Method of producing 2,3-disubstituted indoles

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2,3-disubstituted indoles of general formula (I): , where the method involves the following steps: a) reaction of bromine diol (i): with dialkoxyborane in the presence of a ligand, a palladium catalyst, preferably selected from Pd(OAc)2, PdCl2, PdBr2, Pd2(dba)3, Pd2(dba)3.CHCl3, [Pd(ally)Cl]2,- Pd(CH3CN)2Cl2, Pd(PhCN)2Cl2, Pd/C and encapsulated Pd and a base to obtain a compound of general formula or, alternatively, reaction of compound (i) with a magnesium compound containing 3 alkyl groups, with subsequent treatment with a borate to obtain a compound of general formula ii given above; b) reaction of the product from step (a) with R2-Hal to obtain a compound of general formula I; where: R denotes (C1-C6)alkyl; R2 denotes: , , , , ,

, , , , ;

R3 denotes cyclopentyl: X denotes carboxymethyl; Hal denotes Br or I; or pharmaceutically acceptable salt thereof.

EFFECT: higher efficiency.

12 cl, 4 dwg, 2 tbl, 14 ex

 

RELATED APPLICATIONS

In this application claims the priority of provisional application US No. 60/652072, filed February 11, 2005, the contents of which are included in this description.

The LEVEL of TECHNOLOGY

1. The technical FIELD

The invention relates to a method for producing 2,3-disubstituted indoles, applicable as pharmaceuticals, in particular pharmaceuticals intended to treat infection by the hepatitis C virus (HCV).

2. INFORMATION TECHNOLOGY

Substituted indoles are used as pharmaceuticals. Examples of the substituted indoles, which are used as pharmaceutical agents include anti-inflammatory drugs indomethacin and tropein, antihistaminic agent methacrolein and vasodilator agent Vinpocetine. Other examples of indoles, which are used as pharmaceuticals, are indoles, as disclosed in the application US No. 10/198384, filed July 7, 2002, and provisional application U.S. 60/546213, filed February 20, 2004

One of the key stages of the synthesis of disubstituted indoles is carrying out the reaction in combination with substituents in positions 2, 3 indole and for this combination offered a number of General techniques. An example of one methodology is the use of intermediate dipyridine and palladium cat who lyst as shown in the preliminary application US No. 60/551107 filed March 8, 2004 This technique in the present invention is indicated as method A.

METHOD AND

In another approach uses catalyzed by Pd ingalirovnie 2-bromo - or chloraniline alkynes containing a triple bond within the chain, and it is described in the provisional application US No. 60/553596 filed March 16, 2004 This technique in the present invention is indicated as method In

METHOD IN

Although methods a and b can be used to obtain 2,3-disubstituted indoles, both methods are characterized by certain limitations. If the product contains allpoetry fragment, as in the following case, the technique And can lead to the formation of the polymeric product at a competitive side reaction of the desired product with a nucleophilic reagent, i.e. with a reagent containing zinc.

Similarly, if the Vice-alkynes containing a triple bond within the chain, contain univresity, vinylidene, allpoetry or arylidene fragment, which will compete with 2-halogenosilanes for inclusion in palladium-based catalyst, the method may result in low output.

The way of synthesis ariver the new esters 1-3 catalyzed by palladium boilerhouse developed Miyaura and Murata and synthesis is carried out by the reaction of bis(pinacolato)Debora 1-1 with aryl halides [Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508] or by the reaction of dialkoxybenzene 1-2 with aryl halides or triflate [Murata, M.; Oyama, T.; Watanabe, S., Masuda, Y. J. Org. Chem. 2000, 65, 164]. However, depending on the substrate structure of the optimal conditions of the reaction are often significantly different.

Therefore, in this technical field is required a method of obtaining a 2,3-disubstituted indoles.

SUMMARY of the INVENTION

The present invention relates to a method for producing 2,3-disubstituted indoles of General formula (I):

this method includes the stage

a) introducing into a reaction bromoindole (i):

with dialkoxy-C1-C5-borane in the presence of ligand, a palladium catalyst and a base to obtain the compounds of General formula (ii);

or, alternatively, introducing the reaction of the compound (i) with a compound of magnesium containing 3 alkyl groups, followed by treatment with a borate of obtaining compounds of General formula (ii)above;

b) introducing into the reaction product obtained in stage (a), with:

R2-Hal obtaining the desired product of General formula I:

in which:

R1, R2and R3, X and Hal are defined in the present invention.

The present invention also Rel is referring to the method of obtaining compounds of General formula III:

in which R1-R10defined in this invention.

The present invention also relates to compounds that are active as pharmaceutical tools such as suppressing HCV, and applicable as intermediate products for the synthesis of funds suppressing HCV.

DETAILED description of the INVENTION

Definitions and terms

Terms not specifically defined in the present invention, should be given such values that they would give the specialist in the art given the description and context. However, when used in the present description, unless otherwise specified, the following terms have the specified values and use the following notation.

In groups defined below, the radicals or fragments, in front of a group often specified number of carbon atoms, for example, (C1-C8)alkyl means alkyl group or moiety containing from 1 to 8 carbon atoms, and (C3-C7)cycloalkyl means cycloalkyl group containing in the ring from 3 to 7 carbon atoms. Usually in groups of two or more subgroups, the last named group is the position of the connection of radical, for example, "cycloalkenyl" means a monovalent radical of the formula is cycloalkyl-alkyl and phenylalkyl means a monovalent radical of the formula phenyl-alkyl-. Unless otherwise stated below, all formulas and groups use the usual definitions of terms and the usual valence of the atoms.

The term "alkyl" when used in the present invention alone or in combination with another Deputy, means acyclic, having a linear or branched chain alkyl substituents containing a specified number of carbon atoms.

The term "alkoxygroup" when used in the present invention alone or in combination with another Deputy means an alkyl group as defined above as a substituent attached via an oxygen atom include alkyl-O-.

If the name or the link structure does not provide a specific stereochemistry or isomeric form, it usually refers to all tautomeric forms and isomeric forms and mixtures, as a separate geometric isomers or optical isomers and racemic or nerezisca mixture of isomers of a chemical structure or compound.

The term "pharmaceutically acceptable salt" as used in the present invention include salts formed from pharmaceutically acceptable bases. Examples of suitable bases include choline, ethanolamine and Ethylenediamine. Salts of Na+, K+and CA++also included in the scope of the present invention (see also the publication of a Pharmaceutical Salt. Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19, which is incorporated into this invention by reference).

The term "pharmaceutically acceptable ester" as used in this invention alone or in combination with another Deputy means esters of compounds of formula I in which any of carboxylate molecule, but preferably end carboxypropyl, replaced by alkoxycarbonyl group:

,

in which the fragment of Reof ester selected from the group comprising alkyl (e.g. methyl, ethyl, n-propyl, tert-butyl, n-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 (C1-C4)alkoxygroup. Other suitable esters of the prodrugs described in publication Design ofProdrugs. Bundgaard, H.Ed.Elsevier (1985), which is incorporated into this invention by reference. Such pharmaceutically acceptable esters after injection, the mammal is usually hydrolyzed in vivo and converted into the acid form of the compounds of formula I.

In the above-described esters, unless otherwise stated, any contained alkyl fragment preferably contains from 1 to 16 atom is in carbon, more preferably from 1 to 6 carbon atoms. Any aryl fragment contained in such esters, preferably includes a phenyl group.

In particular, these esters can be represented as (C1-C16)alkilany ether, unsubstituted benzyl ether or benzyl ether, substituted by at least one halogen, (C1-C6)alkyl, (C1-C6)alkoxygroup, the nitro-group or trifluoromethyl.

The following compounds may be denoted by the following abbreviations:

Table I
AbbreviationChemical name
NMP1-Methyl-2-pyrrolidinone
DMAN,N'-Dimethylacetamide
RH3PTriphenylphosphine
Net3or Et3N, or teaThe triethylamine
IPSIsopropyl alcohol
DMAPDimethylaminopyridine
DMFN,N-Dimethylformamide
TBTUO-(Benzotriazol-1-yl)-N,N,N',N'-tetramethylpropylenediamine
MTBEMethyl tert-butyl ether
EGN2-Ethylhexanoate, sodium
THFTetrahydrofuran
EDAC1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
DMEDimethoxyethan
TFFThree(2-furyl)phosphine
HATUO-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylpropylenediamine
THIEFBenzotriazol-1 yloxy-Tris-(dimethylamino)-hexaphosphate
UgorBromo-Tris(dimethylamino)fosfodiesterasa
DCN,N'-dicyclohexylcarbodiimide

GENERAL procedure for the synthesis of

The following synthesis schemes, unless specified otherwise, all replacement group in chemical formula have the same meanings as in General formula (I). The reagents used in the described who's following synthesis schemes, can be obtained as described in the present invention, or, if it is not described in the present invention, or they are commercially available, or can be obtained from commercially available materials by methods known in the art. For example, some of the original substance can be obtained by methods described in the application U.S. 60/546213, filed February 20, 2004

Optimal conditions for and the duration of the reaction may vary depending on the used reagents. Unless otherwise stated, solvents, temperature, pressure and other conditions of the reaction without difficulty can choose a specialist with General training in the art. Specific methods are given in the section on examples of synthesis. Typically the reaction can optionally be monitored using high performance liquid chromatography (HPLC) and the products can be purified by chromatography on silica gel and/or recrystallization.

I. Obtaining bromoindole

The diagram below presents a General method of obtaining the source bromoindole intended for the method proposed in the present invention.

Condensation of a derivative of indole (1) can be used with cycloalkanones (2), such as cyclopropane or cyclohexanone, in the Pris is under aqueous base. Suitable bases include aqueous solution of sodium hydroxide, which can be used to obtain 3-cycloalkenyl R3'(3), which can then be gidrirovanii in the presence of catalytic amounts of palladium on coal and to obtain the derived cycloalkenyl (4). If the Deputy X contains the active group may be required to protect the active groups. For example, if X denotes carboxypropyl, it is possible to carry out methylation of carboxypropyl. At this stage it is also possible to carry out methylation of the indole nitrogen atom of the ring. This is followed by bromination derived indole bromine in acetonitrile and get 2-bromo-3-cycloalkenyl (6).

