Amide compound

FIELD: chemistry.

SUBSTANCE: compounds exhibit antagonistic activity towards the EP4 receptor, which enables use thereof as an active ingredient in a pharmaceutical composition for treating chronic kidney disease or diabetic nephropathy.

EFFECT: high efficiency of the compounds.

27 cl, 228 tbl, 86 ex

 

Description

The technical field to which the invention relates.

The present invention relates to an amide compound which is useful as an active ingredient in pharmaceutical compositions, such as pharmaceutical compositions for the treatment of chronic renal failure and/or diabetic nephropathy.

The level of technology

Prostaglandin E2 (herein called “PGE2”) known as one of the metabolites of the arachidonic acid cascade. PGE2 exerts different types of activity, such as inducing and increasing pain the action of Pro-inflammatory action, anti-inflammatory, uterine contractile activity, reinforcing digestive peristalsis action, evoking action, inhibiting the secretion of gastric acid, the action of angiogenic action, etc.

There are four subtypes, ER, ER, ER and ER, receptors for PGE2, which have a wide distribution in various tissues. It is believed that activation of the receptor ER causes an increase in intracellular CA2+. Receptor ER is one of the receptors, which have different paths for systems of second messengers. It is believed that activation of receptors ER and ER causes the coding adenylate kinase activation and, consequently, increases the intracellular level of camp. In particular, it is believed, is the receptor OR associated with relaxation of smooth muscles, stimulation or inhibition of the inflammatory response, lymphocyte differentiation, hypertrophy or proliferation mesangial cells, secretion of gastrointestinal mucus, etc.

Inhibitor of PGE2 receptor, i.e. the PGE2 antagonist has a binding activity against the PGE2 receptor. That is, the antagonist of PGE2 exerts PGE2-antagonistic activity or PGE2 inhibitory activity. Thus, it is expected that the PGE2 antagonist is a drug for the treatment of diseases caused by PGE2. It is expected that among these receptor antagonist ER is treatment for ER-related diseases, such as renal disease, inflammatory diseases, various pains, etc., in humans and animals. In addition, this antagonist, selective against receptor ER, is preferred from the point of view that he can afford to avoid side effects, based on the subtypes, other than ER, ER and ER.

As a receptor antagonist OR known compound represented by the following formula (patent document 1):

(For definitions of the symbols in the formula refer to the selected publication).

Further, as a ligand of the receptor OR known compound represented by the following formula (patent document 2):

(For definitions of the symbols in the formula refer to the selected publication).

Further, as a receptor antagonist OR known compound represented by the following formula (patent document 3). In this regard, it should be noted that this document is published after the priority date of the present invention.

(For definitions of the symbols in the formula refer to the selected publication).

Further, as a receptor antagonist OR known compound represented by the following formula (patent document 4):

(For definitions of the symbols in the formula refer to the selected publication).

Further, as a receptor antagonist OR known compound represented by the following formula (patent document 5):

(For definitions of the symbols in the formula refer to the selected publication).

Further, as a receptor antagonist OR known compound represented by the following formula (patent document 6):

(For definitions of the symbols in the formula refer to the selected publication).

Further, as ligands of the receptor OR known compounds represented by the following formula (patent document 7):

(Symbols in the formula refer to the selected publication).

Further, as a receptor antagonist ER and/or ER known compound represented by the following formula (patent document 8):

(For definitions of the symbols in the formula refer to the selected publication).

Further, as the antagonist receptor ER known compound represented by the following formula (patent document 9).

(For definitions of the symbols in the formula refer to the selected publication).

Further, as a receptor antagonist OR known compound represented by the following formula (patent document 10). In this regard, the document was published after the priority date of the present invention.

(For definitions of the symbols in the formula refer to the selected publication).

Further, as a receptor antagonist OR known compound represented by the following formula (patent document 11). In this regard, it should be noted that this document was published after the priority date of the present invention.

(For definitions of the symbols in the formula refer to the selected publication).

Documents related to D. the authorized area

Patent documents

Patent document 1: Technical brochure of international publication no WO 2007/121578

Patent document 2: Technical brochure of international publication no WO 2007/143825

Patent document 3: Technical brochure of international publication no WO 2008/104005

Patent document 4: Technical brochure of international publication no WO 2005/021508

Patent document 5: Technical brochure of international publication no WO 2005/105732

Patent document 6: the Technical brochure of international publication no WO 2005/105733

Patent document 7: the Technical brochure of international publication no WO 2008/017164

Patent document 8: the Technical brochure of international publication no WO 03/016254

Patent document 9: the Technical brochure of international publication no WO 2005/061475

Patent document 10: the Technical brochure of international publication no WO 2008/123207

Patent document 11: Technical brochure of international publication no WO 2009/005076

The invention

Problems that must be solved by the present invention

The proposed compound which is useful as an active ingredient in pharmaceutical compositions, such as pharmaceutical compositions for the treatment of chronic renal failure and/or diabetic nephropathy.

Solutions to these problems

AB the ora of the present invention conducted extensive research connections having antagonistic activity against receptor ER, and found that the compound of formula (I) exhibits excellent efficiency, whereby it was established the present invention.

That is, the present invention relates to the compound of formula (I) or salts thereof and pharmaceutical compositions containing the compound of formula (I) or its salt and a pharmaceutically acceptable excipient.

(where

ring D is a group of formula (II), formula (III), formula (IV), formula (V) or formula (VI)

ring D1means a monocyclic or bicyclic nitrogen-containing heterocyclic ring which may be substituted by phenyl,

ring D2means aryl, heterocyclic ring or3-10cycloalkyl,

R41, R42, R43and R44are the same or different from each other and mean-X2In4,

R45means-X1In5,

R46means-H, halogen, C1-6alkyl which may be substituted by one or more halogen or-O-C1-6the alkyl.

V and W are the same or different from each other represent CH or N, provided that in any case, V and W do not mean at the same time N

X1means of communication, With1-6alkylene, (C1-6Alki the Yong)-CONH-, (C1-6alkylene)-O-, (C1-6alkylene)-O-(C1-6alkylen) or (C2-6albaniles,

X2means of communication, With1-6alkylene, (C1-6alkylen)-CONH-, (C1-6alkylene)-O-, (C1-6alkylene)-O-(C1-6alkylen)2-6albaniles, -O-, -S-, -NH-, -N(C1-6alkylene)-, -N(C1-6alkylen)-(C1-6alkylene)- or-O-(C1-6alkylen),

In4means aryl, heterocyclic ring or3-10cycloalkyl, each of which may be substituted by same or different 1 to 5 groups selected from R4,

R4means the group consisting of halogen, -OH, -O-(C1-6the alkyl), -O-(C1-6alkylene)-O-(C1-6of alkyl, aryl which may be substituted, heterocyclic ring which may be substituted, (C1-6alkylene)aryl, (C1-6alkylen)-heterocyclic ring, -O-(C1-6alkylene)aryl and-O-(C1-6alkylen)-heterocyclic ring,

In5represents (i) a bicyclic heterocyclic ring which may be substituted by one or more groups selected from the group consisting of halogen and C1-6the alkyl, or (ii) monocyclic aryl, monocyclic heterocyclic ring or monocyclic3-10cycloalkyl, each of which is substituted by an identical or different groups selected from R5,

R5means the group is stoaway from halogen, -OH, -O-(C1-6the alkyl), -O-(C1-6alkylene)-O-(C1-6of alkyl, aryl which may be substituted, heterocyclic ring which may be substituted, (C1-6alkylene)aryl, (C1-6alkylen)-heterocyclic ring, -O-(C1-6alkylene)aryl and-O-(C1-6alkylen)-heterocyclic ring, provided that when X1means a bond, methylene or ethylene, Y denotes CH, R2means methyl, E ring means phenylene, Z indicates the bond, and R3means CO2N; R5means a group consisting of HE, -O-(C1-6the alkyl), -O-(C1-6alkylene)-O-(C1-6of alkyl, aryl which may be substituted, heterocyclic ring which may be substituted, (C1-6alkylene)aryl, (C1-6alkylen)-heterocyclic ring, -O-(C1-6alkylene)aryl and-O-(C1-6alkylen)-heterocyclic ring,

E ring means phenylene or5-7cycloalkenyl,

R1and R2are the same or different from each other and denote H or C1-6alkyl, provided that when R5means bicyclic heterocyclic ring which may be substituted, R2means N

Y represents CH or N,

Z represents a relationship or With1-6alkylen, and

R3means CO2N or its biological equivalent,

provided that, when ALCO D denotes phenyl, which may be substituted, or pyridyl which may be substituted, Y represents CH and Z represents a relationship, R3means a group other than-CO2N, tetrazolyl and sulfonamide.

In this regard, it should be noted that, unless specified otherwise, when a symbol is used in any chemical formula in this description and in the other chemical formulae, the symbol has the same value.

In addition, the present invention relates to pharmaceutical compositions for preventing or treating chronic renal failure and/or diabetic nephropathy, which contains a compound of the formula (I) or its salt. In this regard, such a pharmaceutical composition comprises an agent for preventing or treating chronic renal failure and/or diabetic nephropathy, which consists of the compounds of formula (I) or its salt.

In addition, the present invention relates to the use of compounds of formula (I) or its salt to obtain a pharmaceutical composition for preventing or treating chronic renal failure and/or diabetic nephropathy, the compound of formula (I) or its salts for use in the prevention and treatment of chronic renal failure and/or diabetic nephropathy and method of prevention or treatment of chronic kidney is insufficient the STI and/or diabetic nephropathy, including the introduction of an effective amount of the compounds of formula (I) or salts thereof to a subject. In this regard, a “subject” is a person or animal not human in need of such prevention or treatment.

The effects of the invention

The compound of formula (I) or its salt are antagonistic against receptor ER activity and can be used as active ingredient in pharmaceutical compositions for preventing and/or treating chronic renal failure and/or diabetic nephropathy.

The method of implementation of the present invention

Below the present invention will be described in detail.

In this specification, “alkyl” includes linear alkyl and branched alkyl. Thus, With1-6alkyl is a linear or branched alkyl having 1-6 carbon atoms, and specifically, for example, stands, ethyl, n-propylene, isopropyl, n-bootrom, isobutyl, second-bootrom, tert-bootrom, n-Pentium, n-hexyl or the like, In one particular embodiment, it is stands, ethyl, n-propylene or isopropyl, in another embodiment, the stands or ethyl and in another embodiment the stands.

“Alkylene” is a divalent group formed by removing any one of hydrogen atoms of the above “alkyl”. So 1-6alkylene is a linear or branched alkylene having 1-6 carbon atoms, and specifically, for example, methylene, ethylene, trimethylene or the like, and in another embodiment, the methylene.

“Albaniles” is a divalent group in which any one or more simple (ordinary) ties in the above-described “alkylene are double bonds, and, therefore, With2-6albaniles is a linear or branched Alcanena having 2-6 carbon atoms, and specifically, for example, vinylene, propylene, isopropylene, isopropylene or the like, and in another embodiment, vinylene.

“Halogen” means F, Cl, Br or I.

Thus, “C1-6alkyl which may be substituted by one or more halogen”represents, along with1-6the alkyl, which is not substituted with halogen, C1-6alkyl, which is substituted by one or more halogen, which are the same or different, and specifically, for example, trifluoromethyl, formation, deformation, 2-foration, 3-forproblem or similar

“Cycloalkyl” is a saturated hydrocarbon ring group, which may be associated bridge connection or may be condensed with a benzene ring. Thus, With3-10cycloalkyl is a saturated carbon ring having 10 carbon atoms and, specifically, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecane, norbornyl, bicyclo[2.2.2]actiom, adamantium, indenolol, 1,2,3,4-tetrahydronaphthyl or the like In one embodiment, it is3-6cycloalkyl and in another embodiment With5-6cycloalkyl. “Monocyclic cycloalkyl” means a monocyclic saturated hydrocarbon ring group, and, therefore, monocyclic3-10cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like “Cycloalkenyl” is a divalent group formed by removing any one of hydrogen atoms of the above “cycloalkyl”. Thus, With5-7cycloalkenyl is, specifically, for example, Cycloheptane-1,3-deylam, cyclohexane-1,3-deylam, cyclohexane-1,4-deylam, cyclopentane-1,3-deylam or Cycloheptane-1,4-deylam and in one embodiment, cyclohexane-1,4-deylam.

“Aryl” means6-14monocrytalline aromatic hydrocarbon ring group, and includes partially gidrirovannoe ring group. Specifically, it means, for example, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl or the like In one embodiment, it is phenyl or naphthyl and in another embodiment, implementation is tvline by phenyl. “Monocyclic aryl” means a monocyclic aromatic hydrocarbon ring group and, specifically, for example, phenyl.

“Heterocyclic ring” means a ring group containing (i) monocyclic 3-8-membered ring containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, and in one embodiment, a 5-7 membered heterocyclic ring, and (ii) bi-tricyclic heterocyclic ring containing 1-5 heteroatoms selected from oxygen, sulfur and nitrogen, which is formed by condensation of the monocyclic heterocyclic ring and one or two selected from a monocyclic heterocyclic ring, a benzene ring, With5-8cycloalkane and C5-8cycloalkene. Atom rings, sulfur or nitrogen, can be oxidized with the formation of oxide or dioxide.

Examples of “heterocyclic ring” include the following groups.

(1) Monocyclic saturated heterocyclic ring group:

i) group containing 1-4 nitrogen atoms, specifically azepane, diazepan, aziridinyl, azetidin, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrazolidine, piperazinil etc.;

ii) group containing 1-3 nitrogen atom and 1 to 2 sulfur atom and/or 1-2 oxygen atom, specifically diamorphine, diazolidinyl, isothiazolinones, oxazolidinyl, morpholinyl etc.;

iii) group containing 1-2 atomiser, specifically, tetrahydrothieno etc.;

iv) group containing 1-2 sulfur atom and 1 to 2 oxygen atoms, specifically oxathiolan and the like; and

v) the group containing 1-2 oxygen atom, specifically oxiranyl, DIOXOLANYL, oxolane, tetrahydropyranyl, 1,4-dioxane etc.

(2) Monocyclic unsaturated heterocyclic ring group:

i) group containing 1-4 nitrogen atom, specifically pyrrolyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridin, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, dihydrotriazine, azepine etc.;

ii) group containing 1-3 nitrogen atom and 1 to 2 sulfur atom and/or 1-2 oxygen atom, specifically, thiazolyl, isothiazolin, thiadiazolyl, dihydrothiazine, oxazolyl, isoxazolyl, oxadiazolyl, oxazinyl etc.;

iii) group containing 1-2 sulfur atom, specifically thienyl, tiepins, dehydrodidemnin, dehydrodidemnin etc.;

iv) group containing 1-2 sulfur atom and 1 to 2 oxygen atoms, specifically dihydroxydiphenyl and the like; and

v) the group containing 1-2 oxygen atom, specifically furyl, pyranyl, oxepin, dioxole etc.

(3) a Condensed polycyclic saturated heterocyclic ring group:

i) group containing 1 to 5 nitrogen atoms, specifically Hinkley, 7-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.2]nonanal etc.;

ii) group containing 1-4 nitrogen atom and 1 to 3 sulfur atom and/or 1-3 oxygen atom is, specifically, createdialogindirectparama etc., and

iii) group containing 1-3 sulfur atom and/or 1-3 oxygen atoms, specifically 2,6-dioxabicyclo[3.2.2]Oct-7-yl, etc.

(4) a Condensed polycyclic unsaturated heterocyclic ring group:

i) group containing 1 to 5 nitrogen atoms, specifically, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, hinely, tetrahydropyranyl, ethanolic, tetrahydroisoquinoline, indazoles, imidazopyridine, benzotriazolyl, tetrachloropyridine, carbazolyl, honokalani, dihydroindole, benzoperylene, naphthyridine, hintline, cinnoline etc.;

ii) group containing 1-4 nitrogen atom and 1 to 3 sulfur atom and/or 1-3 oxygen atoms, specifically benzothiazolyl, dihydrobenzofuran, benzothiadiazoles, imidazothiazoles, imidazothiazoles, benzoxazolyl, benzoxadiazole etc.;

iii) group containing 1-3 sulfur atom, specifically sensational, benzodithiol etc.;

iv) group containing 1-3 sulfur atom and 1 to 3 oxygen atoms, specifically benzoxanthenes, phenoxazines etc., and

v) the group containing 1-3 oxygen atoms, specifically benzodioxolyl, benzofuranyl, isobenzofuranyl, bromanil, benzodithiophene etc.

“Nitrogen-containing heterocyclic ring” means, among the above heterocyclic ring groups ring groups, select the by from i) and ii) (1), i) and (ii) (2), (i) and (ii) (3) and (i) and (ii) (4), etc. In some embodiments, the implementation of such group is the ring group having a bond on the nitrogen atom being part of this ring.

Specific examples of the “monocyclic or bicyclic nitrogen-containing heterocyclic ring” in the ring D1include pyrrole, petrolaturm, percolation, indole, benzimidazole, indazole and 4,5,6,7-tetrahydroindole.

Specific examples of the “heterocyclic ring” in the ring D2include benzothiophene, 4,5,6,7-tetrahedralisation and pyridine.

Specific examples of the “heterocyclic ring” in The4include chenail, ethanolic, oxazole, thiazole and indole.

Specific examples of the “heterocyclic ring” in R4include pyridine, thiazole, oxazole and imidazole.

Particular examples of bicyclic heterocyclic ring” in The5include quinoline, isoquinoline, benzofuran, benzothiophene, benzoxazole and benzothiazole, indole, cinoxacin, naphthylidine, hinzelin, cinnolin and benzimidazole. In the following embodiment, these examples include quinoline, isoquinoline, benzofuran, benzothiophene, benzoxazole and benzothiazole.

Specific examples of the “monocyclic heterocyclic ring” in The5include thiazole, oxazole, pyridine, thiophene, furan, pyrrole, imidazole, triazole, oxadiazole, thiadiazole, irosin, the pyrimidine, pyridazine, piperidine, pyrrolidine, ASEAN, tetrahydropyran, tetrahydrothiopyran and piperazine. In the following embodiment, these examples include thiazole, oxazole, pyridine, thiophene, piperidine and tetrahydrofuran.

Specific examples of the “heterocyclic ring” in R5include piperidine, piperazine, morpholine, thiomorpholine, pyridine, thiazole, oxazole and imidazole. In the following embodiment, these examples include piperidine.

Further, the above ring is described as the name itself rings or a monovalent ring, but if necessary, it can be monovalent, divalent ring group or ring group with a higher valency, formed by the removal of atoms (atoms) of hydrogen in an arbitrary position.

