Derivatives of nor-seco-chimbacine, pharmaceutical composition and method for inhibiting based on thereof

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

 

Prior art

The present invention relates to a derivative of nor-SECO himbacine used as antagonists of thrombin receptor in the treatment of diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina, arrhythmia, heart failure, cerebral ischemia, stroke, neurodegenerative diseases and cancer. Antagonists thrombin receptor also known as antagonists of receptor-activated protease (PAR). Compounds according to the invention also associated with cannabinoid (SW) receptors and are used in the treatment of rheumatoid arthritis, systemic lupus erythematous, multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory diseases of the lungs and gastrointestinal tract and respiratory diseases, such as reversible obstruction of the Airways, chronic asthma and bronchitis. The invention also relates to pharmaceutical compositions containing these compounds.

It is known that thrombin has a number of activities in various cell types, and thrombin receptors are present in these types of cells as a human platelets, smooth muscle cells of blood vessels, endothelial cells and fibroblasts. So waiting for the I, that antagonists thrombin receptor will be useful in the treatment Trombitsky, inflammatory, atherosclerotic and fibroproliferative diseases and other disorders in which thrombin and its receptor play a pathological role.

The peptides of thrombin antagonist of the receptor have been identified on the basis of the research, "structure-activity", which included the replacement of amino acids in the thrombin receptor. In the work Bematowicz et al, J. Med. Chem., 39 (1996), page 4879-4887 as potent antagonists of thrombin receptor described Tetra - and Pentapeptide, for example N-trance-cynnamoyl-p-Phe-p-Phe-Leu-Arg-NH2and N-TRANS-cynnamoyl-p-Phe-p-Phe-Leu-Arg-Arg-NH2. Peptide antagonists of thrombin receptor are also described in WO 94/03479, published February 17, 1994.

Cannabinoid receptors belong to the superfamily of receptors associated with G-protein. They are classified as predominantly neural CB1receptors and mainly peripheral SV2the receptors. These receptors exert their biological activity by regulating the flow of adenylate cyclase and CA2+and+. While the action of receptors CB1mainly associated with the Central nervous system, suggest that the receptors SV2have peripheral activity associated with b is anchialine compression, immunomoduliruushim and inflammation. Thus, it is expected that the agent that selectively bind to the receptor SV2will have therapeutic value in the treatment of diseases associated with rheumatoid arthritis, systemic lupus erythematous, multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory diseases of the lungs and gastrointestinal tract and respiratory diseases, such as reversible obstruction of the Airways, chronic asthma and bronchitis (R.G. Pertwee, Curr. Med. Chem. (5(8), (1999), 635).

Himbacine, piperidinyl alkaloid of the formula

was identified as an antagonist of muscarinic receptor. Total synthesis of (+)-himbacine described in Chackalamannil et al, J. Am. Chem Soc., 118 (1996), page 9812-9813.

The tricyclic himbacine-related compounds have been described as antagonists of thrombin receptor in U.S. patent 6063847.

Summary of invention

The present invention relates to antagonists of thrombin receptor represented by the formula I

or pharmaceutically acceptable salts of these compounds, where:

Z represents -(CH2)n-;where R10no;

or where R3no;

the single dotted line represents an optional double bond;

the double dotted line represents an optional simple communications;

n means 0-2;

R1and R2independently selected from the group comprising: H, alkyl with 1-6 carbon atoms, porozumienie alkyl with 1-6 carbon atoms, diversality alkyl with 1-6 carbon atoms, cryptarithmetic alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, alkenyl with 2-6 carbon atoms, aryl-substituted alkyl with 1-6 carbon atoms, aryl-substituted of alkenyl with 2-6 carbon atoms, Goethe-nourishement alkyl with 1-6 carbon atoms, heteroarylboronic of alkenyl with 2-6 carbon atoms, replacement alkyl with 1-6 carbon atoms, alkyl with 1-6 carbon atoms, a substituted alkoxy group with 1-6 carbon atoms, amino-substituted alkyl with 1-6 carbon atoms, aryl - and titlesonly alkyl with 1-6 carbon atoms, or R1and R2together form a group =O;

R3means H, hydroxy-, alkoxy group with 1-6 carbon atoms, -NR18R19, -SOR16, -SO2R17, -C(O)OR17, -C(O)NR18R19, alkyl with 1-6 carbon atoms, halogen, fluorinated alkyl with 1-6 carbon atoms, defenselessly alkyl with 1-6 carbon atoms, trifloromethyl alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, alkenyl 2-6 carbon atoms, aryl-substituted alkyl with 1-6 carbon atoms, aryl-substituted of alkenyl with 2-6 carbon atoms, heteroaromatic alkyl with 1-6 carbon atoms, heteroarylboronic of alkenyl with 2-6 carbon atoms, replacement alkyl with 1-6 carbon atoms, aminogenesis-tion alkyl with 1-6 carbon atoms, aryl, titlesonly alkyl with 1-6 carbon atoms, alkyl with 1-6 carbon atoms, a substituted alkoxy group with 1-6 carbon atoms or alkyl with 1-6 carbon atoms, substituted alkylamino group with 1-6 carbon atoms;

R34means (N, R3), (H, R43), =O or =NOR17if the optional double bond is absent; R34means R44if the double bond is present;

Het denotes a mono-, bi - or tricyclic heteroaromatic group of 5 to 14 atoms, including from 1 to 13 carbon atoms and 1-4 heteroatoms independently selected from the group comprising N, O and S, where the ring nitrogen atom may form an N-oxide or a Quaternary group with alkyl group of 1-4 carbon atoms, where Het is connected with via a ring carbon atom and where Het group has 1-4 substituent, W, independently selected from the group comprising H, alkyl with 1-6 carbon atoms; porozumienie alkyl with 1-6 carbon atoms; defenselessly alkyl with 1-6 carbon atoms; trifloromethyl alkyl with 1-6 carbon atoms; cycloalkyl with 3-7 carbon atoms; heterocyclyl; heteroseksualci substituted by alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, IT is substituted by alkyl with 1-6 carbon atoms or =O; alkenyl with 2-6 carbon atoms; R21-aryl-substituted alkyl with 1-6 carbon atoms; R21-arylsubstituted of alkenyl with 2-6 carbon atoms; R21-aryloxy; R21-aryl-NH-; heteroaromatic alkyl with 1-6 carbon atoms; heteroarylboronic of alkenyl with 2-6 carbon atoms; heteroaromatic-; heteroaryl-NH-; replacement alkyl with 1-6 carbon atoms; dihydroxyphenyl alkyl with 1-6 carbon atoms; aminosilanes alkyl with 1-6 carbon atoms; alkyl with 1-6 carbon atoms, substituted alkylamino group with 1-6 carbon atoms; di-(alkyl with 1-6 carbon atoms)-aminosilanes alkyl with 1-6 carbon atoms; titlesonly alkyl with 1-6 carbon atoms; alkoxy group with 1-6 carbon atoms; alkenylacyl-group 2-6 carbon atoms; halogen; -NR4R5; -CN; -IT; -COOR17; -COR16; -OSO2CF3; -CH2Och2CF3; alkylthio group with 1-6 carbon atoms; -C(O)NR4R5; -OCHR6is phenyl; phenoxyethyl with 1-6 carbon atoms; -NHCOR16; -NHSO2R16; biphenyl; -C(R6)COOR7; -OC(R6)2C(O)NR4R5; alkoxy group with 1-6 carbon atoms; -C(=NOR17R18; alkoxy group with 1-6 carbon atoms, having the following for stitely: alkyl with 1-6 carbon atoms, amino group, -OH, -COOR17, -NHCOOR17, -CONR4R5, aryl, aryl substituted by 1-3 substituents, independently selected from the group including halogen, -CF3, alkyl with 1-6 carbon atoms, alkoxy group with 1-6 carbon atoms, and-COOR17, aryl, in which adjacent carbon atoms form a ring with methylendioxy-group, -C(O)NR4R5or heteroaryl;

R21- aryl; aryl, in which adjacent carbon atoms form a ring with methylendioxy-group;

R41- heteroaryl; and heteroaryl, in which adjacent carbon atoms form a ring with alkylen group having 3-5 carbon atoms or with methylendioxy-group;

R4and R5independently selected from the group comprising H, alkyl with 1-6 carbon atoms, phenyl, benzyl and cycloalkyl with 3-7 carbon atoms, or R4and R5together represent -(CH2)4-, -(CH2)5- or -(CH2)4NR7-CH2)2- and form a ring with the nitrogen atom to which they are attached;

R6independently selected from the group comprising H, alkyl with 1-6 carbon atoms, phenyl, cycloalkyl with 3-7 carbon atoms, alkyl with 1-6 carbon atoms, substituted cycloalkene with 3-7 carbon atoms, alkyl with 1-6 carbon atoms, a substituted alkoxy group with 1-6 carbon atoms, hydroxy-alkyl with 1-6 carbon atoms, and amino-alkyl with 1-6 atoms in which laroda;

R7denotes H or alkyl with 1-6 carbon atoms;

R8, R10and R11independently selected from the group comprising N, R1and-OR1provided that, when there is an optional double bond, R10no;

R9means H, HE, alkoxy group with 1-6 carbon atoms, halogen or haloalkyl with 1-6 carbon atoms;

In means -(CH2)n3, -CH2-O-,-CH2S-, -CH2NR6-, -C(O)NR6-, -NR6(CO)-,, CIS - or TRANS -(CH2)n4CR12=CR12a(CH2)n5or -(CH2)n4With≡C(CH2)n5-where n3 is 0-5, n4 and n5 is independently 0-2, and R12and R12aindependently selected from the group comprising H, alkyl with 1-6 carbon atoms and halogen;

X is-O - or-NR6-when the double dotted line represents a simple bond or a H-H-HE-or-other20when the bond is absent;

Y represents =O, =S, (H, H), (H, OH) or (H, alkoxy group with 1-6 carbon atoms), when the double dotted line represents a simple bond or, in the absence of communication, Y mean =O, =NOR17, (N, N), (N, HE), (H, SH), (H, alkoxy group with 1-6 carbon atoms) or (N, -other45);

R15is absent when the double dotted line represents a simple bond; R15means H, alkyl with 1-6 carbon atoms, -NR18R19or17when the connection of the no; or Y -orand R15Is h or alkyl with 1-6 carbon atoms;

R16means lower alkyl with 1-6 carbon atoms, phenyl or benzyl;

R17, R18and R19independently selected from the group comprising H, alkyl with 1-6 carbon atoms, phenyl, benzyl;

R20means H, alkyl with 1-6 carbon atoms, phenyl, benzyl, -C(O)R6or-SO2R6;

R21means 1-3 substituent, independently selected from the group comprising hydrogen, -CF3, -OCF3, halogen, -NO2, alkyl with 1-6 carbon atoms, alkoxy group with 1-6 carbon atoms, amino group, substituted alkyl with 1-6 carbon atoms, amino group substituted with two alkyl groups with 1 to 6 carbon atoms, aminol-keel with 1-6 carbon atoms, alkyl with 1-6 carbon atoms, substituted (alkyl with 1-6 carbon atoms)amino group, di(alkyl with 1-6 carbon atoms)aminosilanes alkyl with 1-6 carbon atoms, hydroxyalkyl with 1-6 carbon atoms, -COOR17, -COR17, -NHCOR16, -NHSO2R16, -NHSO2CH2CF3heteroaryl or-C(≡NOR17R18;

R22and R23independently selected from the group comprising hydrogen, R24-alkyl with 1-10 carbon atoms, R24alkenyl with 2-10 carbon atoms, R24-quinil with 2-10 carbon atoms, R27-heterocyclyl the sludge, R25-aryl, R25-aryl-substituted alkyl with 1-6 carbon atoms, R29-cycloalkyl with 3-7 carbon atoms, R29-cycloalkene with 3-7 carbon atoms, -OH, -OC(O)R30, -C(O)OR30, -C(O)R30, -C(O)NR30R31, -NR30R31, -NR30C(O)R31, -NR30C(O)NR31R32, -NHSO2R30, -OC(O)NR30R31, R24-alkoxy group with 1-10 carbon atoms, R24-alkenylamine group with 2-10 carbon atoms, R24-alkyloxy group with 2-10 carbon atoms, R27-heterocyclizations-group

R29-cycloalkane group having 3-7 carbon atoms, R29-cycloalkenyl group having 3-7 carbon atoms, R29-cyclogyl with 3-7 carbon atoms)-NH-,-NHSO2Other16and-CH(=NOR17);

or R22and R10together with the carbon atom to which they are attached, or R23and R11together with the carbon atom to which they are attached, independently form an R42substituted carbocyclic ring of 3 to 10 atoms, or R42-substituted heterocyclic ring of 4 to 10 atoms, where 1-3 of the ring atoms is independently selected from the group comprising-O-, -NH-and-SO0-2-, provided that when R22and R10form a ring, the optional double bond is absent;

R24means 1, 2 or 3 substituent independently selected from the group including hydrogen, halogen, HE, alkoxy group with 1-6 carbon atoms, R35-aryl, (alkyl with 1-10 carbon atoms)-C(O)-, (alkenyl with 2-10 carbon atoms)-C(O)-, (quinil with 2-10 carbon atoms)-C(O)-, heteroseksualci, R26-cycloalkyl with 3-7 carbon atoms, R26-cycloalkene with 3-7 carbon atoms, -OC(O)R30, -C(O)OR30, -C(O)R30, -C(O)NR30R31, -NR30R31, -NR30C(O)R31, -NR30C(O)NR31R32, -NHSO2R30, -OC(O)NR30R31, R24-alkenylamine group with 2-10 carbon atoms, R24-alkyloxy group with 2-10 carbon atoms, R27-heterocyclizations group, R29-cycloalkane group having 3-7 carbon atoms, R29-alkenylamine group, substituted cycle with 3-7 carbon atoms, R29(cycloalkyl with 3-7 carbon atoms)-NH-, -NHSO2Other16and-CH(=NOR17);

R25means 1, 2 or 3 substituent independently selected from the group comprising hydrogen, heteroseksualci, halogen, -COOR36, -CN, -C(O)NR37R38, -NR39C(O)R40, -OR36cycloalkyl with 3-7 carbon atoms, (cycloalkyl with 3-7 carbon atoms)-(alkyl with 1-6 carbon atoms), alkyl with 1-6 carbon atoms)(cycloalkyl with 3-7 carbon atoms)-(alkyl with 1-6 carbon atoms), (haloalkyl with 1-6 carbon atoms)(cycloalkyl with 3-7 carbon atoms)(alkyl with 1-6 carbon atoms), hydroxyalkyl with 1-6 carbon atoms, alkyl C1 to 6 carbon atoms, substituted alkoxy group with 1-6 carbon atoms, and R41-heteroaryl; or two R25groups on adjacent ring carbons form a fused, methylendioxy-group;

R26means 1, 2, or Z substituent, independently selected from the group comprising hydrogen, halogen and alkoxy group with 1-6 carbon atoms;

R27means 1, 2 or 3 substituent independently selected from the group including hydrogen, R28-alkyl with 1-10 carbon atoms, R28alkenyl with 2-10 carbon atoms, R28-quinil with 2-10 carbon atoms,

R28means hydrogen, -HE or alkoxy group with 1-6 carbon atoms;

R29means 1, 2 or 3 substituent independently selected from the group comprising hydrogen, alkyl with 1-6 carbon atoms, -HE, alkoxy group with 1-6 carbon atoms and halogen;

R30, R31and R32independently selected from the group comprising hydrogen, alkyl with 1-10 carbon atoms, alkyl with 1-10 carbon atoms, a substituted alkoxy group with 1-6 carbon atoms, R25-aryl-alkyl with 1-6 carbon atoms, R33-cycloalkyl with 3-7 carbon atoms, R34-cycloalkyl with 3-7 carbon atoms)(alkyl with 1-6 carbon atoms), R25-aryl, heteroseksualci, heteroaryl, heteroseksualci-substituted alkyl with 1-6 carbon atoms and heteroaryl-substituted alkyl with 1-6 carbon atoms;

R33- vador is d, alkyl with 1-6 carbon atoms, HE is alkyl with 1-6 carbon atoms or alkoxy group with 1-6 carbon atoms;

R35- 1-4 substituent, independently selected from the group comprising hydrogen, alkyl with 1-6 carbon atoms, -HE, halogen, -CN, alkoxy group with 1-6 carbon atoms, trihaloacetic group with 1-6 carbon atoms, alkyl with 1-6 carbon atoms)substituted an amino group, di(alkyl with 1-6 carbon atoms)substituted an amino group, -OCF3HE-(alkyl with 1-6 carbon atoms), -Cho, -C(O)(alkyl with 1-6 carbon atoms)amino, -C(O)di(alkyl with 1-6 carbon atoms)amino, -NH2, -NHC(O)(alkyl with 1-6 carbon atoms) and -- N(alkyl with 1-6 carbon atoms) (O)(alkyl with 1-6 carbon atoms);

