Novel vinylogenic acid derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, where A denotes -CH2-, -O- or -NR'-, in which R' denotes hydrogen or C1-6alkyl, or R' and R4 form C2-5alkylene; R1 denotes hydrogen, amine group, C1-6alkyl, hydroxy group, -NR'R", (C0-6alkylene)-NR'R", where R' and R" are independently selected from a group comprising hydrogen, C1-6alkyl, heteroalkyl, formyl, C1-6alkylcarbonyl, arylcarbonyl optionally substituted with halogenalkyl, C1-6alkylsulphonyl, arylsulphonyl or -(C0-6alkylene)-OR', where R' denotes hydrogen, C1-6alkyl, formyl or C1-6alkylcarbonyl; R2 , R2 and R2 independently denote hydrogen, halogen, C1-6alkyl or C1-6alkoxy group; R3 denotes hydrogen, C1-6alkyl, aryl-C1-6alkyl, aryl optionally substituted with halogen, or heteroaryl, where the heteroaryl is a monocyclic or bicyclic ring containing 5-6 ring atoms and at least one aromatic ring containing one or three ring heteroatoms selected fron N, O and S, where the remaining ring atoms are carbon atoms, and the bonding site of the heteroaryl radical must be on the aromatic ring; R4 denotes hydrogen, C1-6alkyl, aryl, C3-7cycloalkyl-C1-6alkyl, aryl-C1-6alkyl; R5 denotes hydrogen or C1-6alkyl; or R4 and R5 together with the carbon atom to which they are bonded, form an optionally substituted C3-7cycloalkyl ring; R6 denotes hydrogen or C1-6alkyl; and pharmaceutically acceptable salts thereof, where the term "aryl" denotes phenyl or naphthyl. The invention also relates to a pharmaceutical composition based on compounds of formula I and having a inhibitory activity towards chymase.

EFFECT: novel compounds which can inhibit chymase are obtained and can be used as medicinal agents.

22 cl, 79 ex, 1 tbl

 

The invention relates to new derivatives venogenic acids of the formula (I),

where

And denotes-CH2-, -O - or-NR'-, where R' denotes hydrogen or C1-6alkyl, or

R' and R4form2-5alkylen;

R1denotes hydrogen, halogen, a nitro-group, a cyano, an amino group, a C1-6alkyl, heteroalkyl,3-7cycloalkyl,3-6alkenyl,3-6quinil, the hydroxy-group,

With1-6alkoxygroup,

-R NR'r", -(C0-6alkylen)-R NR'r"where R' and R" independently are selected from the group including hydrogen, C1-6alkyl, heteroalkyl, formyl, C1-6alkylsulphonyl, optionally substituted C3-7cycloalkylcarbonyl, optionally substituted arylcarbamoyl, optionally substituted heteroarylboronic, optionally substituted heterocalixarenes, C1-6alkylsulfonyl, optionally substituted C3-7cycloalkylcarbonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylboronic and optionally substituted heterocyclisation, or

-(C0-6alkylene)-OR'in which R' denotes hydrogen, C1-6alkyl, heteroalkyl, formyl or1-6alkylsulphonyl;

R2, R2'and R2"independently represent hydrogen, halogen, a cyano, a nitro-group, amino group, mono - or di-is 1-6alkyl substituted an amino group, With1-6alkyl,

With2-6alkenyl,2-6quinil, heteroalkyl, the hydroxy-group or1-6alkoxygroup;

R3denotes hydrogen, halogen, a nitro-group, cyano, amino, mono - or di - C1-6alkyl substituted an amino group, With1-6alkyl, C2-6alkenyl,2-6quinil, heteroalkyl, the hydroxy-group, With1-6alkoxygroup, optionally substituted

With3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted

With3-7cycloalkyl1-6alkyl, optionally substituted aryls1-6alkyl, optionally substituted heteroaryl1-6alkyl or optionally substituted heterocyclic1-6alkyl;

R4denotes hydrogen, halogen, a nitro-group, cyano, amino, mono - or di-C1-6alkyl substituted an amino group, With1-6alkyl, C2-6alkenyl,2-6quinil, heteroalkyl, the hydroxy-group, With1-6alkoxygroup, optionally substituted C3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted

With3-7cycloalkyl1-6alkyl, optionally substituted aryls1-6the alkyl, optional what about the substituted heteroaryl 1-6alkyl or optionally substituted heterocyclic1-6alkyl;

R5denotes hydrogen or C1-6alkyl; or

R4and R5together with the carbon atom to which they are attached, form an optionally substituted C3-7cycloalkyl ring or optionally substituted heterocyclyl ring;

R6denotes hydrogen or C1-6alkyl;

and their prodrugs and pharmaceutically acceptable salts.

In addition, the invention relates to a method and an intermediate connection to obtain the above-mentioned compounds, pharmaceutical preparations containing such compounds, the use of these compounds for pharmaceutical preparations, and also to a method for producing the intermediate.

The compounds of formula (I) inhibit himizu. Chymase is semipretioase with expression system, strictly limited by the subpopulation of fat cells (MARTICLEfat cell). Chymase is only activated when the activation of mast cells and degranulation, which limits the enzyme activity in the MARTICLEpositive tissues. Chymase specifically cleaves a number of pathologically relevant substrates (W.W. Raymond, S.W.Ruggles et al.; JBC 2003 278 (36): 34517-34524), which can activate angiotensin II, endothelin, TGFb, Il1, SCF, collagenase and decomposing proteins, such t is ambino, FN, APO A1,2. This feature makes himizu attractive target in allergic, inflammatory and fibrotic diseases. Indeed, a number of successful experiments on animals with chymase inhibitors have demonstrated efficacy in atopic diseases in animals, vascular violation and atherosclerosis (Doggrell SA, Wanstall J.., Can. J. Physiol. Pharmacol. 2005, Feb; 83(2):123-30; Lindstedt KA, Kovanen GT, Curr. Opin. Lipidol, 2004, Oct; 15(5):567-73; S.E. Reed, H. Kita, J. Allergy Clin. Immunol., 2004, Nov; 114(5):997-1008; Takai S. et al., Eur. J. Pharmacol., 2004, Oct 6; 501(1-3):1-8; S. Takai et al., Trends Pharmacol. Sci., 2004, Oct; 25(10):518-22; Takai s, Miyazaki M., Curr. Vase. Pharmacol., 2003, Jun; 1(2):217-24).

It was found that the inhibition of chymase applicable for modeling allergies, asthma, peripheral arterial occlusal disease, critical limb ischemia, when the vulnerability of patients with sclerotic plaques, unstable angina, congestive heart failure, the left ventricle hypertrophy, ischemic reperfusion disorder, cardiopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, disease Bowel, Crohn's disease, heal wounds (burns/ulcers in diabetes/CLI).

The present invention provides new compounds of formula (I)which are inhibitors of chymase.

If not indicated otherwise, the following definitions to illustrate and explain the meaning and scope of various terms, use the x in the description of the present invention.

The term "halogen" or "holograph" refers to fluorine, chlorine, bromine and iodine, while the preferred fluorine and chlorine.

The term "C1-6alkyl", alone or combination with other groups, denotes a branched or linear monovalent alkyl radical containing from one to six carbon atoms. This term can be exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl. With1-4alkyl is more preferable.

The term "heteroalkyl" means1-6alkyl, substituted by one or more substituents independently selected from the group comprising nitro-group, a hydroxy-group, halogen, cyano, C1-6alkoxygroup, formyl, C1-6alkylsulphonyl, carboxyl,1-6allylthiourea,1-6alkylsulfonyl, C1-6alkylsulfonyl, amino group and mono - or di-C1-6alkyl substituted an amino group. This term can be exemplified by such radicals as 2-hydroxyethyl, performer.

With1-6alkyl substituted with one hydroxy-group or one to three different halogen atoms, is preferred.

The term "C3-7cycloalkyl", alone or combination with other groups, means saturated monovalent cyclic hydrocarbon radical containing from three to seven ring carbon atoms, e.g. the R cyclopropyl, cyclobutyl, cyclohexyl.

The term "C1-6alkoxygroup", alone or combination with other groups, means a group R'-O-, where R' denotes a1-6alkyl.

The term "C2-6alkenyl", alone or combination with other groups, means a linear or branched hydrocarbon residue comprising olefinic bond and containing from two to six carbon atoms, such as, for example, ethynyl, 2-propenyl.

The term "C2-6quinil", alone or combination with other groups, means a linear or branched hydrocarbon residue comprising a triple bond and containing from two to six carbon atoms, such as, for example, ethinyl, 2-PROPYNYL.

The term "C0-6alkylene" means a bond or a linear or branched divalent saturated aliphatic hydrocarbon group containing from 1 to 6 carbon atoms. With0alkylen means the connection.

The term "aryl", alone or combination with other groups, means a phenyl or naftalina group, preferably phenyl group.

The term "heterocyclyl", alone or in combination with other groups, means a non-aromatic mono - or bicyclic radicals containing from 3 to 8 atoms in the ring, in which one or two ring atoms are heteroatoms, chosen from N, O or S(O)n(where n denotes an integer from 0 to 2), while the East is developed ring atoms are carbon atoms.

The term "heteroaryl" means a monocyclic or bicyclic radical of 5 to 12 ring atoms containing at least one aromatic ring with one, two or three ring heteroatoms selected from N, O and S, with remaining ring atoms are carbon atoms. Preferably, the connection point is heteroaryl radical is an aromatic ring.

The term "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted heterocyclyl" and "optionally substituted C3-7microalgal" means, respectively, aryl, heteroaryl, heterocyclyl and

With3-7cycloalkyl, optionally substituted by one or more substituents independently selected from the group comprising halogen, a nitro-group, a cyano, an amino group, a C1-6alkyl, C2-6alkenyl,2-6quinil, the hydroxy-group, With1-6alkoxygroup, mono - or di-C1-6alkyl substituted the amino group and heteroalkyl.

Preferred radicals for chemical groups, the definitions for which are given above specifically described in the examples.

The compounds of formula (I) can form pharmaceutically acceptable acid salt additive. Examples of such pharmaceutically acceptable salts are salts of compounds of formula (I) with physiologically compatible mineral and acids, such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulfonate acid, p-toluensulfonate acid, acetic acid, lactic acid, triperoxonane acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The term "pharmaceutically acceptable salt" refers to salts. The compounds of formula (I), which contain a COOH group can also form salts with bases. Examples of such salts include alkali, alkaline earth and ammonium salts, such as Na-, K-, CA - and trimethylammonium salt. The term "pharmaceutically acceptable salt" also refers to such salts. Acid additive salts as described above are preferred.

"Optional" or "optionally" means that the described event or circumstance can take place, but do not occur and that the description includes instances where the case or circumstance occur, and examples in which they occur. For example, "aryl group optionally substituted alkyl group" means that the alkyl may be present or may not be present, and the description includes situations when the aryl group is substituted by an alkyl group and when and who think the group is not substituted by an alkyl group.

The term "pharmaceutically acceptable excipient" means an excipient that is used when receiving a pharmaceutical composition that is generally safe, non-toxic and is not undesirable biological or other points of view and includes a filler that is acceptable for veterinary use, as well as in pharmaceutical medicine. The term "pharmaceutically acceptable excipient"as used in this specification and claims includes both one and more than one filler.

Compounds having the same molecular formula, but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are referred to as "isomers". Isomers that differ in arrangement of atoms in space are called stereoisomers". Stereoisomers that are not mirror images of each other, are called "diastereoisomers, and stereoisomers, mirroring which do not coincide with each other, are called "enantiomers". When the compound has an asymmetric center, for example, if the carbon atom is linked to four different groups, there may be pairs of enantiomers. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described R - and S-sequences according to the rules of the Ana, Ingold and Prelog or type, in which the molecule rotates the plane of polarized light and designated as programalso and levogyrate (e.g., as (+) or (-)-isomers respectively). Chiral compound can exist in the form of an individual enantiomer, or a mixture of enantiomers. A mixture containing equal proportions of the enantiomers is called a racemic mixture.

The compounds of formula (I) may possess one or more asymmetric center. If not indicated otherwise, the description or name of the individual links in the description and the claims refers to the inclusion of both individual enantiomers and mixtures, racemic or otherwise, and ephimeral and mixtures thereof. Methods for the determination of stereochemistry and the separation of stereoisomers are well known from the art (see discussion in Chapter "Advanced Organic Chemistry", 4th edition, J. March, John Wiley and Sons, New York, 1992).