“CO2H or its biological equivalent” means-CO2H, or another atom or group of atoms that has an electronic or steric configuration equivalent-CO2H, can release acidic protons and has a common biological properties. Examples include CO2H hydroxamic acid (-CO-NH-OH, -CO-NH-O-C1-6alkyl), sulfonamide (-CO-NH-SO2-C1-6alkyl), allcinema (-CO-NH-CN), arylsulfonate (-CO-NH-SO2-C1-6alkyl), -SO2-NH-CO-C1-6alkyl or tetrazolyl, oxadiazolyl, oxadiazolidine, oxa is ediately, thiadiazolyl, diazolidinyl, hydroxyethoxyethyl etc., in another embodiment, these examples include CO2H, arylsulfonate (-CO-NH-SO2-C1-6alkyl), hydroxamic acid (-CO-NH-OH, -CO-NH-O-C1-6alkyl) and tetrazolyl, and in one embodiment, these examples include CO2H. Next, With1-6in biological terms-CO2H can be replaced-IT or-O-C1-6the alkyl.

In this description, the expression “may be substituted” means unsubstituted or substituted by same or different 1 to 5 substituents. In this regard, when there is a variety of substituents, such substituents may be identical or different each other.

Examples of the acceptable substituent of the “aryl which may be substituted”and “heterocyclic group which may be substituted”, in R4and R5include halogen, C1-6alkyl which may be substituted by one or more halogen, -O-(C1-6alkyl which may be substituted by one or more Halogens) and HE.

Further, R46in the formula (II) is a surrogate, which replaces the hydrogen atoms on the atom within the ring, and, for example, when V or W is CH, the hydrogen atom of this SN can be replaced by R46. Thus, the expression “V or W means SN” refers to the case when the hydrogen atom is replaced by R 46, i.e., V or W can be C(R46).

Some embodiments of the compounds of formula (I) or salts thereof are presented below.

(1) the Compound or its salt, in which ring D is a group of formula (II).

(2) the Compound or its salt, in which R46means H, fluorine, chlorine, methyl or trifluoromethyl. In another embodiment, the compound or its salt, in which R46means fluorine, chlorine, methyl or trifluoromethyl. In another embodiment, the compound or its salt, in which R46means trifluoromethyl. In another embodiment, the compound or its salt, in which R46substituted on the atom located in the ring represented by V and W (that is, R46substituted in position 5 or 6 of the indole). In another embodiment, the compound or its salt, in which R46substituted on the atom located in the ring represented by V (i.e. R46substituted in position 5 of the indole). In another embodiment, the compound or its salt, in which R46is fluorine-, chlorine-, methyl - or trifluoromethyl-substituted on the atom within the ring, represented by V. in Another embodiment, the compound or its salt, in which R46substituted by trifluoromethyl atom within the ring, represented by V.

(3) the Compound or its salt, in the cat who where V denotes CH, and W stands for CH. In another embodiment, the compound or its salt, in which V denotes N, and W denotes CH. In another embodiment, the compound or salt, in which V denotes SN and W implies n

(4) the Compound or its salt, in which X1means1-6alkylene or (C1-6alkylene)-O-. In another embodiment, the compound or its salt, in which X1means methylene. In another embodiment, the compound or its salt, in which X1means-CH2CH2-O-.

(5) the Compound or its salt, in which5is a bicyclic heterocyclic ring which may be substituted by one or more groups selected from the group consisting of halogen and C1-6the alkyl. In another embodiment, the compound or its salt, in which5means chenail, ethanolic, benzofuran or sensational, each of which may be substituted by one or more groups selected from the group consisting of halogen and C1-6the alkyl. In another embodiment, the compound or its salt, in which5means chenail, ethanolic, benzofuran or sensational. In another embodiment, the compound or its salt, in which5means chinosol. In another embodiment, the compound or its salt, in which the 5means ethanolic. In another embodiment, the compound or its salt, in which5means benzofuran. In another embodiment, the compound or its salt, in which5means benzofuran. In another embodiment, the compound or its salt, in which5means sensational. In another embodiment, the compound or its salt, in which5means quinoline-2-yl. In another embodiment, the compound or its salt, in which5means quinoline-3-yl. In another embodiment, the compound or its salt, in which5means quinoline-5-yl. In another embodiment, the compound or its salt, in which5means quinoline-6-yl. In another embodiment, the compound or its salt, in which5means quinoline-7-yl. In another embodiment, the compound or its salt, in which5means quinoline-8-yl. In another embodiment, the compound or its salt, in which5means isoquinoline-1-yl. In another embodiment, the compound or its salt, in which5means isoquinoline-3-yl. In another embodiment, the compound or its salt, in which5means isoquinoline-3-yl. In another embodiment, the compound or its salt, to the which In 5means isoquinoline-5-yl. In another embodiment, the compound or its salt, in which5means isoquinoline-7-yl. In another embodiment, the compound or its salt, in which5means monocyclic aryl, monocyclic heterocyclic ring or monocyclic3-10cycloalkyl, each of which is substituted by a group (or groups)selected from R5. In another embodiment, the compound or its salt, in which5means phenyl, substituted with halogen (halogen-free). In another embodiment, the compound or its salt, in which5means monocyclic heterocyclic ring, substituted by aryl. In another embodiment, the compound or its salt, in which5means thiazolyl substituted by phenyl. In another embodiment, the compound or its salt, in which5means pyridyl, substituted phenyl.

(6) the Compound or its salt, in which ring E is 1,4-phenylene or cyclohexane-1,4-deylam. In another embodiment, the compound or its salt, in which ring E is 1,4-phenylene. In another embodiment, the compound or its salt, in which ring E is cyclohexane-1,4-deylam.

(7) the Compound or its salt, in which R1means N.

(8) the Compound or Ecosol, in which R2means H or methyl. In another embodiment, the compound or its salt, in which R2means N.

(9) the Compound or its salt, in which Y represents CH.

(10) the Compound or its salt, in which Z represents a relationship.

(11) the Compound or its salt, in which R3means CO2H. In another embodiment, the compound or its salt, in which R3is the biological equivalent of CO2H.

(12) the Compound or its salt that have a combination of two or more groups described in (1)to(11) above.

The present invention or its salt, which have a combination of two or more groups described in (1)to(11) above, as described in (12), and as their specific examples are the following options for implementation.

(13) the Compound or its salt, in which ring D is a group of formula (II).

(14) the Compound or its salt, in which V denotes SN and W stands for CH.

(15) the Compound or its salt (14), in which ring E is 1,4-phenylene or cyclohexane-1,4-deylam, Z is a bond and R3is-CO2H.

(16) the Compound or its salt (15), in which R1means N and R2means H or methyl.

(17) the Compound or its salt (16), in which Y represents CH and R2means N.

(18) the Compound or its salt (17), in which X1means-CH2CH2-O - and 5means phenyl, substituted with halogen (halogen-free).

(19) the Compound or its salt (18)where E denotes 1,4-phenylene.

(20) the Compound or its salt (18)where E means the cyclohexane-1,4-diyl.

(21) the Compound or its salt (17), in which X1means methylene.

(22) the Compound or its salt (21)where E denotes 1,4-phenylene.

(23) the Compound or its salt (21)where E means the cyclohexane-1,4-diyl.

(24) the Compound or its salt (22) or (23), which5means bicyclic heterocyclic ring which may be substituted by one or more groups selected from the group consisting of halogen and C1-6the alkyl.

(25) the Compound or its salt (24), which5means chenail, ethanolic, benzofuran or sensational, each of which may be substituted by one or more groups selected from the group consisting of fluorine, chlorine and methyl.

(26) the Compound or its salt (25), which5means chenail, which may be substituted by fluorine atom (fluorine atoms). In another embodiment, the compound or its salt (25), which5means quinoline-2-yl which may be substituted by fluorine atom (fluorine atoms). In another embodiment, the compound or its salt (25), which5means quinoline-5-yl. In another embodiment, the soybean is inania or its salt (25), in5means quinoline-6-yl. In another embodiment, the compound or its salt (25), which5means quinoline-7-yl. In another embodiment, the compound or its salt (25), which5means quinoline-8-yl.

(27) the Compound or its salt (25), which5means ethanolic. In another embodiment, the compound or its salt (25), which5means isoquinoline-1-yl. In another embodiment, the compound or its salt (25), which5means isoquinoline-3-yl. In another embodiment, the compound or its salt (25), which5means isoquinoline-5-yl. In another embodiment, the compound or its salt (25), which5means isoquinoline-7-yl.

(28) the Compound or its salt (22) or (23), which5means monocyclic heterocyclic ring which is substituted by 1-5 groups selected from R5and R5means aryl.

(29) the Compound or its salt (28), which5means thiazolyl and R5means phenyl.

(30) the Compound or its salt (28), which5means pyridyl and R5means phenyl.

In addition, specific examples of compounds of formula (I) or their salts include the following compounds:

4-[({[5-chloro-1-(quinoline-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]benzoi the second acid,

TRANS-4-[({[5-methyl-1-(quinoline-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarbonyl acid,

TRANS-4-[({[5-fluoro-1-(quinoline-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarbonyl acid,

4-[({[1-(quinoline-2-ylmethyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]benzoic acid,

TRANS-4-[({[1-(quinoline-2-ylmethyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarbonyl acid,

TRANS-4-[({[5-chloro-1-(isoquinoline-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarbonyl acid,

TRANS-4-[({[1-(isoquinoline-3-ylmethyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarbonyl acid,

TRANS-4-{[({5-chloro-1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexanecarbonyl acid,

4-{[({5-chloro-1-[2-(4-chlorophenoxy)ethyl]-1H-indol-7-yl}carbonyl)amino]methyl}benzoic acid,

TRANS-4-{[({5-chloro-1-[2-(4-chlorophenoxy)ethyl]-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexanecarbonyl acid,

4-{[({1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}benzoic acid,

TRANS-4-{[({1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexanecarbonyl acid,

TRANS-4-{[({1-[(5-vinylpyridin-2-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexanecarbonyl acid,

4-{[({1-[2-(4-chlorophenoxy)ethyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}benzoic acid,

TRANS-4-[({[1-(isoquinoline-3-ylmethyl)-5-methyl-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarbonyl acid,

TRANS-4-[({[5-fluoro-1-(isoquinoline-3-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarbonyl acid,

TRANS-4-[({[6-fluoro-1-(isoquinoline-3-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarbonyl acid,

TRANS-4-[({[1-(1-benzofuran-2-ylmethyl)-5-chloro-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarbonyl acid,

TRANS-4-[({[1-(1-benzofuran-2-ylmethyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarbonyl acid,

TRANS-4-[({[(5-chloropyridin-2-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexanecarbonyl acid and

TRANS-4-{[({1-[(5-chloro-1-benzofuran-2-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarbonyl acid and their salts.

In addition, specific examples covered by the compound of formula (I) or its salt, also include the following compounds:

4-{(1S)-1-[({1-{2-(4-chlorophenoxy)ethyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid,

4-[2-({1-[2-(4-chlorophenoxy)ethyl]-1H-indol-7-yl}carbonyl)-1-methylhydrazino]benzoic acid,

TRANS-4-[({[5-chloro-1-(quinoline-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarbonyl acid,

TRANS-4-[({[1-(4-Chlorobenzyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarbonyl the acid,

TRANS-4-[({[1-(4-Chlorobenzyl)-5-methyl-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarbonyl acid,

4-[({[5-methyl-1-(quinoline-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]benzoic acid,

4-[({[1-(1-benzofuran-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]benzoic acid,

TRANS-4-[({[1-(1-benzofuran-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarbonyl acid,

TRANS-4-[({[1-(1-benzothiophen-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarbonyl acid,

4-[1-methyl-2-({1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1H-indol-7-yl}carbonyl)hydrazino]benzoic acid,

4-{[({5-chloro-1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1H-indol-7-yl}carbonyl)amino]methyl}benzoic acid

and their salts.

As for some of the compounds of formula (I) or their salts, may exist, their tautomers or geometrical isomers, depending on the types of substituents. In this description, the compound of formula (I) or its salt can be described in only one form of isomers, but the present invention includes other isomers, isolated forms of these isomers or a mixture.

In addition, some compounds of formula (I) or their salts may have asymmetric carbon atoms or asymmetry, and therefore, may exist in their optical isomers. The present invention includes an isolated form of an optical isomer of the compound fo the formula (I) or its salt or their mixture.

In addition, pharmaceutically acceptable prodrugs of compounds of formula (I) or salts thereof are also included in the present invention. Pharmaceutically acceptable prodrug referred to as the compound having a group which can be converted into the amino group, hydroxyl group, carboxyl group or the like by solvolysis or under physiological condition. Examples of groups for the formation of prodrugs include groups described in Prog Med., 5, 2157-2161 (1985) or “Pharmaceutical Research and Development” (Hirokawa Publishing Company, 1990), vol.7, Drug Design, 163-198.

In addition, the salt of the compounds of formula (I) is a pharmaceutically acceptable salt of the compounds of formula (I), and some compounds of formula (I) can form acid additive salt and salt with a base depending on the types of substituents. Specifically, examples include acid additive salts with inorganic acids such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, nitric acid, phosphoric acid, etc. and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, detailing the acid, citric acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, p-toluensulfonate acid, aspartic acid, glutamic acid, etc. and salts with inorganic bases, such as salts of sodium, potassium, magnesium, calcium, aluminum and the like, and organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine and the like, salts with various amino acids, such as acetylation and the like, or derivatives of amino acids, ammonium salts, and others.

In addition, the present invention also includes various hydrates or solvate and polymorph modifications of the compounds of formula (I) and salts thereof.

(Methods of obtaining)

The compound of formula (I) or its salt can be obtained by various known synthetic methods, using the characteristics based on their basic structures or types of substituents. At the same time, depending on the types of functional groups, in some cases, from the point of view of methods of preparation, is effective to protect a functional group suitable protecting group (a group which can easily be transformed into the functional group), during the stages from raw materials to intermediate products. Examples of such protective groups include protective groups described in “Greene's Protective Groups in Organic Synthesis (4th

In addition, the prodrug of the compounds of formula (I) or its salt can be obtained by introducing a specific group during the stages from raw materials to intermediate products, in the same way as for the above-mentioned protective groups, or additional conducting the reaction using the obtained compound of formula (I) or its salt. This reaction can be performed using the method known to the experts in this field, such as basic esterification, amidation, dehydration, etc.

Below will be described specific methods for obtaining the compounds of formula (I). Each of these methods of obtaining can also be carried out with reference to the documents listed in this description. In this regard, it should be noted that the method of obtaining the compounds of formula (I) is not limited to the following examples.

(Method of obtaining 1)

This method of production is a method of obtaining the compounds of formula (I) interaction of compound 1A with the compound 1b.

D. the TES interaction carried out using an equivalent amount of compound 1A, compound 1b or excess of each of them, by stirring under cooling to heating, preferably at 20-60°C., usually for 0.1 hour to 5 days, in a solvent which is inert to the reaction, in the presence of a condensing agent. In this case, the solvent is not specifically limited, but examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene or the like, halogenated hydrocarbons such as dichloromethane (DHM), 1,2-dichloroethane (EDC)chloroform or the like, ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane (DME) and the like, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), ethyl acetate, acetonitrile, water or mixtures thereof. As the condensing agent in some cases, this reaction can be preferably used, but are not limited to, 1-hexaphosphate {bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-1-s-3-oxide (HATU), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI.HCl), dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI), diphenylphosphoryl azide, phosphorus oxychloride (Argonaut Technology, Inc., USA) or the like In some cases it may be preferred for this reaction, the use of additives, such as, for example, 1-hydroxybenzotriazole (HOBt) and the like, and in some cases for the smooth progression of the reaction can be agodnym carrying out this reaction in the presence of for example, organic bases such as triethylamine, N,N-diisopropylethylamine (DIPEA), N-methylmorpholine and the like, or inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide and the like, it is Preferable to use a carrier polystyrene isocyanate resin, for example, PS-isocyanate (Argonaut Technology, Inc., USA) or the like, for removal of excess carboxylic acid and the above additives, etc. after completion of the reaction. In addition, you can use the load-bearing Quaternary ammonium salt of polystyrene resin, for example, MP-carbonate (Argonaut Technology, Inc., USA) or the like, for removal of excess carboxylic acid and the above additives, etc. after completion of the reaction.

In addition, you can also use the method in which the compound 1A was transferred to its reactive derivative and then the reactive derivative is subjected to interaction with compound 1b. In this case, examples of the reactive derivative of compound 1A include halides obtained by the interaction with a halogenation agent such as phosphorus oxychloride, thionyl chloride and the like, mixed anhydrides of carboxylic acids, obtained by the interaction with isobutylparaben or the like, active esters obtained by condensation with HOBt or the like, and others. The interaction of the reaction-FPIC the service of derived and compound 1b can be performed by cooling to heating, preferably at 20-60°C., in a solvent which is inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, etc.

In addition, exposing the conditions of the hydrolysis of the compound in which R3is ether carboxylic acids, can be obtained compound of formula (I)in which R3is a carboxylic acid. Similarly, subjecting the compound of formula (I)in which R3Deputy having a protective group suitable conditions of removal of the protective groups can be obtained compound of formula (I), with a Deputy, from which the protective group can be removed in the form of R3.

(Method of obtaining 2)

(In this formula, the ring F represents a monocyclic or bicyclic heterocyclic ring, or monocyclic aryl, U represents a leaving group, and U' represents-B(OH)2or- (OL)OL'. In this case, L and L' are the same or different from each other and represent1-6alkyl, or L and L' can be combined with education2-6alkylene).

The compound (Ib) of the present invention can be obtained by the reaction of a combination of compound (I-a) and compound 2A.

Examples of the leaving group represented by U, include halogen, the group is econsultancy, p-toluensulfonate, tripterocalyx etc.

This reaction is carried out using an equivalent amount of compound (I-a) and compound 2A or excess of each of them, by stirring this mixture at room temperature to heating by boiling under reflux in a solvent which is inert to the reaction, usually for 0.1 hour to 5 days in the presence of a base and containing a palladium catalyst. This reaction is preferably carried out in an atmosphere of inert gas. Used in this case, the solvent is not particularly limited, but examples include aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, such as methanol, ethanol, 2-propanol, butanol and the like, DMF, DMSO, water and mixed solvents them. As a base may be used an inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, etc. as containing the palladium catalyst can be used tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium chloride 1,1'-bis(diphenylphosphino)ferienparadies or so Forth, can be made links to “Metal-Catalized Cross-Coupling Reactions” edited by A.d. Veijere and F. Diederich, 1stEdition, VCH Publishers Inc., 1997 or “Jikken Called kosa (Courses in Experimetal Chemictry) (5 thEdition)” edited by The Chemical Society of Japan, vol.13 (2005) (Maruzen).