R36is hydrogen, alkyl with 1-6 carbon atoms, haloalkyl with 1-6 carbon atoms, di-haloalkyl with 1-6 carbon atoms or triptorelin with 1-6 carbon atoms,

R37and R38independently selected from the group comprising hydrogen, alkyl with 1-6 carbon atoms, aryl-(alkyl with 1-6 carbon atoms), phenyl and cycloalkyl with 3-15 carbon atoms, or R37and R38together represent -(CH2)4-, -(CH2)5-or -(CH2)2-NR39-(CH2)2- and form a ring with the nitrogen atom to which they are attached;

R39and R40independently selected from the group comprising hydrogen, alkyl with 1-6 carbon atoms, Ari is-(alkyl with 1-6 carbon atoms), phenyl and cycloalkyl with 3-15 carbon atoms, or R39and R40in the group-NR39C(O)R40together with the carbon atoms and the nitrogen to which they are attached, form a cyclic lactam, including 5-8 ring members;

R41-1-4 substituent, independently selected from the group comprising hydrogen, alkyl with 1-6 carbon atoms, alkoxy group with 1-6 carbon atoms, alkyl with 1-6 carbon atoms)substituted an amino group, di(alkyl with 1-6 carbon atoms)substituted an amino group, -OCF3HE is alkyl with 1-6 carbon atoms, -Cho and phenyl;

R42- 1-3 substituent, independently selected from the group comprising hydrogen, alkyl with 1 to 6 carbon atoms, alkoxy group with 1 to 6 carbon atoms;

R43- -NR30R31, -NR30C(O)R31, -NR30C(O)NR31R32, -NHSO2R30or-NHCOOR17;

R44- H, alkoxy group with 1-6 carbon atoms, -SOR16, -SO2R17, -C(O)OR17, - C(O)NR18R19, alkyl with 1-6 carbon atoms, halogen, foralkyl with 1-6 carbon atoms, diferuloyl with 1-6 carbon atoms, triptorelin with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, alkenyl with 2-6 carbon atoms, aryl(alkyl with 1-6 carbon atoms), aryl(alkenyl with 2-6 carbon atoms), heteroaryl(alkyl with 1-6 carbon atoms), heteroaryl(alkenyl with 2-6 carbon atoms), hydroxyalkyl with 1-6 carbon atoms is kind, amino(alkyl with 1-6 carbon atoms), aryl, thio(alkyl with 1-6 carbon atoms), alkyl with 1-6 carbon atoms, a substituted alkoxy group with 1-6 carbon atoms or alkyl with 1-6 carbon atoms)amino(alkyl with 1-6 carbon atoms); and

R45- H, alkyl with 1-6 carbon atoms, -COOR16or-SO2.

R2, R8, R10and R11each preferably denote hydrogen. R3preferably means hydrogen, HE, alkoxy group with 1-6 carbon atoms, -other18or alkyl with 1-6 carbon atoms. The variable n is preferably zero. R9- preferably H, HE or alkoxy group. R1- preferably alkyl with 1-6 carbon atoms, more preferably methyl. A double dotted line preferably represents a simple bond; X is preferably-O-, a Y - preferred =0 or (H, HE). In - preferably TRANS-CH=CH-. Het is preferably pyridyl, substituted pyridyl, chinolin or substituted chinosol. Preferred substituents (W) in the Het group is R21-aryl, R41-heteroaryl or alkyl. More preferred are compounds, in which the Het group is 2-pyridyl substituted in the 5-position, R21-aryl, R41-heteroaryl or alkyl, or 2-pyridyl substituted in the 6 position by alkyl. R34- preferably (N,N) or (N,HE).

R22and R23before occhialino are selected from the group including: IT, alkyl with 1-10 carbon atoms, alkenyl with 2-10 carbon atoms, quinil with 2-10 carbon atoms, trifter-alkyl with 1-10 carbon atoms, trifter-alkenyl with 2-10 carbon atoms, trifter-quinil with 2-10 carbon atoms, cycloalkyl with 3-7 carbon atoms, R25-aryl, R25-aryl-alkyl with 1-6 carbon atoms, R25-arylhydroxamic-alkyl with 1-6 carbon atoms, R25-aryl-alkoxy-alkyl with 1-6 carbon atoms, (cycloalkyl with 3-7 carbon atoms)-(alkyl with 1-6 carbon atoms), alkoxy group with 1-10 carbon atoms, (cycloalkyl with 3-7 carbon atoms)-hydroxy group, alkyl with 1-6 carbon atoms, a substituted alkoxy group with 1-6 carbon atoms, HE is alkyl with 1-6 carbon atoms, triptoreline group with 1-10 carbon atoms and R27-heteroseksualci-alkyl with 1-6 carbon atoms. Most preferred are compounds in which R22and R23independently selected from the group comprising alkyl with 1-10 carbon atoms and HE is alkyl with 1-6 carbon atoms.

Connection-antagonists thrombin receptor of the present invention have antidromically, antiatherosclerotic, antirestenotic, anticoagulatory activity and ability to inhibit platelet aggregation. Related thrombosis diseases that can be treated by the compounds of the present invention, are: thrombosis, at rocklers, restenosis, hypertension, angina, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, Trombitsky and thromboembolic stroke, peripheral vascular diseases, other cardiovascular disease, cerebral ischemia, inflammatory disorders and cancer, as well as other disorders in which thrombin and its receptor play a pathological role.

Compounds of the invention that bind to cannabinoid (SW) receptors that are applicable for the treatment of rheumatoid arthritis, systemic lupus erythematous, multiple sclerosis, diabetes, osteoporosis, renal ischemia, stroke, cerebral ischemia, nephritis, inflammatory diseases of the lungs and gastrointestinal tract, and respiratory diseases such as reversible obstruction of the Airways, chronic asthma and bronchitis.

This invention also relates to a method of using the compounds of formula I in the treatment of thrombosis, platelet aggregation, coagulation, cancer, inflammatory or respiratory diseases, including the introduction of the compounds of formula I to a mammal in need of such treatment. In particular, the present invention relates to a method of using the compounds of formula I in the treatment of thrombosis, atherosclerosis, restenosis, hypertension, angina, arrhythmia, heart failure, heart attack miokar is a, glomerulonephritis, termicheskogo strike, slow-bambolina stroke, diseases of the peripheral vessels, cerebral ischemia, cancer, rheumatoid arthritis, systemic lupus erythematous, multiple sclerosis, diabetes, osteoporosis, renal ischemia, stroke, cerebral ischemia, nephritis, inflammatory diseases of the lungs and gastrointestinal tract, reversible airway obstruction, chronic asthma or bronchitis. It is assumed that the compound of this invention may be applicable in the treatment of more than one of these diseases.

In another aspect, the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of the compounds of formula I in a pharmaceutically acceptable carrier.

Detailed description of the invention

If not defined otherwise, the term "alkyl" or "lower alkyl" means an unbranched or branched alkyl chain of 1-6 carbon atoms, similarly, the term "alkoxy" refers to alkoxy groups containing 1-6 carbon atoms.

Foralkyl, diferuloyl and triptorelin mean alkyl chain in which the terminal carbon atom is substituted by 1, 2 or 3 fluorine atoms, e.g.,- CF3, -CH2CF3, -CH2CHF2or-CH2CH2F. Haloalkyl means an alkyl chain substituted by 1-3 galeatomy.

The term "alkenyl" about the means unbranched or branched chains of carbon atoms, having in the chain one or more double bonds, paired or unpaired. Similarly, the term "quinil" means an unbranched or branched chain of carbon atoms having one or more triple bonds in the chain. In the case where the alkyl, Alchemilla or Alchemilla circuit connects the other two variables, and thus is a divalent, use the terms "alkylene", "albaniles and akinyan". Unless otherwise specified, alkeline and alkyline chain include 1-6 carbon atoms.

Substitution of alkyl, alkenyl and etkinlik circuits depends on the chain length and the size and nature of a substitute. Specialists in the art will understand that, while longer chains can carry multiple substituents, a shorter alkyl chain, for example, methyl or ethyl, can have multiple substituents of halogen atoms, in other cases, they probably can only have one or two substituent other than hydrogen. Shorter unsaturated chain, for example, ethynyl or ethinyl are usually unsubstituted, or Vice restricted to one or two groups depending on the number of available carbon bonds.

"Cycloalkyl" means a saturated carbon ring of 3 to 7 carbon atoms, and "cycloalkyl" means the corresponding divalent ring, which is designated with the unity with other groups include all positional and stereoisomers. "Cycloalkenyl" means carbon ring of 3 to 7 atoms containing one or more unsaturated bonds, but which is not aromatic.

"Heteroseksualci" means a saturated ring of 5 or 6 atoms, containing 4-5 carbon atoms and 1 or 2 heteroatoms selected from the group comprising: -O-, -S-and-NR7-connected with the rest of the molecule through a carbon atom. Examples geterotsiklicheskikh groups are 2-pyrrolidinyl, tetrahydrothiophene-2-yl, tetrahydro-2-furanyl, 4-piperidinyl, 2-piperazinil, tetrahydro-4-pyranyl, 2-morpholinyl and 2-thiomorpholine.

"Halogen" refers to fluorine-, chlorine-, bromine - or iodine-radicals.

In the case when R4and R5connected and form a ring with the nitrogen atom to which they are attached, are obtained following rings: 1-pyrrolidinyl, 1-piperidinyl and 1-piperazinil where piperazinilnom ring may be substituted by a group R7the nitrogen atom in the 4 position.

"Dihydroxy-alkyl with 1-6 carbon atoms" refers to an alkyl chain substituted by two hydroxyl groups at two different carbon atoms.

"Aryl" means phenyl, naphthyl, indenyl, tetrahydronaphthyl or indanyl.

"Heteroaryl" means a single ring or fused with benzene ring heteroaromatic group of 5 to 10 atoms, including 2-9 carbon atoms and 1-4 heteroatoms independently selected from the group, Lucaya of N, O and S, provided that the rings do not include adjacent oxygen atoms and/or sulfur. Also includes N-oxides of the ring nitrogen atoms, and compounds in which the ring nitrogen atom is substituted by an alkyl group with 1-4 carbon atoms with the formation of the Quaternary amine. Examples of heteroaryl groups from one ring is pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolin, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and thiazolyl. Examples of heteroaryl groups fused with a benzene ring, are indolyl, hinely, ethanolic, phthalazine, benzothiazyl (i.e. tianeptine), benzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl. Also this includes all positional isomers, for example, 2-pyridyl, 3-pyridyl and 4-pyridyl. W-substituted heteroaryl refers to such groups in which the ring carbon atoms which may be substituted, the substituents defined above, or in which adjacent carbon atoms form a ring with alkalinous or methylenedioxy group, or in which the nitrogen atom in the ring Het can be substituted for R21the aryl or optionally substituted alkyl Deputy defined in W.

The term "Het" means a single ring group fused with a benzene ring, as described above, and the e tricyclic group, such as benzoquinoline (for example, 1,4-or 7,8) or phenanthroline (for example, 1,7; 1,10; or 4.7). Het group connected to the group via a ring carbon atom, for example, Het is 2-pyridyl, 3-pyridyl or 2-chinolin.

Examples of heteroaryl groups in which adjacent carbon atoms form a ring with alkalinous group, are 2,3-cyclopentenopyridine, 2,3-cyclopentenopyridine and 2,3-cycloheptatrien.

The term "optional double bond" refers to the relationship indicated by single dotted line in the middle of the ring structure shown in formula I. the Term "optional simple communication" refers to communication identified in the structure of formula I by a double dotted line between X and the carbon atom that is attached to Y and R15.

The above claims, in which, for example, indicated that R4and R5independently selected from the group of substituents, means that R4and R5are selected independently, and that if the variables R4and R5meet in the molecule more than once, these substituents are selected independently. Specialists in the art will understand that the size and nature of the substituent(s) affect the number of possible substituents.

In the compounds of the present invention has at least one asymmetric carbon atom and therefore all isomers, including deastore the measures and isomers of rotation, considered as an integral part of this invention. The invention includes the (+) -and (-) -isomers both in pure form and as mixtures, including racemic mixtures. The isomers can be obtained by using traditional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of compounds of formula I.

Typical preferred compounds of the present invention have the following stereochemistry:

moreover, the connection just with this stereochemistry is preferred.

Specialists in the art will understand that for some compounds of formula I, one isomer will have greater pharmacological activity than other isomers.

Compounds of the invention with the main group can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of acids suitable for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methansulfonate and other mineral and carboxylic acids well known to specialists in this field of technology. Salt is produced by interaction of the free base with a sufficient quantity is STV desired acid. The free base can be restored by treatment of the salt with a suitable dilute aqueous basic solution, such as diluted aqueous solution of sodium carbonate. The free base is slightly different from its corresponding salt by certain physical properties, such as solubility in polar solvents, but otherwise for the purposes of the invention the salt is equivalent to the corresponding free base.

Some compounds of the invention are acidic (for example, those compounds which have a carboxyl group). These compounds can form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are salts of sodium, potassium, calcium, aluminum, lithium, gold and silver. Also includes salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines followed, hydroxyethylamine, N-methylglucamine and the like.

Compounds of the present invention, generally, the benefits of using processes known in the art, for example, processes described below.

The compounds of formula IA, where n is 0, the optional double bond is absent, a simple relationship exists between X and the carbon atom is linked to Y, X Is-O-, Y =O, - CH=CH-, Het means W-substituted pyridyl, R3, R8, R9, R10 and R11each is hydrogen, a R1and R2match the definitions above can be obtained by condensation of an aldehyde of the formula II, where the variables correspond to the definitions above, with a phosphonate of formula III, where W correspond to the definitions above:

Similar processes can be used to obtain compounds including other optionally substituted Het group. Specialists in the art will understand that the processes are equally applicable to obtain optically active or racemic compounds.

The compounds of formula IA can be converted into the corresponding compounds in which R3IT means, by treatment with reagent Davis ((1S)-(+)-(10-camphorsulfonic)-oxaziridine) and LHMDS (bis(trimethylsilyl)amide and lithium).

The aldehydes of the formula II can be obtained from diene acids, for example, the compounds of formula IIa, where R1means N, and R2means methyl, can be obtained according to the following reaction scheme.

Scheme I:

Alkyne of formula 4 obtained by the known methods etherification with diene acid of formula 3 under normal conditions with the formation of ester 5. Selective restoration of the triple bond of compound 5 using Lindlar catalyst is in the atmosphere of hydrogen gives the intermediate compound 6, which by thermal cyclization at a temperature of about 185°With subsequent treatment with base gives the intermediate compound 7. Ether 7 is subjected to hydrogenation in the presence of platinum oxide to produce an intermediate saturated carboxylic acid, the treatment of which the acid chloride oxalic acid gives the corresponding acid chloride of the acid, which is converted into the aldehyde IIa recovery when using anti-hydride in the presence of palladium catalyst.

Diene acid of formula 3 are commercially available or easily obtained.

The aldehydes of the formula II can also be obtained by opening thiopyrano rings, for example, the compounds of formula IIa as described above, can be obtained according to the following reaction scheme.

Scheme 2:

Alkyne of formula 4 to restore alkene 13 when using Lindlar catalyst in hydrogen atmosphere. Alkene 13 atrificial diene acid of formula 12 in normal conditions, receive ester 14. After thermal cyclization at approximately 185°followed by treatment of the base receive the intermediate connection 15. Ester 15 is converted into the intermediate carboxylic acid and restore the double bond by hydrogenation in the presence of platinum ka is alistor. Then the acid is treated with acid chloride oxalic acid, receive the corresponding acid chloride of the acid, which is converted into the aldehyde 18 recovery when using anti-hydride in the presence of palladium catalyst. Aldehyde fragment of compound 18 is treated regenerating agent type NaBH4and sulfur-containing ring then unlock the treatment reagent type of Raney Nickel, to obtain the alcohol 19. Then the alcohol is oxidized to aldehyde, IIa, when using perruthenate tetrapro-Philarmonia (TRR) in the presence of 4-methylmorpholine N-oxide (NMO).

The phosphonates of formula III, in which W is aryl or R21-aryl, can be obtained when using a process similar to that described below for obtaining triforma-terphenyl-substituted compounds IIIa.

Commercially available derivative of hydroxypyridine when using trip-plate anhydride is converted into the corresponding triflate, which is then combined with commercially available Bronevoy acid in the presence of Pd(0) in the conditions of the Suzuki. The resulting product is converted into the phosphonate by treatment with n-butyllithium with subsequent quenching by diethylphosphonate.