While the broadest definition of the invention previously described, certain compounds of formula (I) are preferred.

i) a Preferred compound according to the invention is a compound of formula (I), where

R3stands With1-6alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryls1-6alkyl or optionally substituted heteroaryl1-6alkyl.

ii) D is ugim preferred compound according to the invention is a compound of formula (I), where

R3represents C1-6alkyl; phenyls1-6alkyl; phenyl, optionally substituted from one to three fluorine atoms; or heteroaryl, optionally substituted from one to three fluorine atoms, in which heteroaryl is a monocyclic aromatic radical having 5 or 6 ring atoms, containing one or two ring nitrogen atom or one ring sulfur atom.

iii) Another preferred compound according to the invention is a compound of formula (I), where R3denotes phenyl.

iv) Another preferred compound according to the invention is a compound of formula (I), where

R1stands With1-6alkyl, -(C0-6alkylen)-R NR'r"where R' and R" independently are selected from the group including hydrogen, C1-6alkylsulphonyl, optionally substituted arylcarbamoyl, optionally substituted heteroarylboronic, optionally substituted arylsulfonyl and optionally substituted heteroarylboronic or -(C0-6alkylene)-OR'in which R' denotes hydrogen or C1-6alkylsulphonyl.

v) Another preferred compound according to the invention is a compound of formula (I), where

R1stands With1-6alkyl, -(C2-6alkylen)-R NR'r"where R' and R" independently are selected from the group including hydrogen, acetyl, arylcarbamoyl, in which the aryl neobyazatelnostyu one or two performanceline groups, and arylsulfonyl or -(C2-6alkylene)-OR'in which R' denotes hydrogen or acetyl.

vi) Another preferred compound according to the invention is a compound of formula (I), where

R1refers to 2-amino-ethyl, 2-acetylaminophenol, 2-acetylamino-2,2-dimethylethyl, methyl, isopropyl or 2-hydroxyethyl.

vii) Another preferred compound according to the invention is a compound of formula (I), where

R2, R2'and R2"independently represent hydrogen, halogen, C1-6alkyl or C1-6alkoxygroup.

viii) Another preferred compound according to the invention is a compound of formula (I), where

two of R2, R2'and R2"denote hydrogen, and the third denotes hydrogen, halogen, C1-6alkyl or C1-6alkoxygroup.

ix) Another preferred compound according to the invention is a compound of formula (I), where

two of R2, R2'and R2"denote hydrogen, and the third denotes hydrogen, chlorine, fluorine, methyl, ethyl or methoxy group.

x) Another preferred compound according to the invention is a compound of formula (I), where

two of R2, R2'and R2"denote hydrogen and the other is a 5 or 6 position of the indole ring and selected from the group comprising hydrogen, chlorine, fluorine, methyl and ethyl.

xi) Another preferred compound p. the invention is a compound of formula (I), where R6denotes hydrogen.

xii) Another preferred compound according to the invention is a compound of formula (I), where

R4denotes hydrogen, C1-6alkyl, optionally substituted C3-7cycloalkyl, optionally substituted aryl, optionally substituted C3-7cycloalkyl1-6alkyl or optionally substituted aryls1-6alkyl and

R5denotes hydrogen or C1-6alkyl; or

R4and R5together with the carbon atom to which they are attached, form an optionally substituted C3-7cycloalkyl ring.

xiii) Another preferred compound according to the invention is a compound of formula (I), where a denotes-CH2-.

xiv) Another preferred compound according to the invention is a compound of formula (I), where a denotes-CH2-, R4denotes phenyl and R5denotes hydrogen.

xv) Another preferred compound according to the invention is a compound of formula (I), where a represents-NR'-, where R' denotes hydrogen or C1-6alkyl.

xvi) Another preferred compound according to the invention is a compound of formula (I), where a represents-NR'-, where R' denotes hydrogen or methyl, R4represents isopropyl and R5denotes hydrogen.

xvii) Another preferred compound in the image is the shadow is a compound of formula (I), where a represents-O-.

xviii) Another preferred compound according to the invention is a compound of formula (I), where a denotes-O-, R4denotes hydrogen, phenyl, C1-6alkyl, optionally substituted C3-7cycloalkyl1-6alkyl or optionally substituted aryls1-6alkyl, and R5denotes hydrogen or C1-6alkyl; or

R4and R5together with the carbon atom to which they are attached, form an optionally substituted C3-7cycloalkyl ring.

xix) Another preferred compound according to the invention is a compound of formula (I), where a denotes-O-, R4denotes phenyl, benzyl, isobutyl, 2-cyclohexylethyl or phenethyl and R5denotes hydrogen or methyl.

XX) Another preferred compound according to the invention is a compound of formula (I), where

R3stands With1-6alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryls1-6alkyl or optionally substituted heteroaryl1-6alkyl, preferably R3stands With1-6alkyl, phenyl, optionally substituted from one to three fluorine atoms, heteroaryl, optionally substituted from one to three fluorine atoms, in which heteroaryl denotes a monocyclic aromatic radical with 5 or 6 ring is diversified atoms, containing one or two ring nitrogen atom, or panels1-6alkyl, in particular phenyl;

R1represents C1-6alkyl, -(C0-6alkylene)R NR'r"where R' and R" independently are selected from the group including hydrogen, C1-6alkylsulphonyl, optionally substituted arylcarbamoyl, optionally substituted heteroarylboronic, optionally substituted arylsulfonyl and optionally substituted heteroarylboronic or -(C0-6alkylene)-OR'in which R' denotes hydrogen or

With1-6alkylsulphonyl, preferably R1stands With1-6alkyl, -(C2-6alkylen)-R NR'r"where R' and R" independently are selected from the group including hydrogen, acetyl, arylcarbamoyl, in which aryl optionally substituted with one or two performanceline groups, and arylsulfonyl or -(C3-7alkylene)-OR'in which R' denotes hydrogen or acetyl, in particular 2-amino-ethyl, 2-acetylaminophenol, 2-acetylamino-2,2-dimethylethyl, methyl, isopropyl or 2-hydroxyethyl;

R2, R2'and R2"independently represent hydrogen, halogen, C1-6alkyl or C1-6alkoxygroup, preferably two of R2, R2'and R2"denote hydrogen, and the third denotes hydrogen, halogen, C1-6alkyl or C1-6alkoxygroup, more preferably two of R2, R2'and R2"about who appoints hydrogen, and the third one denotes hydrogen, chlorine, fluorine, methyl, ethyl or methoxy group, in particular two of R2, R2'and R2"denote hydrogen, and the third is a 5 or 6 position of the indole ring and selected from the group comprising hydrogen, chlorine, fluorine, methyl and ethyl;

R6denotes hydrogen;

R4denotes hydrogen, C1-6alkyl, optionally substituted C3-7cycloalkyl, optionally substituted aryl, optionally substituted C3-7cycloalkyl1-6alkyl or optionally substituted aryls1-6alkyl;

R5denotes hydrogen or C1-6alkyl; or

R4and R5together with the carbon atom to which they are attached, form an optionally substituted C3-7cycloalkyl ring.

xxi) a Preferred compound of group XX) is a compound of formula (I), where

And denotes-CH2-. When a represents-CH2-preferably R is phenyl and R5denotes hydrogen.

xxii) Another preferred compound of group XX) is a compound of formula (I), where

And refers to-NR'-, where R' denotes hydrogen or C1-6alkyl, preferably hydrogen or methyl. When a represents-NR'-, where R' denotes hydrogen or methyl, preferably R4represents isopropyl and R5denotes hydrogen.

xxiii) the Other is repectfully connection group XX) is a compound of formula (I), where

And represents-O-. When a represents-O-, preferably R4denotes hydrogen, phenyl, C1-6alkyl, optionally substituted C3-7cycloalkyl1-6alkyl or optionally substituted aryls1-6alkyl, and R5denotes hydrogen or C1-6alkyl; or

R4and R5together with the carbon atom to which they are attached, form an optionally substituted C3-7cycloalkyl ring.

When a represents-O-, more preferably R4denotes phenyl, benzyl, isobutyl, 2-cyclohexylethyl or phenethyl and R5denotes hydrogen or methyl.

xxiv) Another preferred compound according to the invention is a compound of formula (I), where a denotes-CH2-, -O - or-NR'-, where R' denotes hydrogen or C1-6alkyl.

xxv) Another preferred compound according to the invention is a compound of formula (I), where a represents-NR'-, where R' and R4form2-5alkylen.

xxvi) Another preferred compound according to the invention is a compound of formula (I), which denotes

3-[(5-fluoro-3-methyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-it,

3-[(5-fluoro-3-methyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5-isopropyl-1-methyl-1,5-dihydropyrrol-2-it,

4-Hydroxy-5-isopropyl-3-[(3-methyl-1H-indol-2-yl)phenylmethyl]-1,5-dihydropyrrol--he,

3-[(5-fluoro-3-isopropyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-it,

N-(2-{2-[(5-Benzyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)phenylmethyl]-6-fluoro-1H-indol-3-yl}ethyl)acetamide", she

5-Benzyl-3-{[6-fluoro-3-(2-hydroxyethyl)-1H-indol-2-yl]phenylmethyl}-4-hydroxy-5H-furan-2-it,

3-{[3-(2-amino-ethyl)-6-fluoro-1H-indol-2-yl]phenylmethyl}-5-benzyl-4-hydroxy-5H-furan-2-he; salt with acetic acid,

5-Benzyl-3-[(5-fluoro-3-methyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5H-furan-2-it,

(2-{6-fluoro-2-[(4-hydroxy-5-methyl-2-oxo-5-phenyl-2,5-dihydrofuran-3-yl)phenylmethyl]indol-3-yl}ethyl)acetamide", she

(2-{2-[(4-Hydroxy-5-isobutyl-2-oxo-2,5-dihydrofuran-3-yl)phenylmethyl]indol-3-yl}ethyl)acetamide", she

N-[2-(2-{[5-(2-Cyclohexylethyl)-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl]phenylmethyl}-6-fluoro-1H-indol-3-yl)ethyl]acetamide", she

N-(2-{6-fluoro-2-[(4-hydroxy-2-oxo-5-phenethyl-2,5-dihydrofuran-3-yl)phenylmethyl]-1H-indol-3-yl}ethyl)acetamide", she

N-(2-{2-[(2-Hydroxy-5-oxo-3-phenylcyclidine-l-enyl)phenylmethyl]-1H-indol-3-yl} ethyl)acetamide", she

N-(2-{6-fluoro-2-[(2-hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-1H-indol-3-yl}ethyl)acetamide", she

N-(2-{5-Ethyl-2-[(2-hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-1H-indol-3-yl}ethyl)acetamide", she

N-(2-{2-[(2-Hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-5-methyl-1H-indol-3-yl}ethyl)acetamide", she

2-{[3-(2-amino-ethyl)-6-ethyl-1H-indol-2-yl]phenylmethyl}-3-hydroxy-4-phenylcyclidine-2-network is or

N-(2-{6-Chloro-2-[(2-hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-1H-indol-3-yl}-1,1-dimethylethyl)ndimethylacetamide.

Compounds of the present invention can be obtained, for example, using the General synthetic methods described below.

General synthetic methods

Abbreviations:

DMSO: dimethyl sulfoxide

LDA: sitedisability

THF: tetrahydrofuran

I) the compounds of formula (I) can be obtained according to the following scheme 1:

Scheme 1

where A, R1, R2, R2', R2", R3, R4, R5and R6defined above.

Condensation vinylogous acid III, aldehyde IV and indole V, leading to vinylogous acid I, is carried out in a solvent CH3CN or acid, such as carboxylic acid, for example formic acid or, preferably acetic acid, at a temperature in the range from 20 to 100°C., preferably at 70°C for 1 to 20 hours

II)-(i) the Source of the compounds of formula III (A=Oh) can be obtained according to the following scheme 2:

Scheme 2

where R4and R5defined above.

Aldehydes or ketones VI enter into reaction with methyl ether 3(E)-ethoxyacrylate acid (Miyata, Okiko; Schmidt, Richard R.; Angewandte Chemie (1982), 94(8), 651-2) in solvents of the type diethyl ether or THF in the presence of the basis of the Oia, like sitedisability, at a temperature in the range from -100°C to -50°C, preferably at -80°C receives methyl ether tetronic acid II (A=O).

Cleavage metoxygroup in connection II (A=O) is carried out using a strong mineral acid, such as HI, HBr or Hcl, preferably HBr in water and acetic acid at a temperature in the range from 20°C to 100°C, preferably at 40°C, to obtain the tetronic acid III (A-O).

II)-(ii) starting compound of formula III (A=NH or=N-C1-6alkyl) can be obtained according to the following scheme 3, as described Hofheinz, Werner et al., Helvetica Chimica Acta (1977), 60(2), 660-9 or Hilpert, Hans et al. US Pat. Appl. Publ. (2005), US 2005119329:

Scheme 3

Methyl ester of the amino acid VII is introduced into reaction with ethyl ether chlorocarbonate acid in solvents like diethyl ether, THF or preferably dichloromethane, in the presence of a base, such alkylamine, preferably triethylamine, in a temperature range from 0°C to 60°C, preferably at 22°C receives malonamic VIII (A=NH or=N-C1-6alkyl).

Cyclization of malonamide VIII can be carried out using a strong base, such as Aminata sodium tert-butoxide potassium or, preferably, hexamethyldisilazide potassium in a solvent like diethyl ether, THF, benzene or, preferably, is oluolu, in the temperature range from 0°C to 60°C, preferably at a temperature of 22°C, with derivatization Ternovoi acid IX (A=NH or=N-C1-6alkyl).

Decarboxylation derived Ternovoi acid IX can be carried out in the presence of both weak and strong acids, such as acetic acid and triperoxonane acid, at a temperature in the range from 22°C to 100°C, preferably at 80°C, obtaining Ternovoi acid III (A=NH or=N-C1-6alkyl).

II)-iii) of starting compound of the formula III (A=CH2) can be obtained according to Nguyen, Hanh Nho et al., Journal of the American Chemical Society (2003), 125(39), 11818-11819 or Hamer, Neil K. et al., Tetrahedron Letters (1986), 27(19), 2167-8.

II)-(iv) of starting compound of the formula III can be obtained according to the following literature sources:

11) Hofheinz, Werner et al., Helvetica Chimica Acta (1977), 60 (2), 660-9;

12) Galeotti, Nathalie et al., Journal of Organic Chemistry (1993), 58 (20), 5370-6;

13) Hilpert, Hans et al., U.S. Pat. Appl. Publ. (2005), US 2005 119329;

14) Krepski, Larry R. et al., Tetrahedron Letters (1985), 26 (8), 981-4;

15) Compain, Philippe et al., Synlett (1994), (11), 943-5;

16) Nguyen, Hanh Nho et al., Journal of the American Chemical Society (2003), 125(39), 11818-11819;

17) Hamer, Neil K. et al.. Tetrahedron Letters (1986), 27 (19), 2167-8;

18) Matsuo, Keizo et al., Chemical & Pharmaceutical Bulletin (1984), 32 (9), 3724-9;

19) Mizuno, Hatsuhiko et al., Chemical & Pharmaceutical Bulletin (1975), 23 (3), 527-37;

III) the Source of the compounds of formula IV are commercially available.

