novel IAP inhibitors of general formula , where Q, X1, X2, Y, Z1, Z2, Z3, Z4, R1, R2, R3, R3', R4, R4', R5, R6, and R6', and n assume values given in the description.

EFFECT: compounds can be used as therapeutic agents for treating malignant growths.

15 cl, 33 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound having the structure of formula (I), or its pharmaceutically acceptable salt, wherein specified radicals are presented in the description, and also concerns a compound representing or its pharmaceutically acceptable salt. The present invention declares a pharmaceutical composition possessing inhibitory activity in the relation to 20S proteasome containing a pharmaceutically acceptable carrier or a diluent and a therapeutically effective amount of the compound, and also the invention refers to methods of treating the immune diseases, such as inflammatory intestinal disease, to treating cancer, to treating infection, to treating proliferative diseases, to treating neurodegenerative disease or asthma.

EFFECT: higher clinical effectiveness.

34 cl, 21 ex, 2 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a compound having the structure of formula (I), or its pharmaceutically acceptable salt, wherein specified radicals are presented in the description, and also concerns a compound representing or its pharmaceutically acceptable salt. The present invention declares a pharmaceutical composition possessing inhibitory activity in the relation to 20S proteasome containing a pharmaceutically acceptable carrier or a diluent and a therapeutically effective amount of the compound, and also the invention refers to methods of treating the immune diseases, such as inflammatory intestinal disease, to treating cancer, to treating infection, to treating proliferative diseases, to treating neurodegenerative disease or asthma.

EFFECT: higher clinical effectiveness.

34 cl, 21 ex, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: in claim described are organic compounds of formula I where radicals are given in description, which are applicable for elimination, prevention or alleviation of one or more symptoms, associated with HCV disorders.

EFFECT: obtaining pharmaceutical composition which possesses inhibiting activity with respect to NS3-4 HCV serinprotease, including formula I compound and pharmaceutically acceptable carrier.

30 cl, 25 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: in claim described are organic compounds of formula I where radicals are given in description, which are applicable for elimination, prevention or alleviation of one or more symptoms, associated with HCV disorders.

EFFECT: obtaining pharmaceutical composition which possesses inhibiting activity with respect to NS3-4 HCV serinprotease, including formula I compound and pharmaceutically acceptable carrier.

30 cl, 25 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: in claim described are organic compounds of formula I where radicals are given in description, which are applicable for elimination, prevention or alleviation of one or more symptoms, associated with HCV disorders.

EFFECT: obtaining pharmaceutical composition which possesses inhibiting activity with respect to NS3-4 HCV serinprotease, including formula I compound and pharmaceutically acceptable carrier.

30 cl, 25 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to auristatin peptides, including MeVal-Val-Dil-Dap-norephedrine (MMAE) and MeVal-Val-Dil-Dap-Phe (MMAF), and these peptides were attached to ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting "ligand-drug" conjugates are active in vitro and in vivo.

EFFECT: high activity of the compounds.

118 cl, 19 dwg, 12 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: invention relates to methods for synthesis of nonapeptide ethylamide, having strong LH-RH/FSH-RH activity, of formula pGlu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-NH-C2H5·2AcOH (I), and intermediate compounds for synthesis thereof. The nonapeptide ethylamide is obtained via condensation of a C-terminal tetrapeptide of formula H-D-Ser(But)-Leu-Arg-Pro-NH-C2H5·HCl (II) with a dipeptide of formula: X-Ser-Tyr-OH (IV), where X is a protective group. The obtained N-substituted hexapeptide ethylamide of formula X-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-NH-C2H5·HCl (III) is treated with an unblocking agent to remove the N-protective group, and then condensed with a tripeptide of formula pGlu-His-Trp-OH·HCl (V) and the end product is purified through chromatography and extracted in form of a monoacetate salt.

EFFECT: high output.

4 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention describes a method of producing cyclic depsipeptides of formula (I) via intramolecular cyclisation.

EFFECT: improved method.

14 cl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 4-amino-3-arylamino-6-arylpyrazolol[3.4-d]-pyrimidine derivatives showing antiviral activity. In formula I: the groups A and B independently represent phenyl, naphthyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, pyrazolyl, triazinyl, imidazolyl, furanyl, thienyl, and in each of these groups one to three hydrogen atoms can be independently substituted by the radical R1; R1 can be NO2, CN, CONR22, COOR2, CHO, CONH2, halogen, saturated or unsaturated, linear or branched alkyl with a number of atoms in the chain 1 to 7, saturated or unsaturated, linear or branched alkanole with a number of atoms in the chain 1 to 8, OR2, SR2, NR22, SO2NR32, di- or trifluoromethyl, phenyl; R2 represents hydrogen, CF3, and linear or branched alkyl with a number of atoms in the chain 1 to 7; the radical R3 represents H, benzyl, or linear or branched alkyl with a number of atoms in the chain 1 to 7; the radicals R4 and R5 represent hydrogen.

EFFECT: developing the method for preparing the compound of formula (I) and applying the compounds of the present invention as a biological agent exhibiting antiviral activity, eg for treating picornavirus infections.

9 cl, 6 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: described are novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side with considerable absorption in the region up to 410-420 nm, having general formulae (a)-(k) (structural formula and values of radicals are given in the description), composition which is stabilised with respect to UV radiation and containing novel UV-absorbers, and use of the novel compounds as UV light stabilisers for organic materials.

EFFECT: obtaining novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side.

13 cl, 23 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: described is a novel compound - 6-(2'-amino-2'-carboxyethylthio)-2-methylthio-4-pivaloyloxy-methyl-1,2,4-triazolo[5,1-c] 1,2,4-triazin-7(4H)-one of formula having antiviral action and low toxicity.