(Synthesis of the starting compounds)

Method 1 retrieve the original content

Starting material, compound 1b-1, can be obtained using compound 3A as an initial matter, depending on the type of the Deputy, or by A, or by, as described above. The way And is the way in which the connection 3b restore in connection 3d, which are sideropenia and restoration to the amino group, with the acquisition of the initial substances, compounds 1b-1. On the other hand, the way In is the way in which the connection 3b are occimiano with subsequent recovery, with the receipt of the initial substance, compound 1b-1.

How 2 get the original substance

Compound 1A-1 can be obtained by the reaction of N-alkylation and ester hydrolysis of compounds 4A and compound 4b. The compound (I-a) can be obtained by amidation reaction of compound 1A-1 and compound 1b.

The compound of formula (I) is isolated and purified in the form of the free compounds and their salts, hydrate, solvate or polymorphic substances. Salt of the compounds of formula (I) can be obtained by the conventional reaction of the salt.

Isolation and purification can be performed using conventional chemical operations, that is them as extraction, fractionated (fractional) crystallization, various types of chromatography fractionated etc.

Various isomers can be obtained by selecting the appropriate starting compound or separated using differences in physico-chemical properties among isomers. For example, optical isomers can be obtained using conventional optical separation of racemic compounds (e.g., fractionated crystallization conversion connection diastereomeric salts with optically active bases or acids, chromatography using a chiral column or the like, and others) or can be obtained from the appropriate optically active starting compound.

The pharmacological activity of the compounds of formula (I) or its salt was confirmed by the following test.

Test example 1: Test for evaluating the affinity of the receptor ER rats

Cultivation of cells and transfection

Using coated with collagen Cup 10 cm (Asahi Class) HEK293 cells were cultured in culture medium (D-MEM culture medium was removed by confluentes (90-100% state density) and washed with phosphate buffered saline (PBS) and the cells are then separated using N,N,N',N'-tetrakis(carboxymethyl)Ethylenediamine (EDTA). The number of cells counted and were sown on coated collagen is asku 15 cm to confluently 70%. The following day, the culture medium Opti-MEM at 1.2 ml Cup was added lipofectamine 2000 (Invitrogen) at 60 μl per Cup, followed by keeping at room temperature for 5 minutes. Plasmid, which was insertion OR rat (SEQ ID NO:1) site cloning THE pcDNA3.1-V5-His-topo was added into the Cup and were cultured for 20-24 hours. The cultivation was carried out in a thermostat with CO2(37°C, 5% CO2).

Obtain the membrane fraction

Culture medium was removed with suction, was added 10 ml of chilled PBS for a Cup of 15 cm and the cells were scraped off using a cell scraper (Sumitomo Bakelite). Cells were washed in chilled PBS (1200 rpm, 4°C, 5 min) and then suspended in 6 ml of chilled 20 mm Tris-HCl (pH 7.4; Nakalai Tesque Inc., containing 5 mm EDTA (Nakalai Tesque Inc.) on the Cup, the resulting mixture was homogenized using Polytron and the homogenate was centrifuged (26000 rpm, 20 min, 4°C). The precipitate resuspendable in chilled 20 mm Tris-HCl, again homogenized using Polytron and the homogenate was centrifuged (26000 rpm, 20 min, 4°C). The precipitate resuspendable in 50 mm HEPES (pH 7.5; Dojindo Laboratories) at 1 ml per Cup, homogenized using Polytron and liofilizirovanny at -80°C in the membrane fraction. At this point, part of it was used to measure protein concentration. From what irenie protein concentration was performed in two iterations with the use of the kit for the analysis of protein Bio-Rad (Bio-Rad Laboratories) in accordance with the attached standard Protocol.

The analysis of binding

50 μl of [3H]PGE2 (final concentration 0.3 nm; Perkin Elmer), 100 µl (20 µg per well) membrane fractions obtained from expressing ER cells of rats and 50 μl of the test compounds were mixed in a 96-hole tablet (Sumimoto Bakelite), incubated at room temperature for 1 hour, filtered with suction on the filter UniFilter-96 GF/B (Perkin Elmer) using a FilterMate Harvester (Perkin Elmer) and then washed three times with 300 μl per well chilled buffer for analysis. Breeding [3H]PGE2 and membrane fractions was performed using a buffer for analysis (50 mm HEPES, 10 mm MgCl2and the dilution of the tested compounds and unlabeled PGE2 was performed using DMSO and buffer for analysis. Further, in the case of adding serum albumin human (HSA) breeding was performed using a buffer for analysis, containing 4% HSA (final concentration 1%; Sigma). UniFilter-96 GF/B pre-treated by washing 2 times with 200 μl per well chilled buffer for analysis. UniFilter-96 GF/B filter was dried in the dryer overnight, was added 50 μl per well MicroScint20 (Perkin Elmer) and then measured the radioactivity using a TopCount (Perkin Elmer). To measure nonspecific binding was added unlabeled PGE2 (final concentration 1 μm; Cayman). All measurements were carried out in two iterations and the value specification the definition of binding was determined by subtracting the magnitude of nonspecific binding from total binding. The Ki value was calculated in accordance with customary methods.

The Ki values of several compounds of formula (I) shown in table 1. In this case, the sample mean number the following example compounds.

Test example 2: Test for evaluation of antagonistic activity against receptor OR by measuring the amount of camp in the cells of the Jurkat human

Cultivation of cells

The Jurkat cells (obtained from T-lymphocytic leukemia, human) were cultured with RPMI1640 (supplemented with 10% fetal calf serum) using the F75 flask. After proliferation to polygonfromtext it was added indometacin with a final concentration of 5 μm, and the cells were additionally cultured for 18 hours. Cells were collected in a test tube Spitz 15 ml prepared to obtain 1×106cells/ml, using Cell Banker (Mitsubishi Depending Iatron) and kept at -80°C until used in the analysis. Cells were cultured in CO2-thermostat (37°C, 5% CO2).

HTRF-analysis

For the measurement of camp used set cAMP hirange columns (Cisbio international). Test the connection, PGE2, and these cells were diluted and prepared with buffer for analysis. The tested compound was prepared in such a way as to have a 3-fold concentration with respect to the final concentrations of PGE2 were prepared with the receipt of concentration is 300 nm and Jurkat cells, stored in a frozen state, prepared with obtaining 1×106cells/ml by thawing at 37°C. In 384-well U-bottom black microplate (Corning) were added to the test compound, the cells and PGE2 in the sequence specified in each case in an amount of 5 μl, followed by shaking on a tablet-the shaker and incubation at room temperature for 30 minutes. After incubating 5 μl of the reagent d2, which was dissolved in 0.6 times Lisinym buffer was added to each well, followed by shaking on a tablet-shaker. Then to each well was added 5 ál cryptate europium, which was dissolved in 0.6 times Lisinym buffer, followed by shaking on a tablet-the shaker and incubation at room temperature for 60 minutes with shielding from light. After incubation was measured fluorescence cryptate at 620 nm and the fluorescence d2 at 655 nm using ARVO1420 (Perkin Elmer). camp 280, 70, 17,5, 4,38, 1,09, 0,27 and 0,068 nm was measured simultaneously to obtain the calibration curve. All measurements were performed in two iterations and the degree of inhibition was calculated by determining the number of camp each test sample relative to the value obtained by subtracting the value of camp group without addition of PGE2 from the size of the camp group with the addition of 100 nm PGE2. The value of the IC50expected by way of Logistica is some regression.

In this regard, it should be noted that as a buffer for analysis” and “lisanova buffer”above used the following buffers:

Buffer for analysis; 1xHBSS (buffered saline Hanks, Nissue Pharmaceutical Co., Ltd.), 20 mm HEPES (pH 7.4, Nakarai Tesque), 0.5 mm IBMX (3-isobutyl-1-methylxanthines, WAKO), 0,02% CHAPS (Sigma), 0.1% of bovine serum albumin (Sigma), 2 μm indomethacin (Sigma);

Litany buffer; 50 mm NaPO4, 0.8 M KF, 1% Triton X-100, and 0.2% bovine serum albumin.

The evaluation of the compounds of example 3, example 53, example 57 and example 124 showed values IC50of 0.11 nm, 0,094 nm, 0,037 nm and 0.15 nm, respectively.

Test example 3: Test for evaluation of antagonistic activity against receptor ER rats by measuring the amount of camp

HTRF-analysis of camp rEP4

Cells of Cho, who was forced to Express HER rats were sown in 96-well tablets with 2×104cells/100 μl and cultured overnight. The culture medium was replaced by medium 2 μm indomethacin/0,1% BSA/alpha-MEM and then, after 60 minutes, was replaced by the environment 1 mm IBMX/2 μm indomethacin/0,1% BSA/alpha-MEM. After 10 minutes, was added to test the connection, and then, after 10 minutes, was added PGE2 at a final concentration of 100 nm. Cells were cultured and gave them to interact in CO2-thermostat (37°C, 5% CO2). After 30 minutes, the culture medium was removed and obavljale 100 µl per well of 0.2% Triton X-100-PBS for cell lysis. the camp contained in the solution for lysis of the cells was measured with a set of cAMP hirange columns (Cisbio international). The solution for lysis of the cells was dispersible in 10 μl each, in 384-well U-bottom black microplate (Corning) was added reagent d2 and reagent cryptit europium in the sequence specified in each case in an amount of 5 μl. The microplate was incubated at room temperature for 60 minutes under light shielding. After incubation was measured fluorescence cryptate at 620 nm and the fluorescence d2 at 655 nm using ARVO1420 (Perkin Elmer). camp 280, 70, 17,5, 4,38, 1,09, 0,27 and 0,068 nm was measured simultaneously to obtain the calibration curve. All degrees of inhibition was calculated by determining the number of camp each test sample relative to the value obtained by subtracting a value of camp group without addition of PGE2 from the size of the camp group with the addition of 100 nm PGE2. The value of the IC50was calculated by the method of logistic regression.

As the results of evaluation of the compounds of example 3, example 53, example 57 and example 124 was found values IC500,99 nm, of 0.90 nm, from 0.76 nm and 1.1 nm, respectively.

Test example 4: Test for evaluation of antagonistic activity against receptor ER rats in vivo

A solution of PEG 400:tween 80:water solution of NaHCO3=1:4:5 test compounds were administered orally to the SD rat (male, aged 6 weeks) not atomic and 1 hour later were injected subcutaneously ONO-4819 in the back of a rat. After 30 minutes, lipopolysaccharide (LPS, 0.01 mg/kg) was administered into the tail vein without anesthesia and after 60 minutes was collected 0.5 ml of heparinised blood from the fundus of the eye with anesthetic ether. The blood sample was centrifuged (3000 rpm, 10 minutes) to separate the plasma and then measured the concentration of TNFα in rat plasma using an ELISA kit (see Hepatology Research Journal, vol.21, 252-269, 2001). The value obtained by subtracting the concentration of TNFα in the group treated with ONO-4819, from the concentration of TNFα in the group not treated with ONO-4819, was taken as 100% and used to calculate the degree of inhibition relative to this value for the tested compounds.

The degree of inhibition of several compounds of formula (I) shown in table 2. In this regard, the example represents the number following example compounds.

Test example 5: Test of research actions on urine albumin in rats with induced streptozotocin (STZ) diabetes

Eight male Wistar rats (Crj) were divided into groups with an unbiased urine albumin excretion (UAE) in advance and STZ (50 mg/kg) was administered intravenously. From the next day after STZ injection test connection continuously administered orally and urine were collected periodically in the cell for metabolism studies within 24 hours, to measure the UAE. In this way it may be proved by the action of the tested compounds n is the improvement of early nephropathy in diabetic rat models.

Test example 6: Test steps on renal function in rats with chronic renal failure with 5/6-nephrectomy (5/6 Nx)

For this test used eight male Wistar rats. Two-thirds of the left kidney was cut under pentobarbital anesthesia and after 1 week they removed all of the right kidney. Later, 2 weeks after extraction 5/6 of this kidney, the amount of protein excretion in the urine was measured by 24-hour urine collection in metabolic cages and rats were divided into groups to between groups were not different. Then for 6-8 weeks 5 ml/kg of the test compound, which was suspended in 0.5% MC, is administered orally. The same quantity of solvent (0.5% of MS) was administered orally to the group alleged administration of a medicinal product, which was subjected only laparotomy, and 5/6 Nx-control group. 24-hour urine collection was performed every two weeks.

By measuring the amounts of protein excretion in the urine, plasma creatinine, urea nitrogen and plasma creatinine clearance can be confirmed by the action of the tested compounds to improve chronic renal failure, and in this test it was confirmed that there are compounds exhibiting efficiency.

In addition, the estimated selectivity of the compounds of formula (I) or its salt in the four subtypes of the receptor PE2 (ER, ER, ER and ER). Specifically, for each receptor subtype, data obtained from rats, the inhibition values of camp was measured by adding the test compounds, respectively, in the same manner as in test example 3. In the result, it was shown that the compound of formula (I) or its salt has a selective antagonistic activity or receptor ER.

Based on the results of the above tests, it was confirmed that the compound of formula (I) or its salt has an antagonistic activity against receptor ER and can be used as active ingredient in pharmaceutical compositions for the prevention or treatment of various related OR diseases, etc. are Examples associated with ER diseases include renal diseases such as acute nephritis, acute renal failure, chronic renal failure, diabetic nephropathy syndrome Bartter and the like), inflammatory skin diseases (e.g. sunburn, burns, eczema, dermatitis and the like), ischemic heart disease, caused by arteriosclerosis (e.g., myocardial infarction, angina etc), cerebrovascular disorders caused by arteriosclerosis (e.g., stroke, stroke, including lacunar infarction, thrombosis of cerebral vessels, brain hemorrhage, subarachnoid shall krovoisliania, the heart brain and so on), peptic ulcer (e.g. gastric ulcer, duodenal ulcer and the like), a malignant tumor and its metastasis (for example, cancer of the colon, breast cancer and the like) and the like, or a similar disease in humans and animals, and in one particular embodiment, renal diseases such as chronic renal failure, diabetic nephropathy, etc.

In addition, the compound of formula (I) or its salt can be used as compounds having diuretic effect. Having a diuretic effect, the compound of formula (I) or its pharmaceutically acceptable salt can be used as an agent for the treatment and/or prevention of various types of edema (e.g., swelling of the heart, brain edema, and the like), hypertension, such as malignant hypertension, and the like, premenstrual syndrome, stress, urinary calculus, disease, weak urination, caused by acute or chronic disease, hyperphosphatemia etc.

Pharmaceutical composition containing one or more types of the compounds of formula (I) or its salt as an active ingredient, can be obtained in accordance with a commonly used method, using excipient commonly used in this field, that is, the headlamp is aceticism excipient, the pharmaceutical carrier or other

The introduction can be done in any form for oral administration using tablets, pills, capsules, granules, powders, liquid preparations, or the like; or a parenteral administration using injections such as intraarticular, intravenous or intramuscular injections, suppositories, eye drops, eye ointments, transdermal patches, transmucosal liquid preparations, transmucosal patches, inhalations and the like

As solid compositions for oral administration using tablets, powders, granules or the like In such solid compositions one or more types of active ingredients are mixed with at least one inert excipient. According to the conventional method, the composition may contain inert additives such as a lubricant, a disintegrator, a stabilizing agent and solubilizers agent. If necessary, tablets or pills may be coated with a sugar coating or a film of soluble in the stomach or soluble in the small intestine of the material.

Liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs or the like, in Addition to the inert diluent, the liquid composition may contain an auxiliary agent such as solubilizers agent, onlineuse the agent and suspendisse agent, sweetening matter, flavoring substance, flavor and antiseptic.

Injectable solutions for parenteral administration include sterile aqueous or non-aqueous liquid preparations, suspensions and emulsions. The aqueous solvent includes, for example, distilled water for injection and physiological saline. Examples of the nonaqueous solvent include alcohols such as ethanol. Such a composition may further contain an agent toychest, antiseptics, wetting agent, emulsifying agent, dispersing agent, stabilizing agent or solubility agent. They are sterilized, for example, by filtration through a retaining bacteria filter, mixed with a biocide or irradiation. In addition, they can also be used by the manufacture of sterile solid compositions and dissolving or its suspension in sterile water or a sterile solvent for injection immediately before use.

Agent for external use include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments, etc. Such agents include commonly used basis of ointments, lotions, aqueous or non-aqueous liquid preparations, suspensions, emulsions, etc.

As for transmucosally agents, such as inhalation, transnasal agent, and the like, their use is comfort in the form of solids, liquid or semi-liquid state, and they can be prepared according to conventional known manner. For example, these may be added a known excipient, as well as pH adjustment agent, an antiseptic, a surfactant, a lubricant, a stabilizing agent, thickening agent or the like For introducing them may be used a suitable device for inhalation or blowing. For example, the compound may be administered separately or in the form of a powder prepared mixture or in the form of a solution or suspension in combination with a pharmaceutically acceptable carrier, using conventional known devices or spray device, such as a device for inhalation from a metered introduction, etc. you Can use the inhaler or similar device with a dry powder for use in single or multiple introduction and containing powder capsule. Alternatively, the connection can be in the form of a pressurized aerosol spray which uses an appropriate propellant, for example a suitable gas, such as chlorphenesin, carbon dioxide and the like, or other forms.

By oral administration, the daily dose is preferably from about 0.001 to 100 mg/kg, in one embodiment, from 0.1 to 30 mg/kg, and in another embodiment, at,1 to 10 mg/kg body weight, enter one portion or 2-4 divided doses. In the case of intravenous this daily dose is preferably administered from about 0.0001 to 10 mg/kg of body weight, once a day, or two or more times a day. In addition, transmucosally agent is administered in a dose of from about 0.001 to 100 mg/kg of body weight, once a day, or two or more times a day. This dose is determined appropriately in response to the individual case with regard to symptoms, age, sex, etc.

Although the pharmaceutical composition varies depending on the method of administration, dosage forms, the introduction, types excipients and additives, pharmaceutical composition of the present invention contains from 0.01 to 100 wt.%, in one embodiment, from 0.01 to 50 wt.% one or more compounds of the formula (I) and their salts as the active ingredient.

The compound of formula (I) or its salt can be used in combination with various agents for treating or agents for the prevention of the above diseases, which are considered to be a compound of the formula (I) or its salt are effective. This combination drug may be administered simultaneously or separately and continuously or with the desired time interval. Drugs that have jointly entered, can be obtained separately or can be farm is cautiously composition, containing various agents for treating or agents for the prevention of the above diseases, which are considered to be a compound of the formula (I) or its salt are effective, and the compound of formula (I) or its salt.