IV) the Source of the compounds of formula V are commercially available or can be is obtained according to the following literature sources:

1) But, Beng T. et al., Journal of Medicinal Chemistry(1971), 4 (6);

2) Haseg Contour-Galcera, Marie-Odile et al., Bioorganic & Medicinal Chemistry Letters (2005), 5 (15), 3555-3559;

4) Khalil, Ehab M. et al., Journal of Biological Chemistry (1998), 273 (46), 30321-30327;

5) Nenajdenko, Valentine G. et al., Tetrahedron (2004), 60 (51), 11719-11724;

6) Cheve, Gwenael et al., Medicinal Chemistry Research (2002), 11 (7), 361-379;

7) Mor, Marco et al., Journal of Medicinal Chemistry (1998), 41 (20), 3831-3844;

8) Heath-Brown, B. et al., Journal of the Chemical Society, Abstracts (1965), (Dec.), 7165-78;

9) Bastian, Jolie Anne et al., W.O. Pat. Appl. Publ. (2003), WO/2003016307;

10) D. Nagarathnam et al., Synthetic Communications (1993) 23 (14), 2011-2017;

20) Hengartner, Urs et al., Journal of Organic Chemistry (1979), 44 (22), 3741-7;

21) Yang, Shyh-Chyun et al., Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (1999), 38B(8), 897-904;

22) Tsuchiya, Michihiro et al., international patent application, W08200032 (1982);

23) Pfister, Jurg R. et al., US patent application US 5436264 (1995).

As described above, the compounds of formula (I) are active compounds and inhibit himizu. These compounds, therefore, prevents the activation of angiotensin II, endothelin, TGFb, Il1, SCF, collagenase and destroy proteins such as thrombin, FN, APO A1,2. They can also be applied in the treatment and/or prevention of allergic, inflammatory and/or fibrotic diseases, such as allergies, asthma, peripheral arterial occlusal disease, critical limb ischemia, the vulnerability of patients with sclerotic plaques, unstable angina, congestive heart failure, left ventricular hypertrophy, isemi the mini-reperfusion disorders, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, a disease Bowel, Crohn's disease, wound healing (burns/ulcers in diabetes/CLI).

Prevention and/or treatment of allergic, inflammatory or fibrotic diseases, in particular of atherothrombosis or asthma, are the preferred indications for use.

The invention therefore relates also to pharmaceutical compositions comprising a compound as described above and a pharmaceutically acceptable filler.

The invention likewise includes connections defined above for use as therapeutically active substances, especially as therapeutically active substances for the treatment and/or prevention of allergic, inflammatory and/or fibrotic diseases, such as allergies, asthma, peripheral arterial occlusal disease, critical limb ischemia, the vulnerability of patients with sclerotic plaques, unstable angina, congestive heart failure, left ventricular hypertrophy, ischemic reperfusion disorders, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, a disease Bowel, Crohn's disease, wound healing (burns/ulcers in diabetes/CLI).

The invention relates also to the use of compounds as described above to obtain the drug the funds for the treatment and/or prevention of allergic, inflammatory and/or fibrotic diseases, such as allergies, asthma, peripheral arterial occlusal disease, critical limb ischemia, the vulnerability of patients with sclerotic plaques, unstable angina, congestive heart failure, left ventricular hypertrophy, ischemic reperfusion disorders, cardiopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, a disease Bowel, Crohn's disease, wound healing (burns/ulcers in diabetes/CLI). Such medicines include the connection as described above.

The invention also relates to a method and intermediate compounds for preparing compounds of formula (I), as well as the way to obtain the intermediate compounds.

Inhibition of chymase compounds of the present invention can be demonstrated by analysis of the peptide substrate, as described below.

For chymase was selected substrate containing 4 amino acid peptide (AAPF), as chymotrypsinogen compounds (succinyl-Ala-Ala-Pro-Phe-[7-amino-4-methylcoumarin]; Lockhart BE, et al., Recombinant human mast-cell chymase: an improved procedure for expression in Pichia pasoris and purification of the highly active enzyme. Biotechnol. App. Biochem., published as immediate publication 26 May 2004 as manuscript BA20040074). The peptide was synthesized with a purity of 95% (company Bachem, Bubendorf, Switzerland). Purified chymase formed fat cells of the human skin, poluchenii Calbiochem (Merck Biosciences, San Diego, California, USA). Buffer for analysis contains 0.15 M NaCl, 0,05 M Tris HCl, 0.05% of CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate), 0.1 mg/ml heparin (heparin sodium, the company Sigma, porcine intestinal mucosa), 0.02 mm AAPF-substrate 1 nm chymase at pH 7.4. The analysis was performed in 96-cellular tablet (Packard Optiplate) with 0.05 ml volume at room temperature. Chymase was characterized by the initial rate of increase of fluorescence at 340/440 nm (absorption/emission) from the free 7-amino-4-methylcoumarin allocated substrate. The inhibition activity through inhibiting compounds were read after 30 min pre-incubation with hemati at room temperature in buffer for analysis, not containing AAPF-substrate. The analysis was started after adding the specified concentration AAPF-substrate.

The value of the IC50the active compounds according to the present invention preferably approximately from (1000) until (1) nm, in particular from approximately (30) to (1) nm.

ExampleIC50(nm)
1113
1624
433
6310
675
7215
792

The compounds of formula (I) and/or their pharmaceutically acceptable salts can be used as medicines, for example, in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be introduced, for example, orally, for example in the form of tablets, pills in the shell, coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection or infusion solutions, or tapicerki, for example, in the form of ointments, creams or oils. Oral introduction is preferred.

The pharmaceutical preparation may be carried out using techniques well known to experts in the field of engineering, and lies in making the described compounds of formula (I) and their pharmaceutically acceptable salts, optionally in combination with other therapeutically suitable substances, medicines, prepared according to the officially approved recipe, along with a suitable, inert, therapeutically compatible solid is suspended or liquid carriers and, if necessary, conventional pharmaceutical excipients.

As suitable materials for the media can be used as inorganic and organic materials. So, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carriers for tablets, pellets in the shell, coated tablets and hard gelatin capsules. Suitable carriers for soft gelatin capsules can be, for example, vegetable oils, waxes, fats and semi-solid or liquid polyols (depending on the nature of the active ingredient no carriers, but carriers in the case of soft gelatin capsules). Suitable carriers for the receiving of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and the like. Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils. Suitable carriers for suppositories are, for example, natural and hydrogenated oils, waxes, fats and semi-solid or liquid polyols. Suitable carriers for topical drugs are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, glycols and derivatives of cellulose.

the Usual stabilizers, preservatives, wetting agents and emulsion that improves the consistency agents, flavoring agents, salts for installation osmotic pressure, buffer substances, soljubilizatory, dyes, masking agents and oxidants are considered as pharmaceutical excipients.

The dosage of the compounds of formula (I) can vary within wide limits depending on subject to the control of the disease, age and individual condition of the patient and the route of administration and should, of course, be adjusted to the individual requirements in each particular case. For adult patients, the recommended daily dose is 1 mg to about 1000 mg, in particular from 1 mg to approximately 300 mg depending on the severity of the disease and specific pharmacokinetic profile of the compound can be introduced in the form of one or more daily unit doses, for example from 1 to 3 single doses.

The pharmaceutical preparations contain from 1 to 500 mg, preferably from 1 to 100 mg of the compounds of formula (I).

The following examples illustrate the present invention in more detail. They are, however, in no way limit its scope.

General method a: Obtain methyl tetronic acid esters II (=O)

To a solution of 20 ml of LDA (2-molar in THF) and 130 ml of THF was added when the temperature of -95°C to -100°C Rast is the PR vs. 5.47 g of methyl ester 3(E)-ethoxyacrylate acid in 4.5 ml of THF for 1 min, stirring is continued at this temperature for 5 minutes, then add a pre-cooled (-78°C) solution of aldehyde (33 mmol) in 4.5 ml of THF within 2 minutes After the stirring is continued at a temperature of -100°C for 30 min, and then at -78°C for 1 h, the Cold solution was transferred into 130 ml of ice water, the pH adjusted to 4 using a 6.5 ml of aqueous HCl (37%) and the layers separated. The aqueous layer was twice extracted with dichloromethane, the organic layers washed with brine, dried and evaporated. The remainder chromatographic on silica gel (n-heptane/AcOEt, in various ratios)to give methyl tetronic acid esters II (A=O).

General method B: Getting tetronic acids III (=O)

A mixture of methyl esters of tetronic acid II (A=O, 10 mmol) and 15 ml of aqueous HCl (37%) was stirred at 40°C until the reaction is completed. The resulting suspension is filtered, the residue is washed with ice water and dried. Oil the reaction mixture is extracted with dichloromethane, the organic layers washed with brine, dried and evaporated. The remainder or tracuriroot with a mixture of AcOEt/hexane, or chromatographic using a mixture of dichloromethane/Meon (in different ratios), receiving tetronic acid III (A=O).

General method: Obtaining tetramesh acids III (A=NH or=N-C1-6alkyl)

To the mixture is the methyl esters of amino acids VII (A=NH 2or A=N(H)(C1-6alkyl), 18 mmol) in dichloromethane (60 ml) are successively added at a temperature of 0°C. triethylamine (56 mmol), and ethyl ether chlorocarbonate acid (21.5 mmol) and stirring is continued over night. The suspension is filtered, the filtrate is evaporated and the residue partitioned between dilute aqueous solution of hydrochloric acid and ethyl acetate. The organic layer is dried, evaporated and the residue chromatographic on silica gel using a mixture of cyclohexane/ethyl acetate (2:1 ratio)to give amide of malonic acid VIII (A=NH or=N-C1-6alkyl).

A mixture of amide of malonic acid VIII (A=NH or=N-C1-6alkyl, 7 mmol) in toluene (12 ml) is treated at a temperature of 22°C With a solution hexamethyldisilazide potassium in THF (0,9-molar, 7 mmol) and stirring is continued for 1 to 16 h the Resulting suspension is filtered and the residue dried, getting derived Ternovoi acid IX (A=NH or=N-C1-6alkyl).

The mixture derived Ternovoi acid IX (A=NH or=C1-6alkyl, 7 mmol) in acetic acid (40 ml) and triperoxonane acid (4 ml) is heated under reflux for 1-5 hours the Mixture is evaporated and the residue chromatographic on silica gel using diethyl ether and receiving Ternovoy acid III (A=NH or=N-C1-6alkyl).

Example A: 4-Hydroxy-5-methyl-5-phenyl-5H-furan-2-the n

A1. Using General method a, the acetophenone is introduced into reaction with methyl ether 3(E)-ethoxyacrylate acid, getting rat-4-methoxy-5-methyl-5-phenyl-5H-furan-2-it is in the form of a colorless solid. MS: to 204.1 ([M]+).

A2. rat-4-Methoxy-5-methyl-5-phenyl-5H-furan-2-he (0.50 g) was separated on a Chiralpack AD, using a mixture of n-heptane/ethanol in a ratio of 9:1 and obtaining (S)-4-methoxy-5-methyl-5-phenyl-5H-furan-2-he (0.24 g) as quickly facing peak and (R)-4-methoxy-5-methyl-5-phenyl-5H-furan-2-it (0.24 g) in the form of slower facing peak.

A3. Using General method B, (S)-4-methoxy-5-methyl-5-phenyl-5H-furan-2-he hydrolyzing, obtaining (S)-4-hydroxy-5-methyl-5-phenyl-5H-furan-2-it is in the form of a colorless solid. MS: 190,2 ([M]+). [α]Nm: -420,4° (1%, CHCl3).

A4. Using General method B, (R)-4-methoxy-5-methyl-5-phenyl-5H-furan-2-he hydrolyzing, obtaining (R)-4-hydroxy-5-methyl-5-phenyl-5H-furan-2-it is in the form of a colorless solid. MS: 190,2 ([M]+) [α]Nm: +441,5° (1%, CHCl3).

Example B: rat-5-(2-Cyclohexylethyl)-4-hydroxy-5H-furan-2-he

B1. Using General method a, cyclohexanemethanol (Stratakis, Manolis et al., Journal of Organic Chemistry (2002), 67 (25), 8758-8763) is injected into the reaction with methyl ether 3(E)-ethoxyacrylate acid, getting rat-5-(2-cyclohexylethyl)-4-methoxy-5H-furan-2-it is in the form of a colorless solid. MS: 225,2 ([M+H]+).

B2. Using General method B, the rat-5-(2-qi is logicality)-4-methoxy-5H-furan-2-he hydrolyzing, getting rat-5-(2-cyclohexylethyl)-4-hydroxy-5H-furan-2-it is in the form of a brown oil. MS: 211,1 ([M+H]+).

Example: rat-1-Hydroxy-7a-methyl-5,6,7,7a-tetrahydropyrimidin-3-one

Using General method b methyl ester rat-2-methylpyrrolidine-2-carboxylic acid in turn called in the header of the connection by selecting it in the form of a yellow solid. MS: 154,3 ([M+H]+).

Example D: (R)-5-Benzyl-4-hydroxy-5-methyl-1,5-dihydropyrrol-2-he

Using General method b methyl ester (R)-2-amino-2-methyl-3-phenylpropionic acid in turn called in the header of the connection by selecting it in the form of a white solid. MS: TO 204.1 ([M+H]+).

Example D: (R)-4-Hydroxy-5-isopropyl-5-methyl-1,5-dihydropyrrol-2-he

Using General method b methyl ester (R)-2-amino-2,3-dimethylmaleic acid in turn called in the header of the connection by selecting it in the form of a white solid. MS: 156, 3MM ([M+H]+).

Example E: (R)-4-hydroxy-5-methyl-5-phenyl-1,5-dihydropyrrol-2-he

Using General method b methyl ester (R)-2-amino-2-phenylpropionic acid in turn named in the title compound [literary reference 19]by selecting it in the form of a colorless oil, MS: 190,3 ([M+H]+). [α]365 nm: +360,9° (C=1%, CHCl3).