Otherwise, the compounds of formula I in which W is optionally substituted aryl, can be obtained from compounds of the formula I, in which W oznacza is t-HE when using triflate intermediate product. For example, 3-hydroxy-6-methylpyridin process triisopropylsilyl chloride obtained secure IT group is transformed into the phosphonate as described above, when receiving the intermediate product IIIa. Then triisopropylsilyl-protected intermediate product is introduced into the reaction intermediate product II and remove the protective group under standard conditions. Then, the obtained compound of the formula I, in which W-IT, process triflate anhydride at room temperature in solvent type CH2Cl2; then triplet enter into reaction with optionally substituted by arylboronic acid, for example, optionally substituted his phenylboronic acid, solvent type, toluene, in the presence of Pd(PPh3)4and substrate type K2CO3at elevated temperatures in an inert atmosphere.

The compounds of formula I in which W is substituted by hydroxyl group (e.g. benzyloxy), can be obtained from compounds of the formula I in which W is a hydroxy group, by heating under reflux in a suitable solvent, such as acetone, with a halogen-substituted compound, such as optionally substituted benzyl bromide, in the presence of a base type To a2CO3.

The compounds of formula I in which the group Het is substituted by W is via a carbon atom (for example, in which W is alkyl, alkenyl or arylalkyl) or nitrogen atom (i.e.- NR4R5), can be obtained as shown in Scheme 3, using as an intermediate product of the compounds of formula I in which W means chloroalkyl. The compounds of formula I in which W is a polar group, such as hydroxyalkyl, dihydroxyethyl, -COOH, dimethylamino and SLEEP, can be obtained as shown in Scheme 4, where the source is a compound of formula I, in which W - alkenyl. The following Diagrams 3 and 4 show the well-known reaction conditions for various W-substituted compounds in which X Is-O-, Y=O, R15no, R1is methyl, R2, R3, R9, R10and R11each-H, - CH=CH-, a Het is 2-pyridyl.

Scheme 3

Specialists in the art will understand that reaction, similar to that shown in the diagrams, can be performed with other compounds of formula I, if present Vice-resistant described reaction conditions.

The compounds of formula I in which the optional simple relationship (represented by a double dotted line) is absent, X is HE, Y means HE, R15means N, and the remaining variables correspond to the definitions above, you can get treatment regenerating agent type is'lah (socialogical) of the respective compounds, in which optional simple bond is present, X is-O-, Y represents =O, and R15is missing.

The compounds of formula I in which the optional simple bond is present, X is-O-, Y represents (H, HE), R15no, and the remaining variables correspond to the definitions above, can be obtained by treatment with a reagent of the type DIBAL (hydride diisobutylaluminum) of the corresponding compounds in which optional simple bond is present, X Is-O-, Y=O and R15no. The compounds in which Y represents (H, HE) can be translated into the corresponding compounds in which Y represents H, alkoxy) by the reaction of hydroxy compounds with the corresponding alkanol in the presence of reagent type BF3•OEt2. The compound in which Y represents (H, HE), can also be converted into the corresponding compound in which Y represents the (N, N), processing hydroxy-link BF3•OEt2and Et3SiH in an inert solvent type CH2Cl2at low temperature.

The compounds of formula I in which R9- N, can be converted into the corresponding compounds in which R9is hydroxy, by heating with an oxidizer type of SeO2.

The compounds of formula IB, in which R2- N, R3- H or HE, a W1- R21-aryl, R41- heteroaryl, amino or hydroxyamino deposition is Noah, can be obtained from compounds of the formula IA, in which W is 5-bromo-(compounds of formula 23 or 24), using a number of standard chemical reactions such as the Suzuki reaction, the accession of Stella and Buchwald amination. Figure 5 presents the process for 2.5-dibromopyridine:

Figure 5:

Phosphonate 22 is obtained from the known alcohol 21 in two stages: the alcohol is treated with CH3SO2Cl, get mesilate, which is then replaced by diethylpopion sodium and receive connection 22. The intermediate product 23 can also α-hydroxypyruvate when using reagent Davis to get alcohol 24. And 23, and 24 can be converted into various analogs, as shown in Scheme 6:

Scheme 6:

As shown in Scheme 6, bromide (23 or 24) can be connected with baronowie acids in terms of palladium catalysis (method 1). If Bronevoy acid has a functional group, it can then convert. Similarly, you can connect connection alloleva (method 2), aryl-zinc compounds (method 3) and amines (method 4). For the Heck reaction with vinyl ethers can be entered keto-group, which can then be functionalized (method 5). The imidazoles can be connected when using triflate, copper (I) as catalyst (method 6). Bromide can also pre is ratite in cyanide, which can be subsequently converted, for example, in tetrazol (method 7).

When using the Diels-alder reaction as shown in Scheme 7, it is possible to connect a number of diene acids 3 with alcohol 25 and ester 26 can be subjected to thermal cyclization to obtain a product of the Diels-alder reaction IC:

Scheme 7:

Alcohol 25 is obtained from readily available (R)-(+)-3-butyn-2-ol 27. Alcohol protects as its TBDPS ether (tert-butyldiphenylsilyl ether), alkyne deprotonated and treated with paraformaldehyde, get the alcohol 29. Alkyne reduced to CIS-alkene using Lindlar catalyst in the presence of quinoline, allyl alcohol is oxidised to receive the aldehyde 30, which is converted into alcohol 25.

The compounds of formula ID, in which R is-CH2OS(O)CH3or its derivative, R23is ethyl, R2means N, and the remaining variables correspond to the definitions for IA can be obtained from the corresponding tetrahydropyran-similar by breaking the ring. The compounds of formula ID can be converted into other compounds of formula I, for example, the compounds of formula IE, in which R22means-CH2HE, using well known methods. The reaction is shown in Scheme 8.

Scheme 8:

Similar tetrahydropyran 31 can be obtained from 3-formyl-5,6-dihydro-2H-p is wound (known compound), using a procedure similar to that shown in Scheme 1. The ring can regioselective open when using BBr3and alcohol can be protected by conversion to the acetate ID. After recovery of bromide NaCNBH3followed by acetate unprotect get alcohol IE.

Starting compound for the above-described processes or are commercially available, known in the art, or obtained by using processes well known in the art.

Reactive groups not involved in the above processes can be protected during the reaction the usual protective groups which can be removed after the reaction by standard methods. The following Table shows some typical protective groups:

Table a
Protected groupThe protected group and the Protective group
-COOH-Coolkill-Zoobenthic-Soothenol
-NH2
-HE

The present invention also relates to Pharma is eticheskoi composition, comprising the compound of formula I of this invention and a pharmaceutically acceptable carrier. The compounds of formula I can be applied in any conventional dosage form for oral administration such as capsules, tablets, powders, pills, suspensions or solutions. The compounds and pharmaceutical compositions can be obtained by using conventional pharmaceutically acceptable excipients and additives and conventional techniques. Such pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, components, dezintegriruetsja agents, buffers, preservatives, antioxidants, lubricants, flavorings, thickening agents, colorants, emulsifiers and the like.

Daily dose of the compounds of formula I for the treatment of a disease or condition specified above is from about 0.001 to 100 mg/kg of body weight per day, preferably from about 0.001 to 10 mg/kg Thus, for an average body weight of 70 kg, the dosage level is from about 0.1 to 700 mg of drug per day in a single dose or 2-4 fractional doses. The exact dose, however, determined by the treating physician and depends on the strength of the applied compound, the age, weight, condition and response of the patient.

The following examples of the preparation of starting materials and compounds of formula I. In procedures is used the following abbreviations: room temperature (CT), tetrahydrofuran (THF, THF), diethyl ether (Et2O), methyl (Me), ethyl (Et), ethyl acetate (EtO2AU), dimethylformamide (DMF, DMF), 4-dimethylaminopyridine (DMAP, DMAP), 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), 1,3-dicyclohexylcarbodiimide (DSDC).

Process 1

Stage 1:

Cm. J. Org. Chem., 59 (17) (1994), page 4789.

Step 2:

To a suspension of 60 % NaH (7,42 g, 185,5 mmol, 1.3 EQ.) in 300 ml of THF at 0°C was added dropwise triethylphosphate (37 ml, 186,5 mmol, 1.3 EQ.) and the mixture was stirred at 0°30 minutes was Added the product of Step 1 (14.0 g, 142,7 mmol) and the mixture was stirred at 0°30 minutes the Reaction was stopped by addition of an aqueous solution of NH4Cl (500 ml), THF was evaporated and the aqueous phase was extracted with 3×200 ml Et2O, and the combined organic layer was washed brine (300 ml), dried over MgSO4, was filtered and was evaporated, received the crude mixture, which was chromatographically (5% Et2O-hexane), was obtained 18,38 g (yield 77%) of liquid.

1H NMR (400 MHz, CDCl3) 7,29 (d, 1H, J=15,4), 5.86 (t, 1H, J=7,4), USD 5.76 (d, 1H, J=15,4), 4,18 (q, 2H, J=7,2), 2,22-of 2.15 (m, 2H), 1,74 (d, 3H, J=0,7), of 1.27 (t, 3H, J=7,2), 1.00(t,3H,J=7,7)

13With NMR(100 MHz,CDCl3) 167,29, 149,38, 143.45, 132,04, 115,39, 60,08,22,14, 14,42, 13,58, 12,05

MS: 169 (MN+)

Step 3:

To a solution of the product of Step 2 (6.4 g, 3 mmol) in THF and the Meon (40 ml each) was added a solution of KOH (6.4 g, 114 mmol, 3 EQ.) in N2O (40 ml). The mixture was stirred at room temperature for 2 hours, cooled to 0°and added N2O (100 ml), and 1.HCl (150 ml). The mixture was extracted with EtOAc (3×100 ml), the combined organic layer was washed H2O (150 ml) and brine (150 ml), dried over MgSO4, was filtered and was evaporated, got 5,26 g (yield 99%) of crystalline solid.

1H NMR (400 MHz,CDCl3) 7.40 (d, 1H, J=16), 5.95 (t, 1H, J=7.2), 5.79 (d, 1H, J=16), 2.26-2.19 (m, 2H), 1.78 (s, 3H), 1.04 (t, 3H, J= 7.6)

Step 4:

To a solution of the product of Step 3 (2.0 g, of 14.3 mmol) in CH2Cl2(70 ml) was added sequentially acid chloride oxalic acid (2.5 ml, 28.7 mmol, 2 EQ.) and DMF (33 μl, 3 mol%). The mixture was stirred at room temperature for 1 hour, then evaporated the solvent, was obtained the crude acid chloride acid, which was dissolved in CH2Cl2(70 ml) and cooled to 0°C. was Added DMAP (175 mg, 1,43 mmol, 0.1 EQ.) and a solution of alcohol 4 (2,62 g, 12.8 mmol, 0.9 EQ.) in CH2Cl2(5 ml), then Et2N (4 ml, 28.7 mmol, 2 EQ.). The mixture was stirred at 0°2 hours, diluted with Et2O (200 ml), washed with aqueous solution of NaHCO3and brine (200 ml each) and dried over MgSO4. The solution was filtered, concentrated, the obtained residue was chromatographically (5% EtOAc - hexane), was obtained of 3.56 g (85 %) of light yellow what about the resinous substance.

1H NMR (400 MHz, CDCl3) 7.38-7.33 (m, 6H), 5.93 (t, 1H, J=7.4), 5.77 (d, 1H, J=15.6), 5.62 (q, 1H, J=6.2), 5.20 (s, 2H), 2.25-2.18 (m, 2H), 1.76 (d, 3H. J=0.4), 1.58 (d. 3H, J=6.2),1.03(t,3H,J=7.4)

Step 5:

To a solution of the product of Step 4 (3,19 g, 9.8 mmol) in THF (50 ml) was added Lindlar catalyst (320 mg, 10 wt.%) and quinoline (230 μl, 2.0 mmol, 0.2 EQ.). The suspension was stirred under 1 ATM. H2to transform the source material. The solution was filtered through celite and evaporated. The resin was dissolved in EtOAc (250 ml) and washed 1.HCl (3×100 ml) and the salt of rastvorom (100 ml). The solution was dried over MgSO4, was filtered and was evaporated, got 3,17 g of the crude alkene which was directly used in the next step.

Step 6:

A solution of the product of Step 5 (3,15 g, 9.6 mmol) in m-xylene (100 ml) was heated at 185°10 an hour. The solution was cooled to room temperature and stirred for 1 hour with DBU (290 μl, 1.94 mmol, 0.2 EQ.). The solvent was evaporated, the crude product was chromatographically (10% EtOAc - hexane), was obtained 1.1 g (35 %)Exoproduct.

1H NMR (400 MHz, CDCl3) 7.38-7.34 (m, 5H), 5.45 (br s, 1H), 5.14 (ABq, J=12.0, 22.8, 2H), 4.52 (dq, J=6.1, 8.1, 1H), 3.26-3.23 (m, 1H), 2.87 (dd, J=9.4, 4.6, 1H), 2.62 (dt, J=8.1, 4.5, 1H), 2.54 (br s, 1H), 1.71 (t, J=1.2, 3H), 1.69-1.60 (m, 1H), 1.50-1.44 (m, 1H), 1.20 (d, J=6.4, 3H), 0.77 (t, J=7.4, 3H)

13With NMR (100 MHz, CDCl3) 175.25, 173.04, 137.86, 135.00, 128.38, 128.34, 128.30, 116.54, 76.64, 66.70, at 42.85, at 42.14, 41.40, 37.27, 22.52, 21.65, 20.44, 8.9 [α ]22D=-64.4(c1,CH2Cl2)

Msvr: 329.1754 calculated 329.1753

Step 7:

To a solution of the product of Step 6 (1.35 g, 4.1 mmol) in EtOAc (30 ml) was added 10%Pd-C (140 mg, 10 %weight) and the suspension was stirred under a balloon with H25 hours. The mixture was filtered through celite, concentrated. The crude material was dissolved in Meon (30 ml), was added PtO2(100 mg) and the mixture was shaken in a vessel Parra at 50 lb/in2H2within 2 days. The mixture was filtered through celite and evaporated, got 980 mg (99 %) of the acid in the form of foam.

1H NMR (400 MHz, CDCl3) 4.73-4.66 (m, 1H), 2.71 (dd, J=11.8, 5.4, 1H), 2.68-2.62 (m, 1H), 2.53 (dt, J=10.0, 6.4, 1H), 1.92 (ddd, J= 13.4, 6.0, 2.6, 1H), 1.63-1.57 (m, 1H), 1.52-1.20 (unresolved m, 3H), 1.30 (d, J=5.9, 3H), 0.96 (d, J=6.6, 3H), 0.93-0.89 (m, 1H), 0.80 (t, J=7.5, 3H)

MS:319.1 (MN+DMSO)

Step 8:

To a solution of the product of Step 7 (490 mg, 2.04 mmol) in CH2Cl2(20 ml), was added the acid chloride oxalic acid (360 μl, 4,13 mmol, 2 EQ.) and 1 drop of DMF. The solution was stirred at room temperature for 1 hour, solvent was removed, was obtained the crude acid chloride acid, which was dissolved in toluene (20 ml) and cooled to 0°C. To this solution was added Pd(PPh3)4(236 mg, 0.20 mmol, 0.1 EQ.), then Bu3SnH (825 μl, of 3.07 mmol, 1.5 EQ.). The mixture was stirred 3 hours at 0°With concentrated and chromatographical the Lee (25% EtOAc - hexane), was obtained 220 mg of target compound (48 %) in the form of resin.

1H NMR (400 MHz, CDCl3) 9.72 (d, J=3.6, 1H), 4.70 (dq, J=5.7, 9.5, 1H), 2.71-2.64 (m, 2H), 2.56-2.51 (m, 1H), 1.98 (ddd, J=13.5, 6.1, 2.9, 1H), 1.68-1.59 (m, 3H), 1.52-1.37 (m, 1H), 1.36 (d, J=5.9, 3H), 1.32-1.20 (m, 1H), 1.00 (d, J=6.2, 3H), 0.80 (d, J=7.3, 3H)

Process 2

Stage 1:

Thiopyran anal received according to the procedure described McGinnis and Robinson, J. Chem. Soc., 404 (1941), 407.

Step 2:

To a suspension of 60% NaOH (6.3 g, 158 mmol, 1.3 EQ.) in THF (200 ml) at 0°With added metiltiofosfonata (29 ml, 158 mmol, 1.3 EQ.) and stirred the reaction mixture at 0°With 30 minutes. Then the solution was transferred into a solution of the product of Step 1 (15.6 g, 122 mmol) in THF (100 ml) and stirred at 0°With 1 hour. The reaction was stopped by addition of an aqueous solution of NH4Cl (500 ml) and THF was evaporated. The aqueous phase was extracted with Et2O (3×200 ml) and the combined organic layer was washed N2O and brine (200 ml each). The solution was dried over MgSO4was concentrated and the obtained residue was chromatographically (5% EtOAc - hexane), was obtained 13,0 g (58%), oily substance.