Examples

Methods for obtaining compounds of formula (I) or salts thereof will be described in more detail below based on examples. In this regard, it should be noted that the present invention is not limited to the compounds described in the following examples. In addition, the methods of obtaining the parent compounds will be described in the examples of the preparation, and methods of obtaining known compounds will be described in reference examples. In addition, methods for obtaining the compounds of formula (I) or its salt is not limited to the methods of obtaining the specific examples described below, and the compound of formula (I) or its salt can be obtained by any combination of methods or ways that are obvious to a person skilled in this field.

Example obtain 1

To a mixture of 5-chloro-1H-indole-7-carboxylic acid (500 mg), triphenylphosphine (1.01 g), ethanol (235 mg) and toluene (20 ml) was added dropwise diethylazodicarboxylate (2,2M solution in toluene, of 1.74 ml) at room temperature. After stirring for 2 hours at room temperature the reaction mixture was concentrated under reduced Yes the tion. The obtained residue was purified column chromatography on silica gel (hexane-ethyl acetate), to obtain ethyl 5-chloro-1H-indole-7-carboxylate (550 mg) as a white solid.

Example of getting 2

To a mixture of ethyl-5-(1-hydroxyethyl)thiophene-2-carboxylate (1.01 g), diphenylphosphinite (1,67 g) and toluene (10 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (905 ml) while cooling on ice, followed by stirring for 3 minutes. The reaction mixture was heated to room temperature, followed by stirring for 15 hours. The reaction liquid was washed with water and 1M hydrochloric acid in this order and dried over anhydrous sodium sulfate. Then, after concentration under reduced pressure, the obtained residue was purified column chromatography on silica gel (hexane-ethyl acetate), to obtain ethyl-5-(1-azidoethyl)thiophene-2-carboxylate (of 1.03 g) as a colorless oily substance.

Example of getting 3

To a mixture of ethyl-5-(1-azidoethyl)thiophene-2-carboxylate (1,03 g), THF (20 ml) and water (4 ml) was added triphenylphosphine (2.35 g) at room temperature. The resulting mixture was stirred at 60°C for 3 hours. After leaving the reaction mixture to cool to room temperature, the mixture was concentrated under reduced pressure and subjected to azeotropic distillation with toluol is. The resulting mixture was purified column chromatography on silica gel (chloroform-methanol), was concentrated and to the residue was added a 4M solution of hydrogen chloride in ethyl acetate (1.5 ml). After stirring for 3 minutes, the mixture was again concentrated under reduced pressure. To it was added diisopropyl ether and the precipitated white solid was separated by filtration, to obtain the hydrochloride of the ethyl-5-(1-amino-ethyl)thiophene-2-carboxylate (979 mg) as a white solid.

Example 4

To a mixture of ethyl-1,2,3,4-tetrahydroquinolin-8-carboxylate (1.1 g) and DMF (9.0 ml) was added sodium hydride (55% dispersion in liquid paraffin, 280 mg) at 0°C., followed by stirring at room temperature for 30 minutes. To the reaction mixture was added a solution of 1-(bromacil)-4-chlorobenzene (1.2 g) in DMF (2.0 ml) under cooling on ice, followed by stirring at room temperature for 3 days. To the obtained reaction mixture was added sodium hydride (55% dispersion in liquid paraffin, 280 mg), followed by stirring for 1 day. To the reaction mixture were added water and ethyl acetate and perform liquid separation. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. OST the current was purified column chromatography on silica gel (hexane-ethyl acetate), obtaining ethyl-1-(4-Chlorobenzyl)-1,2,3,4-tetrahydroquinolin-8-carboxylate (510 mg).

Example of getting 5

To a mixture of methyl 3-amino-2-hydroxybenzoate (700 mg) and THF (21 ml) was added 4-chlorophenothiazine (717 mg), followed by stirring at room temperature over night. To the reaction mixture was sequentially added copper iodide (0.87 g) and triethylamine (641 μl), followed by stirring at 60°C over night. The resulting reaction mixture was concentrated under reduced pressure and added to it the methanol, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate (20 ml), the insoluble substances were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=2:1) and then triturated with a mixture of n-hexane-ethyl acetate (10:1, 11 ml), to obtain methyl 2-[(4-chlorophenyl)amino]-1,3-benzoxazole-7-carboxylate (270 mg) as a pale yellow solid.

An example of obtaining 6

To a mixture of methyl 1H-indole-7-carboxylate (100 mg) and DMF (1 ml) was added tert-piperonyl sodium (75 mg) at room temperature, followed by stirring for 5 minutes. To the reaction mixture were added 4-(methyl bromide)benzonitrile (131 mg), followed by stirring at room temp is the temperature for 2 hours. To the mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline solution in this order, dried over anhydrous sodium sulfate and the solvent is then evaporated, to obtain crude methyl-1-(4-cyanobenzyl)-1H-indole-7-carboxylate (211 mg). To a mixture of crude methyl-1-(4-cyanobenzyl)-1H-indole-7-carboxylate (211 mg), THF (10 ml) and methanol (5 ml) was added 1M aqueous sodium hydroxide solution (2.5 ml) and the resulting mixed liquid was stirred at 60aboutWith during the night. After leaving to cool to room temperature, the solvent evaporated under reduced pressure and the obtained residue was added ethyl acetate, followed by extraction with water. The aqueous layer was neutralized by adding 1M hydrochloric acid (2.5 ml) and was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, then the solvent evaporated, to obtain crude 1-(4-carbamoylmethyl)-1H-indole-7-carboxylic acid (230 mg). To a mixture of crude 1-(4-carbamoylmethyl)-1H-indole-7-carboxylic acid (229 mg), hydrochloride of methyl-(S)-4-[1-amino-ethyl]benzoate (123 mg) and HOBt (23 mg) in DMF (3 ml) was added EDCI.HCl (150 μl), followed by stirring at room temperature for 3 hours. To the mixture was added water, followed by extraction with a mixture of ethyl acetate-diet levy ether. The organic layer was washed with water and saturated saline solution in that order and dried over anhydrous sodium sulfate. After evaporation of the solvent to the obtained residue were added methanol. The precipitated solid was separated by filtration and dried, to obtain methyl(S)-4-[1-({[1-(4-carbamoylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoate (142 mg).

Example of getting 7

A mixture of 1-(4-Chlorobenzyl)-1,2,3,4-tetrahydroquinolin-8-carboxylic acid (310 mg), hydrochloride methyl-4-[(1S)-1-amino-ethyl]benzoate (240 mg), EDCI.HCl (210 mg), HOBt (160 mg), pyridine (0.25 ml) and DMF (3,00 ml) was stirred at room temperature for 3 days. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated salt solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane-ethyl acetate), obtaining methyl-4-[(1S)-1-({[1-(4-Chlorobenzyl)-1,2,3,4-tetrahydroquinolin-8-yl]carbonyl}amino)ethyl]benzoate (129 mg).

Example obtain 8

To a mixture of methyl TRANS-4-acetylcyclohexanone (0.5 g) and pyridine (5.0 ml) was added hydroxylamine hydrochloride (0,57 g) under cooling on ice, followed by stirring at room temperature for 24 hours. Poluchenno the reaction mixture was concentrated under reduced pressure. To the mixture was added ethyl acetate and 10% aqueous citric acid solution and the aqueous layer was extracted with ethyl acetate. The organic layer was combined and washed with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate, water and saturated salt solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain methyl-TRANS-4-(N-hydroxyethylamide)cyclohexanecarboxylate (0.45 g).

Example of getting 9

To a mixture of methyl TRANS-4-(N-hydroxyethylamide)cyclohexanecarboxylate (0,44 g) and ethanol (8.0 ml) was added concentrated aqueous ammonia (2.0 ml) and the suspension in ethanol (6.0 ml), Raney Nickel (2.0 ml), followed by stirring at room temperature for 12 hours in an atmosphere of hydrogen at 3.4 ATM. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. To the residue was added diethyl ether, 4M solution of hydrogen chloride-dioxane was added to the mixture while cooling on ice, the precipitated solid substance was separated by filtration and washed with diethyl ether, to obtain the hydrochloride of methyl TRANS-4-(1-amino-ethyl)cyclohexanecarboxylate (0,42 g).

Example 10

To a mixture of 5,6,7,8-tetrahydro-2H-[1]benzothieno[2,3-d][1,3]oxazin-2,4-(1H)-dione (1.5 g) and carbonate is Aliya (1.4 g) was added DMF (15 ml) and the resulting mixture was added methyliodide (1.2 ml) under cooling on ice, followed by stirring at room temperature for 6 hours. To the mixture was added methyliodide (0,61 ml), followed by stirring at room temperature overnight, the reaction mixture was added water (15 ml) and a solid substance was separated by filtration, washed with water and dried under reduced pressure to obtain 1-methyl-5,6,7,8-tetrahydro-2H-[1]benzothieno[2,3-d][1,3]oxazin-2,4-(1H)-dione (1.3 g).

Example of getting 11

To 1-methyl-5,6,7,8-tetrahydro-2H-[1]benzothieno[2,3-d][1,3]oxazin-2,4-(1H)-dione (0.50 g) was added ethanol (20 ml) and sequentially added triethylamine (of 0.44 ml) and hydrochloride methyl-4-[(1S)-1-amino-ethyl]benzoate, followed by heating at boiling under reflux for 18 hours. The reaction mixture was cooled to room temperature and was added a 10% aqueous citric acid solution (15 ml). To the mixture was added ethyl acetate, followed by washing with water, and the resulting organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure the residue was purified column chromatography on silica gel (hexane-ethyl acetate: 90/10-75/25), with methyl-4-[(1S)-1-({[2-(methylamino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)ethyl]benzoate (0,42 g).

Example 12

To methyl 4-[(1S)-1-({[2-(methylamino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]Carbo is Il}amino)ethyl]benzoate (0,41 g) was added 1,3-dimethyl-2-imidazolidinone (4,0 ml) and the resulting mixture was added potassium carbonate (0,30 g) and 1-(methyl bromide)-4-chlorobenzene (0.34 g) under cooling on ice, followed by stirring at 50°C during the night. The reaction mixture was cooled to room temperature, and then thereto was added water, followed by extraction with ethyl acetate. The obtained organic layer was washed with salt solution, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane/ethyl acetate: 15/1-4/1, obtaining methyl-4-[(1S)-1-[({2-[(4-Chlorobenzyl)(methyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl)amino]ethyl}benzoate (0.15 g).

Example of getting 13

To a mixture of methyl 5-bromo-1-(4-Chlorobenzyl)-1H-indole-7-carboxylic acid (300 mg), trimethylboroxine (100 mg), potassium carbonate (165 mg) and 1,4-dioxane (9 ml) was added tetrakis(triphenylphosphine)palladium(0) (46 mg) at room temperature. The resulting mixture was stirred under heating at boiling under reflux, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent evaporated and the obtained residue was purified column chromatography on silica gel (hexane-ethyl acetate), obtaining methyl-1-(4-Chlorobenzyl)-5-methyl-1H-indole-7-carboxylate (60 mg).

Example of getting 14

To a mixture of (3-oxo-1,3-dihydro-2-benzofuran-1-yl)(triphenyl)factorybased (5,1 g) and tetrahydrofuran (50 ml) was added tert-bout XID potassium (1.3 g) and 5-chloro-2-nitrobenzaldehyde (1.0 g) at room temperature in an argon atmosphere, followed by stirring for 5 minutes. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane-ethyl acetate to obtain 3-(5-chloro-2-nitrobenzylidene)-2-benzofuran-1(3H)-she (808 mg).

Example get 15

A mixture of 3-(5-chloro-2-nitrobenzylidene)-2-benzofuran-1(3H)-she (808 mg), recovered iron (750 mg), ammonium chloride (72 mg), water (2.5 ml) and ethanol (25 ml) was stirred at 80°C for 4 hours. The reaction mixture was filtered using celite and the solvent evaporated under reduced pressure. The residue was purified column chromatography on silica gel (hexane-ethyl acetate), to obtain 3-(2-amino-5-chlorobenzylidene)-2-benzofuran-1(3H)-she (466 mg).

Example 16

1-(6-benzoperylene-3-yl)alanon (5,00 g), propane-1,3-diylbis(diphenylphosphine) (1,546 g), DMF (55 ml), methanol (30 ml) and triethylamine (10.5 ml) were mixed and the inner space of the reaction vessel was degirolami and replaced with argon. There was added palladium (II) acetate (842 mg) and then the inner space of the reaction vessel was filled with carbon monoxide and stirred at 70°C for 2 days. After the instructions for cooling to room temperature the reaction mixture was diluted with a mixed solvent of diethyl ether-ethyl acetate and washed with water and saturated saline solution in this order. The organic layer was dried over anhydrous sodium sulfate, then the solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane-ethyl acetate), obtaining methyl-5-acetylpyridine-2-carboxylate (1,16 g).

Example of getting 17

To a solution of 3-(2-amino-5-chlorobenzylidene)-2-benzofuran-1(3H)-she (466 mg) in ethanol (3.5 ml) was added 1M aqueous sodium hydroxide solution (3.4 ml) at room temperature, followed by heating at boiling under reflux for 45 minutes. The reaction mixture was acidified by addition of 1M hydrochloric acid while cooling on ice and stirred at room temperature for 1 hour. The precipitate was separated by filtration and the filtrate was extracted with diethyl ether. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-(5-chloro-1H-indol-2-yl)benzoic acid (295 mg).

Example of getting 18

To a mixture of 2-(5-chloro-1H-indol-2-yl)benzoic acid (217 mg), DMF (4.0 ml) and THF (1.0 ml) was added sodium hydride (55% dispersion in liquid paraffin, 77 mg) at room temperature in an argon atmosphere, followed by stirring for 5 minutes. At room temperature to the resulting sm is si was added methyliodide, with further stirring for 12 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated salt solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain methyl 2-(5-chloro-1-methyl-1H-indol-2-yl)benzoate (270 mg).

Example of getting 19

To a mixture of methyl-4-propenylbenzene acid (0.50 g) and pyridine (5.0 ml) was added hydroxylamine hydrochloride (0.54 g) under cooling on ice, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, to the residue was added ethyl acetate and 10% aqueous citric acid solution and the aqueous layer was extracted with ethyl acetate. The organic layer was combined and washed with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate, water and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and to the residue was added ethanol (15 ml). To the reaction mixture was added a slurry of Raney Nickel (2.0 ml) in ethanol (15 ml) and conjugated aqueous ammonia (3.0 ml), followed by stirring at room temperature for 14 hours in a hydrogen atmosphere of 3 ATM. Insoluble substances is involved in the reaction mixture were separated by filtration through celite and the filtrate was concentrated under reduced pressure. To the residue was added diethyl ether (10 ml) was added while cooling on ice 4M solution of hydrogen chloride/dioxane (1.0 ml). Precipitated crystals were separated by filtration and washed with diethyl ether, to obtain the hydrochloride of methyl-4-(1-aminopropyl)benzoic acid (0.51 g).

Example of getting 20

To a mixture of methyl-5-acetylpyridine-2-carboxylate (1,00 g), THF (24 ml) and methanol (12 ml) was added sodium borohydride (110 mg), followed by stirring at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure, and then to the obtained residue was added a saturated aqueous solution of sodium chloride. After extraction with ethyl acetate the organic layer was dried over anhydrous sodium sulfate. The solvent is evaporated and then dried under reduced pressure to obtain methyl-5-(1-hydroxyethyl)pyridine-2-carboxylate (897 mg).

Example of getting 21

A mixture of methyl-5-(1-hydroxyethyl)pyridine-2-carboxylate (897 mg) and dichloromethane (10 ml) was cooled on ice and the resulting mixture was added triethylamine (1,72 ml) and methanesulfonamide (765 μl). The mixture was stirred while cooling on ice for 3 minutes and then stirred at room temperature for 30 minutes. To the mixture was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and ZAT is m the solvent evaporated under reduced pressure, to obtain a pale yellow oily residue (1,457 g). The obtained residue was mixed with DMF (5 ml) and sodium azide (965 mg), followed by stirring at 60°C for 1 hour. The mixture was allowed to cool to room temperature and thereto was added water, followed by extraction with a mixed solvent of ethyl acetate-diethyl ether. The organic layer was washed with water and saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane-ethyl acetate), to obtain 5-(1-azidoethyl)pyridine-2-carboxylate (828 mg).

Example of getting 22

To a mixture of 3-hydroxy-4-methylbenzoic acid (3.0 g), potassium carbonate (10,9 g) and acetonitrile (60 ml) was added ethyliodide (4.8 ml) while cooling on ice, followed by stirring at 60°C over night. Then to the mixture was added ethyliodide (4.8 ml) and potassium carbonate (5.5 g), followed by stirring overnight. To the reaction mixture were added water (100 ml), followed by extraction with ethyl acetate, and the obtained organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (ethyl acetate/hexane: 5/95), with the floor is the group of ethyl-3-ethoxy-4-methylbenzoate (4.0 g).

An example of retrieving 23

Methyl-(S)-4-(1-acetimidoyl)benzoic acid (and 4.40 g) and conjugate sulfuric acid (15 ml) was mixed at room temperature, was stirred until homogeneous and then cooled on ice. To the mixture was added dropwise a mixture of fuming nitric acid (3 ml) and concentrated sulfuric acid (2 ml) over 30 minutes while maintaining the internal temperature at 10°C or lower. After completion of adding dropwise the mixture was stirred at room temperature for 5 hours. The reaction liquid was poured into a mixture of water with ice, followed by stirring and then extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to obtain methyl(S)-4-(1-acetimidoyl)-3-nitrobenzoate (4.83 g).

Example of getting 24

In hydrogen atmosphere, the mixture of methyl-(S)-4-(1-acetimidoyl)-3-nitrobenzoate (4.83 g), ethyl acetate (30 ml) and 10% palladium on carbon (500 mg) was stirred at room temperature for 18 hours. After completion of the reaction the catalyst was removed by filtration and the solvent evaporated under reduced pressure. To the obtained residue was added ethyl acetate, followed by heating at the boiling reverse was built in the ICOM. The mixture was allowed to cool to room temperature and then the precipitate was separated by filtration, to obtain methyl(S)-3-amino-4-(1-acetimidoyl)benzoate (of 3.31 g).

Example get 25

To a mixture of ethyl-3-ethoxy-4-methylbenzoate (2.0 g), N-bromosuccinimide (1.9 grams) and ethyl acetate (40 ml) was added 2,2'-azobis(2-methylpropionitrile) (15 mg), followed by stirring for 14 hours when heated at the boil under reflux. The mixture was allowed to cool, added to her hexane, the precipitated solid substance was separated by filtration and the resulting filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (ethyl acetate/hexane: 5/95), with ethyl-4-(methyl bromide)-3-ethoxybenzoate (2.4 g).