General method G: Condensation vinylogous acid III, aldehyde IV and indole V

The solution vinylogous acid (1) - Rev. mol), aldehyde (1.3 mmol) and indole (1 mmol) in acetic acid (2 ml) is stirred at 70°C for 16 hours, the Suspension is filtered and the residue is washed with a mixture of MeOH/Et2O (in the ratio 1:10). If there is no precipitation, the solution is purified using preparative HPLC (RP-18, CH3CN/N2Oh, gradient).

Example 1: N-(2-{2-[(4-Hydroxy-5-isopropyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)phenylmethyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-he (literary reference 11) is injected into the reaction with benzaldehyde and N-[2-(1H-indol-3-yl)-ethyl]acetamide", she getting named the title compound as a pale yellow solid. MS: 432,5 ([M+H]+).

Example 2: N-(2-{2-[(3-forfinal)-(4-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)methyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-he (literary reference 11) is injected into the reaction with 3-vorbesuregen and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a yellow solid. MS: OF 450.1 ([M+H]+).

Example 3: N-(2-{2-[(4-Forfinal)-(4-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)methyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 4-hydrox the-5-isopropyl-1,5-dihydropyrrol-2-he (literary reference 11) is injected into the reaction with 4-vorbesuregen and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a yellow solid. MS: 450,3 ([M+H]+).

Example 4: N-(2-{2-[(3,5-Differenl)-(4-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)methyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-he (literary reference 11) is injected into the reaction with 3,5-diferentialglea and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a yellow solid. MS: 468,0 ([M+H]+).

Example 5: Ethyl ester of 2-{2-[(4-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)phenylmethyl]-1H-indol-3-yl}acetic acid

Using General method B, 4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-he (literary reference 11) is injected into the reaction with benzaldehyde and 2-(1H-indol-3-yl)ethanol, getting named the title compound as an orange foam. MS: 433,3 ([M+H]+).

Example 6: 4-Hydroxy-3-{[3-(2-hydroxyethyl)-1H-indol-2-yl]phenylmethyl}-5-isopropyl-1,5-dihydropyrrol-2-he

A solution of ethyl ester of 2-{2-[(4-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)phenylmethyl]-1H-indol-3-yl}acetic acid (40 mg) and LiOH (8.5 mg) in Meon (0.5 ml) is stirred at a temperature of 22°C for 30 min and evaporated. The residue is partitioned between 0.1 to normal water plants is a PR HCl and AcOEt and the organic layer dried and evaporated. The remainder chromatographic on silica gel using a mixture of CH2Cl2/Meon (in the ratio 10:3) and getting named the title compound as an orange foam. MS: TO € 391.1 ([M+H]+).

Example 7: N-(2-{2-[(4-Hydroxy-5-isopropyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)phenylmethyl]-1H-indol-3-yl}ethyl)benzamide

Using General method B, 4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-he (literary reference 11) is injected into the reaction with benzaldehyde and N-[2-(1H-indol-3-yl)ethyl]benzamide, getting named the title compound as a gray solid. MS: 494,3 ([M+H]+).

Example 8: N-(2-{2-[(4-Hydroxy-5-isopropyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)phenylmethyl]-1H-indol-3-yl}ethyl) - for 3,5-bis-cryptomelane

8.1. Obtaining N-[2-(1H-indol-3-yl)ethyl] - for 3,5-bis-cryptomelane

To a solution of 2-(1H-indol-3-yl)ethylamine (1.0 g) in CH2Cl2add at a temperature of 22°C NEt3(1,74 ml) and 3,5-bis-cryptomathematical (1,24 ml), after which stirring is carried out at a temperature of 22°C for 16 hours the Mixture was washed with aqueous solution of NaHCO3and brine, then the organic layer is dried and evaporated, getting named the title compound as a brown solid. MS: 401,3 ([M+H]+).

8.2. Using General method B, 4-hydroxy-5-isopropyl-1,5-dihydropyrrol-he (literary reference 11) is injected into the reaction with benzaldehyde and N-[2-(1H-indol-3-yl)ethyl] - for 3,5-bis-triftormetilfosfinov, receiving N-(2-{2-[(4-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)phenylmethyl]-1H-indol-3-yl}ethyl) - for 3,5-bis-cryptomelane in the form of a red solid. MS: 630,2 ([M+H]+).

Example 9: (2-{2-[(4-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)phenylmethyl]-1H-indol-3-yl}ethyl)amide naphtalenesulfonic acid

Using General method B, 4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-he (literary reference 11) is injected into the reaction with benzaldehyde and [2-(1H-indol-3-yl)ethyl]amidon naphthalene-2-sulfonic acid (literary reference 1), getting named the title compound as an orange solid. MS: 580,3 ([M+H]+).

Example 10: 3-[(5-fluoro-3-methyl-1H-indol-2-yl)phenylmethyl-4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-he

Using General method B, 4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-he (literary reference 11) is injected into the reaction with benzaldehyde and 5-fluoro-3-methyl-1H-indole, getting named the title compound as a yellow solid. MS: 377,1 ([M-H]-).

Example 11: 3-[(5-fluoro-3-methyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5-isopropyl-1-methyl-1,5-dihydropyrrol-2-he

Using General method B, 4-hydroxy-5-isopropyl-1-methyl-1,5-dihydropyrrol-2-he (literary reference 12) is injected into the reaction with benzaldehyde and 5-for-methyl-1H-indole, getting named the title compound as a yellow solid. MS: 391,3 ([M-H]-).

Example 12: 4-Hydroxy-5-isopropyl-3-[(3-methyl-1H-indol-2-yl)phenylmethyl]-1,5-dihydropyrrol-2-he

Using General method B, 4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-he (literary reference 11) is injected into the reaction with benzaldehyde and 3-methyl-1H-indole, getting named the title compound as a yellow solid. MS: 361,0 ([M+H]+).

Example 13: 3-[(5-fluoro-3-isopropyl-1H-indol-2-yl)phenylmethyl-4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-he

13.1. 5-fluoro-3-isopropyl-1H-indole get similar to the method described in the literature reference 10, in the form of a brown oil, MS: 177,0 ([M]+).

13.2. Using General method B, 4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-he (literary reference 11) is injected into the reaction with benzaldehyde and 5-fluoro-3-isopropyl-1H-indole, getting 3-[(5-fluoro-3-isopropyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-it is in the form of an orange solid. MS: 405,2 ([M-H]-).

Example 14: N-(2-{2-[(4-Hydroxy-2-oxo-2,5-dihydrofuran-3-yl)phenylmethyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 4-hydroxy-5H-furan-2-it is introduced into the reaction with benzaldehyde and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting the name is TES in the title compound as an orange foam. MS: TO € 391.1 ([M+H]+).

Example 15: N-(2-{2-[(5-Benzyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)phenylmethyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 5-benzyl-4-hydroxy-5H-furan-2-he (literary reference 13) is injected into the reaction with benzaldehyde and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a white solid. MS: 481,0 ([M+H]+).

Example 16: N-(2-{2-[(5-Benzyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)phenylmethyl]-6-fluoro-1H-indol-3-yl}ethyl)ndimethylacetamide

16.1. N-[2-(6-Fluoro-1H-indol-3-yl)ethyl]ndimethylacetamide

To a solution of 2-(6-fluoro-1H-indol-3-yl)ethylamine (0.88 g) and NEt3of 2.27 ml) in CH2Cl2(8 ml) is added acetic anhydride (0,43 ml) and stirred at 22°C for 1 h the mixture is Then washed with 1-normal aqueous solution of HCl, the organic layer dried and evaporated. The remainder chromatographic on silica gel using a mixture of CH2Cl2/Meon (ratio 25:1), getting named the title compound as a pale yellow oil. MS: 219,1 ([M-H]-).

16.2 Using General method B, 5-benzyl-4-hydroxy-5H-furan-2-he (literary reference 13) is injected into the reaction with benzaldehyde and N-[2-(6-fluoro-1H-indol-3-yl)ethyl]acetamide", she receiving N-(2-{2-[(5-benzyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)phenylmethyl]-6-fluoro-1H-indol-3-yl}ethyl)and Itemid in the form of a white solid. MS: 497.4 M ([M-H]-).

Example 17: N-(2-{2-[(5-Benzyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)phenylmethyl]-5-chloro-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 5-benzyl-4-hydroxy-5H-furan-2-he (literary reference 13) is injected into the reaction with benzaldehyde and N-[2-(5-chloro-1H-indol-3-yl)ethyl]ndimethylacetamide (literary reference 2), getting named the title compound as a white solid. MS: 513,1 ([M-H]-).

Examples 18 and 19: 5-Benzyl-3-{[6-fluoro-3-(2-hydroxyethyl)-1H-indol-2-yl]phenylmethyl}-4-hydroxy-5H-furan-2-he and ethyl ester of 2-{2-[(5-benzyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)phenylmethyl]-6-fluoro-1H-indol-3-yl}acetic acid

Using General method B, 5-benzyl-4-hydroxy-5H-furan-2-he (literary reference 13) is injected into the reaction with benzaldehyde and 2-(6-fluoro-1H-indol-3-yl)ethanol (literary reference 3). The mixture is separated by HPLC, receiving the first named in the title compound as a light brown solid. MS: 456,3 ([M-H]-).

The second fraction contains named the title compound as an orange substance. MS: 498,1 ([M-H]-).

Example 20: N-(2-{2-[1-(5-Benzyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)-2-methylpropyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 5-benzyl-4-hydroxy-5H-furan-2-he (the letter is to become the reference 13) is injected into the reaction with 2-methylpropionamide and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a yellow solid. MS: 445,1 ([M-H]-).

Example 21: N-(2-{2-[1-(5-Benzyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)-3-methylbutyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 5-benzyl-4-hydroxy-5H-furan-2-he (literary reference 13) is injected into the reaction with 3-methylbutyraldehyde and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a yellow solid. MS: 459,1 ([M-H]-).

Example 22

N-(2-{2-[1-(5-Benzyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)-Penta]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 5-benzyl-4-hydroxy-5H-furan-2-he (literary reference 13) is injected into the reaction pentanal and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a white solid. MS: 459,3 ([M-H]-).

Example 23: N-(2-{2-[1-(5-Benzyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)-2-phenylethyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 5-benzyl-4-hydroxy-5H-furan-2-he (literary reference 13) is injected into the reaction phenylacetaldehyde and N-[2-(1H-indol-3-yl)-ethyl]acetamide", she getting named the title compound as a white solid. MS: 493,0 ([M-H]-).

Example 24: N-(2-{2-[1-(5-Benzyl-4-hydroxy-2-oxo-2,5-dihydrofuran the-3-yl)-3-phenylpropyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 5-benzyl-4-hydroxy-5H-furan-2-he (literary reference 13) is injected into the reaction with 3-phenylpropionaldehyde and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a yellow solid. MS: 507,2 ([M-H]-).

Example 25: N-(2-{2-[(5-Benzyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)-(2-forfinal)methyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 5-benzyl-4-hydroxy-5H-furan-2-he (literary reference 13) is injected into the reaction with 2-vorbesuregen and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a white solid. MS: 497,3 ([M-H]-).

Example 26: 3-{[3-(2-amino-ethyl)-6-fluoro-1H-indol-2-yl]phenylmethyl}-5-benzyl-4-hydroxy-5H-furan-2-he; salt with acetic acid

Using General method B, 5-benzyl-4-hydroxy-5H-furan-2-he (literary reference 13) is injected into the reaction with benzaldehyde and 2-(6-fluoro-1H-indol-3-yl)ethylamine, getting named the title compound as a light red foam. MS: 457,1 ([M+H]+).

Example 27: N-(2-{2-[(5-Benzyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)phenylmethyl]-1H-indol-3-yl}ethyl)-N-methylacetamide

Using General method B, 5-benzyl-4-hydroxy-5H-furan-2-he (literary reference 13) is introduced into reaction with what benzaldehyde and N-[2-(1H-indol-3-yl)ethyl]-N-methylacetamide (literary reference 4), getting named the title compound as a pale yellow solid. MS: 493,3 ([M-H]-).

Example 28: N-(2-{2-[(5-Benzyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)phenylmethyl]-5-fluoro-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 5-benzyl-4-hydroxy-5H-furan-2-he (literary reference 13) is injected into the reaction with benzaldehyde and N-[2-(5-fluoro-1H-indol-3-yl)ethyl]ndimethylacetamide (literary reference 5), getting named the title compound as a pale yellow solid. MS: 497.4 M ([M-H]-).

Example 29: N-(2-{2-[(5-Benzyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)phenylmethyl]-1-methyl-1H-indol-3-yl}ethyl)ndimethylacetamide

29.1. N-[2-(l-Methyl-1H-indol-3-yl)ethyl]ndimethylacetamide obtained from 2-(1-methyl-1H-indol-3-yl)ethylamine by acylation as described in example 16.1, in the form of a light green oil, MS: 217,4 ([M+H]+).

29.2. Using General method B, 5-benzyl-4-hydroxy-5H-furan-2-he (literary reference 13) is injected into the reaction with benzaldehyde and N-[2-(1-methyl-1H-indol-3-yl)ethyl]acetamide", she receiving N-(2-{2-[(5-benzyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)phenylmethyl]-1-methyl-1H-indol-3-yl}ethyl)ndimethylacetamide in the form of a red solid. MS: 493,3 ([M-H]-).

Example 30: 5-Benzyl-3-[(5-fluoro-3-methyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5H-furan-2-he

Generally using the method In, 5-benzyl-4-hydroxy-5H-furan-2-he (literary reference 13) is injected into the reaction with benzaldehyde and 5-fluoro-3-methyl-1H-indole, getting named the title compound as a colourless solid. MS: 426,1 ([M-H]-).