II. A common technique to obtain a 2,3-disubstituted indoles from bromoindole

Derived bromoindole (1) can be transformed into derived diallylmalonate (2) by method A, which uses dialkoxybenzene in the presence of ligand, such as THF, palladium catalyst and base. Preferred are the following conditions for the reaction: 1,2 EQ. pinacolborane, 1.5 EQ. Et3N, a catalytic amount of Pd(OAc)2(3 mol.%) and three(2-furyl)phosphine (12 mol.%) in a solvent such as DME or THF. The reaction is carried out at a temperature of 70-80°C.

Alternatively, to obtain the product (2) can use the SQL method C. The method involves the reaction with the compound of magnesium containing 3 alkyl groups, followed by treatment with a borate. The range of acceptable conditions for this reaction is as follows: processing bromoindole 1 compound of magnesium containing 3 alkyl groups such as iso-PrHex2MgLi (from 0.5 to 0.7 EQ.) at a temperature of -20 to 0°C, followed by addition of borate, such as 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolan, at 0°C. Then the derivative of indole (2) you can enter into reaction with the iodine - or bromine derivatives of geterotsiklicheskikh compounds of General formula R2-Hal obtaining the desired product of General formula I.

The ligand - ligand, which can be used in the method proposed in the present invention, includes three(2-furyl)phosphine, allowing the reaction mix type Suzuki in mild conditions. The use of three(2-furyl)phosphine also allows the use of simple inorganic salts, such as2CO3or3RHO4. In addition, three(2-furyl)phosphine can also catalyze the first stage of the method (bilirubine) and thereby allows for two stages of the reaction in the same reactor.

The connection of magnesium is another feature of the present invention is the realization of currency VG-metal 2-bromoindole using compounds of magnesium. Examples of magnesium compounds which can be is about to use, include (G1-G3)MgLi, where G denotes any (C1-C6)alkyl group. The preferred magnesium compound is i-Pr(n-Hex)2MgLi or i-Pr(n-Bu)2MgLi, etc. the Use of compounds of magnesium in the methodology can provide easy formation of 2-indole anion at a temperature above -20°C in the presence of carboxylate groups in position X.

The Foundation is another feature of the present invention is the use of aqueous solutions of bases. The Foundation, which can be used in the method proposed in the present invention include2CO3and K2RHO4.

The reactions in the same reactor in some embodiments, the implementation of the method proposed in the present invention can be implemented in the form ignoreaction obtain 2,3-disubstituted indoles from the intermediate 2-bromoindole catalyzed by palladium boilerhouse and reactions combination by Suzuki. This technique allows you to get a variety of 2,3-disubstituted indoles without the double use of expensive palladium catalyst. Three(2-furyl)phosphine can be used as a common ligand for the two stages of the method (i.e. boilerhouse and reactions combination by Suzuki), and it is the preferred ligand for the method proposed in the present invention.

Receiving the s compounds of General formula III

Derivatives of indole of General formula III, such as described in provisional application U.S. 60/546213, and in particular, in table 1 of the above mentioned applications, it is possible to synthesize in the context of the present invention and preferably according to the General method presented below in figure 1.

Scheme 1

Compounds of General formula III in which R1, R2, R3, R4, R5, R6, R7, R8, R9and R10are as defined above in the present invention, it is preferable to obtain through a combination of carboxylic acids of General formula I' with amines of General formula II, as shown above in scheme 1, using reagents that activate carboxypropyl, well known to specialists in this field of technology. Such reagents include, but are not limited to, TBTU, HATU, BOP, BrOP, EDAC, DCC, isobutylparaben etc. alternatively, the carboxylic acids of General formula I' can be transformed into the corresponding acid chlorides using standard reagents, and then enter in the reaction mix with amino derivatives of General formula II. In cases where R5or R6contains a fragment of a carboxylic acid with an ester protecting group, conduct saponification (by methods well known to experts in the art) and get chechnyaamerican in the form of the free carboxylic acid.

The intermediate carboxylic acid of General formula I can be obtained according to the methods described in WO 03/010141, or according to the methods described in the examples below. The intermediate amines of formula II can be obtained by the General methods presented below in schemes 2 and 3.

Scheme 2

The connections defined in scheme 1, can be obtained from the relevant djaminovich precursors of General formula IV' reaction combination with suitable hydrochloride anhydrides of α,α-disubstituted amino acids. Suitable hydrochloride anhydrides of α,α-disubstituted amino acids can be obtained from the corresponding α,α-disubstituted amino acids as described in WO 03/007945 or WO 03/010141, or according to the method described in the publication of E. S. Uffelman et al. (Org. Lett. 1999, 7, 1157), or using a modified version of the foregoing methods. Then the intermediate amides obtained by reaction combinations, cyclist and receive the intermediate amines of General formula II.

Scheme 3

Alternatively, the intermediate amines of General formula II, shown in scheme 1, can be obtained from the relevant djaminovich precursors of General formula IV by reaction combination with a suitable containing protective group BOC α,α-disubstituted amino acid as shown in scheme 3, using the reagents of the reaction combination is, well-known specialist in the art, such as TBTU, HATU, BOP, BrOP, EDAC, DCC, isobutylparaben etc. containing the Appropriate protective group BOC α,α-disubstituted amino acids can be obtained from the free α,α-disubstituted amino acids under standard conditions, well known to the specialist in the art, such as reaction with Vos2In the presence of a tertiary amine such as triethylamine, etc. Then the intermediate amide obtained by the reaction of the combination, cyclist by heating in the presence of acid, such as acetic acid or hydrochloric acid. The removal of the protective group BOC with the intermediate amine of General formula II, shown in figure 1, is performed using standard reagents well known to the person skilled in the art. Such reagents include, but are not limited to, triperoxonane acid, a solution of Hcl in dioxane and the like,

Diamino precursors of the General formula IV, shown in schemes 2 and 3, preferably get the techniques described in the examples, including any modified methods, and/or through further stages of synthesis known to a person skilled in the technical field.

The intermediate amines of General formula II, shown in figure 1, in which one of R5and R6denotes-CH=C(R 50)-COOR, where R50selected from the group comprising (C1-C6)alkyl and halogen, and where R is, for example, denotes methyl or ethyl, can be obtained from the appropriate intermediate amines of General formula III, or suitably protected derivatives, where one of R5and R6means-COOR, where R denotes, for example, methyl or ethyl, by the techniques presented in the following scheme 4. Although figure 4 specifically illustrates the intermediate amines of General formula II in which R5denotes-CH=C(R50)-COOR, a specialist in the art should understand that, if R is-COOR, presents methods or modified options will lead to a product in which R6denotes-CH=C(R50)-COOR. Specialist in the art should also understand that the methodology presented in scheme 4, or modified options can also be used for turning diamino predecessor of General formula IV'above for schemes 2 and 3, or suitably protected derivative, or an intermediate product suitable for its reception, in which one of R5and R6means-COOR, diamino precursor of the General formula IV', or suitably protected derivative, or an intermediate product which is suitable for receiving the Oia, in which one of R5and R6denotes-CH=C(R50)-COOR, a R50and R are as defined above in the present invention.

Scheme 4

Suitable protected amine intermediate of General formula IIIa'above in scheme 4, can be transformed into an intermediate alcohol of General formula IIIb' by treatment with a suitable reducing reagent, such as diisobutylaluminium etc. Suitable protective group (ZG) include, but are not limited to, urethane protective group, such as BOC (tert-butoxycarbonyl), etc. Getting protected intermediate amines of General formula IIIa of the intermediate amines of General formula II above in scheme 1, can be performed by standard techniques, well known to the person skilled in the technical field.

The intermediate alcohol IIIb' can be transformed into intermediate aldehyde S' using standard oxidizing agents well known to the person skilled in the technical field, such as 1,1,1-Tris(acetoxy-1,1-dihydro-1,2-benzodioxol-3-(1H)-he (also known as periodinane dessa-Martin), etc.

The intermediate aldehyde C' can be transformed into the intermediate amine of General formula IIId' according to standard methods Horner-Emmons or similar techniques, such as the Wittig reaction and the like, well Izv the local specialist in a given field of technology further removal of ZG by standard methods. When the ZG means Vos, such techniques include, but are not limited to, treatment in an acidic environment, such as triperoxonane acid, a solution of Hcl in dioxane and the like,

Pharmaceutically acceptable salts of the compounds disclosed in the present invention include the salts obtained with pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, Hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methansulfonate, formic, benzoic, malonic, naphthalene-2-sulphonic and benzosulfimide acid. Other acids, such as oxalic acid, which is not pharmaceutically acceptable, can be used to obtain salts, used as intermediates in obtaining the compounds and their pharmaceutically acceptable salts joining with acids. Salts obtained with the help of suitable bases include alkali metal salts (e.g. sodium), alkaline earth metals (e.g. magnesium), ammonium and containing N-((C1-C4)alkyl)4+.

Embodiments of the inventions

First cook the NT implementation of the present invention relates to a method for producing 2,3-disubstituted indoles of General formula (I):

this method includes the stage

a) introducing into a reaction bromoindole (i):

with dialkoxy-C1-C5-borane in the presence of ligand, a palladium catalyst and a base to obtain the compounds of General formula ii;

or, alternatively, introducing the reaction of the compound (i) with a compound of magnesium containing 3 alkyl groups, followed by treatment with a borate of obtaining compounds of General formula (ii)above;

b) introducing into the reaction product obtained in stage (a), with:

R2-Hal

obtaining compounds of General formula I;

in which:

R1represents H or (C1-C6)alkyl;

R2denotes Het or aryl containing 5 or 6 ring atoms, Het or aryl optionally substituted with R21;

in which R21denotes 1, 2 or 3 substituent selected from the group comprising-OH, -CN, -N(RN2RN1, halogen, (C1-C6)alkyl, (C1-C6)alkoxygroup, (C1-C6)allylthiourea, Het and-CO-N(RN2RN1;

where these alkyl, alkoxygroup and allylthiourea all optionally substituted by one, two or three halogen atoms;

R3means (C5-C6)cycloalkyl, optionally substituted one to four the volumes halogen;

X represents: H, (C1-C6)alkyl, (C1-C6)alkoxygroup;

Hal represents Br or I;