Example of getting 26

To a mixture of 4-chloro-1H-pyrrole-2-carboxylic acid (0.20 g) and DMF (2.0 ml) was added tert-piperonyl potassium (0.31 g) under cooling on ice, followed by stirring at room temperature for 15 minutes. To the reaction mixture were added 1-methyl bromide-4-chlorobenzene (0,29 g) under cooling on ice, followed by stirring at room temperature for 14 hours. To the reaction mixture was added water at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated salt solution, dried over anhydrous sulfate magney then filtered. The filtrate was concentrated under reduced pressure and the residue was purified column chromatography on silica gel, to obtain 4-chloro-1-(4-Chlorobenzyl)-1H-pyrrole-2-carboxylic acid (0.06 g).

Example of getting 27

To a mixture of sodium nitrite (193 mg) and concentrated sulfuric acid (2 ml) was added dropwise a solution of methyl-(S)-3-amino-4-(1-acetimidoyl)benzoate (600 mg) in acetic acid (6 ml), followed by stirring at room temperature for 30 minutes. To a cooled on ice to a solution of copper chloride (I) (550 mg) in concentrated hydrochloric acid (6 ml) was added dropwise the above reaction mixture, followed by stirring at room temperature for 5 hours. The reaction liquid was poured into a mixture of ice water, followed by extraction with chloroform. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent is evaporated, and the obtained residue was purified column chromatography on silica gel (chloroform-methanol), to obtain methyl(S)-4-(1-acetimidoyl)-3-chlorobenzoate (465 mg).

Example of getting 28

To a mixture of methyl 4-formyl-3-methoxybenzoate (3,30 g) and THF (30 ml) was added dropwise methylmagnesium (3M solution in diethyl ether of 3.60 ml) under cooling on ice. After adding dropwise the mixture was stirred for 1 hour PR is cooling on ice. To the mixture was added saturated aqueous solution of ammonium chloride to stop the reaction, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane-ethyl acetate), obtaining methyl-4-(1-hydroxyethyl)-3-methoxybenzoate (1.92 g).

An example of obtaining 29

To a mixture of 1-(4-bromophenyl)-1-cyclopropylalanine (1.08 g) and THF (10 ml) was added triethylamine (1 ml) and di-tert-BUTYLCARBAMATE (1.25 ml) and the resulting mixture was stirred at room temperature for 16 hours. The solvent was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane-ethyl acetate), to obtain tert-butyl[(4-bromophenyl)(cyclopropyl)methyl]carbamate (1,36 g).

Example 30

To a mixture of methyl-4-(1-hydroxyethyl)-3-methoxybenzoate (1.92 g), diphenylphosphinite (2.76 g) and toluene (20 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.5 ml) at room temperature, followed by stirring at room temperature for 2 days. To the mixture was added THF (10 ml), water (5 ml) and triphenylphosphine (3.0 g) at room temperature and the resulting mixture was stirred at 60°C in those who tell 3 hours. The mixture was allowed to cool to room temperature and the solvent evaporated under reduced pressure, followed by extraction with ethyl acetate. To the organic layer was added a 1M aqueous solution of hydrochloric acid (50 ml) and the desired product was extracted in this water layer. To the aqueous layer was added 1M aqueous sodium hydroxide solution (60 ml) and then the desired product was extracted with ethyl acetate three times. The combined organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue (748 mg) was added 4M solution of hydrogen chloride/1,4-dioxane (4 ml), followed by stirring for 3 minutes and concentrated under reduced pressure. To the residue was added ethyl acetate, followed by stirring at room temperature for 10 minutes and then the precipitate was separated by filtration, to obtain the hydrochloride of methyl-4-(1-amino-ethyl)-3-methoxybenzoate (439 mg).

An example of retrieving 31

A mixture of methyl-(S)-4-(1-acetimidoyl)-3-chlorobenzoate (464 mg) and 2M hydrochloric acid (12 ml) was stirred at 100°C for 2 days. After leaving to cool to room temperature, the mixture was concentrated under reduced pressure, optionally subjected to azeotropic distillation with ethanol is m and dried, obtaining hydrochloride (S)-4-(1-amino-ethyl)-3-chlorbenzoyl acid (428 mg).

Example of getting 32

To a mixture of sodium hydride (0.29 grams, 55% dispersion in liquid paraffin) and DMF (10 ml) was added methyl-4H-furo[3,2-b]pyrrole-5-carboxylate (0.5 g) under cooling on ice, followed by stirring for 10 minutes, and was further added 1-(methyl bromide)-4-chlorobenzene (0,81 g), followed by stirring at room temperature for 4 hours. To the reaction mixture were added 10% aqueous citric acid solution (10 ml), followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure and the residue was purified column chromatography on silica gel (hexane/ethyl acetate: 5/1-3/1), to obtain 4-(4-Chlorobenzyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid (0.35 g).

An example of obtaining 33

Methyl-4-{[(tert-butoxycarbonyl)amino](cyclopropyl)methyl}benzoate (793 mg), methanol (5 ml) and a 4M solution of hydrogen chloride/dioxane (5 ml) were mixed, followed by stirring at room temperature for 2 hours. The solvent is evaporated under reduced pressure and then the residue was added ethyl acetate. The precipitated solid was separated by filtration and dried under reduced pressure, to obtain the hydrochloride of methyl 4-[amino(cyclopropyl)methyl]benzoate (561 mg).

Example get 34

A mixture of 7-bromo-5-methoxy-1H-indole (1.2 g) and THF (12 ml) was stirred at -78°C in argon atmosphere. To the reaction mixture was added dropwise a solution of n-utility in n-hexane (1.65 M, with 9.6 ml) at -50°C or below. The reaction mixture was stirred for 0.5 hour while cooling on ice. The reaction mixture was cooled to -78°C and to it was added dry ice (10 g), followed by slow warming to room temperature. The resulting reaction mixture was poured into 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (THF/hexane=20→60%), with 5-methoxy-1H-indole-7-carboxylic acid (0,60 g).

Example of getting 35

To ethyl-4-(methyl bromide)-3-ethoxybenzoate (2.4 g) was added DMF (24 ml) and sodium azide (0.54 g), followed by stirring at room temperature over night. To the reaction mixture were added water (50 ml), followed by extraction with ethyl acetate, and the obtained organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To the residue was added THF (21 ml) and water (4.0 ml) and then added t is Ivanishin (6.6 g), followed by stirring at room temperature for 1 hour and further at 75°C for 1 hour. The reaction mixture was cooled on ice, brought to pH 2 by addition of 1M aqueous hydrochloric acid and washed with diethyl ether. The aqueous layer was neutralized with saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. While cooling on ice to the residue was added ethyl acetate (4.0 ml) and then 4M solution of hydrogen chloride in ethyl acetate (4.0 ml) and the precipitated solid substance was separated by filtration, washed with ethyl acetate and then dried at 60°C under reduced pressure, to obtain the hydrochloride of the ethyl-4-(aminomethyl)-3-ethoxybenzoate (1.1 g).

Example of getting 36

In an argon atmosphere to a cooled on ice mixture tetrafluoroborate microzone (355 mg) and dichloromethane (15 ml) was added methyl-(S)-3-amino-4-(1-acetimidoyl)benzoate (650 mg) and the resulting reaction mixture was stirred at room temperature for 20 hours. To it was added 1,2-dichlorobenzene (15 ml), dichloromethane is evaporated under reduced pressure and then the resulting mixture was stirred at 160°C for 2 hours. After cooling to room temperature, to the mixture was added saturated aqueous rest the R of sodium bicarbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then the solvent is evaporated under reduced pressure. The residue was purified column chromatography on silica gel (chloroform-methanol), to obtain methyl(S)-4-(1-acetimidoyl)-3-perbenzoate (266 mg).

An example of retrieving 37

To a mixture of methyl 4-cyano-2-methylbenzoate (3.0 g) and methanol (60 ml) was added to the uranyl dichlorobut (8,1 g) under cooling on ice, followed by stirring. To the mixture was slowly added sodium borohydride (3,9 g), followed by stirring at room temperature for 2 hours. While cooling on ice to the reaction mixture were added saturated aqueous ammonia (20 ml), followed by stirring at room temperature for 30 minutes. The resulting solution was filtered through celite and washed with methanol. The filtrate was concentrated under reduced pressure and the obtained residue was added 1M hydrochloric acid (50 ml), followed by washing with diethyl ether. The aqueous layer was brought to pH 8 by addition of saturated aqueous sodium bicarbonate and additionally brought to pH 10 by addition of 1M aqueous sodium hydroxide solution. The resulting mixture was extracted by adding chloroform and the organic layer was dried over anhydrous magnesium sulfate. Added 4M Rast the EOS of hydrogen chloride in dioxane (10 ml), followed by concentration under reduced pressure. The solid is washed with diethyl ether, and then was separated by filtration and dried at 60°C under reduced pressure, to obtain the hydrochloride of methyl-4-(aminomethyl)-3-methylbenzoate (3.0 g).

An example of retrieving 38

1-biphenyl-4-ylmethyl)-1H-indole-7-carboxylic acid (0.20 g), the hydrochloride of methyl-4-[(1S)-1-amino-ethyl]benzoate and HATU were added DMF (4.0 ml), followed by the addition of diisopropylethylamine (0,26 ml) while cooling on ice, and then stirred at room temperature for 22 hours. The resulting mixture was again cooled on ice, was added a 10% aqueous citric acid solution (4.0 ml), the precipitated solid substance was separated by filtration, washed with water and dried at 60aboutWith under reduced pressure, to obtain 4-[(1S)-1-({[1-(biphenyl-4-ylmethyl)-1H-indole-7-ID]carbonyl}amino)ethyl]benzoate (0,30 g).

An example of retrieving 39

To a mixture of CIS-4-(butoxycarbonyl)cyclohexanecarboxylic acid (3.3 g) and thionyl chloride (13 ml) was added DMF (2 drops), followed by stirring at 50°C for 0.5 hours, the Reaction mixture was concentrated under reduced pressure and subjected to azeotropic distillation with toluene, to obtain the residue. A mixture of copper iodide (5.2 g) and THF (13 ml) was stirred at an internal temperature of -40°C in argon atmosphere. To the reaction mixture, dobavljalo drops solution metallice in diethyl ether (1,1M, 55 ml) at an internal temperature of -30 to -40°C for approximately 15 minutes, followed by stirring at the same temperature for 1 hour. The reaction mixture was cooled to an internal temperature of -60°C was added dropwise thereto THF solution (10 ml) described above balance when the internal temperature (-50)-(-60°C) for approximately 5 minutes. The resulting mixture was stirred at the same temperature for 0.5 h and was added dropwise thereto methanol (15 ml), followed by warming to room temperature. To the reaction mixture were added saturated aqueous solution of ammonium chloride and ethyl acetate and the aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed with saturated aqueous ammonium chloride and saturated salt solution, dried over anhydrous magnesium sulfate, then filtered and the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=9:1), obtaining butyl-CIS-4-acetylcyclohexanone (2.2 g).

Example of getting 40

To 5-methyl-1H-indole-7-carboxylic acid (1.1 g), potassium carbonate (1.3 g) was added DMF (22 ml) and then methyliodide (1.3 ml) under cooling on ice. After stirring at room temperature overnight, the reaction mixture was brought to pH 3 by adding 10% aqueous restorational acid. The resulting mixture was extracted with ethyl acetate, the obtained organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane/ethyl acetate: 95/5-85/15), with methyl-5-methyl-1H-indole-7-carboxylate (1.2 g).

An example of retrieving 41

To the mixture cooled on ice methyl-6-hydroxypyridine-2-carboxylate (800 mg), DME (10.5 ml) and DMF (2.6 ml) was added sodium hydride (55% dispersion in oil, 240 mg), followed by stirring for 10 minutes. Was added lithium bromide (910 mg), and then the resulting mixture was stirred at room temperature for 15 minutes, and thereto was added an additional 4-Chlorobenzilate (2.15 g). The resulting mixture was stirred at 65°C for 20 hours. Thereto was added water, followed by extraction with a mixture of ethyl acetate-diethyl ether, the organic layer was washed with water and saturated saline solution in that order and dried over anhydrous sodium sulfate. The solvent is evaporated and the obtained residue was purified column chromatography on silica gel (hexane-ethyl acetate), obtaining methyl-1-(4-Chlorobenzyl)-6-oxo-1,6-dihydropyridines-2-carboxylate (270 mg; example 41A) and methyl-6-[(4-Chlorobenzyl)oxy]pyridine-2-carboxylate (448 mg; example 41b) in the form of a colorless oily substance thus estwenno.

An example of retrieving 42

A mixture of methyl 5-bromo-1H-indole-7-carboxylate (300 mg), 1-methyl-2-pyrrolidinone (6 ml), methanesulfonate sodium (600 mg) and copper iodide (I) (1.10 g) was stirred at 150°C for 17 hours in an argon atmosphere. The resulting reaction mixture was left to cool to room temperature, was added thereto, ethyl acetate, and then insoluble matter was removed by filtration. To the obtained filtrate was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline solution in that order and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane-ethyl acetate), obtaining methyl-5-(methanesulfonyl)-1H-indole-7-carboxylate (91 mg).

An example of retrieving 43

To a mixture of tert-BUTYLCARBAMATE (the ceiling of 5.60 g) and n-propanol (50 ml) was added 0.5 m aqueous sodium hydroxide solution (94 ml) and tert-butylhypochlorite (5,32 ml), followed by stirring at room temperature for 20 minutes. To the reaction mixture was added dropwise a solution in n-propanol (DHQD)2Phal (the 766.5 mg) under cooling on ice. In addition, at the same temperature was added dropwise a solution in n-propanol (80 ml), methyl-4-vinylbenzoate (2.5 g) for 30 minutes and then to the mixture was added Digita the potassium osmate (253,8 mg). The resulting reaction mixture was stirred for 1 hour while cooling on ice, and then stirred at 4°C over night. The resulting reaction mixture was concentrated under reduced pressure and to the residue was added water (250 ml). The aqueous layer was extracted with ethyl acetate (100 ml ×3). The organic layer was combined, washed with 1M aqueous hydrochloric acid solution (200 ml) and saturated salt solution, dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue was purified column chromatography on silica gel (hexane-ethyl acetate=3:1), obtaining methyl-4-{(1R)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}benzoate (850 mg) as a white solid.

An example of retrieving 44

To methyl-1-(4-bromobenzyl)-1H-indole-7-carboxylate (0,63 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (0.56 g), potassium acetate (0.27 g), dichloride bis(triphenylphosphine)palladium(II) (39 mg) and triphenylphosphine (29 mg) was added toluene (6.0 ml), followed by stirring at 110°C in argon atmosphere. After stirring for 5 hours the reaction mixture was purified column chromatography on silica gel (hexane-ethyl acetate=20/1-10/1), to obtain methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-1H-indole-7-carboxylate (0.45 g).

An example of retrieving 45

To a mixture of 7-bromantan-1-ol (1.06 g), triphenyl is spina (1.86 g), 4-chlorophenol (011 mg) and toluene (30 ml) was added dropwise diethylazodicarboxylate (2,2M solution in toluene, and 3.3 ml) at room temperature. After adding dropwise the mixture was stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure and then the resulting residue was purified column chromatography on silica gel (hexane-ethyl acetate), to obtain 7-bromo-1-(4-chlorphenoxy)indane (306 mg).

An example of retrieving 46

To a mixture of 7-bromo-1H-pyrrolo[3,2-c]pyridine (0.16 g) and THF (6.0 ml) was added di-tert-BUTYLCARBAMATE (0.26 g) and N,N-dimethyl-4-aminopyridine (0,010 g) at room temperature, followed by stirring at room temperature for 17 hours. The resulting reaction mixture was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (ethyl acetate/hexane=0-25%), with tert-butyl 7-bromo-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (0,22 g).

An example of retrieving 47

To a mixture of 7-bromoindole (3,3 g) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (33 ml) was added 2-phenyloxirane (2.5 ml) and cesium carbonate (11 g) at room temperature, followed by stirring at 80°C for 12 hours. To the reaction mixture were added ethyl acetate and water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated solution is Oli, was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=4:1), obtaining 2-(7-bromo-1H-indol-1-yl)-1-phenylethanol (5,1 g).

Example obtain 48

A mixture of tert-butyl 7-bromo-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (0.20 g), 1,3-bis(diphenylphosphino)propane (0,028 g), palladium acetate (0.015 g), DMF (4.0 ml), methanol (6.0 ml) and triethylamine (0,28 ml) was stirred at 80°C for 2 days in an atmosphere of carbon monoxide. The reaction mixture was left to cool and the carbon monoxide was replaced with argon. The reaction mixture was diluted with ethyl acetate, washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and then filtered. The residue was purified column chromatography on silica gel (ethyl acetate/hexane=30-60%), with methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (of 0.081 g).

An example of retrieving 49

To a mixture of 4-[(1S)-1-({[1-(4-Chlorobenzyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid (250 mg) and DMF (5 ml) was added 1,1'-carbonyldiimidazole (187 mg) at room temperature, followed by stirring for 5 minutes and then was added 3-(aminosulfonyl)propyl (209 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (173 μl) in that order with further stirring for 3 days. The resulting reaction mixture ohla is given on ice and added to it 10% aqueous citric acid solution (30 ml), followed by stirring for 30 minutes. The precipitated solid was separated by filtration and washed with cold ethanol (4 ml), to obtain 1-(4-chlorbenzyl)-N-[(1S)-1-(4-{[(3-acetoxypropionyl)sulfonyl]carbarnoyl}phenyl)ethyl]-1H-indole-7-carboxamide (210 mg) as a pale yellow solid.

Example of getting 50

To methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-1H-indole-7-carboxylate (0,30 g), pyridine-2-intraformational (0.35 g), trikaliumfosfaatti (0,49 g), palladium(II) chloride (27 mg) and biphenyl-2-yl(DICYCLOHEXYL)phosphine (0.11 g) was added dioxane (12 ml) and water (3.0 ml), followed by stirring at 100°C for 4 hours. The resulting reaction mixture was purified column chromatography on silica gel (hexane/ethyl acetate=5/1-4/1), to obtain methyl-1-(4-pyridine-2-ylbenzyl)-1H-indole-7-carboxylate (0.15 g).