1H NMR (400 MHz, CDCl3) 7.26 (d, J=15.9 Hz, 1H), 6.26 (t, J=4.4 Hz, 1H), 5.78 (dd, J 15.9, 0.6 Hz, 1H), 3.75 (s, 3H), 3.25-3.23 (m, 2H), 2.71 (t, J=5.8 Hz, 2H), 2.57-2.53 (m, 2H).

Step 3:

To a solution of the product E. the APA 2 (13,0 g, 70,6 mmol) in THF and the Meon (50 ml each) was added a solution of KOH (11.9 g, 212 mmol, 3.0 EQ.) in N2O (50 ml). The reaction mixture was stirred at room temperature for 1 hour, diluted with H2O (100 ml) and acidified using 1 N. HCl. The aqueous phase was extracted with EtOAc (3×200 ml) and the combined organic layer was washed N2O and brine (300 ml each). The solution was dried over MgSO4, was filtered and was evaporated, got 11,66 g (97%) of light yellow solid.

1H NMR (400 MHz, CDCl3) 7.34 (d, J=15.6 Hz, 1H), 6.32 (t, J=4.4 Hz, 1H), 5.78 (d, J=15.6 Hz, 1H), 3.26 (d,J=1.6 Hz, 2H), 2.72 (t, J=5.8 Hz, 2H), 2.59-2.55 (m, 2H).

Step 4:

To a solution of 4 (5,2 g) in EtOAc (120 ml) was added Lindlar catalyst (520 mg) and was stirred suspension at 1 ATM. H2. After 45 minutes was added the next portion of the catalyst (500 mg) and stirred the reaction mixture for another 30 minutes. The mixture was filtered through a layer of celite and evaporated, got 5,2 g (99%) of the desired alkene.

1H NMR (400 MHz, CDCl3) 7.38-7.26 (m, 5H), 6.32 (dd, J=11.9, 6.6 Hz, 1H), 5.86 (d, J=12.0 Hz, 1H), 5.18 (s, 2H), 5.12-5.07 (m, 1H), 3.20 (br s, 1H), 1.34 (d, J=6.6 Hz, 3H).

Step 5:

To a solution of the product of Step 3 (2,45 g, 14,39 mmol) in CH2Cl2(60 ml) at 0°With added sequentially DCC (3,27 g, 15,85 mmol, 1.1 EQ.) and DMAP (352 mg, is 2.88 mmol, 0.2 EQ.) and stirred the reaction mixture at 0°With 30 minutes. Add the Yali solution of 3.27 g (15,85 mmol, 1.1 EQ.) the alcohol from Step 4 in 10 ml of CH2Cl2and stirred for 5 hours at 0°and 1 hour at room temperature. The solution was diluted with 350 ml of Et2O and washed 2×200 ml of an aqueous solution of citric acid, 200 ml aqueous solution of NaHCO3and 200 ml of saline solution. The solution was dried over MgSO4was filtered , concentrated and the obtained residue was chromatographically (6% EtOAc - hexane), was obtained 2.1 g (41%) of resin.

1H NMR (400 MHz, CDCl3) 7.38-7.32 (m, 5H), 7.45 (d, J=16.0 Hz, 1H), 6.38-6.34 (m, 1H), 6.26 (t, J=4.6 Hz, 1H), 6.21 (d, J=11.6 Hz, 1H), 6.19 (d, J=11.2 Hz, 1H), 5.85 (dd, J=11.6, 1.2 Hz, 1H), 5.76 (d, J=16.0 Hz, 1H), 5.18 (d, J=1.2 Hz, 2H), 3.24 (d, J=2.0 Hz, 2H), 2.71 (t, 2H, J=5.6 Hz, 2H), 2.56-2.52 (m, 2H), 1.41 (d, J=6.4 Hz, 3H)

Step 6:

A solution of the product of Step 5 (2.1 g, of 5.85 mmol) inm-xylene (50 ml) was heated at 200°6 hours in a sealed vessel. The solution was cooled to room temperature and was stirred with DBU (178 μl, 1,19 mmol, 0.2 EQ.) 1 hour, concentrated and chromatographically (15% EtOAc - hexane), was obtained 1.44 g (69%) of the desiredExoproduct.

1H NMR (400 MHz, CDCl3) 7.39-7.35 (m, 5H), 5.46 (br s, 1H), 5.16 (ABq, J=21.6, 12.0 Hz, 2H), 4.42 (dq, J=9.2, 6.0 Hz, 1H), 3.36-3.33 (m, 2H), 3.08 (dd, J=14.4, 2.4 Hz, 1H), 2.85 (ddd, J= 13.9, 12.4, 2.5 Hz, 1H), 2.72-2.57 (m, 4H), 2.27-2.21 (m, 1H), 1.47-1.25 (m, lH),1.12(d,J=Hz,3H)

Step 7:

To a solution of the product of Step 6 (750 mg, 2?09 mmol) in CH2Cl2(10 ml) at -78°With added BBr3 in CH2Cl2(4,2 ml of 1M solution). The solution was stirred 30 minutes at -78°and for 30 minutes at 0°C, then poured into an aqueous solution of K2CO3(100 ml). The aqueous phase is washed with Et2O (2×50 ml) and again were extracted organic layer with an aqueous solution To a2CO3(50 ml). The combined aqueous phase was acidified using 1 N. HCl and was extracted with EtOAc (3×50ml). The EtOAc layer washed with brine (50 ml), dried over MgSO4, was filtered and was evaporated, received 500 mg (89%) of acid.

1H NMR (400 MHz, CDCl3) 5.50 (br s, 1H), 4.47 (dq, J=9.6, 6.0 Hz, 1H), 3.43-3.39 (m, 1H), 3.36 (d, J=15.6 Hz, 1H), 3.10 (dd, J= 14.0, 2.4 Hz, 1H), 2.91-2.84 (m, 1H), 2.82-2.77 (m, 1H), 2.70 (dd, J=10.6, 4.2 Hz, 1H), 2.69-2.63 (m, 1H), 2.57-2.52 (m, 1H), 2.34-2.29 (m, 1H), 1.53-1.42 (m, 1H), 1.34 (d, J=6.0 Hz, 3H).

Step 8:

To a solution of the product of Step 7 (500 mg, of 1.86 mmol) in Meon (30 ml) was added Asón (3 ml) and PtO2(250 mg) and was dissolved in the suspension at 40 lbs/inch2H2in the vessel Parra for 1.5 days. The catalyst was filtered through a layer of celite, the solution was concentrated and the obtained residue was dissolved in a mixture of AcOH-MeOH-CH2Cl2(0.5:2:97.5 about./about./about.) and filtered through a short column with SiO2received 400 mg (79%) of recovered product in the form of a resin, which when standing hardened.

1H NMR (400 MHz, CDCl3) 4.68 (dq, J=9.4, 5.9 Hz, 1H), 2.76-2.69 (m, 2H), 2.60-2.55 (m, 3H), 2.49 (d, J=11.6 Hz, 1H), 2.10 (br s, 1H), 1.93 (ddd, J=13.5,6.0, 2.7 Hz, 1H), 1.60-1.48 (m, 2H), 1.45-1.19 (m, 3H), 1.33 (d, J=5.6 Hz, 3H).

Step 9:

To a solution of the product of Step 8 (97 mg, 0.36 mmol) in CH2Cl2(4 ml) was added sequentially acid chloride oxalic acid (94 μl) and 1 drop of DMF. The solution was stirred 1 hour at room temperature and concentrated, received the crude acid chloride acid, which was dissolved in toluene (3 ml) and cooled to 0°C. Sequentially added Pd(PPh3)4(42 mg, 0.04 mmol, 0.1 EQ.) and Bu3SnH (94 μl). The reaction mixture was stirred at 0°3 hours, concentrated and the HRO-maturational (25% EtOAc - hexane), was obtained 73 mg (80%) of the aldehyde as a white solid.

1H NMR (400 MHz, CDCl3) 9.75 (d, J=2.8 Hz, 1H), 4.62 (dq, J=9.7, 6.0 Hz, 1H), 2.8-2.70 (m, 2H), 2.65-2.55 (m, 3H). 2.50 (d, J=7.2 Hz), 2.10 (ddd, J=13.2, 6.4, 3.0 Hz, 1H), 1.94 (ddd, J=13.6, 6.0, 3.0 Hz, 1H), 1.69 (dq, J=10.9 Hz, 3.00 Hz, 1H), 1.58-1.48 (m, 1H), 1.42-1.20 (m, 3H), 1.33(d, J=6.4 Hz, 3H).

Step 10:

To a solution of the product of Step 9 (90 mg, 0.35 mmol) in Meon (10 ml) (4:1 vol./about.) when 0°With added excess NaBH4and the reaction mixture was stirred 15 minutes at 0°C. the Reaction was stopped in an aqueous solution of NH4Cl (50 ml) and was extracted with EtOAc (3×20 ml). The combined organic layer was washed brine (50 ml), dried over MgSO4and concentrated, received the crude alcohol. A solution of the alcohol in the Meon-THF (6 ml, 1:1 vol./about.) added is in the flask with excess Raney Nickel, washed with dioxane and THF. The suspension was heated under reflux for 3 hours, cooled, filtered, concentrated and chromatographically (25% EtOAc - hexane), was obtained 54 mg (67%) of target compound in the form of resin.

1H NMR (400 MHz, CDCl3) 4.70 (dq, J=9.7, 5.9 Hz, 1H), 3.73 (dd, J=10.5, 3.4 Hz, 1H), 3.62 (dd, J=10.5, 7.6 Hz, 1H), 2.60-2.53 (m, 1H), 2.46 (ddd, J == 9.6, 7.2, 5.2 Hz, 1H), 1.90 (ddd, J= 13.5, 6.1, 3.1 Hz, 1H). 1.87-1.81 (m,1H), 1.77 (brs. 1H), 1.66-1.59 (m.lH), 1.50 (d, J=6.0 Hz, 3H), 1.48-1.36 (m, 2H), 1.25-1.14 (m, 2H), 0.93 (d, J=6.6 Hz, 3H), 0.78 (d, J=7.5 Hz, 3H)

13With NMR (100 MHz, CDCl3) 178.58, 77.63, 61.79, 45.10, 42.49, 39.37, 38.65, 33.44, 31.96,21.39,19.91,19.74,7.26.

Process 3

Obtained according to the procedure described by Wang et. al. Tet. Lett, 41, (2000), R-4338.

Step 2:

To a solution of the product of Step 1 (20 g, 106 mmol) and Et3N (of 17.8 ml, 128 mmol, 1.2 EQ.) in CH2Cl2(300 ml) at ˜ -30°slowly added CH3SO2Cl (9.1 ml, 118 mmol, 1.1 EQ.). The suspension was stirred for 1 hour, until it was warmed to 0°C. the Reaction mixture was diluted aqueous solution of NaHCO3(500 ml) and the separated organic layer.

The aqueous layer was extracted with Et2O (2×200 ml) and the combined organic layer was washed in an aqueous solution of NaHCO3(2×300 ml) and brine (300 ml).

The solution was dried over MgSO4, was filtered and was evaporated, received untreated mesilate, which is directly used on the track is the next step.

1H NMR: 8.67 (d, J=2.0 Hz, 1H), 7.89 (dd, J=8.4, 2.4 Hz, 1H), 7.33 (d, J=8.4 Hz. 1H), 5.28(s,2H),3.10(s,3H).

Step 3:

To a suspension of 60% NaH (8.5 g, 212 mmol, 2.0 EQ.) in THF (500 ml) at room temperature was added dropwise diethylphosphate (27,1 ml, 213 mmol, 2 EQ.) and the reaction mixture was stirred for 1 hour. To this cloudy solution was added a solution of the product of Step 2 in THF (125 ml) and stirred the reaction mixture was stirred at room temperature for 1 hour. The reaction was stopped by addition of H2O (500 ml), THF was evaporated and the aqueous layer was extracted EtOAc (4×150 ml). The combined organic layer was washed with an aqueous solution To a2CO3(2×300 ml), brine (300 ml), dried over MgSO4was filtered , evaporated, and the crude product was chromatographically (5:95 CH3HE - CH2Cl2received and 31.7 g (97%), oily substance.

1H NMR: 8.59 (d, J=2.0 Hz, 1H), 7.76 (dd, J=8.2, 2.1 Hz, 1H), 7.29 (dd, J=8.2, 2.2 Hz, 1H), 4.12-4.05 (m, 4 H), 3.36 (d, J=22.0 Hz, 2H), 1.27 (t, J=7.0 Hz, 6N)

Process 4

To a solution of the product of the Process 3 (15 g, 49 mmol, 1.5 EQ.) in THF (100 ml) at 0°With added 1M LHMDS in THF (49 ml, 49 mmol, 1.5 EQ.) and the solution was stirred for 30 minutes. To him consistently added Ti(OPr)4(14.4 ml, 49 mmol, 1.5 EQ.) and a solution of the product of the Process 1 (7,3 g, 32 mmol) in THF (30 ml) and the reaction mixture was stirred at room temperature for 45 minutes. The solution is abbasli aqueous solution of potassium tartrate sodium (300ml) and THF was evaporated. The suspension was extracted with EtOAc (4×100 ml) and the combined organic layer was washed brine (100 ml), dried over MgSO4was filtered , concentrated and the crude product was chromatographically (15:85 EtOAc-hexane), was obtained 11.8 g (96%) foam.

1H NMR: 8.58 (d, J=2.4 Hz, 1H), 7.74 (dd, J=8.4, 2.8 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.55 (dd, J=15.6, 10.0 Hz, 1H), 6.45 (d, J=16.0 Hz, 1H), 4.75-4.68 (m, 1H), 2.69-2.56 (m, 2H), 2.32 (dt,J=10.1, 6.5 Hz, 1H), 1.98 (ddd, J= 13.4, 6.6, 2.8 Hz, 1H), 1.67-1.59 (m, 1H), 1.47-1.39 (m, 2H), 1.37 (d, J=5.9 Hz, 3H), 1.31-1.20 (m, 2H), 0.98 (d, J=6.2 Hz, 3H),0.73(t,J=7.5 Hz,3H)

Process 5

To a solution of the product of Process 4 (7.2 g, 19 mmol) in THF (100 ml) at -78°With added 1M LHMDS in THF (23 ml, 23 mmol, 1.2 EQ.). The solution was stirred 30 minutes at -78°C, 30 minutes at 0°and again cooled to -78°C. To this solution was added a solution of (1S)-(+)-(10-camphorsulfonic)oxaziridine (6.0 g, 26 mol, 1.4 EQ.) in THF (50 ml) and the mixture was stirred 1 hour at -78°and 1.5 hours at 0°C. To the solution was added an aqueous solution of NH4Cl (300 ml), THF was evaporated and the aqueous layer was extracted EtOAc (4×100 ml). The combined organic layer was washed brine (100 ml), dried over MgSO4was filtered , concentrated and the crude product was chromatographically (15:20:65 EtOAc-CH2Cl2-hexane), was obtained 6.4 g (85%) foam.

1H NMR: 8.56 (d, J=2.0 Hz, 1H), 7.72 (dd, J=8.4 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.56 (dd, J=15.6, 9.8 Hz, 1H), 6.48 (, J=15.6 Hz, 1H), 4.62-4.55 (m, 1H), 3.72 (br s, 1H), 2.80-2.74 (m, 1H). 2.28 (dd, J=9.6, 5.6 Hz, 1H), 1.81-1.78 (m, 2H), 1.63-1.58 (m, 1H), 1.44-1.27 (m, 3H), 1.37 (d, J=6.0 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 0.73 (t, J=7.5 Hz, 3H)

Process 6

Stage 1:

To a solution of (R)-(+)-3-butyn-2-ol (5 ml, 64 mmol) in CH2Cl2(100 ml) at room temperature was added DMAP (780 mg, 6.4 mmol, 0.1 EQ.), tert-butylchloroformate a (17.4 ml, 67 mmol, of 1.05 equiv.) and Et3N (9.8 ml, 70 mmol, 1.1 EQ.). The reaction mixture was stirred over night, diluted with Et20 (400 ml), washed 1.HCl (2×200 ml), aqueous solution of NaHCO3(200 ml), brine (200 ml), dried over MgSO4, was filtered and was evaporated, received ˜20 g of an oily material, which was used directly in the next step.

Step 2:

To a solution of the product of Step 1 in THF (200 ml) at -78°With added 2.5m BuLi in hexane (30,4 ml, 76 mmol, 1.1 equiv.) the solution was stirred for 1 hour and added solid paraformaldehyde (4.15 g, 138 mmol, 2.0 EQ.). The reaction mixture was stirred 15 minutes at -78°C, 1 hour at room temperature, then stop the reaction by adding aqueous solution of NH4Cl (500 ml). THF was evaporated and the aqueous phase was extracted with EtOAc (3×200 ml). The combined organic layer was washed H2O (2×300 ml) and brine (300 ml), dried over MgSO4was filtered , evaporated and the crude product chromatograph is listed (10% EtOAc - hexane), was obtained 16.5 g (71%) of resin.