L denotes H or a group of the General formula iii:

in which

R4and R7all independently selected from the group comprising H, (C1-C6)alkyl, (C1-C6)alkoxygroup, (C1-C6)allylthiourea, -NH2, -NH(C1-C6)alkyl, -n((c1-C6)alkyl)2and halogen;

one of R5and R6selected from the group comprising COOH, -CO-N(RN2RN1, Het1and (C2-C6)alkenyl, where Het1, (C2-C6)alkenyl and RN1or any heterocycle formed between the RN2and RN1, optionally substituted with R50;

where R50denotes 1, 2 or 3 substituent selected from the group comprising (C1-C6)alkyl, -COOH, -N(RN2RN1, -CO-N(RN2RN1and halogen;

and the other of R5and R6selected from the group comprising H, (C1-C6)alkyl, (C1-C6)alkoxygroup, (C1-C6)allylthiourea and N(RN2RN1;

R8means (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl-(C1-C6)alkyl-;

where these alkyl, cycloalkyl and cycloalkenyl it is certainly contain 1, 2 or 3 substituent selected from the group comprising halogen, (C1-C6)alkoxygroup and (C1-C6)allylthiourea;

R9and R10all independently selected from the group comprising (C1-C6)alkyl; or R9and R10covalently linked to each other to form (C3-C7)cycloalkyl, (C5-C7)cycloalkenyl or 4-, 5 - or 6-membered heterocycle containing 1-3 heteroatoms selected from the group comprising O, N and S;

where these cycloalkyl, cycloalkenyl or heterocycle optionally substituted (C1-C4)alkyl;

RN1selected from the group comprising H, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl-, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl and Het1;

where all these alkali and cycloalkyl optionally contain 1, 2 or 3 substituent selected from the group comprising halogen, (C1-C6)alkoxygroup and (C1-C6)alkylthiols; and

RN2represents H or (C1-C6)alkyl, or

RN2and RN1can be covalently linked to each other to form a 4-, 5-, 6-or 7-membered saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10 - or 11-membered N-containing bicyclic heterocycle, each of which is s optionally contains 1-3 heteroatoms, selected from the group comprising O, N and S;

where the heterocycle or the bicyclic heterocycle formed with RN2and RN1, optionally contains 1, 2 or 3 substituent selected from the group comprising halogen, (C1-C6)alkyl, (C1-C6)alkoxygroup and (C1-C6)allylthiourea;

where Het is defined as a 4-, 5-, 6 - or 7-membered heterocycle containing 1-4 heteroatoms selected from the group comprising O, N and S, which may be saturated, unsaturated or aromatic, or a 8-, 9-, 10 - or 11-membered ring of the bicyclic heterocycle containing 1-5 heteroatoms if possible, selected from the group comprising O, N and S, which may be saturated, unsaturated or aromatic;

or its pharmaceutically acceptable salt.

The second variant implementation of the present invention relates to a method for producing 2,3-disubstituted indoles of General formula (I), in which

R1represents H or (C1-C6)alkyl;

R2denotes Het or aryl containing 5 or 6 ring atoms, Het or aryl optionally substituted with R21;

in which R21denotes 1, 2 or 3 substituent selected from the group comprising-OH, -CN, -N(RN2RN1, halogen, (C1-C6)alkyl, (C1-C6)alkoxygroup, (C1-C6)allylthiourea, Het and-CO-N(RN2RN1 ;

where these alkyl, alkoxygroup and allylthiourea all optionally substituted by one, two or three halogen atoms;

R3denotes cyclopentyl;

X denotes H, (C1-C6)alkyl, (C1-C6)alkoxygroup,

Hal represents I or Br;

L denotes H or a group of the General formula iii:

in which

R4and R7all independently selected from the group comprising H, (C1-C6)alkyl, (C1-C6)alkoxygroup, (C1-C6)allylthiourea, -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2and halogen;

one of R5and R6selected from the group comprising COOH, -CO-N(RN2RN1, Het1and (C2-C6)alkenyl, where Het1, (C2-C6)alkenyl and RN1or any heterocycle formed between the RN2and RN1, optionally substituted with R50;

where R50denotes 1, 2 or 3 substituent selected from the group comprising (C1-C6)alkyl, -COOH, -N(RN2RN1, -CO-N(RN2RN1and halogen;

and the other of R5and R6selected from the group comprising H, (C1-C6)alkyl, (C1-C6)alkoxygroup, (C1-C6)allylthiourea and N(RN2RN1;

R8means (C1-C 6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl-(C1-C6)alkyl-;

where these alkyl, cycloalkyl and cycloalkenyl optionally contain 1, 2 or 3 substituent selected from the group comprising halogen, (C1-C6)alkoxygroup and (C1-C6)allylthiourea;

R9and R10all independently selected from the group comprising (C1-C6)alkyl; or R9and R10covalently linked to each other to form (C3-C7)cycloalkyl, (C5-C7)cycloalkenyl or 4-, 5 - or 6-membered heterocycle containing 1-3 heteroatoms selected from the group comprising O, N and S;

where these cycloalkyl, cycloalkenyl or heterocycle optionally substituted (C1-C4)alkyl;

RN1selected from the group comprising H, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl-, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl and Het1;

where all these alkali and cycloalkyl optionally contain 1, 2 or 3 substituent selected from the group comprising halogen, (C1-C6)alkoxygroup and (C1-C6)alkylthiols; and

RN2represents H or (C1-C6)alkyl, or

RN2and RN1can be covalently linked to drugs other to form a 4-, 5-, 6-or 7-membered saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10 - or 11-membered N-containing bicyclic heterocycle, each of which optionally contains 1-3 heteroatoms selected from the group comprising O, N and S;

where the heterocycle or the bicyclic heterocycle formed with RN2and RN1, optionally contains 1, 2 or 3 substituent selected from the group comprising halogen, (C1-C6)alkyl, (C1-C6)alkoxygroup and (C1-C6)allylthiourea;

where Het is defined as a 4-, 5-, 6 - or 7-membered heterocycle containing 1-4 heteroatoms selected from the group comprising O, N and S, which may be saturated, unsaturated or aromatic, or a 8-, 9-, 10 - or 11-membered ring of the bicyclic heterocycle containing 1-5 heteroatoms if possible, selected from the group comprising O, N and S, which may be saturated, unsaturated or aromatic.

The third option of implementing the present invention relates to a method for producing 2,3-disubstituted indoles of General formula (I), in which

R1represents H or (C1-C6)alkyl;

R2selected from the group including,,,,,, ,,,;

R3means (C5-C6)cycloalkyl, optionally substituted by one to four halogen atoms;

X represents: H, (C1-C6)alkyl, (C1-C6)alkoxygroup,

Hal represents Br or I;

L denotes H or a group of the General formula iii:

in which

R4and R7all independently selected from the group comprising H, (C1-C6)alkyl, (C1-C6)alkoxygroup, (C1-C6)allylthiourea, -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2and halogen;

one of R5and R6selected from the group comprising COOH, -CO-N(RN2RN1, Het1and (C2-C6)alkenyl, where Het1, (C2-C6)alkenyl and RN1or any heterocycle formed between the RN2and RN1, optionally substituted with R50;

where R50denotes 1, 2 or 3 substituent selected from the group comprising (C1-C6)alkyl, -COOH, -N(RN2RN1, -CO-N(RN2RN1and halogen;

and the other of R5and R6selected from the group comprising H, (C1-C6)alkyl, (C1-C6)alkoxygroup, (C1-C6)allylthiourea and N(RN2RN1;/p>

R8means (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl-(C1-C6)alkyl-;

where these alkyl, cycloalkyl and cycloalkenyl optionally contain 1, 2 or 3 substituent selected from the group comprising halogen, (C1-C6)alkoxygroup and (C1-C6)allylthiourea;

R9and R10all independently selected from the group comprising (C1-C6)alkyl; or R9and R10covalently linked to each other to form (C3-C7)cycloalkyl, (C5-C7)cycloalkenyl or 4-, 5 - or 6-membered heterocycle containing 1-3 heteroatoms selected from the group comprising O, N and S;

where these cycloalkyl, cycloalkenyl or heterocycle optionally substituted (C1-C4)alkyl;

RN1selected from the group comprising H, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl-, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl and Het1;

where all these alkali and cycloalkyl optionally contain 1, 2 or 3 substituent selected from the group comprising halogen, (C1-C6)alkoxygroup and (C1-C6)alkylthiols; and

RN2represents H or (C1-C6)alkyl, or

RN2and RN1

where the heterocycle or the bicyclic heterocycle formed with RN2and RN1, optionally contains 1, 2 or 3 substituent selected from the group comprising halogen, (C1-C6)alkyl, (C1-C6)alkoxygroup and (C1-C6)allylthiourea;

where Het is defined as 4-, 5-, 6 - or 7-membered heterocycle containing 1-4 heteroatoms selected from the group comprising O, N and S, which may be saturated, unsaturated or aromatic, or a 8-, 9-, 10 - or 11-membered ring of the bicyclic heterocycle containing 1-5 heteroatoms if possible, selected from the group comprising O, N and S, which may be saturated, unsaturated or aromatic;

or their pharmaceutically acceptable salts.

Another variant of implementation of the present invention relates to a method according to paragraph 1 of the claims, in which

R1means and or (C1-C6)alkyl;

R2denotes Het or aryl containing 5 or 6 ring atoms, Het or aryl optionally substituted with R21;

where R21denotes 1, 2 or 3 substituent, selected isgroup, including-OH, -CN, -N(RN2RN1, halogen, (C1-C6)alkyl, (C1-C6)alkoxygroup, (C1-C6)allylthiourea, Het and-CO-N(RN2RN1;

where these alkyl, alkoxygroup and allylthiourea all optionally substituted by one, two or three halogen atoms;

R3denotes cyclopentyl;

X denotes a carboxymethyl;

Hal represents Br or I;

L denotes H or a group of the General formula iii:

in which

R4and R7all independently selected from the group comprising H, (C1-C6)alkyl, (C1-C6)alkoxygroup, (C1-C6)allylthiourea, -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2and halogen;

one of R5and R6selected from the group comprising COOH, -CO-N(RN2RN1, Het1and (C2-C6)alkenyl, where Het1, (C1-C6)alkenyl and RN1or any heterocycle formed between the RN2and RN1, optionally substituted with R50;

where R50denotes 1, 2 or 3 substituent selected from the group comprising (C1-C6)alkyl, -COOH, -N(RN2RN1, -CO-N(RN2RN1and halogen;

and the other of R5and R6selected from the group comprising H, (C1-C6)alkyl, (C1-C6)alkoxygroup (C 1-C6)allylthiourea and N(RN2RN1;