Example 31: N-(2-{6-fluoro-2-[(4-hydroxy-2-oxo-5-phenyl-2,5-dihydrofuran-3-yl)phenylmethyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 4-hydroxy-5-phenyl-5H-furan-2-he (literary reference 14) is injected into the reaction with benzaldehyde and N-[2-(6-fluoro-1H-indol-3-yl)ethyl]ndimethylacetamide (example 18.1), getting named the title compound as a light brown solid. MS: 485,0 ([M+H]+).

Example 32: 3-{[3-(2-amino-ethyl)-6-ethyl-1H-indol-2-yl]phenylmethyl}-4-hydroxy-5-phenyl-5H-furan-2-he

Using General method B, 4-hydroxy-5-phenyl-5H-furan-2-he (literary reference 14) is injected into the reaction with benzaldehyde and 2-(6-ethyl-1H-indol-3-yl)ethylamine (literary reference 8), getting named the title compound as a white solid. MS: 453,3 ([M+H]+).

Example 33: N-(2-{6-fluoro-2-[(4-hydroxy-5-methyl-2-oxo-5-phenyl-2,5-dihydrofuran-3-yl)phenylmethyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 4-hydroxy-5-methyl-5-phenyl-5H-furan-2-he (example A2) is injected into the reaction with benzaldehyde and N-[2-(6-fluoro-1H-indol-3-yl)ethyl]acetamido the (example 18.1), getting named the title compound as a light brown solid. MS: 499,5 ([M+H]+).

Example 34: N-(2-{2-[(4-Hydroxy-5-isobutyl-2-oxo-2,5-dihydrofuran-3-yl)phenylmethyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 4-hydroxy-5-isobutyl-5H-furan-2-he (literary reference 14) is injected into the reaction with benzaldehyde and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a white solid. MS: 441,1 ([M+H]+).

Example 35: ethyl ester of 2-{2-[(4-hydroxy-5-isobutyl-2-oxo-2,5-dihydrofuran-3-yl)phenylmethyl]-1H-indol-3-yl}acetic acid

Using General method B, 4-hydroxy-5-isobutyl-5H-furan-2-he (literary reference 14) is injected into the reaction with benzaldehyde and 2-(1H-indol-3-yl)ethanol, getting named the title compound as an orange solid. MS: 448,1 ([M+H]+).

Example 36: N-(2-{2-[(4-Hydroxy-2-oxo-1-oxa-Spiro[4.5]Dec-3-EN-3-yl)phenylmethyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 4-hydroxy-1-oxa-Spiro[4.5]Dec-3-EN-2-he (literary reference 15) is injected into the reaction with benzaldehyde and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a white solid. MS: 459,1 ([M+H]+).

Example 37: N-(2-{2-[(5-Cyclohexylmethyl-4-is hydroxy-2-oxo-2,5-dihydrofuran-3-yl)phenylmethyl]-6-fluoro-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 5-cyclohexylmethyl-4-hydroxy-5H-furan-2-he (literary reference 13) is injected into the reaction with benzaldehyde and N-[2-(6-fluoro-1H-indol-3-yl)ethyl]ndimethylacetamide (example 18.1), getting named the title compound as a pale red solid. MS: 503,0 ([M-H]-).

Example 38: N-[2-(2-{[5-(2-Cyclohexylethyl)-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl]phenylmethyl}-6-fluoro-1H-indol-3-yl)ethyl]ndimethylacetamide

Using General method B, 5-(2-cyclohexylethyl)-4-hydroxy-5H-furan-2-he (B2) is injected into the reaction with benzaldehyde and N-[2-(6-fluoro-1H-indol-3-yl)ethyl]ndimethylacetamide (example 18.1), getting named the title compound as a pale green solid. MS: FROM 517.2 ([M-H]-).

Example 39: N-(2-{6-fluoro-2-[(4-hydroxy-2-oxo-5-phenethyl-2,5-dihydrofuran-3-yl)phenylmethyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method B, 4-hydroxy-5-phenethyl-5H-furan-2-he (literary reference 13) is injected into the reaction with benzaldehyde and N-[2-(6-fluoro-1H-indol-3-yl)ethyl]ndimethylacetamide (example 18.1), getting named the title compound as a pale red solid. MS: 511,1 ([M-H]-).

Example 40: N-[2-(6-fluoro-2-{[4-hydroxy-2-oxo-5-(3-phenylpropyl)-2,5-dihydrofuran-3-yl]phenylmethyl}-1H-indol-3-yl)ethyl]ndimethylacetamide

Use the UYa General method b 4-hydroxy-5-(3-phenylpropyl)-5H-furan-2-he (literary reference 13) is injected into the reaction with benzaldehyde and N-[2-(6-fluoro-1H-indol-3-yl)ethyl]ndimethylacetamide (example 18.1), getting named the title compound as a pale red solid. MS: 525,2 ([M-H]-).

Example 41: N-(2-{2-[(2-Hydroxy-5-oxocyclopent-1-enyl)phenylmethyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method a, 3-hydroxycyclopent-2-northward (literary reference 16) is injected into the reaction with benzaldehyde and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a pink solid. MS: 387,4 ([M-H]-).

Example 42: N-(2-{2-[(2-Hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method a, 3-hydroxy-4-phenylcyclidine-2-northward (literary reference 17) is injected into the reaction with benzaldehyde and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a pink solid. MS: 465,0 ([M+H]+).

Example 43: N-(2-{6-fluoro-2-[(2-hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method a, 3-hydroxy-4-phenyl-cyclopent-2-northward (literary reference 17) is injected into the reaction with benzaldehyde and N-[2-(6-fluoro-1H-indol-3-yl)ethyl]ndimethylacetamide (example 18.1), produces the mentioned title compound as a pink solid. MS: 483,5 ([M+H]+).

Example 44: N-(2-{2-[(2-Hydroxy-5-oxo-3-phenylcyclidine-1-enyl)pyridine-2-yl-methyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method a, 3-hydroxy-4-phenylcyclidine-2-northward (literary reference 17) is injected into the reaction with pyridine-2-carbaldehyde and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a white solid. MS: 466,3 ([M+H]+).

Example 45: N-(2-{2-[(2-Hydroxy-5-oxo-3-phenylcyclidine-1-enyl)pyridine-3-ylmethyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method a, 3-hydroxy-4-phenylcyclidine-2-northward (literary reference 17) is injected into the reaction with pyridine-2-carbaldehyde and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a light brown solid. MS: 466,3 ([M+H]+).

Example 46: N-(2-{2-[(2-Hydroxy-5-oxo-3-phenylcyclidine-1-enyl)-(1H-imidazol-4-yl)methyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method a, 3-hydroxy-4-phenylcyclidine-2-northward (literary reference 17) is introduced into reaction with 3H-imidazole-4-carbaldehyde and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a light brown solid. MS: 455,0 ([M+H]+).

Example 47: N-(2-{2-[(2-Hydroxy-5-oxo-3-phenylcyclidine-1-enyl)-(1H-imidazol-2-yl)IU is Il]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method a, 3-hydroxy-4-phenylcyclidine-2-northward (literary reference 17) is introduced into reaction with 1H-imidazole-2-carbaldehyde and N-[2-(1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a light brown solid. MS: 455,0 ([M+H]+).

Example 48: N-(2-{5-Ethyl-2-[(2-hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method a, 3-hydroxy-4-phenylcyclidine-2-northward (literary reference 17) is injected into the reaction with benzaldehyde and N-[2-(5-ethyl-1H-indol-3-yl)ethyl]ndimethylacetamide (literary reference 6), getting named the title compound as an orange solid. MS: 493,4 ([M+H]+).

Example 49: 2-{[3-(2-amino-ethyl)-5-methyl-1H-indol-2-yl]phenylmethyl}-3-hydroxy-4-phenylcyclidine-2-Aenon

Using General method a, 3-hydroxy-4-phenylcyclidine-2-northward (literary reference 17) is injected into the reaction with benzaldehyde and 2-(5-ethyl-1H-indol-3-yl)ethylamine, getting named the title compound as an orange solid. MS: 437,1 ([M+H]+).

Example 50: N-(2-{2-[(2-Hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-5-methyl-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method a, 3-hydroxy-4-phenylcyclidine-2-northward (Literatur what I reference 17) is injected into the reaction with benzaldehyde and N-[2-(5-methyl-1H-indol-3-yl)ethyl]ndimethylacetamide (literary reference 7), getting named the title compound as an orange solid. MS: 479,0 ([M+H]+).

Example 51: 2-{[3-(2-amino-ethyl)-6-ethyl-1H-indol-2-yl]phenylmethyl}-3-hydroxy-4-phenylcyclidine-2-Aenon

Using General method a, 3-hydroxy-4-phenylcyclidine-2-northward (literary reference 17) is injected into the reaction with benzaldehyde and 2-(6-ethyl-1H-indol-3-yl)ethylamine (literary reference 8), getting named the title compound as a light brown solid. MS: 451,0 ([M+H]+).

Example 52: N-(2-{6-Ethyl-2-[(2-hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-1H-indol-3-yl}ethyl)ndimethylacetamide

52. N-[2-(6-Ethyl-1H-indol-3-yl)ethyl]ndimethylacetamide obtained from 2-(6-ethyl-1H-indol-3-yl)ethylamine (literary reference 8)as described in example 16.1.

52.2. Using General method a, 3-hydroxy-4-phenylcyclidine-2-northward (literary reference 17) is injected into the reaction with benzaldehyde and N-[2-(6-ethyl-1H-indol-3-yl)ethyl]acetamide", she receiving N-(2-{6-ethyl-2-[(2-hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-1H-indol-3-yl}ethyl)ndimethylacetamide in the form of a light brown solid substances. MS: 493,1 ([M+H]+).

Example 53: 2-{[3-(2-Amino-2-methylpropyl)-6-chloro-1H-indol-2-yl]phenylmethyl}-3-hydroxy-4-phenylcyclidine-2-Aenon

Using General method a, 3-hydroxy-4-phenylcyclidine-2-northward (Literatur what I reference 17) is injected into the reaction with benzaldehyde and 2-(6-chloro-1H-indol-3-yl)-1,1-dimethylethylamine (synthesized analogously to the method see literature reference 9), getting named the title compound as a pale yellow solid. MS: 485,4 ([M+H]+).

Example 54: N-(2-{6-Chloro-2-)(2-hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-1H-indol-3-yl}-1,1-dimethylethyl)ndimethylacetamide

54.1. N-[2-(6-chloro-1H-indol-3-yl)-1,1-dimethylethyl]ndimethylacetamide obtained from 2-(6-chloro-1H-indol-3-yl)-1,1-dimethylethylamine (synthesized analogously to the method described in the literature reference 9) by acylation as described in example 16.1.

54.2. Using General method a, 3-hydroxy-4-phenylcyclidine-2-northward (literary reference 17) is injected into the reaction with benzaldehyde and N-[2-(6-chloro-1H-indol-3-yl)-1,1-dimethylethyl]ndimethylacetamide, receiving N-(2-{6-chloro-2-[(2-hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-1H-indol-3-yl}-1,1-dimethylethyl)ndimethylacetamide in the form of light yellow solid. MS: 527,3 ([M+H]+).

Example 55: N-(2-{6-Chloro-2-[(2-hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-5-methoxy-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method a, 3-hydroxy-4-phenylcyclidine-2-northward (literary reference 17) is injected into the reaction with benzaldehyde and N-[2-(6-[chloro-5-methoxy-1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a pale red solid. MS: 529,3 ([M+H]+).

Example 56: N-(2-{2-[(2-Hydroxy-5-oxo-phenylcyclidine-1-enyl)phenylmethyl]-6-methoxy-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method a, 3-hydroxy-4-phenylcyclidine-2-northward (literary reference 17) is injected into the reaction with benzaldehyde and N-[2-(6-methoxy-1H-indol-3-yl)ethyl]ndimethylacetamide (literary reference 7), getting named the title compound as a pale red solid. MS: 495,5 ([M+H]+).

Example 57: N-(2-{2-[(2-Hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-5-methoxy-1H-indol-3-yl}ethyl)ndimethylacetamide

Using General method a, 3-hydroxy-4-phenylcyclidine-2-northward (literary reference 17) is injected into the reaction with benzaldehyde and N-[2-(5-methoxy-1H-indol-3-yl)ethyl]acetamide", she getting named the title compound as a pale red solid. MS: 495,4 ([M+H]+).

Example 58: 3-{[6-Fluoro-3-(2-hydroxyethyl)-1H-indol-2-yl]phenylmethyl}-4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-he

Using General method G, rat-4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-he (literary reference 11) is injected into the reaction with benzaldehyde and 2-(6-fluoro-1H-indol-3-yl)ethanol, getting named the title compound as a pale yellow solid. MS: 409,1 ([M+H]+).

Example 59: 2-[(5-fluoro-3-methyl-1H-indol-2-yl)phenylmethyl]-1-hydroxy-7a-methyl-5,6,7,7a-tetrahydropyrimidin-3-one

Using General method G, rat-1-hydroxy-a-methyl-5,6,7,7a-tetrahydropyrimidin-3-one (example C) enter into reaction with benzaldehyde and 5-fluoro-3-methyl-1H-indole, getting named the title compound as a red solid. MS: TO € 391.1 ([M+H]+).

Example 60: 3-[(5-fluoro-3-methyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5,5-dimethyl-1,5-dihydropyrrol-2-he

Using General method G, rat-4-hydroxy-5,5-dimethyl-1,5-dihydropyrrol-2-he (literary reference 18) is injected into the reaction with benzaldehyde and 5-fluoro-3-methyl-1H-indole, getting named the title compound as a yellow solid. MS: 365,1 ([M+H]+).

Example 61: (R)-5-Benzyl-3-[(5-fluoro-3-methyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5-methyl-1,5-dihydropyrrol-2-he

Using General method G, (R)-5-benzyl-4-hydroxy-5-methyl-1,5-dihydropyrrol-2-he (example G) is injected into the reaction with benzaldehyde and 5-fluoro-3-methyl-1H-indole, getting named the title compound as a yellow solid. MS: 441,1 ([M+H]+).