An example of retrieving 51

To 2-(7-bromo-1H-indol-1-yl)-1-phenylethanol (0,70 g) was added DMF (7.0 ml), tert-butyl(chloro)dimethylsilane (0,47 g) and imidazole (0,23 g), followed by stirring at room temperature for 25 hours. To the reaction mixture were added 10% aqueous citric acid solution (15 ml), followed by extraction with ethyl acetate, and the obtained organic layer was washed with salt solution. After drying over anhydrous sodium sulfate and concentration under reduced pressure the obtained oktetakakao column chromatography on silica gel (hexane/ethyl acetate=99/1-90/10), to obtain 7-bromo-1-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-phenylethyl)-1H-indole (0,92 g).

An example of retrieving 52

To 7-bromo-1-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-phenylethyl)-1H-indole (0,91 g) was added digidrirovanny THF (30 ml) and a solution in hexane n-utility (1,6M, 5,2 ml) at -78°C with replacement (ar) argon. The resulting mixture was heated from -78°C to -5°C, followed by stirring for 30 minutes. The resulting reaction mixture was again cooled to -78°C and added to it the dry ice, followed by stirring at room temperature. To the mixture was added diethyl ether, followed by washing 1M aqueous solution of sodium hydroxide. The resulting aqueous layer was brought to pH 3 with 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated salt solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane/ethyl acetate=3/1), obtaining 1-[(S)-2-phenylphenyl]-1H-indole-7-carboxylic acid (0.34 g).

Example of getting 53

To methyl-1H-indole-7-carboxylate (1.5 g) was added DMF (15 ml) and to the mixture was added tert-piperonyl potassium (1.5 g) under cooling on ice, followed by stirring for 10 minutes. Was added 4-(methyl bromide)biphenyl (2.8 g), followed by the stirring at room temperature for 19 hours. The resulting reaction mixture was again cooled on ice and added to it 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane/ethyl acetate=97/3-95/5), with methyl-1-(biphenyl-4-ylmethyl)-1H-indole-7-carboxylate (2.5 g).

An example of retrieving 54

To methyl-1-(biphenyl-4-ylmethyl)-1H-indole-7-carboxylate (2.5 g) was added methanol (20 ml), THF (20 ml) and 1M aqueous sodium hydroxide solution (10 ml), followed by stirring at 60°C for 16 hours. To the reaction mixture were added 10% aqueous citric acid solution (20 ml), followed by extraction with ethyl acetate, and the organic layer was washed with salt solution. After dehydration over anhydrous sodium sulfate, filtration and concentration under reduced pressure the resulting residue was treated with diisopropyl ether, utverjdali and was separated by filtration. The obtained solid was purified column chromatography on silica gel (chloroform/methanol=99/1-97/3), obtaining 1-(biphenyl-4-ylmethyl)-1H-indole-7-carboxylic acid (0,99 g).

Example of getting 55

To (6-piperidine-1-espiridion-3-yl)methanol (0,61 g) was added dropwise a methylene chloride (6.0 m is) and thionyl chloride (1.0 ml) under cooling on ice. In addition, to the mixture was added a catalytic amount of DMF, followed by stirring at room temperature for 2 hours. To the mixture was added methylene chloride (5.0 ml) and thionyl chloride (1.0 ml), followed by stirring at 60°C over night. The resulting reaction mixture was concentrated under reduced pressure, and thereto was added DMF (10 ml). Then thereto was added methyl-1H-indole-7-carboxylate (0.56 g) and tert-piperonyl potassium (1.3 g) under cooling on ice, followed by stirring at room temperature for 3 hours. The reaction mixture was extracted by adding ethyl acetate and water and the organic layer was washed with salt solution, dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane/ethyl acetate=95/5-70/30), with methyl-1-[(6-piperidine-1-espiridion-3-yl)methyl]-1H-indole-7-carboxylate (0.12 g).

An example of receiving 56

To methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-1H-indole-7-carboxylate (0.15 g), 1,1'-bis(diphenylphosphino)ferienparadies (14 mg), cesium fluoride (0.17 g) and 3-bromopyridine (79 mg) was added dioxane (4.5 ml), followed by stirring at 100°C for 21 hours in an argon atmosphere. The resulting reaction mixture was purified column chromatography on what silicagel (hexane/ethyl acetate=2/1-1/1), obtaining methyl-1-(4-pyridine-3-ylbenzyl)-1H-indole-7-carboxylate (0,13 g).

An example of retrieving 57

To a mixture of (1-phenylpiperidine-4-yl)methanol (958 mg), methyl-1H-indole-7-carboxylate (590 mg) and toluene (20 ml) was added (tributylphosphine)acetonitrile (1.0 g) at room temperature. The resulting mixture was stirred at 100°C for 1 day. The residue was purified column chromatography on silica gel (hexane-ethyl acetate), obtaining methyl-1-[(1-phenylpiperidine-4-yl)methyl]-1H-indole-7-carboxylate (163 mg).

An example of retrieving 58

Added 4-phenylthiophene-2-methanol (0.21 g), toluene (2.0 ml) and a catalytic amount of pyridine and was added dropwise thionyl chloride (0.16 ml) under cooling on ice. After stirring at room temperature for 3 hours the reaction mixture was concentrated under reduced pressure, subjected isotropes distillation with toluene and dried at 60°C under reduced pressure to obtain 2-chloromethyl)-4-phenylthiophene (0,22 g).

Example retrieve 59

To a mixture of methyl 4-bromo-1-(4-Chlorobenzyl)-1H-pyrrole-2-carboxylate (0,72 g) and DMF (21 ml) was added phenylboric acid (0,30 g), sodium carbonate (0,58 g), water (3.0 ml) and tetrakis(triphenylphosphine)palladium (0,13 g), followed by stirring at 100°C for 24 hours. To the reaction mixture were added ethyl acetate and water and the insoluble matter was separated by Phil what trevanian through celite. The organic layer was washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (ethyl acetate/hexane=0-10%), with methyl-1-(4-Chlorobenzyl)-4-phenyl-1H-pyrrole-2-carboxylate (0.26 g).

Example of getting 60

To a mixture of tert-butyl 4-{[7-({(S)-1-[4-(methoxycarbonyl)phenyl]ethyl}carbarnoyl)-1H-indol-1-yl]methyl}piperidine-1-carboxylate (1,67 g) and THF (20 ml) was added 4M solution of hydrogen chloride in ethyl acetate (2.0 ml) at room temperature, followed by stirring for 1 hour. The resulting reaction mixture was stirred at 60°C for 6 hours. The resulting reaction mixture was concentrated under reduced pressure. The residue was washed with ethyl acetate and diethyl ether, separated by filtration and dried under reduced pressure, to obtain the hydrochloride of methyl-4-[(1S)-1-({[1-(piperidine-4-ylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoate (1,46 g).

An example of retrieving 61

To a mixture of the hydrochloride of methyl-4-[(1S)-1-({[1-(piperidine-4-ylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoate (150 mg) and dichloromethane (2.0 ml) was added triacetoxyborohydride sodium (210 mg) and benzaldehyde (70 mg) at room temperature, followed by stirring for 3 days. To the reaction mixture we use the and water. In addition, the resulting mixture was podslushivaet the addition of 1M aqueous sodium hydroxide solution and was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain methyl 4-{(1S)-1-[({1-[(1-benzylpiperidine-4-yl)methyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoate (121 mg) as a white solid.

An example of retrieving 62

To methyl 1-(1,3-benzoxazol-2-ylmethyl)-1H-indole-7-carboxylate (0,22 g), methanol (2.0 ml) and THF (2.0 ml) was added 1M aqueous sodium hydroxide solution (1.0 ml), followed by stirring at 70°C for 14 hours. The resulting reaction mixture was cooled on ice, was added a 10% aqueous solution of citric acid, the precipitated solid substance was separated by filtration and washed with water and with a mixture of diethyl ether/hexane (1/1), to obtain 1-{2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-1H-indole-7-carboxylic acid (0.18 g).

An example of retrieving 63

To a mixture of methyl-4-{[(1H-benzimidazole-2-ylcarbonyl)amino]methyl}benzoate (230 mg), potassium carbonate (257 mg) and DMF (4.6 ml) was added p-chlorobenzamide (191 mg), followed by stirring at room temperature for 2.5 days. To the reaction mixture were added water (30 ml), followed by extraction with ethyl acetate (30 ml). Organic SL is th then washed with saturated aqueous sodium bicarbonate and saturated salt solution and dried over anhydrous magnesium sulfate. After filtration and concentration, the obtained residue was washed with methanol (2 ml), to obtain methyl 4-[({[1-(4-Chlorobenzyl)-1H-benzimidazole-2-yl]carbonyl}amino)methyl]benzoate (269 mg) as a white solid.

Example of getting 64

To a mixture of ethyl-5-chloro-1H-indole-7-carboxylate (3.0 g) and acetic acid (30 ml) was added cyanoborohydride sodium (2.5 g), followed by stirring at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure and the residue was brought to pH 8 by addition of saturated aqueous sodium bicarbonate. After extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was treated with a mixture of diethyl ether/hexane (1/5), utverjdali and was separated by filtration. To the obtained solid substance was added ethyl acetate (10 ml) and 4M mixture of hydrogen chloride in ethyl acetate (10 ml), followed by concentration under reduced pressure. To the residue was added diethyl ether/hexane (1/5), a solid substance was separated by filtration and dried under reduced pressure, to obtain the hydrochloride of the ethyl-5-chloroindole-7-carboxylate (1.6 g).

Example getting 65

A mixture of ethyl-1-[(5-bromopyridin-2-yl)methyl]-5-chloro-1H-indole-7-carboxylate (0,30 g), (9,9-dimethyl-N-xanthene-4,5-diyl)bis(WPPT is niphophila) (88 mg), tert-butoxide sodium (0.12 g), piperidine (84 mg), Tris(dibenzylideneacetone)diplegia(0) (70 mg) and digidratirovannogo toluene (6.0 ml) was barbotirovany with argon for 10 minutes, followed by stirring at 110°C for 2 hours. The reaction mixture was filtered through celite and washed with diethyl ether. To the filtrate was added saturated aqueous sodium bicarbonate, followed by extraction with diethyl ether, and the organic layer was washed with a saturated solution of salt. After drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure the residue was purified column chromatography on silica gel (hexane/ethyl acetate=1/1), to obtain ethyl 5-chloro-1-[(5-piperidine-1-espiridion-2-yl)methyl]-1H-indole-7-carboxylate (0,23 g).

An example of retrieving 66

A mixture of 2-fluoro-5-(trifluoromethyl)benzonitrile (1000 mg), 5-chloro-1H-indole (800 mg), potassium carbonate (1.8 g) and DMSO (10 ml) was stirred at 100°C for 14 hours. The resulting reaction mixture was cooled to room temperature and added to it water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated salt solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-(5-chloro-1H-indol-1-yl)-5-(trifluoromethyl)benzonitrile (1.66 g).

Example the floor is placed 67

To a mixture of 2-(5-chloro-1H-indol-1-yl)-5-(trifluoromethyl)benzonitrile (1.66 g) and ethylene glycol (18 ml) was added 1M aqueous sodium hydroxide solution (26 ml) at room temperature, followed by stirring at 180°C for 16 hours. The resulting reaction mixture was cooled to room temperature and neutralized by adding 1M hydrochloric acid (26 ml), followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-(5-chloro-1H-indol-1-yl)-5-(trifluoromethyl)benzoic acid (1,67 g).

Example of getting 68

To a mixture of ethyl-1-(1,2,3,4-tetrahydroisoquinoline-7-ylmethyl)-5-(trifluoromethyl)-1H-indole-7-carboxylate (0.14 g) and ethyl acetate (10 ml) was added manganese dioxide (0,30 g) at room temperature. The reaction liquid was stirred for 6.5 hours under conditions of heat by boiling under reflux. In addition, to the reaction liquid was added toluene (10 ml) and manganese dioxide (0,30 g) at room temperature, followed by stirring at 110°C for 1 day and then at 130°C for 1 day. The resulting reaction liquid was left to cool to room temperature and filtered using celite and the filtrate was concentrated PR is the reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=75:25-30:70), to obtain ethyl-1-(isoquinoline-7-ylmethyl)-5-(trifluoromethyl)-1H-indole-7-carboxylate (85 mg).

Example of getting 505

To a mixture of the hydrochloride of 4-bromo-3-chloro-2-methylaniline (1.0 g), sodium acetate (0.5 g) and acetic acid (15 ml) was added N-iodosuccinimide (1.0 g) under cooling with water. The resulting reaction mixture was stirred at room temperature for 3.5 hours. To the reaction mixture were added ethyl acetate and water and podslushivaet it by adding potassium carbonate. Then there was the operation of separation of the liquid and the organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=100:1-90:10), to obtain 4-bromo-3-chloro-6-iodine-2-methylaniline (1.3 g).

Example of getting 506

To a mixture of N-[2-methyl-3-(trifluoromethyl)phenyl]ndimethylacetamide (6.2 g) and acetic acid (40 ml) was added a solution of bromine in acetic acid (10 ml) under cooling with water. The resulting reaction liquid was stirred at room temperature overnight and then at 50°C for 2 hours. In addition, to the reaction liquid was added bromine (1.5 ml) under cooling with water, followed by stirring at 50°C for 1 day. In addition to the, to the reaction liquid was added bromine (2.0 ml) under cooling with water, followed by stirring at 50°C for 1 day. In addition, to the reaction liquid was added bromine (2.0 ml) under cooling with water, followed by stirring at 50°C for 4 days. The resulting reaction liquid was poured into ice water (approximately 200 g)were added thereto ethyl acetate, followed by neutralization with potassium carbonate. Spent the operation of separation of the liquid and the organic layer was washed with an aqueous solution of sodium thiosulfate and a saturated saline solution in this order, dried over anhydrous sodium sulfate and then evaporated under reduced pressure to obtain N-[4-bromo-2-methyl-3-(trifluoromethyl)phenyl]ndimethylacetamide (9.0 g).

Example of getting 507

To a mixture of tert-butyl 5-bromo-7-(methyl bromide)-6-chloro-1H-indole-1-carboxylic acid (7.2 g) and acetonitrile (50 ml) was added 4-methylmorpholine-4-oxide (2.7 g) at room temperature. The resulting reaction mixture was stirred at 50°C for 7 hours and then at 70°C during the night. The reaction mixture was concentrated under reduced pressure, was added thereto ethyl acetate and water and spent the operation of the separation fluid. The organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was purified column is a chromatography on silica gel (hexane:ethyl acetate=100:0-90:10), obtaining tert-butyl-5-bromo-6-chloro-7-formyl-1H-indole-1-carboxylic acid (2.9 g).

Example of getting 508

To a mixture of tert-butyl 5-bromo-6-chloro-7-formyl-1H-indole-1-carboxylic acid (2.9 g), sodium dihydrophosphate (2.0 g), 2-methyl-2-butene (2.6 g), water (10 ml) and 1,4-dioxane (30 ml) was added sodium chloride (1.8 g) under cooling on ice. The resulting reaction mixture was stirred under cooling on ice for 1 hour and then at room temperature for 5 hours. The resulting reaction mixture was concentrated under reduced pressure, was added ethyl acetate and water and spent the operation of the separation fluid. The organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and then evaporated under reduced pressure to obtain 5-bromo-1-(tert-butoxycarbonyl)-6-chloro-1H-indole-7-carboxylic acid (3.1 g).

Example of getting 509

To a mixture of 5-bromo-1-(tert-butoxycarbonyl)-6-chloro-1H-indole-7-carboxylic acid (0.3 g), water (2.0 ml) and methanol (6.0 ml) was added potassium carbonate at room temperature. The reaction mixture was stirred at 70°C for 5.5 hours. The resulting reaction mixture was concentrated under reduced pressure, and thereto was added ethyl acetate and water, followed by acidification with 1M hydrochloric acid. Then there was the operation of separation of the liquid and the organic layer washed asystem salt solution, was dried over anhydrous sodium sulfate and then evaporated under reduced pressure to obtain 5-bromo-6-chloro-1H-indole-7-carboxylic acid (0,22 g).

An example of obtaining 510

To a mixture of N-[4-bromo-2-methyl-3-(trifluoromethyl)phenyl]ndimethylacetamide (9.0 g) and ethanol (40 ml) was added concentrated hydrochloric acid at room temperature. The reaction mixture was stirred at 100°C for 4 hours. The resulting reaction mixture was left to cool to room temperature and thereto was added ethyl acetate and water, followed by alkalinization with potassium carbonate. Then there was the operation of separation of the liquid and the organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate 90:10 to 60:40), with 4-bromo-2-methyl-3-(trifluoromethyl)aniline (6,9 g).

Example of getting 511

To a mixture of 4-amino-3-bromo-5-iodobenzonitrile (1.0 g), copper iodide (60 mg) and triethylamine (10 ml) was added dichloride bestlifeinsurance (0,22 g) in an argon atmosphere and was degirolami twice with argon. To the mixture was added amenitieseven (0,47 ml) while cooling on ice, followed by stirring at room temperature for 24 hours. Insoluble matters in the reaction mixture was separated filtered is eating through celite and the filtrate was concentrated under reduced pressure. To the residue was added 10% aqueous citric acid solution and ethyl acetate and insoluble matter was again removed by filtration. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, soda and saturated salt solution, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (hexane:chloroform=2:1), to obtain 4-amino-3-bromo-5-[(trimethylsilyl)ethinyl]benzonitrile (0,81 g).

Example of getting 512

To a mixture of 4-amino-3-bromo-5-[(trimethylsilyl)ethinyl]benzonitrile (0,80 g) and tetrahydrofuran (3.0 ml) was added 1M solution of tetrabutylammonium in THF (3.0 ml) under cooling on ice, followed by stirring at room temperature for 0.5 h To the reaction mixture was added water under cooling on ice, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (chloroform/hexane=30-50%), with 4-amino-3-bromo-5-ethynylbenzoate (0,57 g).

Example of getting 513

To a mixture of tert-butyl 5-bromo-7-methyl-6-(triptorelin)-1H-indole-1-carboxylic acid (1.2 g) and tetrachloride is gerada (20 ml) was added N-bromosuccinimide (0,70 g) and 2,2'-azobis(2-methylpropionitrile) (20 mg) at room temperature. The reaction mixture was stirred at 90°C for 18 hours. The resulting reaction mixture was left to cool to room temperature and filtered through celite to remove insoluble substances. The filtrate was evaporated under reduced pressure and to the residue was added acetonitrile (20 ml), followed by adding 4-methylmorpholine-4-oxide (0.50 g) under cooling on ice. The resulting reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was evaporated under reduced pressure, was added thereto ethyl acetate and water and spent the operation of the separation fluid. The organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=100:0-90:10), to obtain tert-butyl 5-bromo-7-formyl-6-(trifluoromethyl)-1H-indole-1-carboxylic acid (0.26 g).