R8means (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl-(C1-C6)alkyl-;

where these alkyl, cycloalkyl and cycloalkenyl optionally contain 1, 2 or 3 substituent selected from the group comprising halogen, (C1-C6)alkoxygroup and (C1-C6)allylthiourea;

R9and R10all independently selected from the group comprising (C1-C6)alkyl; or R9and R10covalently linked to each other to form (C3-C7)cycloalkyl, (C5-C7)cycloalkenyl or 4-, 5 - or 6-membered heterocycle containing 1-3 heteroatoms selected from the group comprising O, N and S;

where these cycloalkyl, cycloalkenyl or heterocycle optionally substituted (C1-C4)alkyl;

RN1selected from the group comprising H, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl-, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl and Het1;

where all these alkali and cycloalkyl optionally contain 1, 2 or 3 substituent selected from the group comprising halogen, (C1-C6)alkoxygroup and (C1-C6)alkylthiols; and

RN2denotes H Il is (C 1-C6)alkyl, or

RN2and RN1can be covalently linked to each other to form a 4-, 5-, 6-or 7-membered saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10 - or 11-membered N-containing bicyclic heterocycle, each of which optionally contains 1 to 3 heteroatoms selected from the group comprising O, N and S;

where the heterocycle or the bicyclic heterocycle formed with RN2and RN1, optionally contains 1, 2 or 3 substituent selected from the group comprising halogen, (C1-C6)alkyl, (C1-C6)alkoxygroup and (C1-C6)allylthiourea;

where Het is defined as a 4-, 5-, 6 - or 7-membered heterocycle containing 1-4 heteroatoms selected from the group comprising O, N and S, which may be saturated, unsaturated or aromatic, or a 8-, 9-, 10 - or 11-membered ring of the bicyclic heterocycle containing 1-5 heteroatoms if possible, selected from the group comprising O, N and S, which may be saturated, unsaturated or aromatic.

Another variant of implementation of the present invention relates to a method of obtaining compounds of General formula III:

this method involves the following stages:

a) introducing into a reaction bromoindole (iv):

with dialkoxybenzene in prisutstvujuwuju, palladium catalyst and a base to obtain the compounds of General formula (v);

b) introducing into the reaction product obtained in stage (a), with:

R2-Hal

to obtain the desired product of General formula III,

in which:

R1represents H or (C1-C6)alkyl;

R2denotes Het or aryl containing 5 or 6 ring atoms, Het or aryl optionally substituted with R21;

in which R21denotes 1, 2 or 3 substituent selected from the group comprising-OH, -CN, -N(RN2RN1, halogen, (C1-C6)alkyl, (C1-C6)alkoxygroup, (C1-C6)allylthiourea, Het and-CO-N(RN2RN1;

where these alkyl, alkoxygroup and allylthiourea all optionally substituted by one, two or three halogen atoms;

R3means (C5-C6)cycloalkyl, optionally substituted by one to four halogen atoms;

X represents: H, (C1-C6)alkyl, (C1-C6)alkoxygroup,

Hal represents Br or I;

L denotes H or a group of the General formula iii:

in which

R4and R7all independently selected from the group comprising H, (C1-C6)alkyl, (C1-C6)alkoxygroup, (C1-C6)Ala is stogroup, -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2and halogen;

one of R5and R6selected from the group comprising COOH, -CO-N(RN2RN1, Het1and (C2-C6)alkenyl, where Het1, (C2-C6)alkenyl and RN1or any heterocycle formed between the RN2and RN1, optionally substituted with R50;

where R50denotes 1, 2 or 3 substituent selected from the group comprising (C1-C6)alkyl, -COOH, -N(RN2RN1, -CO-N(RN2RN1and halogen;

and the other of R5and R6selected from the group comprising H, (C1-C6)alkyl, (C1-C6)alkoxygroup, (C1-C6)allylthiourea and N(RN2RN1;

R8means (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl-(C1-C6)alkyl-;

where these alkyl, cycloalkyl and cycloalkenyl optionally contain 1, 2 or 3 substituent selected from the group comprising halogen, (C1-C6)alkoxygroup and (C1-C6)allylthiourea;

R9and R10all independently selected from the group comprising (C1-C6)alkyl; or R9and R10covalently linked to each other to form (C3-C7)cycloalkyl, (C5-C7)cycloalkenyl or 4-, 5-or 6-membered heterocycle, containing 1-3 heteroatoms selected from the group comprising O, N and S;

where these cycloalkyl, cycloalkenyl or heterocycle optionally substituted (C1-C4)alkyl;

RN1selected from the group comprising H, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl-, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl and Het;

where all these alkali and cycloalkyl optionally contain 1, 2 or 3 substituent selected from the group comprising halogen, (C1-C6)alkoxygroup and (C1-C6)alkylthiols; and

RN2represents H or (C1-C6)alkyl, or

RN2and RN1can be covalently linked to each other to form a 4-, 5-, 6-or 7-membered saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10 - or 11-membered N-containing bicyclic heterocycle, each of which optionally contains 1-3 heteroatoms selected from the group comprising O, N and S;

where the heterocycle or the bicyclic heterocycle formed with RN2and RN1, optionally contains 1, 2 or 3 substituent selected from the group comprising halogen, (C1-C6)alkyl, (C1-C6)alkoxygroup and (C1-C6)allylthiourea;

where Het is defined as a 4-, 5-, 6 - or 7-membered gets recycl, containing 1-4 heteroatoms selected from the group comprising O, N and S, which may be saturated, unsaturated or aromatic, or a 8-, 9-, 10 - or 11-membered ring of the bicyclic heterocycle containing 1-5 heteroatoms if possible, selected from the group comprising O, N and S, which may be saturated, unsaturated or aromatic.

Another variant of implementation of the present invention relates to catalyzed by palladium way of bilirubine in which dialkoxybenzene represents 4,4,5,5-tetramethyl-1,3,2-dioxaborolan.

Another variant of implementation of the present invention relates to a method of obtaining compounds of General formula I, in which the borate used for the exchange of Br-Mg is isopropoxy-4,4,5,5,5-tetramethyl-1,3,2-dioxaborolan.

Another variant of implementation of the present invention relates to a method for obtaining compounds of General formula I, in which stage (a) includes a step of introducing into the reaction bromoindole formula (vi):

with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane obtaining (vii)

b) introducing into the reaction product obtained in stage (a), with:

or

with the receipt:

C) carrying out hydrolysis with NaOH to obtain (ix:

In another embodiment of the present invention the ligand is three(2-furyl)phosphine or 2-(dicyclohexylphosphino)biphenyl for the conversion of vi to vii using catalyzed by Pd boilerhouse and three(2-furyl)phosphine for the conversion of vii to viii with Pd catalyzed reaction mix by Suzuki.

In another embodiment of the present invention, the palladium catalyst is selected from the group comprising Pd(OAc)2, PdCl2, PdBr2Pd2(dba)3Pd2(dba)3.CHCl3, [Pd(ally)Cl]2, PD(CH3SP)2CL2Pd(PhCN)2Cl2Pd/C and encapsulated Pd.

In another embodiment of the present invention for Pd catalyzed boilerhouse, which is the conversion of vi to vii, the solvent is DME or THF and the base is triethylamine. For the reaction combinations by Suzuki solvent is DME, THF or 2-propanol and the base is potassium phosphate or potassium carbonate.

In another embodiment, the present invention is a reagent for the exchange of the bromine-magnesium is a magnesium compound containing 3 alkyl group, (G1-G3)MgLi, where G denotes any (C1-C6)alkyl group, and preferably, if (G1-G3)MgLi selected from the group including i-Pr(n-Hex)2MgLi i-Pr(n-Bu) 2MgLi, n-Bu3MgLi.

All literature cited in the present invention, including published in journals or abstracts or appropriate presents in the United States or other countries applications, issued U.S. or other countries, patents or any other publication in its entirety is included in the present invention by reference, including any tables, drawings and texts contained in the cited literature.

EXAMPLES SYNTHESIS

Compounds shown in table 2, was obtained in accordance with those specified in the table examples.

Table 2
Example No.AR
1
2
3
4
5
b
7
8
9
10
11

Example 1: Ignoreaction bilirubine/mix by Suzuki

To a solution of 2-bromoindole (1) (13,45 g to 40.0 mmole) in dry DME (100 ml) was added Et3N (13.4 ml, 96,0 mmole), tri-(2-furyl)phosphine (2) (1,11 g, 4.8 mmole, of 0.12 EQ.) and Pd(OAc)2(269,4 mg, 1.2 mmole, 0.03 EQ.). The mixture was degirolami with N2and to the mixture at room temperature was added dropwise, pinacolborane (14,12 ml, 94,40 mmole, 2.36 EQ.). The resulting mixture was heated to 70°C. and stirred at this temperature for 1 6 h, after which the reaction was completed. Thus obtained reaction mixture is directly used in the subsequent reaction combinations.

To the reaction mixture containing penatration (3) (20,0 mmole in 71,4 ml of DME), obtained through the above-described barelyawake, was sequentially added N2O (11 ml, 15% of the volume of DME), K3RHO4·H2On (25,0 g, 108,56 mmole, 5.4 EQ.) and (4) (6.5 g, 22,82 mmole, 1.1 EQ.). The reaction mixture was heated to 0°C and stirred at this temperature for about 7 hours, after which, according to HPLC, the reaction was completed. The reaction mixture was cooled to room temperature and the reaction was stopped with 100 ml of 10% aqueous solution of NaCl. Then the mixture was extracted with EtOAc (2×120 ml) and the combined organic layers were dried over Na2SO4and evaporated in a rotary evaporator. The crude solid was dispersible in 20 ml of cold acetone and then was filtered. The solid was further washed with 2 portions of cold acetone (2×10 ml) and received 6,23 g of the product (5) as a yellowish solid (75%yield, purity 97,9%).

1H NMR (300 MHz, Dl3) δ to 8.94 (2H, s), 8,15 (1H, s), 7,81 to 7.75 (2H, m), of 3.96 (3H, s), 3,90 (3H, s), of 3.73 (1H, m), 2,20-of 1.95 (6H, m), 1,74-1,71 (2H, m);

13C NMR (100 MHz, CDCl3) δ 168,1, 158,8, 157,7, 138,2, 135,6, 129,2, 124,6, 123,4, 121,0, 119,8, 118,2, 112,6, 52,0, 36,8, 33,3, 31,9, 26,7.