1H NMR: 7.77-7.74 (m, 2H), 7.71-7.68 (m, 2H), 7.46-7.36 (m, 6H), 4.53 (tq, J=1.8, 6.5 Hz, 1H), 4.08 (dd, J=6.2, 1.8 Hz), 2.82 (d, J=6.4 Hz, 3H), 1.07 (s, 9H)

Example 1

To a solution of phosphonate (650 mg, a 2.01 mmol, 2 EQ.) in THF (8 ml) at 0°With added BuLi in hexano (790 μl of 2 M solution, 2.0 mmol, 2 equiv.) the mixture was stirred for 10 minutes, then was added Ti(OPr)4(590 μl, 2.0 mmol, 2 EQ.) and stirred the solution at room temperature for 10 minutes. Was added a solution of the product of the Process 1 (220 mg, 0.98 mmol) in THF (3 ml) and stirred the reaction mixture at room temperature for 1.5 hours. To the solution was added an aqueous solution of Rochelle salts (100 ml) and THF was evaporated. The aqueous phase was extracted with EtOAc (3×30 ml) and the combined organic layer was washed brine (50 ml). The solution was dried over MgSO4was concentrated and the obtained residue was chromatographically (20% EtOAc - hexane), was obtained target compound (240 mg, 62%) as a resin.

1H NMR (400 MHz, CDCl3) 8.78 (d, J=2.0, 1H). 7.82 (dd, J-2.4, 8.0, 1H), 7.44 (dt, J=5.7, 8.1, 1H), 7.36 (dt, J=1.2, 7.7, 1H), 7.30-7.25 (m, 2H), 7.09 (ddt, J=2.5, 1.0, 8.4, 1H), 6.61 (dd,J= 15.3, 8.6, 1H), 6.56 (d,J=15.3, 1H), 4.78-4.71 (t,1H), 2.71-2.61 (m, 2H), 2.36 (dt,J= 10.0, 6.4, 1H), 1.99 (ddd, J= 13.5, 6.1, 2.9. 1H), 1.68-1.61 (m,1H), 1.51-1.44 (m, 2H), 1.42 (d. J=5.9, 3H), 1.39-1.22 (m, 2H), 0.99 (d, J=6.6, 3H), 0.76 (t, J=7.5. 3H)

FAB MCBP (mass spectrometry high-resolution bombardment with accelerated atom is MIS): 394.2184, calculated: 394.2182

Calculated data analysis for C25H28FNO2·HCl: C, 69.84; H, 6.80; N, 3.26. Obtained: C, 71.00; H, 6.96; n 3.19.

Using similar procedures with the appropriate phosphonate was obtained compound 1A:

1H NMR (400 MHz, CDCl3) 8.73 (bs, 1H), 7.84 (dt, J=2.0, 8.0, 1H), 7.44 (dt, J=1.7, 7.7, 1H), 7.40-7.34 (m, 1H), 7.30 (d, J=8.0, 1H), 7.25 (dt, J=7.6, 1.1, 1H), 7.18 (ddd, J=10.6, 8.4, 1.2, 1H), 6.62 (dd, J=15.1, 8.6, 1H), 6.56 (d, J=15.1, 1H), 4.79-4.72 (m, 1H), 2.71-2.61 (m, 2H), 2.36 (dt, J=10.0, 6.5, 1H), 1.99 (ddd, J=13.5, 6.1, 2.9, 1H), 1.70-1.57 (m, 1H), 1.51-1.44 (m, 2H), 1.42 (d, J=5.9, 3H), 1.39-1.22 (m, 2H), 0.99 (d, J=6.6, 3H), 0.76 (t, J-7.3, 3H)

FAB MCBP: 394.2184 calculated: 394.2182.

Example 2

To a solution of the product of the Process 2 (50 mg, 0.22 mmol) in CH2Cl2(3 ml) was added NMO (78 mg, 0.67 mmol, 3 EQ.) and 4 Å molecular sieves (50 mg). After stirring for 10 minutes was added TRAR (8 mg, 0.02 mmol, 0.1 EQ.) and continued stirring for another 40 minutes. The reaction mixture was diluted with Et2O (20 ml), filtered through celite and concentrated. The residue was filtered through a short column with SiO2using as eluent 30% EtOAc - hexane, received 38 mg of the aldehyde.

In another flask with phosphonate (210 mg, 0,56 mmol, 3.3 EQ.) in THF (1.5 ml) at 0°C was added a 2 M solution of BuLi in hexano (224 μl, of 0.56 mmol, 3.3 EQ.) and stirred the reaction mixture for 20 mine is. Was added to the solution of the above aldehyde in 1.5 ml THF and the mixture was stirred 1 hour at 0°C. the Solution was diluted with EtOAc (20 ml), washed with H2About (2×20 ml) and brine (20 ml), dried over MgSO4was filtered , concentrated and purified preparative TLC (25% EtOAc - hexane)received 9 mg of the target compound.

1H NMR (400 MHz, CDCl3) 8.79 (d, J=2.4 Hz, 1H), 7.85 (dd, J=8.4, 2.6 Hz, 1H). 7.81 br s, 1H), 7.76 (d, J=7.2 Hz, 1H), 7.67-7.58 (m, 2H), 7.31 (d, J=7.6 Hz, 1H), 6.63 (dd, J=15.6, 9.2 Hz, 1H), 6.57 (d, J 15.6 Hz, 1H), 4.79-4.72 (m, 1H), 2.71-2.61 (m, 2H), 2.37 (dt, J=10.0, 6.4 Hz, 1H), 2.00 (ddd, J=13.5, 6.3, 2.7 Hz, 1H), 1.64-1.56 (m, 1H), 1.51-1.23 (m, 4H), 1.42 (d, J=6.2 Hz, 3H). 1.00 (d, J=6.6 Hz, 3H), 0.77 (t, J=7.5 Hz, 3H)

FAB MCBP: 446.2306 (MN+calculated: 446.2280.

Using similar procedures were obtained the following compounds:

Example 3

1H NMR (400 MHz, CDCl3) At 8.62 (d, J=2.0 Hz, 1H), 7.76 (dd, J=8.0, 2.4 Hz, 1H), 7.51-7.48 (m, 1H), 7.37-7.26 (m, 4H), 6.65-6.55 (m, 2H), 4.78-4.71 (m, 1H), 2.71-2.61 (m, 2H), 2.36 (dt, J=10.0. 6.4 Hz, 1H), 1.99 (ddd, J=13.7, 6.3, 2.9 Hz, 1H), 1.68-1.61 (m, 1H), 1.50-1.45 (m, 2H), 1.43 (d, J=5.6 Hz. 3H), 1.33-1.25 (m, 2H), 0.99 (d, J=6.4 Hz, 3H), 0.76 (t, J=7.4 Hz, 3H)

[α]20D+13.2°(C 0.5, Meon);

FAB MCBP: 410.1891 (MN+calculated: 410.1887

Example 4

1H NMR (400 MHz, CDCl3) 8.75 (d, J=2.0 Hz, 1H), 7.80 (dd, J=8.2, 2.0 Hz, 1H), 7.54 (br s, 1H), 7.46-7.34 (m, 3H), 7.29 (d, J=8.0 Hz, 1H), 6.61 (dd, J=15.3, 9.0 Hz, 1H), 6.56 (d, J=15.3 Hz, 1H), 4.78-4.71 (m, 1H), 2.70-2.60 (m, 2H), 2.31 (dt, J=10.1, 6.5 Hz, 1H) 1.98 (ddd, J=13.5, 6.4, 2.9 Hz, 1H), 1.71-1.64 (m, 1H), 1.49-1.43 (m, 2H), 1.40 (d, J=6.0 Hz, 3H), 1.33-1.21 (m, 2H), 0.99 (d, J=6.4 Hz, 3H), 0.75 (t, J=7.4 Hz, 3H) <76504-097-A-N in 2A>

[α]20D=+23.1°(C 0.5, Meon)

FAB MCBP: 410.1887 (MN+calculated: 410.1887

Example 5

1H NMR (400 MHz, CDCl3) 8.58 (d, J=2.0 Hz, 1H), 7.72 (dd, J=8.0, 2.0 Hz, 1H), 7.50 (dd, J=8.0, 1.6 Hz, 1H), 7.31-7.21 (m, 3H), 6.63 (dd, J=15.5, 8.8 Hz, 1H), 6.57 (d, J=15.5 Hz, 1H), 4.78-4.71 (m, 1H), 2.71-2.61 (m, 2H), 2.36 (dt, J=10.0, 6.4 Hz, 1H), 1.99 (ddd, J=13.6, 6.4. 2.8 Hz, 1H), 1.68-1.61 (m, 1H), 1.50-1.45 (m, 2H), 1.43 (d, J=6.0 Hz, 3H), 1.35-1.22 (m, 2H), 0.99 (d, J=6.4 Hz, 3H), 0.76 (t, J=7.4 Hz, 3H)

[α]20D=+5.8°(C 0.4, Meon)

FAB MCBP: 444.1491 (MH+calculated: 444.1497.

Example 6

To a solution of the product of Example 1 (540 mg, 1.37 mmol) in THF (8 ml) at -78°C was added a 1M solution of LHMDS in THF (1.65 ml of 1.65 mmol, 1.2 EQ.). The solution was stirred 15 minutes at -78°and for 30 minutes at 0°C. the Solution was again cooled to -78°and the solution was added (1S)-(+)-(10-camphorsulfonic)oxaziridine (475 mg, 2.10 mmol, 1.5 EQ.) in THF (4 ml). The reaction mixture was stirred at -78°With 15 minutes, then left to slowly warm to room temperature. To the mixture was added an aqueous solution of NH4Cl (100 ml) and was extracted with EtOAc (3×30 ml). The combined organic layer was washed with 30 ml brine, dried over MgSO4concentrated and chromatographically (15:20:65 EtOAc:CH2Cl 2-hexane), received 390 mg (69%) of resin.

1H NMR: 8.78 (d, J=2.4 Hz, 1H), 7.82 (dd, J=8.2, 2.6 Hz, 1H), 7.44 (dt, J=6.0, 8.0 Hz, 1H), 7.37-7.35 (m, 1H), 7.29-7.25 (m, 2H), 7.09 (ddt, J=1.0, 2.4. 8.3 Hz, 1H), 6.67-6.58 (m, 2H), 4.67-4.60 (m, 1H), 2.85-2.79 (m, 2H), 2.32 (dq, J=1.5, 5.7 Hz, 1H), 1.89-1.82 (m, 1H), 1.79-1.75 (m, 1H), 1.70-1.61 (m, 2H), 1.54-1.46 (m, 1H), 1.45 (d, J=6.0 Hz, 3H), 1.43-1.32 (m, 1H), 0.99 (d, J=6.6 Hz, 3H), 0.78 (t, J=7.5 Hz, 3H).

The process of joining Suzuki illustrated by heating a solution of the bromide from the Process 4 or 5 with Bronevoy acid (1.0 to ,.0 equiv.) To2CO3(4 equiv.) and Pd(PPh3)4(from 5 to 10 mol%.) in a mixture of toluene:EtOH:H2O (4:2:1, vol/about./about.) at 100°C to complete the reaction. The reaction mixture was diluted with H2O, extracted with EtOAc and washed organic layer with brine, dried over MgSO4filter, concentrate and purify by chromatography, get the required connections.

When using the above-described process of joining Suzuki were obtained the following compounds:

Example 7

1H NMR: 8.54 (dd, J=2.2, 0.6 Hz, 1H), 7.62 (dd, J=8.0, 2.2 Hz, 1H), 7.31-7.25 (m, 4H), 7.22-7.20 (m, 1H), 6.65-6.56 (m, 1H), 4.67-4.60 (m, 1H), 3.20 (br s, 1H), 2.89-2.80 (m, 1H), 2.34 (ddd, J=10.1, 5.7, 1.5 Hz, 1H), 2.30 (s, 3H), 1.91-1.77 (m, 2H), 1.70-1.64 (m, 1H), 1.55-1.43 (m, 2H), 1.45 (d, J=6.0 Hz, 3H), 1.39-1.25 (m, 1H), 0.98 (d, J=6.50 Hz, 3H), 0.79 (t, J=7.5 Hz, 3H)

EXAMPLE 8

1H NMR: 8.80 (d, J=2.0 Hz, 1H), 7.84 (dd, J=8.2, 2.2 Hz, 1H), 7.58 (d, J=7.6 Hz, 2H), 7.47 (t, J=7.4 Hz, 2H), 7.39 (t, J=7.2 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 6.65-6.55 (m, 2H), 4.67-4.60 (m, 1H), 3.56 (br s, 1H), 2.87-2.81 (m, 1H), 2.34 (dd, J=9.6, 5.6 Hz, 1H), 1.87-1.80 (m, 2H), 1.70-1.63 (m, 1H), 1.53-1.33 (m, 3H), 1.44 (d, J=6.0 Hz, 3H), 0.98 (d, J=6.5 Hz, 3H), 0.79 (t, J=7.4 Hz, 3H).

Also, when using the process of joining Suzuki with the appropriate reagents were obtained following structure:

where R3, R22, R23and W are defined in the following table (Me is methyl, Et is ethyl and Ph is phenyl):

ExampleR3R22R23WAnalytical data
8BNMeEtMCBP (MN+) 444.2165
8SNMeEtMCBP (MH+) 394.2184
8DNMeEtMCBP (MN+) 394.2184
8ENMeEtMCBP (MH+) 410.1891
8FNMeEtMCBP (MN+) 410.1887
8GNMeEtMCBP (MH+) 444.1491

tr>
8HNNPhMCBP (MH+) 428.2026
8INNPhMCBP (MH+) 428.2027
8JNMeEtMCBP (MH+) 418.2381
8KNMeEtMCBP (MH+) 433.2490
8LNMeEtMCBP (MH+) 447.2648
8MNMeEtMCBP (MH+) 483.2319
8NNMeEtMCBP (MH+) 390.2441
8ONMeEtMCBP MH +) 390.2437
8PNMeEtMCBP (MH+) 444.1490
8QMeMeEtMCBP (MH+) 408.2346
8RHEMeEtMCBP (MH+) 406.2380
8SOHMeEtMCBP (MH+) 406.2376
8TOHMeEtMCBP (MH+) 398.1788
8UOHMeEtMCBP (MH+) 432.1392
8VOHMeEtMCBP (MH+) 393.2181
8WOHMeEtMCBP (MH+) 417.2178
8XOHMeEtMCBP (MH+) 417.2178
8ZOHMeEtMCBP (MH+) 434.2330
8AAOHMeEtMCBP (MH+) 449.2440
8ABOHMeEtMCBP (MH+) 463.2599
8ACOHMeEtMCBP (MH+) 435.2275
8ADOHMeEtMCBP (MH+) 449.2446
8AEOHMeEtMCBP (MH+) 435.2279
8AFOHMeEtMCBP (MH+) 449.2442
8AGOHMeEtMCBP (MH+) 422.2332
8AHOHMeEtMCBP (MH+) 422.2332
8AI HHEtMCBP (MH+) 380.2028
8AJHPhMeMC (MH+) 442.1
8AKHPhMeMC (MH+) 458.1
8ALOHMeEtMCBP (MH+) 463.2589
8AMOHMeEtMCBP (MH+) 463.2593
8ANOHMeEtMCBP(MH+) 477.2750

AHEMeEtMCBP (MH+) 392.2227
SAPHEMeEtMCBP (MH+) 434.2695
8AQHEMeEtMCBP (MH+/sup> ) 398.1788
8ARHEMeEtMCBP (MH+) 382.2020
8ASHEMeEtMCBP (MH+) 435.2282
8ATHEMeEtMCBP (MH+) 424.0945
8AUOMeMeEtMC (MH+) 450.1
8AVHEMeEtMC (MH+) 436.1
8AWOMeMeEtMC (MH+) 436.1
8AXHEMeEtMCBP (MH+) 480.2752
8AYHEMeEtMCBP (MH+) 436.2489
8AZHEMeEtMCBP (MH+) 434.2325

VAHEMeEtMCBP (MH+)436.2489
WHENEtMC (MH+) 392.2
Air forceHENEtMC (MH+) 396.3
8BDHENEtMC (MH+) 368.4
WEHEMeEtMCBP (MH+) 408.2169
8BFHEMeEtMCBP (MH+) 456.1941
8BGHENMeMCBP (MH+) 382.1813
VNHENMeMCBP (MH+) 3891863
8BIHENMeMCBP (MH+) 365.1871
8BJHEMeEtMCBP (MH+) 440.2243
VKHENMeMCBP (MH+) 378.2064
8BLHENMeMCBP (MH+) 364.1919
WMHEMeEtMCBP (MH+) 449.2435
8BNHEMeEtMCBP (MH+) 463.2604
VOHEMeEtMCBP (MH+) 477.2751
WRHEMeEtMCBP (MH+) 450.2640

Example 9

To the product of the Process 5 (to 0.127 mmol) in anhydrous toluene (5 ml) was added aniline (0,254 mmol, 2 equiv.) potassium phosphate (0,380 mmol, 3 equiv.) the palladium acetate (6,5% mol) and 2-(dicyclohexylphosphino)biphenyl (13 mol%). After the reaction mixture was let in N2within 2 minutes, then was heated to 120°in a sealed vessel. After 16 hours the reaction mixture was cooled to room temperature, poured into water and was extracted with Et2O (3). The combined extract was washed with saline, dried over MgSO4, filtered and evaporated to dryness. After purification with flash chromatography (2-5% CH3HE in CH2Cl2) was obtained the desired product with a yield of 66%.