Example of getting 514

To a mixture of 4-amino-3-bromo-5-ethynylbenzoate (0,57 g) and 1-methyl-2-pyrrolidinone (12 ml) was added tert-BUTYLCARBAMATE (0,57 g) under cooling on ice, followed by stirring at room temperature for 24 hours. To the reaction mixture were added 10% aqueous citric acid solution while cooling on ice, followed by extraction with ethyl acetate. The organic layer was washed with water, feast upon the authorized aqueous solution of sodium bicarbonate, water and saturated salt solution, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain 7-bromo-1H-indole-5-carbonitrile (0.55 g).

Example of getting 515

To a mixture of methyl TRANS-4-[({[5-bromo-6-chloro-1-(isoquinoline-3-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylate (0.28 g), sodium formate (0.10 g) and DMSO (5.0 ml) was added tetrakis(triphenylphosphine)palladium (20 mg) at room temperature. The resulting reaction mixture was stirred at 70°C for 2 hours and then at 90°C for 3 hours. In addition, to the reaction mixture were added sodium formate (0.10 g) and tetrakis(triphenylphosphine)palladium (40 g) in that order at room temperature, followed by stirring overnight at 90°C. To the reaction liquid were added ethyl acetate and water, and insoluble substances were removed by filtration through celite. The filtrate was subjected to the operation of separation of the liquid and the organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was purified column chromatography on silica gel (methanol:chloroform=0:100-5:95), with methyl-TRANS-4-[({[6-chloro-1-(isoquinoline-3-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid (0.124 g).

An example of retrieving 51

To a mixture of methyl TRANS-4-[({[5-bromo-6-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid (75 mg), triethylamine (0.1 ml) and methanol (5.0 ml) was added 10% palladium on carbon (80 mg) under cooling on ice. The resulting reaction liquid was stirred at room temperature for 1 day in an atmosphere of hydrogen. Insoluble substances of the reaction liquid was removed by filtration through celite and the residue was evaporated under reduced pressure. To the residue was added ethyl acetate and water and spent the operation of the separation fluid. The organic layer is washed with 5% aqueous citric acid solution and saturated saline solution in this order, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=80:20-50:50), with methyl-TRANS-4-[({[6-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid (41 mg).

Connection examples get shown in the tables below were obtained according to the method, like that shown in the examples of the preparation above, using appropriate starting materials. The structure of the compounds of examples of the preparation shown in table 3-136, and methods of obtaining and physical data of the compounds of examples of the preparation are shown in tables 201-211.

Example 1

RA is Toru methyl-4-[(1S)-1-({[1-(4-Chlorobenzyl)-1,2,3,4-tetrahydroquinolin-8-yl]carbonyl}amino)ethyl]benzoate (129 mg) in THF (2.0 ml) and methanol (1.0 ml) was added 1M aqueous sodium hydroxide solution (1.0 ml) at room temperature, with further stirring for 2 days. The reaction mixture is neutralized by adding 1M hydrochloric acid (1.0 ml) at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane-ethyl acetate). The obtained product was dissolved in ethyl acetate (2.0 ml) and the resulting solution was added a 4M solution of hydrogen chloride in acetate (2.0 ml) at room temperature, followed by stirring for 1 day. The solvent is evaporated under reduced pressure, the residue was washed with ethyl acetate, separated by filtration and dried under reduced pressure, to obtain the hydrochloride of 4-[(1S)-1-({[1-(4-Chlorobenzyl)-1,2,3,4-tetrahydroquinolin-8-yl]carbonyl}amino)ethyl]benzoic acid (97 mg).

Example 2

To a mixture of 1-(4-Chlorobenzyl)-1H-indole-7-carboxylic acid (0.20 g), hydrochloride methyl-4-(aminomethyl)-3-chlorobenzoate (0.18 g) and HATU (0.32 g) in DMF (4.0 ml) was added diisopropylethylamine (0,29 ml) while cooling on ice, followed by stirring at room temperature for 14 hours. After cooling again on the ice to the mixture was added 5% aqueous citric acid solution (8.0 ml) and OSA is built solid substance was separated by filtration, then washed with water and diisopropyl ether and dried at 60°C under reduced pressure. To obtain the solid was added methanol (3.0 ml), THF (3.0 ml) and 1M aqueous sodium hydroxide solution (2.0 ml), followed by stirring at 60°C for 2 hours. The resulting reaction mixture was left to cool, added to it 10% aqueous citric acid solution (5.0 ml), the precipitated solid substance was separated by filtration, washed with water and dried at 60°C under reduced pressure to obtain 3-chloro-4-[({[1-(4-Chlorobenzyl)-1H-indol-7-yl]carbonyl}amino)methyl]benzoic acid (0.24 g).

Example 3

To methyl 4-[(1S)-1-({[1-(biphenyl-4-ylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoate (to 0.30 g) was added methanol (4.0 ml) and THF (4.0 ml) and 1M aqueous sodium hydroxide solution (3.0 ml), followed by stirring at 65°C for 2 hours and then at room temperature for 3 days. To the reaction mixture were added 10% aqueous citric acid solution (4.0 ml), the precipitated solid substance was separated by filtration, washed with water and with a mixture of diethyl ether/hexane (1/1) and dried at 60°C under reduced pressure, to obtain 4-[(1S)-1-({[1-(biphenyl-4-ylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid (0.25 g).

Example 4

To a mixture of 4-[(1S)-1-({[1-[(6-chloropyridin-3-yl)methyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid (0.15 g), is anivorano acid (84 mg), tribalista (0,22 g), palladium chloride (II) (9,2 mg) and biphenyl-2-yl(DICYCLOHEXYL)phosphine (36 mg) was added dioxane (6.0 ml), water (1.5 ml), followed by stirring at 100°C for 1 hour. The reaction mixture is brought to pH 3 by adding 10% aqueous citric acid solution. The mixed liquid was filtered through celite and the filtrate was extracted with ethyl acetate. The organic layer was washed with salt solution, dried over anhydrous sodium sulfate, then filtered and the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane/THF=2/1-1/1), to obtain 4-{(1S)-1-[({1-[(6-vinylpyridin-3-yl)methyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid (66 mg).

Example 5

To 4-{(1S)-1-[({1-[(6-chloropyridin-3-yl)methyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid (95 mg) was added ethanol (2.0 ml) and piperidine (65 ml), followed by stirring at room temperature over night. After concentration under reduced pressure, thereto was added DMSO (1.0 ml), piperidine (65 μl) and tert-piperonyl potassium (61 mg), followed by stirring at 80°C for 2 hours. To the reaction mixture were added 10% aqueous citric acid solution (10 ml), followed by extraction with ethyl acetate. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (chloroform/methanol=99/1-95/5), to obtain 4-{(1S)-1-[({1-[(6-ethoxypyridine-3-yl)methyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid (0,0 mg).

Example 6

To a mixture of 1-(4-chlorbenzyl)-N-[(1S)-1-(4-{[(3-acetoxypropionyl)sulfonyl]carbarnoyl}phenyl)ethyl]-1H-indole-7-carboxamide (200 mg), THF (3 ml) and methanol (3 ml) was added 1M aqueous sodium hydroxide solution (1.7 ml), followed by stirring at room temperature over night. The reaction mixture is brought to pH 4 by addition of 1M hydrochloric acid (1.7 ml) and further thereto was added water (20 ml), followed by stirring at room temperature for 30 minutes. The precipitated solid was separated by filtration, washed with water (4 ml) and then washed with cold ethanol (3 ml), to obtain 1-(4-chlorbenzyl)-N-[(1S)-1-(4-{[(3-hydroxypropyl)sulfonyl]carbarnoyl}phenyl)ethyl]-1H-indole-7-carboxamide (80 mg) as a pale yellow solid.

Connection examples are shown in tables below were obtained according to the method, like that shown in the above examples, using appropriate starting materials. The structure of the compounds of examples are shown in tables 137-200, and methods of obtaining and physical data of the compounds of examples are shown in tables 212-223.

In addition, other options implemented the I the compounds of formula (I) or salts thereof are shown in tables 224-228. Such compounds can be easily obtained using the methods of obtaining the above methods described in the examples of ways obvious to experts in the field, or modified methods.

In addition, in the tables below, the following abbreviations.

PRP: number of sample receipt (case when in the examples get more then an example of reception “/Cl”means that the compound of this example of getting selected as hydrochloride); approx.: the number of the example (case when in the examples after the number of the example is “/Cl”means that the compound of this example is highlighted as hydrochloride); no: number of compounds; structure: structural formula (Ac: acetyl, TMS: trimethylsilyl, TBS: tert-butyldimethylsilyl); synthesis: the method get (some examples or examples of the preparation above, the number of sample is received or the number of the sample obtained in the same way. For example, this means that the compound of example getting 69 was obtained in the same way as the compound of example obtaining 38); data: physicochemical data (the values of the measured NMR-C: δ (ppm)1H-NMR in CDCl3The NMR-D: δ (ppm)1H-NMR in DMSO-d6, FAB+: FAB-MS (cation), FAB: FAB-MS (anion), ESI+: ESI-MS(cation), ESI-: ESI-MS (anion), APCI+: APCI-MS (cation) EI: EI-MS (cation), CI+: CI-MS (cation), APCI/ESI+: APCI/MS (cation) or ESI-MS (cation) PSI/ESI (anion); TPL: melting point (°C, decomposition)).

Industrial applicability

The compound of formula (I) or its salt have antagonistic activity against receptor ER and can be used as active ingredient in pharmaceutical compositions for preventing and/or treating chronic renal failure and/or diabetic nephropathy.

Free text list of sequences

The following list of sequences under a numeric number <400> describes the nucleotide sequence ER rat (SEQ ID NO:1).

1. The compound or its pharmaceutically acceptable salt, where the compound is selected from the group consisting of
4-[({[5-chloro-1 -(quinoline-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]benzoic acid
TRANS-4-[({[5-methyl-1-(quinoline-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid,
TRANS-4-[({[5-fluoro-1-(quinoline-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid,
4-[({[1-(quinoline-2-ylmethyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]benzoic acid
TRANS-4-[({[1-(quinoline-2-ylmethyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid,
TRANS-4-[({[5-chloro-1-(isoquinoline-3-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid,
TRANS-4-[({[1-(isoquinoline-3-ylmethyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid,
TRANS-4-{[({5-chloro-1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexanecarboxylic acid,
4-{[({5-chloro-1-[2-(4-chlorophenoxy)ethyl]-1H-indol-7-yl)carbonyl)amino]methyl}benzoic acid,
TRANS-4-{[({5-chloro-1-[2-(4-horfe is hydroxy)ethyl]-3-H-indol-7-yl}carbonyl)amino]methyl}cyclohexanecarboxylic acid,
4-{[({1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}benzoic acid,
TRANS-4-{[({1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexanecarboxylic acid,
TRANS-4-{[({1-[(5-vinylpyridin-2-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexanecarboxylic acid,
4-{[({1-[2-(4-chlorophenoxy)ethyl]-5-(trifluoromethyl)-1H-indol-7-yl} carbonyl)amino]methyl}benzoic acid,
TRANS-4-[({[1-(isoquinoline-3-ylmethyl)-5-methyl-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid,
TRANS-4-[({[5-fluoro-1-(isoquinoline-3-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid,
TRANS-4-[({[6-fluoro-1-(isoquinoline-3-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid,
TRANS-4-[({[1-(1-benzofuran-2-yl)methyl)-5-chloro-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid,
TRANS-4-[({[1-(1-benzofuran-2-yl)methyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid,
TRANS-4-[({[(5-chloropyridin-2-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexanecarboxylic acid, and
TRANS-4-{[({1-[(5-chloro-1-benzofuran-2-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid.

2. Pharmaceutical composition having antagonistic aktivnosti respect HER receptor, containing the compound according to claim 1 or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.

3. Pharmaceutical composition for treating chronic renal insufficiency or diabetic nephropathy, containing a compound according to claim 1 or its pharmaceutically acceptable salt.

4. The use of compounds according to claim 1 or its pharmaceutically acceptable salt to obtain a pharmaceutical composition for treating chronic renal insufficiency or diabetic nephropathy.

5. The compound according to claim 1 or its pharmaceutically acceptable salt for use in the treatment of chronic renal insufficiency or diabetic nephropathy.

6. A method of treating chronic renal insufficiency or diabetic nephropathy, comprising an introduction to the subject an effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt.

7. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is 4-[({[5-chloro-1-(quinoline-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]benzoic acid.

8. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is a TRANS-4-[({ [5-methyl-1-(quinoline-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid.

9. The compound according to claim 1 or its pharmaceutically acceptable salt, the de connection represents TRANS-4-[({[5-fluoro-1-(quinoline-2-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid.

10. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is 4-[({[1-(quinoline-2-ylmethyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]benzoic acid.

11. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is a TRANS-4-[({[1-(quinoline-2-ylmethyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid.

12. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is a TRANS-4-[({[5-chloro-1-(isoquinoline-3-ylmethyl)-1H-indol-7-yl]carbonyl} amino)methyl]cyclohexanecarboxylic acid.

13. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is a TRANS-4-[({[1-(isoquinoline-3-ylmethyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid.

14. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is a TRANS-4-{[({5-chloro-1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexanecarboxylic acid.

15. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is 4-{[({5-chloro-1-[2-(4-chlorophenoxy)ethyl]-1H-indol-7-yl}carbonyl)amino]methyl}benzoic acid.

16. The compound according to claim 1 or its pharmaceutically acceptable salt, where the connection is abitrans-4-{[({5-chloro-1-[2-(4-chlorophenoxy)ethyl]-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexanecarboxylic acid.

17. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is 4-{[({1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}benzoic acid.

18. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is a TRANS-4-{[({1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl} cyclohexanecarboxylic acid.

19. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is a TRANS-4-{[({1-[(5-vinylpyridin-2-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexanecarboxylic acid.

20. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is 4-{[({1-[2-(4-chlorophenoxy)ethyl]-5-(trifluoromethyl)-1H-indol-7-yl} carbonyl)amino]methyl} benzoic acid.

21. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is a TRANS-4-[({[1-(isoquinoline-3-ylmethyl)-5-methyl-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid.

22. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is a TRANS-4-[({[5-fluoro-1-(isoquinoline-3-ylmethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid.

23. The compound according to claim 1 or its pharmaceutically acceptable salt, where the Association represents TRANS-4-[({[6-fluoro-1-(isoquinoline - 3-ylmethyl)-1H-indol-7-yl]carbonyl)amino)methyl]cyclohexanecarboxylic acid.

24. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is a TRANS-4-[({[1-(1-benzofuran-2-yl)methyl)-5-chloro-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid.

25. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is a TRANS-4-[({[1-(1-benzofuran-2-yl)methyl)-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid.

26. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is a TRANS-4-[({[(5-chloropyridin-2-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl}carbonyl)amino]methyl}cyclohexanecarboxylic acid.

27. The compound according to claim 1 or its pharmaceutically acceptable salt, where the compound is 4-{[({1-[(5-chloro-1-benzofuran-2-yl)methyl]-5-(trifluoromethyl)-1H-indol-7-yl]carbonyl}amino)methyl]cyclohexanecarboxylic acid.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of general formula:

or its pharmaceutically acceptable salt wherein the ring A represents a phenyl group which can contain 1-3 substitutes specified in a group of substitutes, or a thienyl group which can contain 1-3 substitutes specified in a group of substitutes α; L represents a single bond or a group of formula -NRC CO- (wherein Re represents a hydrogen atom), the ring B represents C6-14 aryl group which can contain 1-3 substitutes specified in a group of substitutes α, or a 5-10-member heterocyclic group which can contain 1-3 substitutes specified in a group of substitutes α; the X, Y, Z , R1 and R2 , R3, R4, R5 and R6 radical values are presented in cl.1 of the patent claim which possess an effect of Aβ protein production inhibition or an effect of BACE1 inhibition.

EFFECT: preparing the compound which is applicable as a preventive or therapeutic agent for neurodegenerative disease caused by Aβ.

13 cl, 35 tbl, 285 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, namely to method of obtaining 3,3'-(1,2-phenylene)-bis-1,5,3-dithiazepinane and 3,3'-[methylene-bis-(1,4-phenylene)]-bis-1,5,3-dithiazepinane of general formula (1):

, R=1,2-C6H4; 4-C6H4-CH2C6H4-4, which lies in the following: α,ω-diamines (1,2-phenylenediamine or 4,4'-diaminodiphenylmethane) is subjected to interaction with 1,3,6-oxadithiapinane in presence of catalyst Sm(NO3)3·6H2O in mole ratio α,ω-diamine : 1,3,6-oxadithiapinane : Sm(NO3)3·6H2O = 10 : 20 : (0.3-0.7) in chlorophorm and argon atmosphere for 2.5-3.5 h.

EFFECT: elaborated is method of obtaining novel compounds, which cam be applied as antibacterial, antifungal and antiviral agents, as biologically active complexing agents, selective sorbents and extractants of precious metals, special reagents for suppression of vital activity of bacteria in various technical media.

1 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclopropylamine derivatives of formula: or its pharmaceutically acceptable salt, wherein: one of R1 and R2 means a group of formula -L2-R6a-L3-R6b; the other of R1 and R2 means H, C1-10alkyl, C1-10alkoxy, halogen, CN; each R3, R3a R3b independently means H, C1-6alkyl, trifluoromethyl, C1-10alkoxy, CN; R4 and R5 taken together with a nitrogen atom whereto each attached form a non-aromatic cycle of formula: R7, R8, R9 and R10 each H, C1-10alkyl; R6a means cyanophenyl, phenyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, [1,2,3]triazolyl, [1,2,4]triazolyl, azepanyl, azetidinyl, azetidin-2-onyl, pyridazin-3(2H)-onyl, pyridin-2(1H)-onyl, pyrimidin-2(1H)-onyl, pyrrolidin-2-onyl, benzothiazolyl wherein the pyridinyl and pyrimidinyl groups optionally contain 1-3 substitutes specified in a group consisting of C1-10alkyl and C1-10alkoxy; R6b means H; L means - [C(R16)(R17)]k; L2 means a bond, C2-10alkylene, -O-, -C(=O)-, -NH-, -N(R16)C(=O), -C(=O)N(R16) and -N(C1-6alkyl)-;L3 means a bond; R15 means H, C1-6alkyl, C1-6alkoxycarbonyl, amido and formyl R16 , R17 in each specific case means H, C1-6alkyl; Rx and Ry in each specific case independently mean H, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, fluorine, diC1-6alkylamino; k is equal to 1, 2 or 3; m is equal to 2.

EFFECT: compounds show H3 receptor inhibitory activity that makes them applicable in a pharmaceutical composition.