Example 2:

Into the flask were placed pinacolborane (of 383.0 mg, 1.0 mmole), 2-idioten (231,0 mg, 1.1 mmole), Pd(OAc)2(11.2 mg, 0.05 mmole), THF (46.4 mg, 0.2 mmole), K2CO3(690,0 mg, 5 mmole), water (3 ml) and DME (2 ml). After 3 cycles of evacuation/filling argon, the mixture was heated to 80°C. After 30 min HPLC showed that boronat has slashdowns. According to HPLC the ratio of the peak areas of the C-H, product combinations and dimer was approximately 3.2:92,7:4,1. After cooling the reaction mixture to room temperature the URS was added EtOAc (5 ml). The aqueous layer was separated and was extracted with EtOAc (2×10 ml). The combined organic extracts were washed with brine (10 ml), dried over Na2SO4and concentrated in vacuum. The crude product was purified by chromatography on silica gel and got indole (0.31 g, 91%).

1H NMR (300 MHz, CDCl3) δ 8,10 (1H, s), 7,78 (1H, d, J=6.3 Hz), 7,71 (1H, d, J=6.3 Hz), 7,49 (1H, d, J=3,9 Hz), 7.18 in-7,10 (1H, m), to 7.09 (1H, d, J=0.9 Hz), of 3.94 (3H, s), to 3.64 (3H, s), 3,21 (1H, m), 2,01-of 1.88 (6H, m), 1,68-1,65 (2H, m);

13C NMR (100 MHz, Dl3) δ 168,2, 137,2, 133,1, 132,0, 129,8, 129,2, 127,9, 127,3, 123,4, 120,0, 119,9, 119,8, 112,1, 52,0, 37,5, 33,5, 30,8, 26,5.

Example 3:

Into the flask were placed pinacolborane (of 383.0 mg, 1.0 mmole), 1-fluoro-4-iadanza (244,2 mg, 1.1 mmole), Pd(OAc)2(11.2 mg, 0.05 mmole), THF (46.4 mg, 0.2 mmole), K2CO3(690,0 mg, 5 mmole), water (3 ml) and DME (2 ml). After 3 cycles of evacuation/filling argon, the mixture was heated to 80°C. After 90 min HPLC showed that boronat has slashdowns. According to HPLC the ratio of the peak areas of the C-H, product combinations and dimer was approximately 10,7: 87,3 is 2.0. After cooling the reaction mixture to room temperature, was added EtOAc (5 ml). The aqueous layer was separated and was extracted with EtOAc (2×10 ml). The combined organic extracts were washed with brine (10 ml), dried over PA2SO4and concentrated in vacuum. The crude product was purified p is the power chromatography on silica gel and got indole (0.28 g, 80%).

1H NMR (300 MHz, Dl3) δ 8,11 (1H. s), 7,80 (1H, d. J=6.3 Hz), of 7.70 (1H, d, J=6.3 Hz), 7,34-7,31 (2H, m), 7,20-7,14 (2H, m), 3,98 (3H, s), 3,55 (3H, s), to 3.02 (1H, m), 2,02-1,89 (6H, m), of 1.26 (2H, bs);

13With NMR (100 MHz, CDCl3) δ 168,3, 139,9, 137,0, 132,5, 132,5, 129,6, 123,0, 112,0, 119,7, 117,4, 115,7, 115,5, 112,0, 51,9, 37,4, 33,5, 30,8, 26,4.

Example 4:

Into the flask were placed pinacolborane (of 383.0 mg, 1.0 mmole), 2-chloro-5-yodellin (263,4 mg, 1.1 mmole), Pd(OAc)2(11.2 mg, 0.05 mmole), THF (46.4 mg, 0.2 mmole), K2CO3(690,0 mg, 5 mmole), water (3 ml) and DME (2 ml). After 3 cycles of evacuation/filling argon, the mixture was heated to 80°C. After 30 min HPLC showed that boronat has slashdowns. According to HPLC the ratio of the peak areas of the C-H, product combinations and dimer was approximately 8,0:90,2:1,8. After cooling the reaction mixture to room temperature, was added EtOAc (5 ml). The aqueous layer was separated and was extracted with EtOAc (2×10 ml). The combined organic extracts were washed with brine (10 ml), dried over Na2SO4and concentrated in vacuum. The crude product was purified by chromatography on silica gel and got indole (0.32 g, 86%).

1H NMR (300 MHz, CDCl3) δ to 8.45 (1H, d, J=1,8 Hz)to 8.12 (1H, s), 7,80 (1H, d,J=6.3 Hz), 7,74-to 7.68 (2H, m), to 7.50 (1H, d, J=6.3 Hz), of 3.96 (3H, s), 3,62 (3H, s), 2,98 (1H, m), 2.05 is-1,89 (6H, m), 1,69-of 1.66 (2H, m);

13With NMR (100 MHz, CDCl3) δ 168,1, 151,6, 151,0, 140,5, 137,5, 135,5, 129,2, 126,8, 124,2, 123,7, 120,2, 120,0, 119,1,112,1, 52,0, 37,3, 33,5, 31,0, 26,4.

Example 5:

Into the flask were placed pinacolborane (of 383.0 mg, 1.0 mmole), brobinson (172,7 mg, 116 μl, 1.1 mmole), Pd(OAc)2(11.2 mg, 0.05 mmole), THF (46.4 mg, 0.2 mmole), K2CO3(690,0 mg, 5 mmole), water (3 ml) and DME (2 ml). After 3 cycles of evacuation/filling argon, the mixture was heated to 80 Scares 120 min HPLC showed that boronat has slashdowns. According to HPLC the ratio of the peak areas of the C-H, product combinations and dimer was approximately 13,2:80,0:6,8. After cooling the reaction mixture to room temperature, was added EtOAc (5 ml). The aqueous layer was separated and was extracted with EtOAc (2×10 ml). The combined organic extracts were washed with brine (10 ml), dried over Na2SO4and concentrated in vacuum. The crude product was purified by chromatography on silica gel and got indole (0.25 g, 76%).

1H NMR (300 MHz, CDCl3) δ 8,11 (1H, s), 7,79 (1H, d, J=6.3 Hz), 7,72 (1H, d, J= 6.3 Hz), 7,52-7,37 (5H. m), of 3.95 (3H, s), of 3.60 (3H, s), of 3.07 (1H, m), 2,04-of 1.88 (6H, m), l 66-l,63(2H,m);

13C NMR (100 MHz, CDCl3) δ 168,3, 141,1, 137,0, 131,9, 130,7, 129,6, 128,4, 122,8, 119,8, 119,6, 117,2, 112,0, 51,9, 37,3, 33,4, 30,9, 26,4.

Example 6:

Into the flask were placed pinacolborane (of 383.0 mg, 1.0 mmole), iadanza (204,0 mg, 1.1 mmole), Pd(OAc)2(11.2 mg, 0.05 mmole), THF (46.4 mg, 0.2 mmole), K2CO3(690,0 mg, 5 mmole), water (3 ml) and DME (2 ml). The village is e 3 cycles of evacuation/filling argon, the mixture was heated to 80°C. After 60 min HPLC showed that boronat has slashdowns. According to HPLC the ratio of the peak areas of the C-H, product combinations and dimer was approximately 3.6:95,5:0,9. After cooling the reaction mixture to room temperature, was added EtOAc (5 ml). The aqueous layer was separated and was extracted with EtOAc (2×10 ml). The combined organic extracts were washed with brine (10 ml), dried over Na2SO4and concentrated in vacuum. The crude product was purified by chromatography on silica gel and got indole (0,30 g, 91%).

1H NMR (300 MHz, CDCl3) δ 8,11 (1H, s), 7,79 (1H, d, J=6.3 Hz), 7,72 (1H, d, J=6.3 Hz), 7,52-7,37 (5H, m), of 3.95 (3H, s), of 3.60 (3H, s), of 3.07 (1H, m), 2,04-of 1.88 (6H, m), 1,66-to 1.63 (2H, m);

13With NMR (100 MHz, CDCl3) δ 168,3, 141,1, 137,0, 131,9, 130,7, 129.6, 128,4, 122,8, 119,8, 119,6, 117,2, 112,0, 51,9, 37,3, 33,4, 30,9, 26,4.

Example 7:

Into the flask were placed pinacolborane (of 383.0 mg, 1.0 mmole), 4-iodization (270,7 mg, 1.1 mmole), Pd(OAc)2(11.2 mg, 0.05 mmole), THF (46.4 mg, 0.2 mmole), K2CO3(690,0 mg, 5 mmole), water (3 ml) and DME (2 ml). After 3 cycles of evacuation/filling argon, the mixture was heated to 80°C. After 30 min HPLC showed that boronat has slashdowns. According to HPLC the ratio of the peak areas of the C-H, product combinations and dimer was approximately 9,1: 90,3: 1,6. After cooling the reaction mixture to room temperature, was added EtOAc (5 ml). Water lyrics by the nd was separated and was extracted with EtOAc (2×10 ml). The combined organic extracts were washed with brine (10 ml), dried over Na2SO4and concentrated in vacuum. The crude product was purified by chromatography on silica gel and got indole (0.31 g, 83%).

1H NMR (300 MHz, CDCl3) δ 8,12-with 8.05 (3H, m), 7,80 (1H, d, J=6.6 Hz), 7,72 (1H, d, J=6.3 Hz), to 7.50 (2H, d, J=6.0 Hz), of 3.96 (3H, s), 3,62 (3H, s), 3,05 (1H, m), 2,68 (3H, s), 2,04-1,90 (6H, m), 1,67-of 1.64 (2H, m);

13C NMR (100 MHz, CDCl3) δ 197,6, 168,2, 139,6, 137,4, 136,8, 136,6, 130.9, 129,5, 129,0, 128,4, 127,5, 123,3, 120,0, 119,9, 118,0, 112,1, 52,0, 37,3, 33,4, 31,1, 26,7, 26,4.

Example 8:

Into the flask were placed pinacolborane (of 383.0 mg, 1.0 mmole), 4-identified (299,2 mg, 1.1 mmole), Pd(OAc)2(11.2 mg, 0.05 mmole), THF (46.4 mg, 0.2 mmole), K2CO3(690,0 mg, 5 mmole), water (3 ml) and DME (2 ml). After 3 cycles of evacuation/filling argon, the mixture was heated to 80°C. After 30 min HPLC showed that boronat has slashdowns. According to HPLC the ratio of the peak areas of the C-H, product combinations and dimer was approximately 7.5: 89,9: 2,6. After cooling the reaction mixture to room temperature, was added EtOAc (5 ml). The aqueous layer was separated and was extracted with EtOAc (2×10 ml). The combined organic extracts were washed with brine (10 ml), dried over Na2SO4and concentrated in vacuum. The crude product was purified by chromatography on silica gel and got indole (0,33, 3%).