EFFECT: compound can be used in medicine.

1 cl, 1 ex, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and synthesis of heterocyclic compounds - 5,6-dihydro-7H-pyrrolo[1,2-d][1,4]benzodiazepin-6-one derivatives of formula 1a-e by boiling 2-amino-N-(2-furan-2-yl-phenyl)-acetamides in a mixture of glacial acetic acid and concentrated hydrochloric acid with subsequent treatment with sodium bicarbonate while boiling.

EFFECT: method is characterised by simple execution.

2 tbl, 5 ex

Polycyclic compound // 2451685

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a new polycyclic compound with general formula (I-1) and (1-3) or a pharmaceutically acceptable salt thereof where X1- -CR1 =CR2 - where R1 and R2 independently stand for hydrogen or C1-6 alkyl while Het stands for a radical of the following formulae: that may be substituted 1-3 times additionally described is a pharmaceutical composition containing such compound and intended for prevention or treatment of diseases caused by β-amyloid.

EFFECT: production of a pharmaceutical composition prevention or treatment of diseases caused by β-amyloid.

7 cl, 392 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to compounds that may be applied for HIV infection treatment or prevention or for AIDS or AIDS-associated complex treatment. According to the invention, the compounds represent compounds with formula I, where A stands for A1 , A2 , A3 or A4 and R1, R2, R3, R4a, R4b, R5, R6, Ar, X1, X2, X4, X4 and X5 having values specified in the patent claim. Additionally, this invention relates to a pharmaceutical composition containing the said compounds.

EFFECT: production of compounds possessing inhibition activity with regard to HIV reverse transcriptase.

22 cl, 3 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an amorphous form of N-{2- fluorine-5-[3-(thiophen-2-carbonyl)-pyrazolo[1,5-a]-pyrimidin-7-yl]-phenyl}-N-methyl-acetamide, methods for preparing it.

EFFECT: preparing the pharmaceutical compositions for GABA-receptor inhibition containing said form, and also to using them as a drug for treating and/or preventing anxiety, epilepsy, sleeping disorder and sleeplessness, for induction of sedative-hypnotic effect, for anaesthesia and muscular relaxation and for time modulation required for sleep induction and duration.

12 cl, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted pyrazolopyrimidines derivatives of formula , wherein Y1, Y2, Y3, Y4 represent N or C-, wherein at least, two groups of Y1-Y4 represent carbon atom, R1 represents chlorine or bromine, R2-R7 represent, e.g. hydrogen, methyl or ethyl; and R10 and R11 independently represent, e.g. hydrogen or C1-C6alkyl, their optical isomers and pharmaceutically acceptable salts. Also, the invention refers to using said compounds for treating and preventing a number of acute and chronic mGluR5 related neurological disorders, such as, e.g. pains of various character, dyskinesia, Parkinson's disease, anxiety disorder, Alzheimer's disease and others, a pharmaceutical composition containing specified compounds and methods for preparing them.

EFFECT: compounds are strong mGluR5 modulators.

21 cl, 2 tbl, 274 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel acid-additive salts of pyrrolopyrimidinone derivative, represented by formula (1) which is selected from gentisate, maleate, citrate, fumarate and semitartrate salts, which possess improved properties in their application, in particular higher stability.

EFFECT: invention also relates to method of obtaining acid-additive salts of pyrrolopyrimidinone derivative, represented by formula (1) and to pharmaceutical composition, containing them, for treatment and prevention of erectile dysfunction, pulmonary arterial hypertension, chronic obstructive lung disease, benign prostate gland hypertrophy and diseases of lower urinary tract.

11 cl, 30 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In formula (I): X denotes a single bond or a binding group selected from -CO, -SO2-, -CS- or -CH2-; Y denotes a single bond or a divalent binding group obtained from a cyclic structure selected from benzene, pyridine, pyrimidine, pyrazole, imidazole, thiazole, thiophene, quinoline, benzoimidazole, benzothiazole, benzopyrazole, naphthalene and benzothiophene; X and Y are simultaneously single bonds; Z denotes a hydrogen atom or a substitute selected from a group A; m equals 1 or 2; n equals 0-3; in group A and group B, R, R' and R" can, respectively and independently, be identical or different and denote a hydrogen atom or -C1-6-alkyl; said -C1-6-alkyl can be substituted with a group selected from -OH, -O(C1-6-alkyl),-CONH2, -CONH(C1-6-alkyl), -CON(C1-6-alkyl)2, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2); Sus denotes a C3-C7 saturated or a C5-C10 unsaturated hydrocarbon ring or a nitrogen-containing C3-C7 heterocyclic ring containing 1-4 nitrogen atoms or containing an additional O, S atom; said C1-6 alkylene in groups A and B can be substituted in positions 1-3 with a -N(C1-6- alkyl)2 group, values of radicals R1, A1, T, B and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, a PI3K inhibitor and a medicinal agent having PI3K inhibitor properties against a proliferative diseases such as a malignant tumour.

EFFECT: high efficiency of using the compounds.

21 cl, 645 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and a method of producing bis-2,4-dialkyl-1,5,3-dithiazepan-3-yls of general formula (1): R=Me, Et, nPr, nBu, which involves reaction of a prepared mixture of ethane dithiol and aldehyde at 0°C (acetic or propionic or butyric or valeric) with hydrazine hydrate (60%) with molar ratio aldehyde: ethane dithiol: hydrazine=40:20:10 at temperature 0°C and atmospheric pressure for 2-4 hours.

EFFECT: method of producing novel compounds which can be used as antibacterial, antifungal and antiviral agents.

1 cl, 1 tbl, 1 ex

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