10 cl, 7 dwg, 44 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, where R1 denotes C1-C8-alkylaminocarbonyl, which is optionally substituted with a 5- or 6-member heterocyclic ring containing 3-4 ring heteroatoms selected from a group consisting of oxygen, nitrogen and sulphur, where the ring can be optionally substituted with C1-C8-alkyl or C1-C8-alkoxy group ; R2 denotes C1-C3-alkyl or a halogen; one of R3 and R4 denotes R6, and the other denotes R7; R5 denotes hydrogen or halogen; R6 denotes hydrogen, hydroxy group amino group, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxy, -OR8 or C1-C8-halogenalkyl; R7 denotes hydrogen, OR11, halogen, carboxy, -SO2R8, cyanogroup or C1-C8-halogenalkyl, or when R4 denotes R7, then R7 can also denote -NR12 R13 ; R8 R11 independently denote C1-C8-alkyl or C3-C8-cycloalkyl, which can be optionally substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group or di-C1-C8-alkyl)amino group; any R9 denotes C1-C8-alkyl or C3-C8-cycloalkyl, which can optionally be substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group, di(C1-C8-alkyl)amino group or a 5- or 6-member heterocyclic ring containing one or two ring heteroatoms selected from a group consisting of oxygen and nitrogen, where the ring can optionally be substituted with C1-C8-alkyl, and R10 denotes hydrogen or C1-C8-alkyl; or R9 and R10 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which can contain one or two additional nitrogen heteroatoms, where the ring can be optionally substituted with C1-C8-alkyl; any R12 denotes C1-C8-alkyl or C3-C8-cycloalkyl which can be optionally substituted with di(C1-C8-alkyl)aminogroup, and R13 denotes hydrogen or C1-C8-alkyl; or R12 and R13 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which contains one or two additional nitrogen heteroatoms, where the ring can optionally be substituted with C1-C8-alkyl.

EFFECT: possibility of using the compounds to produce a pharmaceutical agent for treating diseases mediated by phosphatidylinositol-3 kinase.

6 cl, 3 tbl, 181 ex

FIELD: chemistry.

SUBSTANCE: invention relates to oxazolidinone derivatives of formula (I) or pharmaceutically acceptable salts thereof, synthesis method thereof and pharmaceutical compositions containing said derivatives which are used as an antibiotic. Oxazolidinone derivatives, where R1 and R1' independently denote hydrogen or fluorine; R2 denotes -OR7, fluorine, monophosphate or metal phosphate; and R7 denotes hydrogen, C1-3alkyl or an acylated amino acid group, where the amino acid is alanine, glycine, proline, proline, isoleucine, leucine, phenylalanine, β-alanine or valine; R3 denotes hydrogen, a C1-4alkyl group which is unsubstituted or substituted cyano, , -(CH2)m-OR7 (m equals 0, 1, 2, 3, 4) or a ketone group. Oxazolidinone derivatives of formula (I) have antibacterial activity against different human and animal pathogens.

EFFECT: oxazolidinone derivatives, having inhibiting activity towards a wide range of bacteria and having low toxicity.

27 cl, 4 tbl, 73 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula (I): or to any of its stereoisomers, or to any mixture of their stereoisomers, or to their pharmaceutically acceptable salts where Ra, Rb and Rc independently represent hydrogen, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, arylalkyl, formyl or alkylcarbonyl; Rd represents a heteroaryl group; where said heteroaryl group means a 5-6-member aromatic heterocyclic group which contains one or two heteroatoms in the ring structure, specified from nitrogen (N) or sulphur (S) and where the heteroaryl group is optionally substituted with one or more substitutes independently specified from the group including: halogeno, hydrazino and alkoxy. Also the invention refers to a pharmaceutical composition, the application of a chemical compound under any of cl. 1-6, as well as to a method of GABAa-receptor complex modulation in the central nervous system.

EFFECT: preparation of the new biologically active compounds exhibiting gamma-amino-butyric acid (GABAa) receptor complex modulating activity in the central nervous system.

11 cl, 10 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): , optical isomers of said compounds, as well as salts thereof having peroxisome proliferator-activated receptor subtype y (PPARy) modulating property. Values of R1, R2, X, Ar1 and Ar2 are given in the formula of invention.

EFFECT: preparation of compositions based on said compounds, as well as use of said compounds in cosmetic and pharmaceutical industry.

11 cl, 30 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or its pharmaceutically acceptable salt or its solvate, where ring A is a monocyclic heterocyclic group optionally substituted with 1-2 substitutes selected from the following group A, where the monocyclic heterocyclic group is selected from 1-pyrrolidinyl group, 2-oxopyrrolidin-1-yl group, piperidine group, 2-oxopiperidin-1-yl group, 1-piperazinyl group, morpholine group, 3-oxomorpholin-4-yl group, thiomorpholine group, 1,1-dioxoisothiazolin-2-yl group, 2-pyridyl group, 2-thiazolyl group and 1,2,4-oxadiazol-3-yl group; group A consists of a halogen atom, C1-4alkyl group, -(CH2)n-ORa1 and -CORa2, where Ra1 and Ra2 are identical or different and each of them is a hydrogen atom or a C1-4alkyl group and n equals 0; R1 is a C1-6alkyl group optionally substituted with 1 substitute selected from the following group B; group B consists of -ORb1, where Rb1 is a C1-4alkyl group; R2 is a hydrogen atom, C1-4alkyl group or -OR11, where R11 is an atom, C1-4alkyl group; R3 and R4 are identical or different and each is a halogen atom; R5 is a halogen atom; m equals 0 or 1; and R6 is a hydrogen atom. The invention also relates to a pharmaceutical composition, anti-HIV agent, HIV integrase inhibitor, anti-HIV compositions which contain an active ingredient in form of a formula I compound; to use of formula I compounds to prepare an anti-HIV agent and HIV integrase inhibitor; to a method of preventing or treating infectious diseases caused by HIV and to a method of inhibiting HIV integrase in mammals, involving administration of formula I compounds.

EFFECT: useful biological properties.

27 cl, 9 tbl, 67 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I , where: R1, R2, R3 and R4 independently from each other mean hydrogen, F, CI, Br, I; R5 designates hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, or cycloalkyl with 3, 4, 5 or 6 C atoms; R6 designates hydrogen; R7 and R8 independently from each other mean hydrogen, W means CrH2r or CsH2S-2; and one or more CH2-groups in C2H2r and CsH2s-2 can be substituted with NR17, oxygen or S; R17 means hydrogen, alkyl with 1, 2, 3 or 4 C atoms; r means 1, 2, 3, 4, 5 or 6; s means 2, 3 or 4; X designates-with C(O)- or -S(O)2-; Z means -C(O)- or a bond; and also to their pharmaceutically acceptable salts and trifluoroacetates. The invention also concerns application of the compounds of formula I, and also to a pharmaceutical composition.

EFFECT: preparation of new biologically active compounds exhibiting NHE3 inhibiting activity.

16 cl, 64 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, and more specifically to novel ethyl 5-R1-7-R2-1'-benzyl-3,3-dimethyl-1,2' -dioxo-5'-phenyl- 1',2,2',3,4,10-hexahydro-1H-spiro[acridine-9,3'-pyrrol]-4'-carboxylates of formula , where R1=H, Me; R2=H, OMe; R3=H, Me, OMe, Br, and to a method for synthesis of the said compounds.

EFFECT: obtaining novel compounds which can be used as primary products for synthesis of novel heterocyclic systems and in pharmacology as compounds with analgesic activity.

5 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to a method of producing α,ω-bis-(1,5,3-dithiazepinan-3-yl)-alkanes of general formula (1):

n=1-8, which involves reaction of α,ω-alkanediamines of general formula H2N-CH2-(CH2)n-NH2, where n=1-8, with tert-N-butyl-1,5,3-dithiazepinane in chloroform in the presence of a SmCl3·6H2O catalyst with molar ratio α,ω-alkanediamine:tert-N-butyl-1,5,3-dithiazepinane:SmCl3·6H2O = 10:20:(0.3-0.7) at room temperature (about 20°C) for 2.5-3.5 hours.

EFFECT: method of obtaining novel α,ω-bis-(1,5,3-dithiazepinan-3-yl)-alkanes which can be used as antibacterial, antifungual and antiviral agents, as biologically active complexing agents, selective sorbents and extractants of precious metals, special reagents for inhibiting bacterial activity in different process media (from light industry to oil industry).

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 3-aza-bicyclo[3.3.0]octane derivatives of formula , where R1 and R2 are hydrogen, C1-4alkyl or fluorine; R3 is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl, trifluoromethoxy group and halogen; 2,3-dihydrobenzofuranyl; 2,3-dihydrobenzo[1,4]dioxynyl; or isoxazolyl, pyridyl, indazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, pyrrolo[2,1b]thiazolyl, imidazo[ 1,2-a]pyridinyl or imidazo[2,1-b]thiazolyl, where said groups are unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, halogen and trifluoromethyl; A is or ; R4 is C1-4alkyl or -NR6R7; R6 is hydrogen or C1-4alkyl; R7 is hydrogen or C1-4alkyl; and D is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl and halogen; or a pharmaceutically acceptable salt of such a compound. 3-aza-bicyclo[3.3.0]octane derivatives or a pharmaceutically acceptable salt thereof are used as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: novel 3-aza-bicyclo[3,3,0]octane derivatives as nonpeptide antagonists of human orexin receptors.

9 cl, 1 tbl, 85 ex

FIELD: chemistry.

SUBSTANCE: invention relates phenyl pyrrole derivatives formula (I) where: A denotes =NOR4, O; R4 denotes, C1-C6 alkyl; R1 denotes C1-C6 alkyl, C1-C6 alkoxy, halogen-C1-C6 alkyl, halogen-C1-C6 alkoxy, NH2, mono- C1-C6 alkylamino, halogen-mono-C1-C6 alkylamino, di(C1-C6 alkyl)amino, halogen-di-(C1-C6 alkyl)amino; or A and R1 together with the carbon atom with which they are bonded form a 5- or 6-member heterocyclic aromatic group or a heterocyclic group with partially or completely reduced saturation, which can be benzo-condensed, can contain 1-3 heteroatoms selected from N, O and S, which can be substituted and contain 1 or 2 α substitutes; R2 denotes phenyl which can be substituted with 1 or 2 α substitutes, or a 6-member heteroaryl group containing 1 or 2 N atoms, which can be substituted with 1 or 2 α substitutes; R3 denotes OH, C1-C6 alkoxy, values of α are given in claim 1, or a pharmaceutically acceptable salt thereof.

EFFECT: compounds exhibit glucokinase activating activity, which enables use thereof in treating diabetes.

51 cl, 1 tbl, 132 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining α,ω-bis-(1,5,3-dithiazepinan-3-yl)-alkanes, which can be applied as antibacterial, antifungal and antiviral agents, as biologically active complexing agents, selective sorbents and extractants of precious metals, special reagents for suppression of vital activity of bacteria in various technical media (from light industry to oil). Essence of method lies in interaction of α,ω-alkanediamine with 1,3,6-oxadithiapinane in presence of catalyst SmCl3·6H2O with mole ratio α,ω-alkanediamine : 1,3,6-oxadithiapinane : SmCl3·6H2O=10:20:(0.3-0.7) at temperature ~20°C and atmospheric pressure for 2.5-3.5 h. Output of α,ω-bis-(1,5,3-dithiazepinan-3-yl)-alkanes (1) constitutes 72-85%.

EFFECT: increase of compound application efficiency.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, in which R1 denotes hydrogen or C1-6alkyl; R2 denotes isooxazolyl group, substituted with C1-6alkyl; RB denotes -CF3, -CHF2, -CH2F, or C1-6alkyl. The invention also relates to pharmaceutical compositions for treating cancer which contain the disclosed compounds.

EFFECT: obtaining novel compounds and a pharmaceutical compositions based on said compounds, which can be used in medicine for treating cancerous diseases.

15 cl, 77 dwg, 10 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new substituted heteroaryl derivatives of general formula I: , wherein: A means N, CR7-10, with A at the most twice meaning N; W means O, S or NR4, the values B, C, R7-10 are presented in clause 1 of the patent claim. The method for preparing the compound I is described.

EFFECT: compounds show analgesic activity that enables using them for a variety of diseases, especially acute pain, neuropathic, chronic or inflammatory pain.

16 cl, 2 tbl, 307 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I),

, where groups and radicals R1, R2 independently denote H, C1-8-alkyl or C3-7-cycloalkyl, where the alkyl or cycloalkyl group can be mono- or poly-substituted with identical or different groups R11; or R2 denotes a -CH2- or -CH2-CH2- bridge which is bonded with a group Y, and R1 is as defined above, or denotes a group selected from C1-4-alkyl-CO-, C1-4-alkyl-O-CO-, (C1-4-alkyl)NH-CO- or (C1-4-alkyl)2N-CO-, where the alkyl groups can be mono- or polyfluorinated; or R1 and R2 form an alkylene bridge such that R1R2N- denotes a group selected from: azetidine, pyrrolidine, piperdine, azepan, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine, piperazine, in which the free amino group is substituted with R13, piperidin-4-one, morpholine, thiomorpholine, 4-C1-4-alkoxy iminopiperidin-1-yl and 4-hydroxy iminopiperidin-1-yl. Wherein, when R1 and R2 form an alkylene bridge, one or more H atoms in the alkylene bridge can be substituted with identical or different groups R14, and X denotes a C1-3-alkylene bridge which can contain one, two or three identical or different C1-3-alkyl substitutes; and Y denotes a group of subformula selected from: and , where the group can be mono-substituted with a substitute R20; Z denotes -CH2-CH2- or -C(=O)-CH2-; U, V both denote CH, one of groups U, V denotes N, and the other of U, V denotes CH, where CH can be substituted with L; and L independently denotes halogen, cyano or C1-3-alkyl; and k equals 0, 1 or 2; W is selected from a group consisting of -CH2-O- and -O-CH2-; B is selected from a group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thiophenyl and thiazolyl; each of which can be mono- or poly-substituted with identical or different substitutes R20; radicals R11, R13, R14, R20 assume values given in claim 1. The invention also relates to a pharmaceutical composition containing at least one compound of formula I and having action on MCH receptor.

EFFECT: disclosed pharmaceutical compositions are useful in treating metabolic disorders or eating disorders, especially obesity, bulimia, anorexia, hyperphagia and diabetes.

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives, having HIV replication inhibiting properties, or pharmaceutically acceptable salts thereof. In formula (1): R1 denotes hydrogen; R2 and R3 independently denote hydrogen; R7 and R8 denote C1-6alkyl; R4 denotes cyano; R9 denotes C1-6alkyl optionally substituted with cyano, C2-6alkenyl substituted with cyano, C2-6alkynyl optionally substituted with cyano; R5 denotes C1-6alkyl optionally substituted with Ar or Het; C2-6alkenyl optionally substituted with Ar or Het; C2-6alkynyl optionally substituted with Ar or Het; C3-7cycloalkyl; Ar; Het; R6 denotes H, Het; Y denotes -OR11, -NR12R13; R11 denotes hydrogen or C1-6alkyl optionally substituted with hydroxy, C1-6alkoxy or pyridyl; R12 denotes hydrogen or C1-6alkyl; R13 denotes hydrogen or C1-6alkyl; or R12 and R13 together with a nitrogen atom, which is substituted by said two substitutes, form a morpholinyl; imidazolyl; X denotes -NR1-; Het denotes 5- or 6-member completely saturated ring, where one or two ring members are heteroatoms, each independently selected from nitrogen and sulphur, and where the rest of the ring members are carbon atoms; and where any member of the heterocycle with a nitrogen heteroatom can optionally be substituted with C1-6alkyl; where the 5- or 6-member ring can optionally be annelated with a benzene or thiophene ring; each aryl independently denotes phenyl or phenyl substituted with one substitute selected from C1-6alkoxy.

EFFECT: high efficiency of using said compounds.

7 cl, 4 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing mono-(di-, tetra-)methyl-1,2-bis-(1,3,5-dithiazinan-5-yl)ethanes of general formula (1-3): , (1) R1=CH3, R2, R3, R4=H (2) R1, R3=CH3, R2, R4=H (3) R1, R2, R3, R4=CH3, which involves reaction of hydrogen sulphide-saturated aqueous solution of (37%) formaldehyde and acetaldehyde with 1,2-diaminoethane with molar ratio of initial reagents 1,2-diaminoethane: formaldehyde: acetaldehyde: hydrogen sulphide equal to 10:50:10:40 to obtain (1), 10:40:20:40 to obtain (2), 10:20:40:40 to obtain (3), at temperature 40°C and atmospheric pressure for 2.5-3.5 hours.

EFFECT: method of obtaining novel compounds which can be used as selective sorbents and extraction agents of precious metals, agents for protecting leather, fur and textile from biodeterioration, biologically active substances with respect to different microorganisms and sulphate-reducing bacteria.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 1,2-bis-(2,4,6-trialkyl-1,3,5-dithiazinan-5-yl)ethanes of general formula (1): . The method involves reaction of a hydrogen sulphide-saturated aldehyde of formula RCHO, where R=CH3, C2H5, n-C3H7, n-C4H9, n-C5H11, with 1,2-diaminoethane with molar ratio of initial reagents 1,2-diaminoethane: aldehyde: hydrogen sulphide equal to 10:60:40 at temperature 40°C and atmospheric pressure for 2.5-3.5 hours.

EFFECT: method of obtaining novel compounds which can be used as selective sorbents and extraction agents of precious metals, agents for protecting leather, fur and textile from biodeterioration, biologically active substances with respect to different microorganisms and sulphate-reducing bacteria.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) (lb) in which A denotes a benzene ring; Ar denotes naphthalenyl which optionally contains 1-3 substitutes independently selected from a group comprising C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, hydroxy group, C1-C6alkoxy group, halogen, heteroalkyl, heteroalkoxy group, nitro group, cyano group, amino- and mono- or di- C1-C6alkyl-substuted amino group; R1 denotes hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy group, carboxy group, heteroalkyl, hydroxy group optionally substituted with heterocyclylcarbonyl-C1-C6alkyl or R1 denotes N(R')(R")-C1-C6alkyl or N(R')(R")-carbonyl- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, heteroalkyl, phenyl-C1-C6alkyl; or R1 denotes R'-CO-N(R")-C1-C6alkyl, R'-O-CO-N(R")- C1-C6alkyl- or R'-SO2-N(R")- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cyclalkyl, C3-C7cycloalkyl- C1-C6alkyl or optionally substituted phenyl; R2, R2' and R2" independently denote hydrogen, halogen, cyano group, C1-C6alkyl, halogenated C1-C6alkyl or C1-C6alkoxy group; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to use of compounds in any of claims 1-9, as well as to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds with chymase inhibiting activity.

14 cl, 128 ex

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