1H NMR (300 MHz, CDCl3) δ 8,13 (1H, s), 7,83-7,73 (4H, m), 7,50 (2H, J=6.0 Hz), to 3.92 (3H, s)and 3.59 (3H, s), 3,03 (1H, m), 2,03-1,90 (6H, m), of 1.65 (2H. bs);

13With NMR (100 MHz, CDCl3) δ 168,1, 139,2, 137,4, 135,6, 131,1, 129,4, 125,5, 125,4, 123,4, 120,1, 119,9, 118,1, 112,2, 51,9, 37,3, 33,5, 31,0, 26,4, 25,2.

Example 9:

Into the flask were placed pinacolborane (of 383.0 mg, 1.0 mmole), iterator (226,6 mg, 1.1 mmole), Pd(OAc)2(11.2 mg, 0.05 mmole), THF (46.4 mg, 0.2 mmole), K2CO3(690,0 mg, 5 mmole), water (3 ml) and DME (2 ml). After 3 cycles of evacuation/filling argon, the mixture was heated to 80°C. After 45 min HPLC showed that boronat has slashdowns. According to HPLC the ratio of the peak areas of the C-H, product combinations and dimer was about 3.3:85,3:11,4. After cooling the reaction mixture to room temperature, was added EtOAc (5 ml). The aqueous layer was separated and was extracted with EtOAc (2×10 ml). The combined organic extracts were washed with brine (10 ml), dried over Na2SO4and concentrated in vacuum. The crude product was purified by chromatography on silica gel and got indole (0.27 g, 81%).

1H NMR (300 MHz, CDCl3) δ 8,77 (2H, bs), at 8.60 (1H, s), 8,16 (1H, s), 7,82-7,76 (2H, m), of 3.96 (3H, s), of 3.78 (3H, s), 3,20 (1H, m), 2,08-of 1.92 (6H, m), 1,72 was 1.69 (2H, m);

13C NMR (100 MHz, CDCl3) δ 168,0, 147,4, 146,6, 144,4, 143,2, 138,0, 135,3, 129,0, 124,2, 120,5, 120,3, 120,0, 112,4, 52,0, 37,3, 33,6, 31,3, 26,5.

Example 10:

Into the flask were placed pinacolborane (of 383.0 mg, 1.0 mmole), 2-yodellin (226,6 mg, 1.1 mmole), Pd(OAc)2(11.2 mg, 0.05 mmole), THF (46.4 mg, 0.2 mmole), K2CO3(690,0 mg, 5 mmole), water (3 ml) and DME (2 ml). After 3 cycles of evacuation/filling argon, the mixture was heated to 80°C. After 60 min HPLC showed that boronat has slashdowns. According to HPLC the ratio of the peak areas of the C-H, product combinations and dimer was approximately 23.5:74,2:2,3. After cooling the reaction mixture to room temperature, was added EtOAc (5 ml). The aqueous layer was separated and was extracted with EtOAc (2×10 ml). The combined organic extracts were washed with brine (10 ml), dried over Na2SO4and concentrated in vacuum. The crude product was purified by chromatography on silica gel and got indole (0,23 g, 68%).

1H NMR (300 MHz, CDCl3) δ 8,81 (1H, d, J=0.6 Hz), 8,14 (1H, s), 7.83-of 7.75 (3H, m), 7.46 (1H, d, J=5.4 Hz), 7,35 (1H, m), of 3.95 (3H, s), 3,74 (3H, s), 2,04 (1H, m), 2,04 is 1.91 (6H, m), 1,69-of 1.66 (2H, m);

13C NMR (100 MHz, CDCl3) δ 168,3, 151,4, 150,0, 139,1, 137,5, 136,3, 129,4, 126,2, 123,4, 122,6, 120,1, 119,7, 118,6, 112,2, 51,9, 37,3, 33,4, 31,1, 26,5.

Example 11:

Into the flask were placed pinacolborane (766,0 mg, 2.0 mmole), 2-iadanza (514,9 mg, 2.2 mmole), Pd(OAc)2(of 22.4 mg, 0.1 mmole), THF (of 92.9 mg, 0.4 mmole), K2CO3(1380 mg, 10 mmole), water (6 ml) and DME (4 ml). After 3 cycles of evacuation/filling argon recip is nnow the mixture was heated to 80°C. After 30 min HPLC showed that boronat has slashdowns. According to HPLC the ratio of the peak areas of the C-H, product combinations and dimer was approximately 4.6: 94,5: 0,9. After cooling the reaction mixture to room temperature, was added EtOAc (5 ml). The aqueous layer was separated and was extracted with EtOAc (2×10 ml). The combined organic extracts were washed with brine (10 ml), dried over PA2SO4and concentrated in vacuum. The crude product was purified by chromatography on silica gel and got indole (0.64 g, 88%).

1H NMR (300 MHz, CDCl3) δ 8,11 (1H, s), 7,80 (1H, d, J=6.3 Hz), 7,71 (lH,d,J=6.3 Hz), 7,21 (2H, d, J=6.6 Hz), 7,00 (2H, d, J=6.3 Hz), 3,92 (3H. s)a 3.83 (3H, s), of 3.56 (3H, s), of 3.07 (1H, m), 2,02-to 1.87 (6H, m), 1,65-of 1.62 (2H, m);

13With NMR (100 MHz, CDCl3) δ 168.4, 159,8, 141,1, 136,9, 131,9, 129,7, 124,0, 122,6, 119,8, 119,5, 117,0, 114.0, 112,0, 55,3, 51,9, 37,5, 33,4, 30,8, 26,4.

Example 12: Getting bromoindole

In one embodiment, the present invention relates to the following common multi-stage method for the synthesis of intermediate compounds of General formula I, represented in the diagram below, I, as well as to individual stages and the accompanying interim products:

Condensation indolocarbazoles acid with Cyclopentanone in the presence of an aqueous solution of sodium hydroxide gave cyclopentanecarbonyl acid, which was first made is the presence of catalytic amounts of palladium on coal and with a total output equal to 80%, receive appropriate cyclopentanecarbonyl acid. Double methylation-carboxypropyl and nitrogen atom with methylcarbonate in NMP at 130°C gave the methyl ester of N-methylcarbamate with the release of 90%. Bromination of indocarbocyanine bromine in acetonitrile gave 2-bromo-3-cyclopentanecarboxylate with the release of 90%.

Example 13: Getting boronate (3) using boilerhouse catalyzed by Pd

In dried in a drying Cabinet three-neck round bottom flask of 1 l equipped with a refrigerator, temperature control, and addition funnel, was placed bromide (50 g, 148, 7mm mmole), dry THF (500 ml), Et3N (49,6 ml, 357 mmole), 2-dicyclohexylphosphino (2,08 g, 6 mmole) and Pd(dAc)2(0.33 g, 1.5 mmole). In the addition funnel was put pinacolborane (32,4 ml, 223 mmole) and the system was pumped for 5-10 min and was filled by N2. Then to the reaction mixture dropwise added, pinacolborane and after completion of the addition (about 30-45 min) the mixture was heated at 60°C. until completion of the reaction (according to HPLC).

The residue was filtered and washed with THF (100 ml) and the filtrate evaporated to dryness. The crude product was dispersively in the Meon (200 ml) for about 15 min and then was filtered. The filter cake was washed with another portion of M WHICH HE (100 ml) and then dried in air to constant mass (53,74 g, yield 94%, purity 97%).

Example 14: Getting boronate (3) by exchanging Br-Mg with the use of magnesium compounds

To a solution of i-PrMgCl (9.75 ml, 19.5 mmole, 2 M in THF) in 22.5 ml THF at 0°C was added n-HexLi (16,96 ml, 39 mmole, 2.3 M in hexane). The resulting mixture was stirred for 10 minutes, the Concentration of the solution i-Pr(n-Hex)2MgLi in THF were 0.4 M

In another flask was placed a solution of intelbased (33,6 g of 0.1 mol) in THF (30 ml). After cooling the solution to -15°C was added dropwise i-Pr(n-Hex)2MgLi, maintaining the temperature in the flask is equal to about -15°C. the Reaction was completed after about 15 min after the addition.

To the resulting solution at -15°C was added undiluted 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (40,8 ml of 0.2 mol). The mixture was allowed to warm to room temperature. After stirring for 30 min at room temperature, the reaction mixture was diluted with EtOAc and aqueous solution of NH4Cl. The organic layer was separated and washed with water. Removal of solvent gave an oily product. The oil was diluted with Meon (about 30 ml). Solution a short time, was stirred at room temperature and formed a solid residue. The solid is collected, dried in vacuum and directly used for the reaction combinations by Suzuki.

1Mr. YAM is (300 MHz, CDCl3) δ 8,07 (1H, s), 7,73 (1H, d, J=6.6 Hz), to 7.68 (1H, d, J=6.3 Hz), 3,99 (3H, s), of 3.96 (3H, s), 3,88 (1H, m), 2,02-of 1.94 (6H, m), of 1.78 and 1.75 (2H, m), of 1.37(12H,s);

13C NMR (100 MHz, CDCl3) δ 166,1, 137,6, 130,4, 127,2, 122,0, 118,5, 116,7, 110,2, 81,4, 49,7, 35,1, 31,8, 30,2, 24,6, 22,6.

Bromoindole containing the 2' position of the group, are not cyclopentyl, can be obtained by the above General method.

1. The way to obtain 2,3-disubstituted indoles of General formula (I):

this method involves the following stages (a) introducing into a reaction bromoindole (i):

with dialkoxybenzene in the presence of ligand, a palladium catalyst, preferably selected from Pd(OAc)2, PdCl2, PdBr2Pd2(dba)3Pd2(dba)3·CHCl3, [Pd(ally)Cl]2Pd(CH3CN)2Cl2Pd(PhCN)2Cl2Pd/C and encapsulated Pd and the Foundation of obtaining compounds of General formula ii;

or alternative introduction in the reaction of the compound (i) with a compound of magnesium containing 3 alkyl groups, followed by treatment with borate to obtain compounds of the above General formula ii;
b) introducing into the reaction product obtained in stage (a), with:
R2-Hal
obtaining compounds of General formula I;
in which:
R1means (C1-C6)alkyl;
R2selected from the group including
,,,,,
,,,,;
R3denotes cyclopentyl:
X denotes a carboxymethyl;
Hal represents Br or I;
or its pharmaceutically acceptable salt.