Example 62: (R)-3-[(5-fluoro-3-methyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5-isopropyl-5-methyl-1,5-dihydropyrrol-2-he

Using General method G, (R)-4-hydroxy-5-isopropyl-5-methyl-1,5-dihydropyrrol-2-he (example D) is injected into the reaction with benzaldehyde and 5-fluoro-3-methyl-1H-indole, getting named the title compound as a pale yellow solid. MS: 393,1 ([M+H]+).

Example 63 N-{2-[((R)-4-Hydroxy-5-methyl-2-oxo-5-phenyl-2,5-dihydro-1H-pee the rol-3-yl)phenylmethyl]-6-methyl-1H-indol-3-ylmethyl}ndimethylacetamide

63.1 Oxime 6-methyl-1H-indole-3-carbaldehyde

To a solution of 6-methyl-1H-indole-3-carbaldehyde (0.96 g, literary reference 20) in ethanol (30 ml) is added at a temperature of 22°C. hydroxylamine hydrochloride (0,46 g) and sodium acetate (0.54 g), after which the mixture is stirred for 3 hours Then the mixture is evaporated, the residue tracuriroot with water and with a mixture of dichloromethane/n-heptane (1:1 ratio) and dried, obtaining mentioned in the title compound (yield 0.96 g) as a pink solid. MS: 175,3 ([M+H]+).

63.2-(6-Methyl-1H-indol-3-yl)methylamine

To a mixture of oxime 6-methyl-1H-indole-3-carbaldehyde (0.66 g) and NiCl2·6N2On (0.97 g) in methanol (60 ml) is added to individual portions at a temperature of 22°C borohydride sodium (totaling 3.04 g). The suspension is filtered and the filtrate is evaporated. The residue is partitioned between aqueous solution of NH3(1%) and ethyl acetate, the organic layer is dried and evaporated, to give crude named the title compound as a yellow semi-solid substances (0.68 g).

63.3 N-(6-Methyl-1H-indol-3-ylmethyl)ndimethylacetamide

To a solution of S-(6-methyl-1H-indol-3-yl)methylamine (0.24 g) in dichloromethane (4 ml) is added acetic anhydride (0,14 ml) and pyridine (0,13 ml) and stirred at 22°C for 20 minutes the Mixture was washed with aqueous solution of HCl (1 is normal), the organic layer dried and evaporated. The remainder of cromatografia on silica gel, using a mixture of dichloromethane/methanol (in the ratio of 70:1) and getting named the title compound as a colourless foam (0.15 g). MS: 203,1 ([M+H]+).

63.4 Using General method G, (R)-4-hydroxy-5-methyl-5-phenyl-1,5-dihydropyrrol-2-he (F) is injected into the reaction with benzaldehyde and N-(6-methyl-1H-indol-3-ylmethyl)ndimethylacetamide, getting named the title compound as a white solid. MS: 478,4 ([M-H]-).

Example 64: (R)-4-Hydroxy-5-methyl-3-[(3-methyl-1H-indol-2-yl)phenylmethyl]-5-phenyl-1,5-dihydropyrrol-2-he

Using General method G, (R)-4-hydroxy-5-methyl-5-phenyl-1,5-dihydropyrrol-2-he (synthesized analogously to the method described in the literature reference 11, and also in the literary reference 19) is injected into the reaction with benzaldehyde and 3-methyl-1H-indole, getting named the title compound as a yellow foam. MS: 409,2 ([M+H]+).

Example 65: (R)-3-[(3,5-Dimethyl-1H-indol-2-yl)phenylmethyl-4-hydroxy-5-methyl-5-phenyl-1,5-dihydropyrrol-2-he

Using General method G, (R)-4-hydroxy-5-methyl-5-phenyl-1,5-dihydropyrrol-2-he (synthesized analogously to the method described in the literature reference 11, and also in the literary reference 19) is injected into the reaction with benzaldehyde and 3,5-dimethyl-1H-indole (literary reference 21), getting named the title compound as a yellow foam. MS: 423,3 ([M+H]sup> +).

Example 66: (R)-3-[(3,6-Dimethyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5-methyl-5-phenyl-1,5-dihydropyrrol-2-he

Using General method G, (R)-4-hydroxy-5-methyl-5-phenyl-1,5-dihydropyrrol-2-he (synthesized analogously to the method described in the literature reference 11, and also in the literary reference 19) is injected into the reaction with benzaldehyde and 3,6-dimethyl-1H-indole (literary reference 22), getting named the title compound as a yellow foam. MS: 423,3 ([M+H]+).

Example 67: (R)-3-[(5-fluoro-3-methyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5-methyl-5-phenyl-1,5-dihydropyrrol-2-he

Using General method G, (R)-4-hydroxy-5-methyl-5-phenyl-1,5-dihydropyrrol-2-he (synthesized analogously to the method described in the literature reference 11, and also in the literary reference 19) is injected into the reaction with benzaldehyde and 5-fluoro-3-methyl-1H-indole, getting named the title compound as light yellow foam. MS: 425,4 ([M-H]-).

Example 68: 5-Benzyl-3-[(5-fluoro-3-methyl-1H-indol-2-yl)thiophene-2-ylmethyl]-4-hydroxy-5H-furan-2-he

Using General method G, rat-5-benzyl-4-hydroxy-5H-furan-2-he (literary reference 13) is introduced into reaction with thiophene-2-carbaldehyde and 5-fluoro-3-methyl-1H-indole, getting named the title compound as a red solid. MS: 434,3 ([M+H]+.

Example 69: 5-Benzyl-3-[(5-fluoro-3-methyl-1H-indol-2-yl)thiophene-3-ylmethyl]-4-hydroxy-5H-furan-2-he

Using General method G, rat-5-benzyl-4-hydroxy-5H-furan-2-he (literary reference 13) is introduced into reaction with thiophene-3-carbaldehyde and 5-fluoro-3-methyl-1H-indole, getting named the title compound as a colourless solid. MS: 434,3 ([M+H]+).

Example 70: N-(2-{6-Chloro-2-[(4-hydroxy-5-methyl-2-oxo-5-phenyl-2,5-dihydrofuran-3-yl)phenylmethyl]-1H-indol-3-yl}-1,1-dimethylethyl)ndimethylacetamide

70.1. N-[2-(6-Chloro-1H-indol-3-yl)-1,1-dimethylethyl]ndimethylacetamide

2-(6-Chloro-1H-indol-3-yl)-1,1-dimethylethylamine (synthesized analogously to the method described in the literature reference 9) acelerou as described in example 63.3, getting named the title compound as a brown semi-solid substance.

70.2. Using General method G, rat-4-hydroxy-5-methyl-5-phenyl-5H-furan-2-he (synthesized according to example A3) is injected into the reaction with benzaldehyde and N-[2-(6-chloro-1H-indol-3-yl)-1,1-dimethylethyl]ndimethylacetamide, getting named the title compound as a light brown solid. MS: 543,3 ([M+H]+).

Example 71: N-(2-{5-Chloro-2-[(4-hydroxy-5-methyl-2-oxo-5-phenyl-2,5-dihydrofuran-3-yl)phenylmethyl]-1H-indol-3-yl}-1,1-dimethylethyl)ndimethylacetamide

71.1. N-[2-(5-[Chloro-1H-indol-3-yl)-,1-dimethylethyl]ndimethylacetamide

2-(5-Chloro-1H-indol-3-yl)-1,1-dimethylethylamine (literary reference 23) acelerou as described in example 63.3, getting named the title compound as a colourless solid. MS: 263,1 ([M-H]-).

71.2. Using General method G, rat-4-hydroxy-5-methyl-5-phenyl-5H-furan-2-he (synthesized according to example A3) is injected into the reaction with benzaldehyde and N-[2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]ndimethylacetamide, getting named the title compound as a light brown solid. MS: 543,3 ([M+H]+).

Example 72 N-{2-[((R)-4-Hydroxy-5-methyl-2-oxo-5-phenyl-2,5-dihydrofuran-3-yl)phenylmethyl]-6-methyl-1H-indol-3-ylmethyl}ndimethylacetamide

Using General method G, (R)-4-hydroxy-5-methyl-5-phenyl-1,5-dihydropyrrol-2-he (example A4) is injected into the reaction with benzaldehyde and N-(6-methyl-1H-indol-3-ylmethyl)ndimethylacetamide (from example 63.3), getting named the title compound as a yellow solid. MS: 479,4 ([M-H]-).

Example 73: N-{2-[((8)-4-Hydroxy-5-methyl-2-oxo-5-phenyl-2,5-dihydrofuran-3-yl)phenylmethyl]-6-methyl-1H-indol-3-ylmethyl}ndimethylacetamide

Using General method G, (S)-4-hydroxy-5-methyl-5-phenyl-1,5-dihydropyrrol-2-he (example A3) is injected into the reaction with benzaldehyde and N-(6-methyl-1H-indol-3-ylmethyl)ndimethylacetamide (from example 63.3), getting named the title compound as a yellow Tverdov the matter. MS: 479,4 ([M-H]-).

Example 74: (R)-4-Hydroxy-5-methyl-3-[(3-methyl-1H-indol-2-yl)phenylmethyl]-5-phenyl-5H-furan-2-he

Using General method G, (R)-4-hydroxy-5-methyl-5-phenyl-1,5-dihydropyrrol-2-he (example A4) is injected into the reaction with benzaldehyde and 3-methyl-1H-indole, getting named the title compound as a yellow solid.

MS: 408,4 ([M-H]-).

Example 75: (R)-3-[(3,5-Dimethyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5-methyl-5-phenyl-5H-furan-2-he

Using General method G, (R)-4-hydroxy-5-methyl-5-phenyl-1,5-dihydropyrrol-2-he (example A4) is injected into the reaction with benzaldehyde and 3,5-dimethyl-1H-indole (literary reference 21), getting named the title compound as a light brown solid. MS: 422,5 ([M-H]-).

Example 76: (R)-3-[(3,6-Dimethyl-1H-indol-2-yl)phenylmethyl]-4-hydoxy-5-methyl-5-phenyl-5H-furan-2-he

Using General method G, (R)-4-hydroxy-5-methyl-5-phenyl-1,5-dihydropyrrol-2-he (example A4) is injected into the reaction with benzaldehyde and 3,6-dimethyl-1H-indole (literary reference 22), getting named the title compound as a light brown solid. MS: 422,4 ([M-H]-).

Example 77: (R)-3-[(5-fluoro-3-methyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5-methyl-5-phenyl-5H-furan-2-he

Ispolzuemyi method G, (R)-4-hydroxy-5-methyl-5-phenyl-1,5-dihydropyrrol-2-he (example A4) is injected into the reaction with benzaldehyde and 5-fluoro-3-methyl-1H-indole, getting named the title compound as a yellow solid. MS: 426,1 ([M-H]-).

Example 78: 3-Hydroxy-2-[(3-methyl-1H-indol-2-yl)phenylmethyl]-4-phenylcyclidine-2-Aenon

Using General method G, rat-3-hydroxy-4-phenylcyclidine-2-northward (literary reference 17) is injected into the reaction with benzaldehyde and 3-methyl-1H-indole, getting named the title compound as a red solid. MS: 394,1 ([M+H]+).

Example 79: 2-[(5-fluoro-3-methyl-1H-indol-2-yl)phenylmethyl]-3-hydroxy-4-phenylcyclidine-2-Aenon

Using General method G, rat-3-hydroxy-4-phenyl-cyclopent-2-northward (literary reference 17) is injected into the reaction with benzaldehyde and 5-fluoro-3-methyl-1H-indole, getting named the title compound as a red solid. MS: 412,0 ([M+H]+).

Example

Coated tablets containing the following ingredients can be obtained with the standard method:

IngredientPills
Engine:
The compound of formula (I)10.0 mg200.0 mg
Microcrystalline cellulose23,5 mgto 43.5 mg
Water lactose60,0 mg70.0 mg
Polydon C12.5 mg15,0 mg
Sodium starch glycolate12.5 mg17,0 mg
Magnesium stearate1.5 mg4.5 mg
(The mass of the nucleus)120,0 mg350,0 mg
Film wrapper:
The hypromellose3.5 mg7,0 mg
Polyethylene glycol 60000.8 mg1.6 mg
Talc1.3 mg2.6 mg
Iron oxide (yellow)0.8 mg 1.6 mg
Titanium dioxide0.8 mg1.6 mg

The active ingredient is sifted and mixed with microcrystalline cellulose, after which the mixture granularit with a solution of polyvinylpyrrolidone in water. The granulate is mixed with sodium starch glycolate and magnesium stearate and pressed, getting kernel weight of 120 or 350 mg, respectively. Kernel varnished using an aqueous solution/suspension of the above mentioned film shell.

Example B

Capsules containing the following ingredients can be obtained with the standard method:

IngredientsPer capsule
The compound of formula (I)25.0 mg
Lactose150,0 mg
Maize starch20.0 mg
Talc5.0 mg

Ingredients sifted, mixed and this mixture is filled capsules of size 2.

The example In

Injection solutions have the following composition:

The compound of formula (I)the 3.0 is g
The polyethylene glycol 400150,0 mg
Acetic acidto obtain pH 5.0
Water for injection solutionsto 1.0 ml

The active ingredient dissolved in a mixture of polyethylene glycol 400 in water for injection (using the part). The pH value was adjusted to 5.0 using acetic acid. The volume was adjusted to 1.0 ml by adding the remaining amount of water. The solution is filtered, filled them with bubbles corresponding volume and sterilized.