1H NMR: 8.31 (d, J=2.8 Hz, 1H), 7.40 (dd, J=2.8, 8.5 Hz, 1H), 7.30-7.26 (m, 2H), 7.15 (d, J=8.5 Hz, 1H), 7.07 (dd, J=0.9, 8.5 Hz, 1H), 6.97 (t, J=7.4 Hz, 1H), 6.50 (d, J=15.6 Hz, 1H), 6.25 (dd, J=10.4, 15.6 Hz, 1H), 6.14 (s, 1H), 4.60-4.56 (m, 1H), 4.43 (br s, 1H), 2.79-2.76 (m, 1H), 2.31 (dd, J=5.6, 9.2 Hz, 1H), 1.91-1.79 (m, 2H), 1.65-1.58 (m, 1H), 1.41-1.35 (m, 2H), 1.39 (d, J=6.0 Hz, 3H), 1.31-1.25 (m, 1H), 0.95 (d, J=6.4 Hz, 3H), 0.77 (t, J=7.4 Hz, 3H)

Using similar procedures were obtained the compounds of formula

where W is defined in the table below:

ExampleWAnalytical data
9AMsvr (MN+) 385.2490
9V Msvr (MN+) 415.2601
9SMsvr (MN+) 414.2593
9DMsvr (MH+) 399.2278

Example 10

Stages 1-3:

Step 1: a Suspension of alkyne Process 6 (3.1 g, 9.2 mmol), quinoline (215 μl, 1.8 mmol, 0.2 EQ.) and Lindlar catalyst (310 mg, 10 wt.%) in EtOAc (50 ml) was stirred under 1 ATM. H2(balloons)passing the reaction was monitored by NMR. After completion of the reaction the mixture was filtered through a layer of celite, washed with 1 N. HCl and brine, dried over MgSO4, was filtered and was evaporated, received ˜3.4 g of resin, which is directly used in the next step.

Step 2: To a mixture of the product of Stage 1 and NaHCO3(1.54 g, and 18.3 mmol, 2 EQ.) in CH2Cl2(30 ml) at room temperature was added a reagent dessa-Martin (4,28 g, 10.1 mmol, 1.1 EQ.) and stirred for 1 hour. The reaction mixture was diluted with Et2O (60 ml) and a solution of Na2S2O3·5H2O (4,55 g, and 18.3 mmol, 2 EQ.) and NaHCO3(1.54 g, and 18.3 mmol, 2 EQ.) in N20 (100 ml) and thoroughly mixed to separate the two layers. Separated the organic layer and the aqueous layer was extracted with Et2O(2× 50 ml). The combined organic layer was washed with an aqueous solution of Na2S2O3/NaHCO3(100 ml), brine (100 ml), dried over MgSO4, was filtered and was evaporated, received ˜3.5 g of the aldehyde, which is directly used in the next step.

Step 3:

To a solution of the phosphonate of the formula(3,9 g, 12.1 mmol, 1.3 EQ.) in THF (30 ml) at 0°C was added 60% NaH in mineral oil (480 mg, 12,0 mmol, 1.3 EQ.) and stirred the mixture for 20 minutes. Was added a solution of the product of Step 2 in THF (15 ml) and after stirring for 1 hour at 0°the reaction mixture was diluted aqueous solution of NH4Cl (200 ml). THF was evaporated and the aqueous layer was extracted EtOAc (3×75 ml). The combined organic layer was washed brine (100 ml), dried over MgSO4was filtered , evaporated and chromatogra-firvale the remainder (5% EtOAc - hexane), was obtained 4.0 g (87%) of resin.

1H NMR: 8.75 (d, J=2.0 Hz, 1H), 7.76 (dd, J=8.0, 2.4 Hz, 1H), 7.73-7.66 (m, 4H), 7.47-7.26 (m, 9H), 7.19 (d, J=8.0 Hz, 1H), 7.09 (ddt, J=1.1, 2.5, 8.4 Hz, 1H), 7.00 (ddd, J=15.3, 11.5, 1.1 Hz, 1H), 6.52 (d, J=15.2 Hz, 1H), 6.05-5.99 (m, 1H), 5.74-5.69 (m, 1H), 4.93-4.86 (m, 1H), 1.28 (d, J=6.4 Hz, 3H), 1.06 (s, 3H)

Step 4:

To a solution of salelologa ester (4.0 g, 7,88 mmol) in THF (30 ml) at 0°C was added a 1M solution of TBAF in THF (11.8 ml of 11.8 mmol, 1.5 EQ.) and stirred the reaction mixture at room temperature for 6 hours. A mixture of p is bavlyali aqueous solution of NH 4Cl (150 ml), THF was evaporated and the aqueous layer was extracted EtOAc (3×60 ml). The combined organic layer was washed N2About (50 ml), brine (50 ml), dried over MgSO4was filtered , evaporated and chromatographically the remainder (30% EtOAc - hexane), was obtained 2.0 g (94%) of resin.

1H NMR: 8.80 (d, J=2.0 Hz, 1H), 7.81 (dd, J=8.0, 2.4 Hz, 1H), 7.64 (ddd, J=15.1, 11.5, 1.1 Hz, 1H), 7.44 (dt, J= 5.6, 7.9 Hz, 1H), 7.38-7.33 (m, 2H), 7.30-7.26 (m, 1H), 7.09 (ddt, J=1.0, 2.5, 8.3 Hz, 1H), 6.67 (d, J=7.6 Hz, 1H), 6.24 (t, J=11.2 Hz, 1H), 5.70-5.65 (m, 1H), 5.07-5.00 (m, 1H), 1.35 (d, J=6.4 Hz, 3H)

Step 5:

To a solution of the alcohol of Step 4 (110 mg, 0.41 mmol) and acid (85 mg, 0.61 mmol, 1.5 EQ.) in CH2Cl2(2 ml) was added DCC (130 mg, to 0.63 mmol, 1.5 EQ.) and DMAP (10 mg, 0.08 mmol, 0.2 EQ.) and was stirred at 0°C to complete the reaction. The reaction mixture was diluted with Et2O (50 ml), washed with aqueous solution of NaHCO3(2×20 ml) and brine (20 ml), dried over MgSO4was filtered , concentrated and the residue was chromatographically (10% EtOAc - hexane), received 135 mg (84%) of resin.

1H NMR: 8.79 (d, J=2.4 Hz, 1H), 7.81 (dd, J=8.0, 2.4 Hz, 1H), 7.67 (ddd, J=15.3, 11.5. 1.2 Hz, 1H), 7.47-7.27 (m, 5H), 7.15 (ddt, J=2.0, 1.0, 8.3 Hz, 1H), 6.71 (d, J=15.6 Hz, 1H), 6.29 (dt, J=0.8, Hz, 1H), 6.11-6.00 (m, 1H), 5.88 (t, J= 7.6 Hz, 1H), 5.63 (t, J=10.0 Hz, 1H), 2.24-2.16 (m, 2H), 7.76 (d, J=0.8 Hz, 3H), 1.43 (d, J=6.4 Hz, 3H), 1.00 (t, J=7.6 Hz, 3H)

Step 6:

The solution tetraena Stage 5 (130 mg) in toluene (10 ml) was stirred in a sealed vessel at 185°With those who tell 7 hours was cooled to room temperature and mixed with 10 μl of DBU for 3 hours. The solution was concentrated and purified by preparative chromatography, was obtained 63 mg (49%) of resin.

1H NMR: 8.72 (d, J= 2.0 Hz, 1H), 7.77 (dd, J 8.4, 2.4 Hz, 1H), 7.41 (dt, J=6.0, 8.0 Hz, 1H), 7.36-7.31 (m, 2H), 7.26-7.22 (m, 1H), 7.06 (ddt, J=1.0, 2.7, 8.3 Hz, 1H), 6.66 (d, J=16.0 Hz, 1H), 6.47 (dd, J=15.8, 9.8 Hz, 1H), 5.62-561 (m, 1H), 4.55 (dq, J=4.0, 6.4 Hz, 1H), 3.27-3.24 (m, 1H), 2.80-2.75 (m, 1H), 2.56-2.52 (m, 1H), 2.02-1.97 (m, 1H), 1.78 (d, J=1.5 Hz, 3H), 1.69-1.59 (m, 1H), 1.50-1.45 (m, 1H), 1.41 (d, J=6.4 Hz, 3H), 0.92 (t, J=7.4 Hz, 3H)

Using similar procedures were obtained compound of the following structure

where R11, R22, R23and W are defined in the table (Me is methyl, Et is ethyl, Bn - benzyl):

ExampleR22R23R11WMsvr (MN+)
10ANHH350.1565
10VMe-CH2OBnH484.2299
10CMeH-CH2OBn484.2294
10DMeH Et392.2021
10THMeMeH378.1870
10FMeHMe378.1870
10GMeHH364.1714
10HMe-CH2OHH394.1821

Example 11

Through a solution of compound 4 (100 mg), 2(tri-n-butylstannyl)pyridine (292 mg) and Pd(PPh3)4(31 mg) in toluene (5 ml) in a sealed vessel missed N2and the solution was heated at 120°With during the night. The reaction mixture was diluted aqueous solution of NH4Cl was extracted with EtOAc, dried over MgSO4was filtered , concentrated and chromatographically the remainder (2% CH3HE-CH2Cl2), received 83 mg of resin.

The resin was dissolved in THF (5 ml)was cooled to -78°C, was added a 1M solution of LHMDS in THF (290 ml), stirred at 0°1 hour, then was cooled to - 78°C. To the mixture was added a solution of (18)-(+)-(10-camphorsulfonic)oxaziridine (76 mg) in Tgppost stirring for 1.5 hours the reaction was stopped by addition of an aqueous solution of NH 4Cl and extracted with EtOAc. The organic layer was washed with saline, dried over MgSO4was filtered , concentrated and the residue was purified preparative TLC, received 20 mg of the target compound. Msvr: 393.2185 (MN+calculated: 393.2178.

Using similar procedures were also received and the following connections:

where W is defined in the table below:

ExampleWMsvr (MN+)
11A394.2127
11B399.1750

Example 12

Step 1: To a solution of oxazole (75 μl, 1.1 mmol) in THF (2 ml) at -78°C was added a solution of 2.5m BuLi in hexano (465 μl, 1.2 mmol, 2.2 EQ.) and the reaction mixture was stirred for 30 minutes. Added a 0.5m solution of ZnCl2in Et2O (4.3 ml, 2.2 mmol, 4 equiv.) and stirred the mixture for 30 minutes at -78°and for 30 minutes at 0°C.

Step 2: Separate the suspension of Pd(PPh3)2Cl2(37 mg, 0.05 mmol) in THF at 0°C was added a 2.5m solution of BuLi in hexano (43 μl, 0.11 mmol) and stirred suspension of 20 minutes. This solution was added to zincato Stage 1, then add the product of the Process 4 (200 mg, 0.5 mmol) and the mixture n is gravely under reflux overnight. The mixture was cooled, diluted aqueous solution of NH4Cl (60 ml) and was extracted with EtOAc (3×20 ml). The combined organic layer was washed with saline (20 ml), dried over MgSO4was filtered , evaporated and purified preparative TLC, received 29 mg of resin. Msvr: 367.2025 (MH+calculated 367.2022

Example 13

Step 1: a solution of the product of the Process 5 (60 mg, 0.15 mmol), Et3N (26 μl, 0,19 mmol, 1.2 equiv.) bis(diphenylphosphino)propane (3 mg, 7 μmol, 5 mol%), Pd(OAc)2(1.7 mg, 7.6 μmol, 5 mol%) and vinyl n-propyl ether (85 μl, 0.76 mmol, 5 EQ.) in DMF (1.5 ml) was heated in a sealed vessel for 2 hours at 100°C, cooled to room temperature and was stirred with 2 N. HCl (2 ml) for 2 hours. The reaction mixture was diluted aqueous solution of NaHCO3, was extracted with EtOAc, dried over MgSO4was filtered , concentrated and the residue was purified preparative TLC, received 25 mg of ketone.

Step 2: a solution of the product of Step 1 (13 mg, 36 mmol) and hydroxylamine hydrochloride (8 mg, 0.12 mmol) in pyridine (0.5 ml) was stirred overnight at room temperature. The reaction mixture was diluted aqueous solution of NH4Cl (30 ml) and was extracted with EtOAc (2×10 ml), the combined organic layer was washed with saline (10 ml), dried over MgSO4was filtered , concentrated and the residue was purified preparative TLC,received 13 mg of target compound in the form of resin.

Msvr: 373.2113 (MN+calculated 373.2127.

Using similar procedures, there was obtained the following compound:

Ave. 13-2: SVR: 387.2300 (MN+)

Example 14

Through a mixture of the product of the Process 5 (100 mg, 0.25 mmol), imidazole (35 mg, 0.51 mmol, 2.0 equiv.) complex of benzene and triftoratsetata copper (I) (13 mg, was 0.026 mmol, 0.1 EQ.), 1,10-phenanthroline (46 mg, 0.26 mmol, 1 EQ.), dibenzylideneacetone (56 mg, was 0.026 mmol, 0.1 EQ.) and Cs2CO3(125 mg, 0.38 mmol, 1.5 equiv.) in m-xylene (3 ml) in a sealed vessel missed argon and was heated at 130°With during the night. The mixture was cooled to room temperature, diluted aqueous solution of NH4Cl (40 ml) and was extracted with CH2Cl2(3×10 ml). The combined organic layer was washed with saline (10 ml), dried over MgSO4was filtered , concentrated and the residue was purified preparative TLC was obtained 43 mg (44%) of target compound.

Msvr: 382.2133 (MN+calculated: 382.2131

Using a similar procedure was obtained the following compound:

Ave. 14-2: SVR: 396.2286 (MH+)

Example 15

Through a mixture of the product of the Process 5 (1.0 g, 2.54 mmol), Zn(CN)2(300 mg, 2.56 mmol, 1 equiv.) Pd2(dba)3(Tris(dibenzyl inceton)dipalladium (0)) (116 mg, 0.13 mmol, 5 mol%) and diphenylpiperazine (170 mg, 0.31 mmol, 12 mol%) in DMF (10 ml) and H2O (100 μl, 1%vol.) in a sealed vessel missed argon and heated at 120°C for 5 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (150 ml) and washed with H2About (3×50 ml), brine (50 ml), dried over MgSO4was filtered , evaporated and the crude product was chromatographically (30% EtOAc - hexane), was obtained 800 mg (93%) of arycanda.

A mixture of arycanda (100 mg, 0.29 mmol), NaN3(115 mg, 1.77 mmol, 6 equiv.) and NH4Cl (95 mg, 1.78 mmol, 6 equiv.) in DMF (2 ml) in a sealed vessel was heated at 120°With during the night. The mixture was cooled to room temperature, diluted with H2O (10 ml), was extracted with Ch2Cl2was concentrated and the crude product was subjected to preparative TLC, received 50 mg of target compound in the form of solids.

Msvr: 384.2033 (MH+calculated: 384.2036.

Example 16

Stage 1:

To a solution of compound 31A (where W is the 3-forfinal) (480 mg, 1.2 mmol) in CH2Cl2added a 1M solution of BBr3in Ch2Cl2(11.7 ml, 11.7 mmol, 10 EQ.) and the reaction mixture was heated under reflux for 2.5 hours, then diluted aqueous solution of NaHCO3(100 ml). After stirring for 30 minutes, separated the organic layer and the aqueous layer EC is was tragically CH 2Cl2(2×40 ml). The combined organic layer was washed in an aqueous solution of NaHCO3(100 m), brine (100 ml), dried over MgSO4, was filtered and was evaporated, received the crude alcohol.

The crude alcohol was dissolved in CH2Cl2(12 ml), cooled to 0°and sequentially added AU2(225 μl, 2.4 mmol, 2 equiv.) DMAP (27 mg, 0.24 mmol, 0.2 EQ.) and Et3N (0.5 ml, 3.6 mmol, 3 EQ.). After stirring for 2 hours the reaction mixture was diluted with EtOAc (80 ml), washed with aqueous solution of NaHCO3(2×50 ml) and brine. The solution was dried over MgSO4was filtered , evaporated and the residue was chromatographically (40% EtOAc - hexane), was obtained 350 mg (56%) of the compound of Example 16-a as a white foam.