2. The method according to claim 1 for use in catalyzed by palladium bilirubin, which when used in catalyzed by palladium bilirubin specified dialkoxybenzene represents 4,4,5,5-tetramethyl-1,3,2-dioxaborolan.

3. The method according to claim 1 obtain the compounds of General formula I, in which when used in the exchange of Br-Mg specified Borat is isopropoxy-4,4,5,5,5-tetramethyl-1,3,2-dioxaborolan.

4. The method of obtaining compounds of General formula (ix):

comprising (a) reaction of bromoindole formula (vi):

with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane in the presence of ligand, a palladium catalyst, preferably selected from Pd(OAc)2, PdCl2, PdBr2Pd2(dba)3Pd2(dba)3·CHCl3, [Pd(ally)Cl]2Pd(CH3CN)2Cl2Pd(PhCN)2Cl2Pd/C and encapsulated Pd and grounds with obtaining (vii)

b) introducing into the reaction product obtained in stage (a), with:

with the receipt:

(C) carrying out hydrolysis with NaOH to obtain (ix):

5. The method of obtaining compounds of General formula (ix):

comprising (a) reaction of bromoindole formula (vi):

where alkyl represents preferably (C1-C6)alkyl, for example ethyl, n-propyl, tert-butyl or n-butyl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane in the presence of ligand; palladium catalyst, preferably selected from Pd(OAc)2, PdCl2, PdBr2Pd2(dba)3Pd2(dba)3·CHCl3, [Pd(ally)Cl]2Pd(CH3CN)2Cl2Pd(PhCN)2Cl2Pd/C and encapsulated Pd and grounds with obtaining (vii)

b) introducing into the reaction product obtained in stage (a), with:
or
with the receipt:

c) if necessary, carrying out hydrolysis with NaOH to obtain (ix):

6. The method according to claims 1, 4 or 5, in which the ligand is three(2-furyl)phosphine or 2-(dicyclohexylphosphino)biphenyl for the conversion of i to ii or vi vii using catalyzed by Pd borili the Finance and three(2-furyl)phosphine for the conversion of the product of stage a) in a compound of formula I or vii viii using Pd catalyzed reaction mix by Suzuki.

7. The method according to claims 1, 4 or 5, in which for Pd catalyzed boilerhouse, which is the transformation of i, ii or vi to vii, the solvent is DME (dimethoxyethane) or THF (tetrahydrofuran) and the base is triethylamine, the reaction mix by Suzuki solvent is DME, THF or 2-propanol and the base is potassium phosphate or potassium carbonate.

8. The method according to claims 1, 4 or 5, in which the reagent for the exchange of the bromine-magnesium is a magnesium compound containing 3 alkyl group, (G1-G3)MgLi, where G denotes any (C1-C6)alkyl group.

9. The method according to claim 8, in which (G1-G3)MgLi selected from the group including i-Pr(n-Hex)2MgLi or i-Pr(n-Bu)2MgLi, n-Bu3MgLi.

10. The method according to claim 1, wherein the compound of formula (I)obtained by the above method, is:



 

Same patents:

FIELD: chemistry.

SUBSTANCE: described are novel 1,2,4-triazolones of general formula (I):

, where A denotes N and values of other radicals are given in the claim, which are vasopressin receptor inhibitors, synthesis method thereof and use thereof to prepare medicinal agents for treating and/or preventing diseases, particularly for treating and/or preventing cardiovascular diseases.

EFFECT: high efficiency of using said derivatives.

6 cl, 512 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of formula (1) in free form or in form of a salt. In formula (1): X1 and X2 all independently denote halogen; A denotes a radical of formula where (R1)1-2 denotes 1-2 identical or different substitutes selected from a group comprising C1-C4-alkyl, halogen-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, R2R3N-C1-C4-alkyl, halogen, hydroxy group, C1-C4-alkoxy group, halogen-C1-C4-alkoxy group, C1-C4-alkylthio group, C1-C4-alkanoyl, C1-C4-alkanoylamino group, C1-C4-alkylsulphonylamino group, C1-C4-alkylsulphonyl, C1-C4-alkylthionyl, NR2R3 and morpholinyl; or A denotes a radical of formula where ring (a) denotes a 5-member heterocyclic ring containing 1 or 2 heteroatoms selected from a group comprising O and N, which can further be substituted with C1-C4-alkyl, and which is annelated in positions 3 and 4; and R2 and R3 all independently denote hydrogen or C1-C4-alkyl. The invention also relates to a parasite control composition containing said compounds, a parasite control method on warm-blooded animals and use of compounds of formula (1) to prepare a parasite control composition.

EFFECT: high efficiency of using said compounds.

11 cl, 7 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound of formula A

the radicals R1, R2, R3, R4, R5, R25, R26, U, T, W, V, Y are those as specified in clause 1 of the patent claim. Also, the invention refers to a method for preparing the compound of formula A, the drug based on this compound applied for treating disorders or diseases which are at least partially mediated by vanilloid receptor VR1 /NRPV1, as well as use of this compound for preparing the drug.

EFFECT: there are prepared and described new compounds which can be effective in treating diseases which are at least partially mediated by vanilloid receptor VR1 /NRPV1.

43 cl, 367 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted methyl-amines of general formula 1, having serotonin 5-HT6 receptor antagonist properties. In formula 1 , W is naphthalene, indolysin or quinoline; R1 is hydrogen, fluorine, chlorine, methyl; R2 is hydrogen, fluorine, methyl, phenyl, thiophen-2-yl, furan-2-yl, pyridyl, piperazin-1-yl or 4-methylpiperazin-1-yl; R3 is methyl; or W is benzene, R3 assumes the value given above; R1 is 3-Cl, R2 is 3-piperazin-1-yl or 3-(4-methylpiperazin-1-yl); or R1 is hydrogen, R2 is phenyl or pyridyl; or R1 is hydrogen, fluorine, chlorine, methyl; R2 is 4-piperazin-1-yl or 4-(4-methylpiperazin-1-yl); or W is oxazole, R3 is optionally substituted methyl; R1 is chlorine or fluorine, R2 is methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is piperazin-1-yl, 4-methylpiperazin-1-yl, or R1 is chlorine, fluorine or methyl; R2 is furan-2-yl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is furan-2-yl, R3 is (tetrahydrofuran-2-yl)methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is thiophen-2-yl, R3 is 2-methoxyethyl, or R1 is chlorine or fluorine, R2 is thiophen-2-yl, R3 is methyl.

EFFECT: compounds can be used to treat central nervous system (CNS) diseases, such as psychiatric disorders, schizophrenia, anxiety disorders, as well as for improving mental capacity, for treating obesity or for studying the molecular mechanism of inhibiting serotonin 5-HT6 receptors.

15 cl, 27 dwg, 2 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel antibacterial chinolin derivatives of formula (1a), their stereochemically isomeric forms, N-oxides and pharmaceutically acceptable salts and solvates , where p equals 1; q equals 0, 1, 2, 3 or 4; R1 represents hydrogen, halogen, aryl or Het; R2 represents hydrogen or alkyloxy; R3 represents arylalkyl; each R4 and R5 independently represent hydrogen or alkyl; R7 represents hydrogen, alkyl or aryl; where aryl is selected from phenyl or naphtyl and is optionally substituted with 1, 2 or 3 substituents selected from hydroxy, halogen, cyano, nitro, amino, mono- or dialkylamino, alkyl, C2-6alkenyl, optionally substituted with phenyl, halogenalkyl, alkyloxy, halogenalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl or mono- or dialkylaminocarbonyl; where Het is selected from furanyl, thienyl, pyridinyl, benzofuranyl, optionally substituted with 1, 2 or 3 substituents selected from halogen, hydroxyl, alkyl or alkyloxy.

EFFECT: compounds can be used for creation of preparations on their base for treatment of bacterial infection

21 cl, 4 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (IC-2), to their pharmaceutically acceptable salts, N- oxides or solvates. In formula (IC-2) Z represents carbomoyl group, which can be replaced with C1-4 alkyl or hydroxy; R1 represents C1-8 alkyl or C1-8 alkoxy; R4 and R4-1 each independently represent hydrogen atom or C1-8 alkyl; m represents integer number from 1 to 5, when m equals 2 or larger number, all R1 can have same or different values. Invention also relates to compounds, representing 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-napthlenyl}methyl)-3-azetidinecarbonic acid, 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalinyl}methyl)-3- azetidinecarbonic acid and other, given in formula of claimed invention.

EFFECT: obtaining pharmaceutical composition, which has agonistic activity with respect to EDG-1, EDG-6 and/or EDG-8, containing as active component invention compound, to method of prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8 invention compounds, to method of prevention and/or treatment of disseminated sclerosis and method of immune reaction suppression and/or induction of lymphopenia, to application of invention compounds for obtaining medication for prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8, to application of compounds for obtaining medication for prevention and/or treatment of disseminated sclerosis, to application of compounds for obtaining immunodepresant and/or medication inducing lymphopenia and to crystal forms of some individual compounds.

17 cl, 10 dwg, 5 tbl, 251 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2,6-substituted-4-monosubstituted aminopyrimidines of formula (I) or pharmaceutically acceptable salts thereof, which have prostaglandin D2 receptor antagonist properties. In formula R1 is 2,4-dichlorophenyl or 4-trifluoromethoxyphenyl, and when R1 is 2,4-dichlorophenyl, R2 is 3-carboxypyrrolidinyl, 3,5-di-(1-hydroxy-1-methylethyl)phenyl, 3-aminopiperdin-1-yl, 4-aminopiperidin-1-yl, 4-acetamidepiperidin-1-yl, 1-methyl-2-carboxy-2,3-dihydro-1H-indol-5-yl, 3-(1-tert-butylsulphonylaminocarbonyl-1-methylethyl)phenyl, 3-(1-dimethylaminosulphonylaminocarbonyl-1-methylethyl)phenyl, 3-(1-thiomorpholin-4-ylcarbonyl-1-methylethyl)phenyl, 3-(1-aminocarbonyl-1-methylethyl)phenyl, 3-(1-dimethylaminocarbonyl-1-methylethyl)phenyl, 3-carboxymethylpiperidin-1-yl, 3-methylsulphonylaminocarbonylpiperidin-1-yl, 3-ethylsulphonylaminocarbonylpiperidin-1-yl, 3-tert-butylsulphonylaminocarbonylpiperidin-1-yl, 3-trifluoromethylsulphonylaminocarbonylpiperidin-1-yl, 3-[(1H-tetrazol-5-yl)aminocarbonyl]piperidin-1-yl, 3-aminocarbonylpiperidin-1-yl, 3-dimethylaminocarbonylpiperidin-1-yl, 3-dimethylaminosulphonylaminocarbonylpiperidin-1-yl or 2-carboxy-2,3-dihydrobenzofuran-5-yl, and when R1 is 4-trifluoromethoxyphenyl, R2 is 3-(1-methyl-1-carboxyethyl)piperidinyl, 3-carboxypiperidinyl, 3-methylsulphonylaminocarbonylpiperidin-1-yl, 5-carboxythiophen-2-yl. The invention also relates to a pharmaceutical composition containing the said compounds.