Example D

Soft gelatin capsules containing the following ingredients can be obtained with the standard method:

The contents of the capsules
The compound of formula (I)5.0 mg
Yellow wax8.0 mg
Gidrirovannoe soybean oil8.0 mg
Partially hydrogenated vegetable oil34,0 mg
Soybean oil110,0 mg
The mass content of the AC is Sula 165,0 mg
Gelatin capsule
Gelatin75,0 mg
Glycerol 85%32,0 mg
The Karion 838.0 mg (dry matter)
Titanium dioxide0.4 mg
Iron oxide (yellow)1.1 mg

The active ingredient is dissolved in warm melt the other ingredients, the mixture is filled soft gelatin capsules of appropriate size. Filled soft gelatin capsules are processed according to conventional procedures.

Example D

A wafer containing the following ingredients can be obtained with the standard method:

The compound of formula (I)50.0 mg
Lactose, finely ground powder1015,0 mg
Microcrystalline cellulose (AVICEL PH 102)1400,0 mg
The sodium carboxymethyl cellulose14,0 mg

Polyvinylpyrrolidone K 3010.0 mg
Magnesium stearate10.0 mg
Flavorings1.0 mg

The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose, after which the mixture granularit with a mixture of polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and flavors and fill with a mixture of the wafer.

1. The compounds of formula (I)

where a denotes-CH2-, -O - or-NR'-, where R' denotes hydrogen or C1-6alkyl, or R' and R4form2-5alkylen;
R1denotes hydrogen, an amino group, With1-6alkyl, hydroxy-group, -NR'r R", (C0-6alkylen)-R NR'r"where R' and R" are independently selected from the group comprising hydrogen, C1-6alkyl, heteroalkyl, formyl, C1-6alkylsulphonyl, arylcarbamoyl optionally substituted by halogenation, C1-6alkylsulfonyl, arylsulfonyl or -(C0-6alkylene)-OR', where R' denotes hydrogen, C1-6alkyl, formyl or1-6alkylsulphonyl;
R2, R2'and R2"independently represent hydrogen, halogen, C1-6alkyl or C1-6alkoxygroup;
R3indicates water is od With1-6alkyl, aryl-C1-6alkyl, aryl optionally substituted with halogen, or heteroaryl where heteroaryl means a monocyclic or bicyclic ring containing 5 to 6 ring atoms, and at least one aromatic ring containing one, two or three ring heteroatoms selected from N, O and S, with remaining ring atoms are carbon atoms, and the connection point heteroaryl radical must be on the aromatic ring;
R4denotes hydrogen, C1-6alkyl, aryl, C3-7cycloalkyl-C1-6alkyl, aryl-C1-6alkyl;
R5denotes hydrogen or C1-6alkyl; or
R4and R5together with the carbon atom to which they are attached, form an optionally substituted C3-7cycloalkyl ring;
R6denotes hydrogen or C1-6alkyl;
and their pharmaceutically acceptable salts;
where the term "aryl" means phenyl or naphthyl.

2. Compounds according to claim 1, where R3stands With1-6alkyl, aryl, optionally substituted with halogen, heteroaryl, aryl-C1-6alkyl.

3. Compounds according to one of claims 1 and 2, where R3stands With1-6alkyl; phenyl-C1-6alkyl; phenyl, optionally substituted from one to three fluorine atoms; or heteroaryl where heteroaryl denotes a monocyclic aromatic radical with 5 and and 6 ring atoms, containing one or two ring nitrogen atom or one ring sulfur atom.

4. Compounds according to one of claims 1 and 2, where R3denotes phenyl.

5. Compounds according to one of claims 1 and 2, where R1stands With1-6alkyl, -(C0-6alkylen)-R NR'r"where R' and R" are independently selected from the group comprising hydrogen, C1-6alkylsulphonyl, optionally substituted halogenation arylcarbamoyl, arylsulfonyl or -(C0-6alkylene)-OR', where R' denotes hydrogen or C1-6alkylsulphonyl.

6. Compounds according to one of claims 1 and 2, where R1stands With1-6alkyl, -(C2-6alkylen)-R NR'r"where R' and R" are independently selected from the group comprising hydrogen, acetyl, arylcarbamoyl, optionally substituted with one or two performanceline groups, and arylsulfonyl, or -(C2-6alkylene)-OR', where R' denotes hydrogen or acetyl.

7. Compounds according to one of claims 1 and 2, where R1refers to 2-amino-ethyl, 2-acetylaminophenol, 2-acetylamino-2,2-dimethylethyl, methyl, isopropyl or 2-hydroxyethyl.

8. Compounds according to one of claims 1 and 2, where two of R2, R2'and R2"denote hydrogen, and the third denotes hydrogen, halogen, C1-6alkyl or C1-6alkoxygroup.

9. Compounds according to one of claims 1 and 2, where two of R2, R2'and R2"denote hydrogen, and the third denotes hydrogen, chlorine, FPO is, methyl, ethyl or methoxy group.

10. Compounds according to one of claims 1 and 2, where two of R2, R2'and R2"denote hydrogen, and the third is a 5 or 6 position of the indole ring and selected from the group comprising hydrogen, chlorine, fluorine, methyl and ethyl.

11. Compounds according to one of claims 1 and 2, where R6denotes hydrogen.

12. Compounds according to one of claims 1 and 2, where a denotes-CH2-.

13. Compounds according to one of claims 1 and 2, where a denotes-CH2-, R4denotes phenyl and R5denotes hydrogen.

14. Compounds according to one of claims 1 and 2, where a represents-NR'-, where R' denotes hydrogen or C1-6alkyl.

15. Compounds according to one of claims 1 and 2, where a represents-NR'-, where R' denotes hydrogen or methyl, R4represents isopropyl and R5denotes hydrogen.

16. Compounds according to one of claims 1 and 2, where a represents-O-.

17. Compounds according to one of claims 1 and 2, where a denotes-O-, R4denotes hydrogen, phenyl, C1-6alkyl, C3-7cycloalkyl-C1-6alkyl or aryl-C1-6alkyl, and R5denotes hydrogen or C1-6alkyl; or R4and R5together with the carbon atom to which they are attached, form an optionally substituted C3-7cycloalkyl ring.

18. Compounds according to one of claims 1 and 2, where a denotes-O-, R4denotes phenyl, benzyl, isobutyl, 2-cyclog xylitol or phenethyl and R 5denotes hydrogen or methyl.

19. Compounds according to claim 1, selected from the group including
3-[(5-fluoro-3-methyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-it,
3-[(5-fluoro-3-methyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5-isopropyl-1-methyl-1,5-dihydropyrrol-2-it,
4-hydroxy-5-isopropyl-3-[(3-methyl-1H-indol-2-yl)phenylmethyl]-1,5-dihydropyrrol-2-it,
3-[(5-fluoro-3-isopropyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5-isopropyl-1,5-dihydropyrrol-2-it,
N-(2-{2-[(5-benzyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)phenylmethyl]-6-fluoro-1H-indol-3-yl}ethyl)acetamide", she
5-benzyl-3-{[6-fluoro-3-(2-hydroxyethyl)-1H-indol-2-yl]phenylmethyl}-4-hydroxy-5H-furan-2-it,
3-{[3-(2-amino-ethyl)-6-fluoro-1H-indol-2-yl]phenylmethyl}-5-benzyl-4-hydroxy-5H-furan-2-he; salt with acetic acid,
5-benzyl-3-[(5-fluoro-3-methyl-1H-indol-2-yl)phenylmethyl]-4-hydroxy-5H-furan-2-it,
(2-{6-fluoro-2-[(4-hydroxy-5-methyl-2-oxo-5-phenyl-2,5-dihydrofuran-3-yl)phenylmethyl]indol-3-yl}ethyl)acetamide", she
(2-{2-[(4-hydroxy-5-isobutyl-2-oxo-2,5-dihydrofuran-3-yl)phenylmethyl]indol-3-yl}ethyl)acetamide", she
N-[2-(2-{[5-(2-cyclohexylethyl)-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl]phenylmethyl}-6-fluoro-1H-indol-3-yl)ethyl]acetamide", she
N-(2-{6-fluoro-2-[(4-hydroxy-2-oxo-5-phenethyl-2,5-dihydrofuran-3-yl)phenylmethyl]-1H-indol-3-yl}ethyl)acetamide", she
N-(2-{2-[(2-hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-1H-indol-3-yl} ethyl)acetamide", she
N-(2-{6-fluoro-2-[(2-hydroxy-5-oxo-3-encyklopedi-1-enyl)phenylmethyl]-1H-indol-3-yl}ethyl)acetamide", she
N-(2-{5-ethyl-2-[(2-hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-1H-indol-3-yl}ethyl)acetamide", she
N-(2-{2-[(2-hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-5-methyl-1H-indol-3-yl}ethyl)acetamide", she
2-{[3-(2-amino-ethyl)-6-ethyl-1H-indol-2-yl]phenylmethyl}-3-hydroxy-4-phenylcyclidine-2 northward or
N-(2-{6-chloro-2-[(2-hydroxy-5-oxo-3-phenylcyclidine-1-enyl)phenylmethyl]-1H-indol-3-yl}-1,1-dimethylethyl)ndimethylacetamide.

20. Pharmaceutical composition having inhibitory activity against chymase, including a connection according to one of claims 1 to 19 and a pharmaceutically acceptable filler.

21. Compounds according to one of claims 1 and 2, having inhibitory activity against chymase.

22. Compounds according to one of claims 1 and 2 for use as therapeutically active substances for the treatment and/or prevention of allergic, inflammatory or fibrotic diseases.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described novel compounds of formula (I), where R1 represents hydroxymethyl; R2 is selected from -C(O)NR4R5; HET-1 represents 5- or 6-member heteroaryl ring, bound by atom C; R3 represents halogeno; R4 and R5 together with nitrogen atom, to which they are bound, can form heterocyclyl ring system, as it is defined for HET-3; HET-3 represents possibly substituted azetidinyl; m equals 1; n equals 0, 1 or 2; or their pharmaceutically acceptable salt, which can be applied as glucokinase (GLK) activators or active ingredient of pharmaceutical compositions, also described are methods of obtaining them.

EFFECT: creation of novel compounds applied as glucokinase (GLK) activators in treatment of diabetes.

13 cl, 40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I , in which A denotes hydrogen, B denotes methyl or B is in a trans-position relative oxygen; X denotes CH2; Y denotes a group of formula , , ,

, or ;

, in which the left-hand bond is to an oxygen atom, and the right-hand bond is to the group R; R denotes 5-indolyl; in form of a free base or an acid addition salt. The invention also relates to a pharmaceutical composition, to use of compounds in any of claims 1-7, to a method of preventing and treating psychiatric and neurodegenerative disorders in a person, as well as a method of treating and preventing diseases or pathological condition in which α7 nAChR activation plays a role.

EFFECT: obtaining novel biologically active compounds having α7 nAChR agonist activity.

16 cl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds which are N-substituted 1,4-diazabicyclo[2.2.2.]octane derivatives. The offered compounds exhibit antiviral activity and can find application in medicine as active components for the development of dosage forms used for treating viral diseases.

EFFECT: higher antiviral activity of the compound.

7 dwg, 4 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds of formulae and , in which radicals and symbols assume values defined in the formula of invention, e.g. to 1H-indazoles, 1,2-benzisoxazoles and 1,2-benzisothiazoles. Said compounds are receptor ligands of the α-7 nAChR subtype. The invention also relates to a pharmaceutical composition containing the said compounds.

EFFECT: possibility of using the said compounds to make medicinal agents for treating diseases associated with impaired functioning of nicotinic acetylcholine receptors and their abnormal functioning, primarily in brain cells.

46 cl, 85 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula I and their pharmaceutically acceptable salts. In structural formula I , X is oxygen; Y is oxygen; Y1 Y2, R7 and R4 represent H; X1 and X2 are independently selected from a group consisting of hydrogen, an alkyl group containing 1 to 5 carbon atoms, in which one or more hydrogen atoms of the alkyl group can be substituted with a halogen, aryl group containing 6 to 10 carbon atoms or a cycloalkyl group containing 3 to 9 carbon atoms, or a 5-9-member heterocyclic group with 2 heteroatoms selected from N and O, or a cycloalkyl group containing 5 to 9 carbon atoms; values of the rest of the radicals are given in the formula of invention. The invention also pertains to a pharmaceutical composition having properties of selective inhibitors of type IV phosphodiesterase, containing a therapeutically effective amount of the invented compound.

EFFECT: increased effectiveness of the compounds.

6 cl, 23 ex

FIELD: chemistry.

SUBSTANCE: described is a compound selected from formulae , , , , and , where X1 denotes CH; X2-X5 each independently denotes CH or C-, where -C represents the point where group B is bonded and where one of X2-X5 denotes -C; X7-X10 each independently denotes CH or CR2; X18-X21 each independently denotes CH or CR5; X22 and X23 each independently denotes CH or CR12, where at least one of X22 and X23 denotes CR12; X24 denotes CH; B denotes CH2 or C=O; B1 denotes CH; Y denotes oxygen or sulphur; Z denotes O; m equals 2; R denotes hydrogen or R denotes each indendently (C1-C6)alkyl, (C3-C8)cycloalkyl, halogen, imidazolyl substituted with (C1-C6)alkyl and/or an oxo group or OR9; R9 denotes hydrogen, (C1-C6)alkyl which is unsubstituted or substituted with once or several times with fluorine, or (C4-C8)cycloalkylalkyl; R12 denotes a (C1-C6)alkoxy group which is substituted once or several times with fluorine, unsubstituted thiazolyl, thiazolyl which is substituted with (C1-C6)alkyl, unsubstituted oxazolyl, dihydropyranyl, tetrahydropyranyl or tetrahydropyranyloxy, and pharmaceutically acceptable salts of the said compounds. Described also are pharmaceutical compositions containing the said compounds.

EFFECT: invention relates to ligands of nicotinic acetylcholine receptors (nAChR), activation of nAChRs and treatment of diseases associated with defective or with functional disorders of nicotinic acetylcholine receptors, especially in the brain.