Msvr: 530.1336 calculated: 530.1342

Step 2:

A mixture of compound of Example 16 (53 mg, 0.1 EQ.), NaCNBH3(32 mg, 0.5 mmol, 5 equiv.) in NMRA (hexamethylphosphoramide) (1 ml) was stirred 4 hours at 80°C, cooled to room temperature, diluted with H2O (30 ml) and was extracted with EtOAc (3×15 ml). The combined organic layer was washed with saline (20 ml), dried over MgSO4was filtered , concentrated and purified preparative TLC, received 27 mg of resin. This product solution was added To the2CO3(32 mg) in a mixture of CH3HE-H2About (2 ml, 9:1 vol./about.) and the solution was stirred 1 hour at ControlTemplate. The mixture was diluted with H2O (30 ml), was extracted with EtOAc (3×10 ml), the combined organic layer was washed with saline (10 ml), dried over MgSO4was filtered , concentrated and filtered through a short column with SiO2received 17 mg (72%) of the compound of Example 16 In resin.

Msvr: 410.2126 calculated: 410.2131.

Using similar procedures were obtained compound of the following structure

where R3, R22, R23and W are defined in the table (Me is methyl, Et is ethyl):

Et
Ex.R3R22R23WMCBP (MH+)
16CH-CH2OHEt410.2138
16DN-CH=N-OHEt423.2090
EH-CH=N-OMeEt437.2235
16FN-CH=N-OEtEt451.2396
16Ghe-CH2OH426.2075

The following compositions are examples of some dosage forms of the present invention. In each of them the term "active ingredient" means a compound of formula I.

EXAMPLE AS Tablets

No.Ingredientmg tabletmg tablet
1The active ingredient100500
2Lactose USP122113
3Corn starch, food quality, in the form of a 10% paste in purified water3040
4Corn starch, food grade4540
5Magnesium stearate37
Only300700

The way to obtain

Mix Components 1 and 2 in a suitable mixer for 10-15 minutes. Granularit mixture with Component No. 3. If necessary, passed through a coarse sieve (for example, 1/4", 0,63 cm). Dry the wet granules. If necessary, sift the dried granules, mix them with Component # 4 and mix for 10-15 minutes. Add Component # 5 and mix for 1-3 minutes. Press the mixture up to a certain size and weight on a suitable tablet press machine.

The EXAMPLE IN Capsules

No.Ingredientmg tabletmg tablet
1The active ingredient100500
2Lactose USP106123
3Corn starch, food grade4070
4Magnesium stearate NF47
Only250700

The way to obtain

Mix Components 1, 2 and 3 in a suitable blender for 10-15 minutes. Add Component # 4 and mix for 1-3 minutes. To encapsulate the machine fill with a mixture of suitable capsules of hard gelatin, which consists of two parts.

The activity of the compounds of formula I can be determined by the following methods.

Testing methodology antagonists thrombin receptor In Vitro:

Getting [3H]haTRAP (TRAP - a peptide that activates the thrombin receptor)

A(pF-F)R(ChA)(hR)(I2-Y)-NH2(1,03 mg) and 10% Pd/C (5,07 mg) suspended in DMF (250 μl) and diisopropylate is Amina (10 μl). The vessel was attached to the tritium line was frozen with liquid nitrogen and evacuated. Then the flask was added gaseous tritium (342 MCI) and stirred 2 hours at room temperature. After completion of the reaction was removed excess tritium, and the peptide solution was diluted in DMF (0.5 ml) and filtered to remove the catalyst. DMF solution of the crude peptide was diluted with water and liofilizirovanny to remove labile tritium. Solid peptide was again dissolved in water and repeated the process of lyophilization. The tritium-containing peptide ([3H]haTRAP) was dissolved in 0.5 ml of 0.1% aqueous solution of TFU and purified HPLC under the following conditions: column, Vydac 18, 25 cm × 9.4 mm I.D.; mobile phase, (A) 0.1% OF TFU in water, (C) 0.1% OF TFU in CH3CN; gradient (a/b) from 100/0 to 40/60 over 30 minutes; flow rate 5 ml/min; detection, UV 215 nm. Radiochemical purity of [3H]haTRAP was 99% according to HPLC. Was received dose 14.9 MkI with a specific activity of 18.4 CI/mmol.

Obtaining membranes of platelets

Membranes of platelets were obtained by the modified method of Natarajan et al (Nata-rajan et al, Int. J. Pepide Protein Res. 45:145-151 (1995)) of 20 units of platelet concentrates obtained from the Blood Center North Jersey Blood Center (East Orange, NJ) within 48 hours after collection. All steps were performed at 4°in terms of biological safety. The platelets were centrifuged at 100×g for 20 minutes at 4°for the removal of erythrocytes. The supernatant decantation and centrifuged for 15 minutes at 3000×g for the deposition of platelets. Platelets resuspendable in 5mm Tris-HCl, pH 7.5, 5mm EDTA to a final volume of approximately 200 ml and centrifuged at 4400×g for 10 minutes This step was repeated twice more. Platelets resuspendable in 5 mm Tris-HCl, ph 7.5, 5 mm EDTA to a final volume of approximately 30 ml and homogenized by 20 strokes in a homogenizer Downs. The membrane was besieged at 41000×g, resuspendable in 40-50 ml of 20mm Tris-HCl, pH 7.5, 1 mm EDTA, 0.1 mm of dithiothreitol and aliquots of 10 ml were frozen in liquid N2and stored at -80°C. To complete the preparation of the membrane aliquots were thawed, pooled and homogenized with 5 strokes of the homogenizer Downs. The membrane was besieged and washed three times in 10 mm triethanolamine - HCl, pH 7.4, 5 mm EDTA and resuspendable 20-25 ml of 50 mm Tris-HCl, pH 7.5, 10 mm MgCl2, 1 mm EGTA and 1% DMSO. Aliquots of membranes were frozen in liquid N2and kept at - 80°C. Membranes were stable for at least 3 months. Of the 20 units concentrates usually received 250 mg of membrane protein. The protein concentration was determined by Lowry method (Lowry et al, J. Biol. Chem., 193:265-275 (1951)).

High-performance study of the binding of thrombin receptor with radioligands

Antagonists thrombin receptor was examined by the modified study of light is ivania thrombin receptor with radioligands, described by Ahn et al. (Ahn et al, Mol. Pharmacol., 51:350-356 (1997)). The study was performed in 96-well tablets Nunc (Cat. No. 269620) in a final volume of 200 μl. Membranes of platelets and [3H]haTRAP diluted to 0.4 mg/ml and 22.2 nm, respectively, in the buffer for binding (50 mm Tris-HCl, pH 7.5, 10 mm MgCl21 mm EGTA, 0.1% BSA). The original solutions (10 mm in 100% DMSO) of the studied compounds were then diluted 100% DMSO. Unless otherwise specified, to each well was added 10 μl of the diluted solution of compounds and 90 μl of radioligand (final concentration of 10Nm in 5% DMSO) and initiated the reaction by adding 100 μl of membranes (40 μg protein/well). Significant inhibition of binding of 5% DMSO was observed. Compounds were tested in three concentrations of 0.1, 1 and 10 μm). The tablets covered and gently shaken in a shaker, Lab-Line Titer Plate Shaker for 1 hour at room temperature. Filter plates Packard UniFilter GF/C and soaked at least 1 hour in 0.1% polyethylenimine. Incubated the membranes were collected when using a Packard FilterMate Universal Harvester and quickly washed 4 times with 300 μl of ice-cold solution (50mm Tris-HCl, pH 7.5, 10 mm MgCl2, 1mm of EGTA). To each well was added to scintillation mixture of MicroScint 20 (25 μl) and tablets accounted for scintillation counter Packard TopCount Microplate Scintillation Counter. Specific binding was defined as the difference between total binding and nonspecific hydrogen bonds is a W, observed in the presence of excess (50 μm) unlabeled haTRAP. % inhibition of compound binding of [3H]haTRAP with thrombin receptors was calculated according to the following equation:

Materials

A(pF-F)R(ChA)(hR)Y-NH2and A(pF-F)R(ChA)(hR)(I2-Y)-NH2were synthesized by AnaSpec Inc. (San Jose, CA). The purity of these peptides was >95%. Gaseous tritium (97%) were purchased IN/US Systems Inc. Trisorber. Scintillation mixture of MicroScint 20 was purchased in Packard Instrument Co.

The Protocol for platelet aggregation Ex vivo in whole blood of Cynomolgus monkeys with a drug and blood collection

Cynomolgus monkeys in the minds placed in the chair and leave to rest for 30 minutes. In the brachial vein catheter with a needle for injection of the study drug. Another catheter with needle injected into another shoulder or saphenous vein and used for sampling blood. In those cases, when the compound is administered orally, use only one catheter. A blood sample (1-2 ml) taken in a vacuumized tube thrombin inhibitor CVS 2139 (100 µg/0.1 ml saline) as an anticoagulant. Then within 30 minutes intravenous drug. Blood samples (1 ml) are taken at 5, 10, 20, 30 minute, during, and 30, 60, 90 minutes after injection. In experiments with oral administration of the drug to animals is th metered by using volumetric cannula. Blood samples taken on 0, 30, 60, 90, 120, 180, 240, 300, 360 minute after injection. 0.5 ml of blood is used for aggregation are full of blood, and the other 0.5 ml to determine the concentration of the drug or its metabolites in the plasma. The aggregation is carried out immediately after collection of the blood sample as described below.

Aggregation whole blood

A blood sample of 0.5 ml is added to 0.5 ml of physiological solution and heated to 37°in aggregometry Chronolog whole blood. At the same time the impedance of the electrode is heated to 37°With physiological solution. A blood sample with a stirrer is placed in the heating block, the sample is placed impedance electrode and run the program. Perform a program to stabilize the baseline and then spend 20 gauge Ω check. 20 Ω equals 4 blocks on the chart, issued by a computer program. Pipettes with variable volume (5-25 ál) add agonist (ha TRAP) and write down the curve of aggregation within 10 minutes Write down the value of the maximum aggregation after 6 minutes after addition of the agonist.

The procedure of platelet aggregation In vitro

The study of platelet aggregation was performed according to the method Bednar et al. (Bednar, C., Condra, C., Gould, R.J., ad Connolly, T.M., Throm. Res., 77:453-463 (1995)). Blood was obtained from healthy people who do not take aspirin for at least 7 days, by venipuncture using ACD as anticoagulant. PLA is mu platelet-rich, was obtained by centrifugation at 100×g for 15 minutes at 15°C. the Platelets were besieged at 3000×g and washed twice in physiological buffer solution with addition of 1 mm of EGTA and 20 µg/ml apyrase for inhibition of aggregation. The aggregation was performed at room temperature in a physiological buffer solution with addition of 0.2 mg/ml human fibrinogen. The compounds and platelets pre-incubated in 96-well tablets with a flat bottom for 60 minutes. Aggregation was initiated by addition of 0.3 microns haTRAP or 0.1 u/ml thrombin and rapid shaking of the mixture on a shaker, Lab-Line Titer Plate Shaker (speed 7). The percentage of aggregation was monitored by the increase in light transmittance at 405 nm in the device Spectromax Plate Reader.

Antitumor procedure In vivo

Research on models of breast cancer man in naked mice were conducted according to the procedure described by S. Even-Ram et al., Nature Medicine. 4, 8 (1988), str-914.

The study of binding to cannabinoid receptor SV

Binding to human cannabinoid receptor SW conducted according to the method Showalter, et al (1996, J. Pharmacol Exp Ther. 278(3), 989-99) with minimal modifications. All studies were performed in a final volume of 100 μl. The compounds resuspendable to 10 mm in DMSO, then serially diluted in solution (50 mm Tris, pH .1, 3 mm MgCl21 mm EDTA, 50% DMSO). Aliquots (10 ál) of each diluted sample was transferred to individual wells of 96-hole tablet for micrometrology. Membranes from CHO cells/Ki, transformed human SV (Receptor Biology, Inc), resuspendable in the buffer for binding (50 mm Tris, pH of 7.1, 3 mm MgCl2, 1mm EDTA, 0.1% of bovine serum albumin, free fatty acids), then added to the reaction of binding (˜15 µg in 50 µl per study). Reactions were initiated by addition of [3H] CP-55,940, diluted in buffer for binding (specific activity = 180 CI/mmol; New England Nuclear, Boston, Mass.). The final concentration of the ligand in the binding assays was of 0.48 nm After incubation at room temperature for 2 hours, the membrane was collected by filtration through pre-treated (0.5% polyethylenimine; Sigma P-3143) filter plates GF-S (Unifilter-96, Packard) using a 96-well device for collecting cells TomTec Mach 3U (Hamden, Ct). Tablets 10 times washed in 100 μl of buffer for binding and left of the membrane to air dry. The radioactivity on the membrane was determined after addition of scintillation fluid Packard Omniscint 20 when using scintillation and luminescence counter for tablets TopCount Microplate Scintillation and Luminescence Counter (Packard, Meriden, Ct). Nonlinear regression analysis was performed using the AI program Prism 20b (GraphPad Software, San Diego, Ca).

When using the above methods the study found that for representative compounds of formula I, the value of the IC50in relation to the thrombin receptor (i.e. the concentration at which an observed 50% inhibition of thrombin receptor) ranged from 1 to 1000 nm, preferably 1-100 nm, most preferably 1-20 nm. The value of Ki for CV ranged from 1 to 1000 nm, preferably 1-200 nm, most preferably 1-100 nm.

Table 1
Example No.Activity, Ki (nmol)
16
1A7
210
38,5
410
54
610
712
82
8B10
8S6
8D7
8E9,5
8F10
8G4
8J11
8K19
8L7
8M20
8N 7
8O17
8P190
8Q8
8R12
8S13
8T7
8U31
8V23
8W8
8X7
8Z10
AA16
AV14
8ºC20

Example No.Activity, Ki (nmol)
8AD12
AE9
8AF19
8AG63
EN111
A15
8AJ143
AC307
8AL6
AM5
8AN3
A2
AR3
8AQ2
8AR3
8AS150
AT161
8AU 30
8AV23
8AW50
ACH190
8AY12
8AZ8
VA66
W6
VS3
VS3
8BD27
WE27
8BF50
8BG3
VN17
W130
8BJ22
VK14

Example No.Activity, Ki (nmol)
8BL15
WM110
8BN20
VO52
WR20
9230
9A24
9S170
9D100
1010
10V250
10D200
10TH21
10F777
11 24
11A78
11B57
12135
14700
14-2379
16A125
16B25
16C15
16D28
E12
16F34
16G28

1. Derivative of nor-SECO himbacine represented by structural formula (I)

or its pharmaceutically acceptable salt, where

Z represents -(CH2)n-;

the double dotted line represents a simple bond;

n means 0-2;

R1and R2independently selected from the group comprising h, alkyl with 1 to 6 carbon atoms;

R3means H, hydroxy, alkoxygroup with 1-6 carbon atoms, -C(O)OR17or alkyl with 1-6 carbon atoms;

Het means a monocyclic heteroaromatic group of 6 atoms, containing 5 carbon atoms and 1 heteroatom, which selects N, where Het is connected with via a ring carbon atom and where Het group has 1 Deputy, W, independently selected from the group including Br, heteroseksualci, represents the speaker a group, consisting of 4 carbon atoms and 1 heteroatom selected from N; heteroseksualci representing the group consisting of 4 carbon atoms and 1 heteroatom selected from N, substituted IT is substituted by alkyl with 1-6 carbon atoms or =O, R-aryl-NH-; -C(=NOR17R18; R21-aryl; R41- heteroaryl, representing a group of 5-6 atoms containing 3-5 carbon atoms and 1-4 heteroatoms independently selected from the group N, S and O;

R8and R10independently selected from the group comprising R1;

R9means N;

R11selected from the group comprising R1and CH2OBn, where Bn denotes benzyl;

In means -(CH2)n4CR12=CR12a(CH2)n5where n4 and n5 mean independently Oh, and R12and R12aindependently selected from the group comprising H, alkyl with 1-6 carbon atoms;

X is-O-;

Y represents =O;

R15no, because the double dotted line represents a simple bond;

R16means lower alkyl with 1-6 carbon atoms;

R17and R18independently selected from the group comprising H, alkyl with 1-6 carbon atoms;

R21means 1-3 substituent, independently selected from the group comprising hydrogen, -CN, -CF3, halogen, alkyl with 1-6 carbon atoms, alcox the group with 1-6 carbon atoms, hydroxyalkyl with 1-6 carbon atoms, -COR17, -NHSO2R16or-C(=NOR17R18;

R22independently selected from the group including hydrogen, R24-alkyl with 1-10 carbon atoms, R25-aryl, -CH=N-OH, -CH=N-OMe, and-CH=N-OEt;

R23independently selected from the group comprising hydrogen, R24-alkyl with 1-10 carbon atoms, R25-aryl, and-CH2OBn, where Bn denotes benzyl;

R24means 1, 2 or 3 substituent independently selected from the group comprising hydrogen, halogen, -HE, alkoxygroup with 1-6 carbon atoms,

R25means hydrogen;

R41means 1-4 substituent, independently selected from the group comprising hydrogen, halogen, alkyl with 1-6 carbon atoms, alkoxy group with 1-6 carbon atoms, alkyl with 1-6 carbon atoms)substituted an amino group, di(alkyl with 1-6 carbon atoms)substituted an amino group, -OCF3HE is alkyl with 1-6 carbon atoms, -Cho and phenyl.