EFFECT: high efficiency of using said compounds.

3 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzimidazole derivatives of formula

and pharmaceutically acceptable salts and esters thereof, where R1 denotes C1-10alkyl, lower alkoxy group-lower alkyl, lower alkoxy group-carbonyl-lower alkyl, C3-6cycloalkyl, C3-6cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, di(phenyl)-lower alkyl, heterocyclyl, such as piperidinyl, tetrahydropyranyl, 2-oxo-pyrrolidinyl-lower alkyl, where the cycloalkyl, phenyl or heterocyclyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, lower alkoxy group, lower alkoxy group-carbonyl, morpholinyl, formylamino group and halogen; R2 denotes hydrogen or lower alkyl; R3 denotes lower alkyl, C3-6cycloalkyl, partially unsaturated cyclohexyl, phenyl, phenyl-lower alkyl, pyridinyl, benzodioxolyl, tetrahydropyranyl, where the phenyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising a halogen, lower alkyl, lower alkoxy group, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2; R4 denotes: a) heteroaryl which is an aromatic 5-6-member monocyclic ring or a 9-10-member bicyclic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and/or sulphur, which is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, phenyl, lower alkoxy group, -N(lower alkyl)2, oxo group, NH2, halogen, cyano group and morpholinyl; b) unsubstituted naphthyl, naphthyl or phenyl, which are substituted with 1-3 substitutes independently selected from a group comprising halogen, hydroxy group, NH2, CN, hydroxy-lower alkyl, lower alkoxy group, lower alkyl-carbonyl, lower alkoxy group-carbonyl, sulphamoyl, di-lower alkyl-sulphamoyl, lower alkyl-sulphonyl, thiophenyl, pyrazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, 2-oxopyrrolidinyl, lower alkyl, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2, carbamoyl, lower alkenyl, benzoyl, phenoxy group and phenyl which is optionally substituted with 1-2 substitutes independently selected from halogen and fluoro-lower alkyl; or c) if R3 denotes cycloalkyl and R1 denotes cycloalkyl, then R4 can also denote phenyl; R5, R6, R7 and R8 independently denote H, halogen, lower alkoxy group or lower alkyl, or R6 and R7, which are bonded to each other, form a 6-member aromatic carbocyclic ring together with carbon atoms to which they are bonded; provided that the compound of formula (I) is not selected from a group comprising butylamide 2-[2-(2-chlorophenyl)benzoimidazol-1-yl]-4-methylpentanoic acid and 2-(2-benzo[1,3]dioxol-5-ylbenzoimidazol-1-yl)-N-benzyl-butyric acid amide. The invention also relates to a pharmaceutical composition based on the formula I compound.

EFFECT: novel benzimidazole derivatives which are useful as farnesoid X receptor antagonists are obtained.

30 cl, 379 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R1 is a 3-7-member carbocyclic ring and n is a number ranging from 1 to 8, and the rest of the radicals are described in the claim.

EFFECT: possibility of using such compounds and compositions in therapy as metabotropic glutamate receptor modulators.

33 cl, 367 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry. Pharmaceutical compositions including, at least, one compound of formula where -X- represents, for instance, group of formula and Y represents, for instance, group of formula or its pharmaceutically acceptable salts, esters or amides, or pro-drugs and pharmaceutically acceptable carrier, which is acceptable in therapy, can be applied for modulation in vitro and in vivo processes of binding, mediated by binding of E-, P- or L- selectin.

EFFECT: obtaining novel floroglucin derivatives.

9 cl, 10 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinoline derivatives of formula or pharmaceutically acceptable salts thereof, where n equals 0 or 1; when n equals 0, then R1 is hydrogen or methyl, R2 is hydroxyl, and R3 is hydrogen; and when n equals 1, R1 is hydrogen, and one of R2 and R3 is hydroxyl, and the other of R2 and R3 is hydrogen. The invention also relates to specific compounds of formula (I) and a method of producing compounds of formula (I).

EFFECT: novel quinoline derivatives are obtained, having high P2X7 antagonist activity.

9 cl, 1 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1 and salts thereof, fungicidal compositions based on said compounds, a plant disease control method using compounds of formula , as well as intermediate compounds of formulae and . Values of radicals are given in the description.

EFFECT: high efficiency of the compounds.

14 cl, 20 dwg, 284 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel azoles of general formula 1A and 1B and pharmaceutically acceptable salts thereof, having activity on hepatitis C and hepatitis GBV-C virus. Said compounds have NS5A viral protein ligand properties and can be used as active components for a pharmaceutical composition and a medicinal agent for treating diseases caused by said viruses. In general formula 1A and 1B, the solid lines accompanied by dotted lines denote a single or double bond, wherein if one of them is a single bond, the other is a double bond; X and Y optionally assume different values and denote a nitrogen, oxygen or sulphur atom or a NH group; R1 and R2 optionally denote identical radicals 2.1-2.20, in which the asterisk (*) indicates site of the bond to azole fragments. Said fragments and values of A and B are given in the claim.

EFFECT: more value of the compounds.

10 cl, 1 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a new medication possessing antiviral, antibacterial and fungicide activity and representing 2-(2,5-dimethyl)pyrazolyl-3-hydroxy-4(3H)-chinazolinon with formula I Additionally, the invention relates to a method: for production of compounds with formula I. The method consists in subjecting 3-hydroxy-4(3H)-chinazolinon to interaction with hydrazine resulting in formation of 2-hydrazino-3-hydroxy-4(3H)-chinazolinon that is then subjected to interaction with acetyl acetone to produce the target product.

EFFECT: production of new medication possessing antiviral, antibacterial and fungicide activity.

2 cl, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

Iap inhibitors // 2451025

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, pharmaceutics.

SUBSTANCE: invention refers to a compound - 6-(4-benzylpiperazino)-1,3-dimethyluracyl dihydrochloride of formula I showing antispasmodic and bronchial spasmolytic activity.

EFFECT: invention extends the range of antispasmodic and bronchial spasmolytic low-toxic agents.

3 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula where R1 denotes C1-C6alkyl; W denotes pyrazolyl, triazolyl or imidazolyl; R14 denotes phenyl or a 6-member heteroaromatic ring containing 1-3 nitrogen ring atoms, which is may be substituted with at least one substitute selected from F, Cl, CN and CF3; R3 denotes phenyl, substituted with a trifluoromethyl substitute; R4 denotes hydrogen or C1-C6alkyl; X denotes -C1-C6alkylene-Y-, and Y denotes a single bond, and the alkylene group is a straight or branched C1-C6alkylene, possibly substituted with OH, CO2R66 or C1-C3alkoxy; R5 denotes phenyl or pyridinyl, substituted with -S(O)vR21; or R5 denotes an unsubstituted C3-C6cycloalkyl ring; or R5 can also denote H; R21 denotes hydrogen, C1-C6alkyl or C3-C8cycloalkyl; v equals 1 or 2; and R66 denotes hydrogen or C1-C6alkyl; or pharmaceutically acceptable salts thereof. The invention also relates to a method of producing said compounds, intermediate compounds and a pharmaceutical composition for treating or reducing the risk of disease or condition, in which inhibiting neutrophil elastase activity based on compounds of formula (I) is useful.

EFFECT: obtaining novel compounds which can be used in medicine to treat or reduce the risk of disease or condition in which inhibiting neutrophil elastase activity is useful.

19 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of formula (1) in free form or in form of a salt. In formula (1): X1 and X2 all independently denote halogen; A denotes a radical of formula where (R1)1-2 denotes 1-2 identical or different substitutes selected from a group comprising C1-C4-alkyl, halogen-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, R2R3N-C1-C4-alkyl, halogen, hydroxy group, C1-C4-alkoxy group, halogen-C1-C4-alkoxy group, C1-C4-alkylthio group, C1-C4-alkanoyl, C1-C4-alkanoylamino group, C1-C4-alkylsulphonylamino group, C1-C4-alkylsulphonyl, C1-C4-alkylthionyl, NR2R3 and morpholinyl; or A denotes a radical of formula where ring (a) denotes a 5-member heterocyclic ring containing 1 or 2 heteroatoms selected from a group comprising O and N, which can further be substituted with C1-C4-alkyl, and which is annelated in positions 3 and 4; and R2 and R3 all independently denote hydrogen or C1-C4-alkyl. The invention also relates to a parasite control composition containing said compounds, a parasite control method on warm-blooded animals and use of compounds of formula (1) to prepare a parasite control composition.

EFFECT: high efficiency of using said compounds.

11 cl, 7 ex, 2 tbl

FIELD: pharmacology.

SUBSTANCE: invention refers to the area of chemistry, chemical and pharmaceutical industry and medicine and refers to compounds of formula (1) that can be useful as antipsychotic drugs. Described compounds of formula (1) are the derivatives of 5H-dibenzo[b, e][1, 4]diazepine or its pharmacologically acceptable salts with acid and application of the compounds. Compounds of formula (1) possess higher activity compared to clozapine.

EFFECT: improved antipsychotic effect.

8 cl, 23 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are offered 5-substituted quinazolinone compounds having general structural formulas (II), (III) and (IV) or their pharmaceutically acceptable salts and stereomers. The radicals and symbols in the structural formulas presented below are designated as shown in the patent claim.

EFFECT: there are disclosed the methods for using and the pharmaceutical compositions of quinazolinone compounds.

16 cl, 58 ex

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