69 cl, 55 ex

FIELD: chemistry.

SUBSTANCE: described is a compound selected from a group consisting of formula II formula III and formula IV , or its salt or ester, where G1 is selected from a group which includes - (CR1R2)n-, n equals 0 or 1; R1 and R2 are independently selected from a group which includes hydrogen; X1, X2 and X3 are independently selected from a group consisting of hydrogen, optionally substituted lower alkyl, halogen, optionally substituted lower alkoxy, G2 is a heterocycloalkyl linker optionally substituted with X4 and X5, where the heterocycloalkyl linker is selected from a group consisting of piperazinyl, 3,6-dihydro-2N-pyridinyl, [1,4]diazepanyl, 3,9-diazabicyclo[3,3,1]nonyl; X4 and X5 are independently selected from a group consisting of hydrogen and optionally substituted lower alkyl; CO2R; R is selected from a group consisting of optionally substituted lower alkyl and hydrogen; G3 is a bond; G4 is selected from a group consisting of hydrogen, aryl, selected from phenyl which is optionally substituted with a lower alkyl, halogen, lower haloalkyl or lower haloalkoxy; heteroaryl selected from pyridinyl which is optionally substituted with a halogen or lower haloalkyl; and optionally substituted cycloheteroalkyl selected from 1,3-benzodioxolyl. Described also are specific compounds and a pharmaceutical composition.

EFFECT: disclosed compounds are used as modulators of receptors activated by a peroxisomal proliferator.

5 cl, 2 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I) or their pharmaceutically acceptable salts, where symbols assume values given in the description, where the said compounds are chemokine receptor (CCR-1) antagonists. Also described is a method of inhibiting the chemokine receptor to reduce inflammation in mammals.

EFFECT: possibility of use in treating inflammatory diseases.

8 cl, 160 ex

FIELD: medicine.

SUBSTANCE: there are described new diazabicyclic aryl derivatives of general formula (I), where A', A", L and B, n possess the values as specified in the description which are cholinergic ligands to nicotinic acetylcholine receptors, as well as a based pharmaceutical composition. Owing to their pharmacological profile, the compound according to the invention, can be effective in treating such various diseases or disorders, as those associated with the cholinergic system of central nervous system (CNS), peripheral nervous system (PNS), as those associated with plain muscle contraction, endocrine diseases or disorders, neurodegenerative diseases or disorders, diseases or disorders involving inflammation, pain and abstinence symptoms caused by termination of abusing the chemical substances.

EFFECT: effective with regard to various diseases.

16 cl, 3 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel antibacterial compounds of formula (I). Compounds of formula (I) Q-NH-CO-R3, where Q stands for group of the following structure , R1 represents hydrogen, halogen, hydroxy, amino, mercapto, alkyl, heteroalkyl, alkeloxy, heteroalkyloxy, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, cycloalkyloxy, alkylcycloalkyloxy, heterocycloalkyloxy or heteroalkylcycloalkyloxy, X1, X2, X3, X4, X5 and X6 each independently on each other represent nitrogen atom or group of formula CR2, R2 represents hydrogen, halogen or hydroxy, amino, alkyl, alkenyl, alkinyl or heteroalkyl group, R3 is selected from the following groups R5 represents group of formula -B-Y, where B represents alkylene, alkenylene, alkinylene, -NH- or heteroalkylene, and Y represents aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl or heteroalkylcycloalkyl, or their pharmaceutically acceptable salt, solvate, hydrate or pharmaceutically acceptable composition, as well as to pharmaceutical composition, which possesses antibacterial activity, based on said compounds and to their application for preparation of medication, intended for treatment of bacterial infections.

EFFECT: obtained and described are compounds, which can be useful in medicine.

9 cl, 147 ex

FIELD: chemistry.

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

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

33 cl, 367 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds which are methyl-3-azabicyclo[3.3.0]octane-7-carboxylate, N-methyl-3-azabicyclo[3.3.1]nonane-7-carboxamide, N-propyl-3-azabicyclo[3.3.1]nonane-7-carboxamide, or pharmaceutically acceptable salts thereof. The invention also relates to compounds selected from a group, a pharmaceutical composition, methods of treating or preventing central nervous system disorders, as well as use of compounds in any of claims 1-4.

EFFECT: obtaining novel biologically active compounds having activity on neural nicotinic acetylcholine receptor.

11 cl, 14 ex, 7 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) or pharmaceutically acceptable salts thereof, where Q is CH or N; R2 is C1-C4 alkyl or C3-C4-cycloalkyl; Y is R5-O; where R5 is propynyl; X is selected from a group consisting of aryl, heteroaryl, C1-C5-alkyloxy, heterocycloalkyl, arylamino, heteroarylamino, heteroaryl-C1-C4-alkylamino, aryloxy, aryl-C1-C2-alkyloxy or C3-C6-cycloalkyl-C1-C4-alkyloxy, each of which is optionally substituted with 1-3 times; the optional substitute(s) for X is(are) independently selected from a group comprising halogen, cyano, trifluoromethyl, nitro, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkyloxy-C1-C4-alkoxy, -SMe, SO2-C1-C2-alkyl, -NMe2, - C(O)O-C1-C5-alkyl, -SCF3, -SO2-NH2, -SO2-C2-alkyl-OH, -CONH2, -COMe, - CONH-C1-C4-alkyl, -CONMe2, -NHCOMe, -CH2COOEt, -OCH2COOEt, -CH2- cyclopropyl, and each R3 and R4 is H; where aryl denotes phenyl or naphthyl; heteroaryl denotes monocyclic or bicyclic hydrocarbon containing 5-10 ring atoms, one or more of which are heteroatoms selected from O, N or S; heterocyclyl denotes piperidinyl or benzodioxolyl; or a compound or pharmaceutically acceptable salt thereof, selected from a group comprising (4-dimethylaminophenyl)-[4-(4-cyclopropylphenyl)-6-propargyloxyquinazolin-2-yl]methanone, (3-sulphamoylphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, [3-(2-hydroxyethanesulphonyl)phenyl]amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, (3-methylsulphanylphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, (3-methanesulphonylphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, and (5-ethanesulphonyl-2-hydroxyphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4- dihydroquinazoline -2-carboxylic acid. The invention also relates to a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel benzoquinazoline derivatives, which are useful in treating bone disorders, are obtained.

6 cl, 128 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound presented by general formula (I) where values of Rx, R3, R4, X and A substitutes are described in the patent claim, inhibiting tyrosine kinase of EGF receptor and HER2 tyrosine kinase, as well as to using the compound of formula (I) and pharmaceutical composition containing this compound or its pharmaceutically acceptable salt.

EFFECT: preparation of the tyrosine kinase inhibiting compound.

14 cl, 19 ex, 53 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel derivatives of 1H-imidazole of formula I, in which R1 represents hydrogen, halogen atom, C1-3-alkyl group, and said C1-3-alkyl groupcan include 1-3 fluorine atoms or R1 represents cyclopropyl, piano, or methylsulfanyl group, R2 represents phenyl group, which can be substituted with 1 substituent Y, selected from methoxy, chlorine, fluorine, trifluoromethyl and cyano, or R2 represents pyridyl group, on condition that R2 is not 6-methyl-2-pyridyl group, or R2 represents fully saturated 6-7-member monocyclic, condensed bicyclic ring system or benzothiazolyl, benzodioxane or thiazole group, and said groups can be substituted by 1 fluorine atom, or R2 represents group of general formula CH2-R5, in which R5 represents phenyl group or fully saturated 7-member condensed bicyclic carbocyclic ring system, or R5 represents piperidine or tetrahydrofuran ring system, which can be substituted by methyl, or R2 represents methylsulfonylamino(C3)alkyl group, R3 represents hydrogen, halogen atom, C1-6-alkylsulfonyl, cyanogroup, or R3 represents C1-8-alkyl group, and said C1-8-alkyl group can be substituted by 1-3 fluorine atoms, or R3 represents phenyl group, which is substituted by substituent Y, where Y has value, specified above, or R3 represents furanyl group, R4 represents one of subgroups (i) or (ii), where R6 represents C4-8-branched or linear alkyl group or naphtyl group, R7 represents hydrogen atom, linear C1-6-alkyl group, R8 represents C2-6-alkyl group, substituted by 1-3 fluorine atoms, or R8 represents C3-8-cycloalkyl group, piperidine group, C3-8-cycloalkyl- C1-2-alkyl group, tetrahydrofuranyl- C1-2-alkyl group, C5-10-bicycloalkyl group, C5-10-bicycloalkyl-C1-2-alkyl group, C6-10-tricycloalkyl group, C6-10-tricycloalkyl-C1-2-alkyl group, and said groups can be substituted by 1-3 substituents, selected from methyl or hydroxyl, or R8 represents phenyl group, substituted by 1-2 substituents Y, specified above, or R8 represents naphtyl, 1,2,3,4-tetrahydronaphtyl or indanyl group, and said groups can be substituted by 1 substituent Y, or R8 represents phenyl- C1-3-alkyl group, diphenyl- C1-3-alkyl group, and said groups can be substituted ob their phenyl ring by 1 substituent Y, where Y has value specified above, or R8 represents benzyl group, substituted by 2 substituents Y, or R8 represents quinilinyl, pyridinyl, benzimidazole or naphtylmethyl group which can be substituted by substituent Y, where Y has value, specified above, or R8 represents asabicyclo[3,3,0]octanyl group, on condition that R8 is neither 6-methoxybenzothiazole-2-yl group, nor [3-chlor-5-(trifluoromethyl)pyrid-2-yl]methyl group, or R7 and R8 together with nitrogen atom, to which they are bound, form saturated, non-aromatic, monocyclic or bicyclic heterocyclic group, including only one nitrogen atom, having 7-10 ring atoms, which can be subslituted by 3 C1-3-alkyl groups, or R7 and R8 together with nitrogen atom, to which they are bound, form saturated, monocyclic heterocyclic group, optionally including another N atom, having 6 ring atoms, and said heterocyclic group is substituted by C1-3-alkyl groups, on condition that R7 and R8 together with nitrogen atom, to which they are bound, do not form trimethylsubstituted asabicyclo[3,3,0]octanyl group, as well as their stereoisomers and pharmacologically acceptable salts of said formula (I) compounds and their stereoisomers Invention also relates to intermediate compounds of formula XIV, pharmaceutical composition based on formula I compound, method of obtaining such pharmaceutical composition and application of formula T compound.

EFFECT: obtained are novel derivatives of IH-imidazole, which are modulators of cannabinoid CB2-receptors.

8 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: tricyclic compounds of formula I: $ substituted with heterocycle are disclosed, or pharmaceutically acceptable salt or solvate of specified compound, isomer or racemic mixture, where stands for optional double link, dotted line stands for link or does not stand for link, which results in double or single link according to requirements of valency and where A, B, G, M, X, J, n, Het, R3, R10, R11, R32 and R33 and other substituents are such as indicated in formula of invention. Invention also relates to pharmaceutical compositions, which contain them, method of thrombin receptor or cannabinoid receptor inhibition, and to method for treatment of disease related to thrombosis, atherosclerosis, restenosis, hypertension, stenocardia, arrhythmia, cardiac failure and cancer by administration of specified compounds.

EFFECT: production of compounds having properties of antagonists of thrombin receptors.

33 cl, 6 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel antiviral active components which are substituted 2-aminomethyl-1-benzyl-1H-benzo[d]imidazoles of general formula 1 or pharmaceutically acceptable salts thereof, a pharmaceutical composition, antiviral medicinal agents, a method of preventing and treating viral diseases, especially those cause by hepatitis C virus (HCV). In general formula 1

, R1 denotes one or two substitutes of a cyclic system, including a hydrogen atom, C1-C3 alkyl, C1-C3 alkyloxy or a halogen atom; R2 denotes a hydrogen atom or C1-C3 alkyl; R3 and R4 denote identical substitutes of amine groups, including hydrogen, C1-C2 alkyl, C1-C3-alkanoy, optionally substituted furanoyl; optionally substituted or optionally annelated with a 5-6-member azaheterocyclic ring of phenyl; or R3 and R4 together with a nitrogen atom with which they are bonded form a morpholin4-yl, 4- (C1-C3 alkylsubstituted)-piperazin-1-yl, and R1 and R2 assume values given above, or piperidin-1-yl, provided that R1 assumes the value given above, R2 denotes C1-C3 alkyl, or provided that R1 denotes hydrogen or o-fluorine, R2 assumes the value given above.

EFFECT: improved method.

7 cl, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

EFFECT: novel heterocyclic derivatives of formula I, having aspartyl protease inhibiting properties, are obtained.

16 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel methods for synthesis of formula I compound (Iclaprim) which relates to dihydrofolate reductase inhibitors

,

as well as to intermediate compounds used in said methods.

EFFECT: design of novel efficient methods for synthesis of formula I compound (Iclaprim).

13 cl, 2 tbl, 30 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel chromane derivatives of formula I: or their pharmaceutically acceptable salts, where: m equals 0 or 1; p equals 2; q equals 2; Ar is phenyl which is possibly substituted with a halogen atom; each R1 is independently a halogen; R2 is ; n equals 1 or 2; each of R3 and R4 is independently hydrogen or C1-12-alkyl; each of R5 and R6 is independently hydrogen or C1-12-alkyl; and each of R7 and R8 is independently hydrogen or C1-12-alkyl; or one of R7 and R8 is hydrogen and the other is a 5- or 6-member heterocyclyl containing one nitrogen atom, or R7 and R8 together with the nitrogen atom with which they are bonded can form an amidinyl group, a urea group, a guanidinyl group or a pyrrolidine ring which is possibly substituted with an amine group.

EFFECT: obtaining novel chromane derivatives and pharmaceutical compositions having 5-HT6 and/or 5-HT2a receptor modulator activity.

22 cl, 11 ex, 1 tbl

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