2. Derivative of nor-SECO himbacine according to claim 1, where n is 0; R1means alkyl with 1-6 carbon atoms; R2, R8, R10and R11each means hydrogen;

R9means N; R3means hydrogen, HE, alkoxygroup with 1-6 carbon atoms or alkyl with 1 to 6 carbon atoms.

3. Derivative of nor-SECO himbacine according to any one of claim 1 or 2, where In the means-CH=CH-; Het denotes iridal, W-substituted pyridyl; and W implies R21-aryl, or R41-heteroaryl, representing a group of 5-6 atoms, inclusive 3-5 carbon atoms and 1-4 heteroatoms independently selected from the group N, S and O.

4. Derivative of nor-SECO himbacine according to any one of claim 1, 2 or 3, where R and R23independently selected from the group comprising alkyl with 1-6 carbon atoms, R25aryl and HE is alkyl with 1-6 carbon atoms.

5. Derivative of nor-SECO himbacine according to claim 1, selected from the group comprising the compounds of formula

where R3, R22, R23and W are defined in the following table (Me is methyl, Et is ethyl and Ph is phenyl):

and the compounds of formula

where R11, R22, R23and W are defined in the table (Me is methyl, Et is ethyl, Bn - benzyl):

6. Pharmaceutical composition, irradiation of the surrounding inhibitory activity against receptors activated protease (PAR), characterized in that it comprises an effective amount of a derivative of nor-SECO himbacine formula (I) according to any one of claims 1 to 5 and a pharmaceutically acceptable filler.

7. A method of inhibiting thrombin receptor comprising the administration to a mammal of the active substance in an effective amount, characterized in that the active substance is injected derivative of nor-SECO himbacine formula (I) according to any one of claims 1 to 5.

8. Method of inhibiting cannabinoid receptors, comprising the administration to a mammal of the active substance in an effective amount, characterized in that the active substance is injected derivative of nor-SECO himbacine formula (I) according to any one of claims 1 to 5.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention elates to derivatives of benzothiazole of the general formula (I): wherein R means hydrogen atom, -(CH2)n-phenyl optionally substituted with a substitute chosen from the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl or -N(R')-C(O)-(lower)-alkyl, -(CH2)n-pyridinyl optionally substituted with (lower)-alkyl, -(CH2)n-(C3-C6)-cycloalkyl optionally substituted with hydroxy-group, -(CH2)n-benzo[1,3]dioxolyl, -(CR'2)-thiophenyl, -(CR'2)n-thiazolyl optionally substituted with (lower)-alkyl, -(CH2)n-C(O)-thiophenyl optionally substituted with halogen atom, -(CH2)-furanyl optionally substituted with (lower)-alkyl, -(CHR')n-benzofuran-1-yl, -(CH2)n-benzo[b]thiophenyl, -(CH2)n-N(R')-C(O)-phenyl optionally substituted with halogen atom or (lower)-alkoxy-group. -(CH2)n-C(O)-phenyl optionally substituted with (lower)-alkoxy-group, -(CH2)n-C(O)-2,3-dihydrobenzo[1,4]dioxine-6-yl, -(CH2)n-N(R')-C(O)-pyridinyl, -(CH2)n-tetrahydrofuranyl, -CH-biphenyl, -CH-(phenyl)pyridinyl, -(CH2)n-1-oxo-(CH2)n-CH-(phenyl)tetrahydropyranyl, -(CH2)n-1-oxo-1,2,3,4-tetrahydroquinoline-3-yl or -(CH2)n-S-[1,3,4]thiadiazol-2-yl optionally substituted with amino-group; R' means hydrogen atom or (lower)-alkyl and independently of one another in case R'2; n = 0, 1, 2, 3 or 4. Also, invention relates to a medicament possessing high affinity to adenosine A2A-receptors and high selectivity with respect to A1-receptors and comprising one or more derivatives of benzothiazole of the formula (I) and pharmaceutically acceptable excipients. Invention provides using derivatives of benzothiazole as ligands of adenosine receptors.

EFFECT: valuable medicinal properties of compounds and medicament.

13 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-oxo-1-pyrrolidine of the formula (I) or their pharmaceutically acceptable salts wherein X means -CA1NR5R6 or -CA1-R8 wherein A1 and A2 mean independently oxygen atom; R1 means hydrogen atom (H), (C1-C20)-alkyl, (C6-C10)-aryl or -CH2-R1a wherein R1a means (C6-C10)-aryl; R3 means H, -NO2, nitrooxy-group, C≡N, azido-group, -COOH, amido-group, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C6-C10)-aryl, thiazolyl, oxazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, pyrimidinyl, triazolyl, pyridinyl, -COOR11, -COR11 wherein R11 means (C1-C12)-alkyl; R3a means H, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl or (C6-C10)-aryl; R5 and R6 are similar or different and each means independently H, (C1-C6)-alkyl, and R8 means -OH and wherein each alkyl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, isothiocyanate, -OH, -NO2, -CN, azido-group, (C3-C6)-cycloalkyl and (C6-C10)-aryl;, and wherein each (C6-C10)-aryl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, -NH2, -NO2, azido-group, (C1-C6)-alkoxy-group, (C1-C6)-alkyl and (C1-C6)-halogenalkyl, and wherein each alkenyl can be substituted independently with at least one substitute chosen from halogen atom and -OH, and under condition that at least one radical among R and R3a differs from H, and when compound represent a mixture of possible isomers then X means -CONR5R6; A2 means oxygen atom, and R1 means H, -CH3, -C2H5, -C3H7, and when each R1 and R3a means H and A2 means oxygen atom and X means -CONR5R6 then R3 differs from -COOH, -CH, -COOR11, amido-group, naphthyl, phenyl rings substituted with (C1-C6)-alkoxy-group or halogen atom in para-position in naphthyl or phenyl ring. Compounds of the formula (I) can be used in pharmaceutical compositions for treatment of epilepsy, epileptogenesis, convulsions, epileptic seizures, essential tremor and neuropathic pain.

EFFECT: improved method of synthesis, valuable medicinal properties of derivatives and pharmaceutical compositions.

27 cl, 3 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds 2,6-di-tert.-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazole-4-yl}phenol, 2,6-di-tert.-butyl-4-[4-(hydroxymethyl)-1,3-oxazole-2-yl]phenol, 4-methylphenyl-2-[4-(1,1-biphenyl-4-yl)-1H-imidazole-2-yl]ethylcarbamate and others or their pharmaceutically acceptable salts. Also, invention relates to using these compounds for preparing a medicinal agent possessing one of the following three activities: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulating activity with respect to sodium channels. Proposed derivatives of thiazole, oxazole or imidazole possess one of the following species of pharmacological activity: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulation of sodium channels.

EFFECT: valuable biochemical and biological properties of derivatives.

34 cl, 119 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

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

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

11 cl, 2 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (1): wherein Y means -O-, -S- or -N(R2)- wherein R2 means hydrogen atom, (C1-C10)-alkyl or aralkyl; Z means 2,5-furanyl, 2,5-thiophenyl, 4,4'-stilbenyl or 1,2-ethyleneyl residue; R1 means hydrogen or halogen atom, (C1-C10)-alkyl, (C1-C10)-alkoxy-group, cyano-group, -COOM or -SO3M wherein M means hydrogen atom or alkaline or alkaline-earth metal atom. Method for synthesis involves carrying out the reaction of compound of the formula (2): with dicarboxylic acid of the formula: HOOC-Z-COOH (3) or with it ester wherein Y, Z and R1 have values given above in N-methylpyrrolidone or N,N-dimethylacetamide medium in the presence of an acid catalyst and optionally in the presence of an accessory solvent able to remove water from the reaction mixture.

EFFECT: improved method of synthesis.

11 cl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of sulfonamide of the general formula (I): wherein A means a substitute chosen from 5- or 6-membered heteroaromatic ring comprising 1 or 2 heteroatoms chosen from oxygen (O), nitrogen (N) or sulfur (S) optionally substituted with 1 or 2 halogen atoms, (C1-C4)-alkyl or phenyl radical, or 5- or 6-membered heteroaryl radical comprising 1 or 2 atoms of O, N or S; bicyclic heteroaromatic ring comprising from 1 to 3 heteroatoms chosen from O, N or S and optionally substituted with 1 or 2 halogen atoms or (C1-C4)-alkyl; R1 means hydrogen atom (H), (C1-C4)-alkyl, benzyl; n means 0, 1, 2, 3 or 4; R2 means -NRR5 or the group of the formula: wherein a dotted line means optional chemical bond; R, R4 and R5 mean independently H or (C1-C4)-alkyl; or one of its physiologically acceptable salts. Compounds of the formula (1) possess antagonistic activity with respect to serotonin HT6-receptors that allows their using in pharmaceutical composition and for preparing a medicament.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

10 cl, 2 tbl, 7 ex

FIELD: organic chemistry, anti-microbial preparations.

SUBSTANCE: invention relates to compounds useful as anti-microbial agents. Claimed compounds are effective against to certain human and animal pathogens, including Gram-positive aerobic bacteria such as multi-resistant staphylococcus, streptococcus and enterococcus, as well as anaerobic organisms such as species Bacterioides spp. and Clostridia spp., and acid resistant organisms such as Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium spp.

EFFECT: new anti-microbial agents.

2 ex, 5 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel class of 5-membered heterocyclic compounds of the general formula (I): or cosmetically acceptable salts. Invention describes a compound represented by the formula (I) and its pharmaceutically or cosmetically acceptable salt wherein R1 is chosen from linear or branched (C1-C12)-alkyl, (C3-C7)-cycloalkyl, phenyl, naphthyl, C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatoms when they present are chosen independently from oxygen (O), nitrogen (N) or sulfur (S) atom and substituted optionally wherein substitutes are chosen from the first group comprising halogen atom, hydroxy0, nitro-, cyano-, amino- oxo-group and oxime, or from the second group comprising linear or branched (C1-C8)-alkyl wherein a substitute from indicated second group is optionally substituted with R10, or wherein heteroaryl is substituted with -CH2-C(O)-2-thienyl; Y is absent or chosen from the group consisting of (C1-C12)-alkyl-Z or (C2-C8)-alkyl wherein Z is chosen from sulfur, oxygen or nitrogen atom; A and B are chosen independently from nitrogen atom (N), -NH, -NR6, sulfur, oxygen atom to form heteroaromatic ring system; R2, R3 and R4 are chosen independently from the first group comprising hydrogen, halogen atom, or R3 and R4 form phenyl ring in adjacent positions; R5 is absent or chosen from the group comprising -CH2-phenyl, -CH2(CO)R7, -CH2(CO)NHR8 and -CH2(CO)NR8R9 that are substituted optionally with R10; R6, R7, R8 and R are chosen independently from the group comprising linear or branched (C1-C8)-alkyl, (C3-C7)-cycloalkyl, C5-heterocycloalkyl, benzylpiperidinyl, phenyl, naphthyl, heteroaryl, alkylheteroaryl, adamantyl, or R8 and R9 form piperidine ring, and R means 3,4-ethylenedioxyphenyl wherein substitutes in indicated group are substituted optionally with R10, and heteroaryl means C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatom when they present are chosen independently from O, N or S; R10 is chosen from halogen atom, hydroxy-, nitro-, cyano-, amino-, oxo-group, perhalogenalkyl-(C1-C6) or oxime; X means halide ion under condition that when groups/substitutes present at the same or at adjacent carbon or nitrogen atoms then can form optionally 5-, 6- or 7-membered ring optionally containing one o some double bonds and containing optionally one or some heteroatoms chosen from O, N or S. Also, invention describes a method for synthesis of these compounds, their therapeutic and cosmetic using, in particular, in regulation of age and diabetic vascular complications. Proposed compounds show effect based on the triple effect as agent destroying AGE (terminal products of enhanced glycosylation), inhibitors of AGE and scavengers of free radicals that do their suitable in different therapeutic and cosmetic using. Also, invention relates to pharmaceutical and cosmetic compositions comprising these compounds and to methods for treatment of diseases caused by accumulation of AGE and/or free radicals in body cells. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds.

73 cl, 4 tbl, 63 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes novel derivatives of N-triazolylmethylpiperazine of the general formula (I): , wherein R1 means hydrogen atom or (lower)-alkyl; R2 means (lower)-alkyl, di-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, cycloalkyl with 5-6 carbon atoms in cycle, pyridinyl-(lower)-alkyl, possibly bi-substituted phenyl-(lower)-alkyl, phenyloxy-(lower)-alkyl substituted with halogen atom in phenyl ring; R3 means (lower)-alkyl, (lower)-alkyloxycarbonyl-(lower)-alkyl or (C5-C6)-cycloalkyl, or both R2 and R3 in common with nitrogen atom to which they are bound form substituted pyrrolidine ring or cyclic group of the formula (a): , wherein A means nitrogen, oxygen atom, methylene or methylidene group wherein its double bond is formed in common with adjacent carbon atom at position 3 of the group (a), and if A means nitrogen atom then this nitrogen atom has substitute R4', and in this case n means 2 or 3, and R4' means (lower)-alkyl, possibly substituted phenyl-(lower)-alkyl, possibly substituted pyridyl, pyridyl-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, pyrimidyl-(C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(lower)-alkyl or morpholinyl-(lower)-alkyl; R4 and R5 mean hydrogen atom and in all cases n means a whole number from 1 to 2; R4 means hydrogen atom, (lower)-alkyl, (lower)-alkoxy-(lower)-alkyl, (lower)-alkoxycarbonyl, (lower)-alkoxycarbonyl-(lower)-alkyl, di-(lower)-alkylamino-(lower)-alkyl, phenyl, pyrrolidinyl, pyrrolidinyl-(lower)-alkyl, pyridyl or piperidinyl, cyclohexyl, cyclohexyl-(lower)-alkyl, phenyl-(lower)-alkyl, pyridyl monosubstituted with (lower)-alkyl, phenyl-(lower)-alkyl monosubstituted with (lower)-alkyl, pyrimidyl, pyridyl-(lower)-alkyl, morpholinyl-(lower)-alkyl; R5 means hydrogen atom, (lower)-alkyl or (lower)-alkoxy-(lower)-alkyl, or R4 and R5 taken in common mean spiroethylenedioxy-group bound with carbon atom of the group (a), (C3-C4)-alkylene bound with two adjacent atoms of the group (a) or phenyl anellated by two adjacent carbon atoms of the group (a), and their physiologically acceptable acid-additive salts also. Also, invention relates to methods for synthesis of these compounds, a medicinal agent based on thereof and intermediate compound in synthesis of novel compounds. Novel compounds are antagonists of neurokinin receptors and display effect in peripheral region preferably and can be used in treatment of functional and inflammatory disorders of digestive tract.

EFFECT: improved preparing method, valuable medicinal properties of derivatives.

10 cl, 4 tbl, 4 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

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

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of amide of the general formula (I)

wherein X means -CH; Y means -CH or nitrogen atom (N); m = 1 or 2; R1 means (C1-C6)-alkyl, (C1-C)-alkoxy-group, N,N-di-[(C1-C6)-alkyl]-amino-group, heterocyclyl-(C1-C6)-alkyl wherein heterocyclyl represents piperazinyl or homopiperazinyl; n = 3; R2 means halogen atom, (C1-C6)-alkyl; R3 means hydrogen atom; Q means phenyl optionally substituted with cyano-group, or pyridyl optionally substituted with morpholino-group, or their pharmaceutically acceptable salts, to methods for synthesis of indicated compounds, pharmaceutical compositions containing thereof and their using in treatment of diseases or states mediated by cytokines.

EFFECT: improved preparing methods, valuable medicinal properties of compounds and pharmaceutical compositions.

10 cl, 2 tbl, 7 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to anthranylamide derivative selected from compound of formula I or N-oxides thereof, wherein R1 represents methyl, F, Cl, Br; R2 represents F, Cl, Br, I, CF3; R3 represents CF3, Cl, Br, OCH2CF3; R4a represents C1-C4-alkyl; R4b represents H, CH3; and R5 represents Cl, Br, and agriculturally acceptable salt thereof. Also disclosed are composition for pest controlling containing biologically effective amount of formula I and at least one additional component selected from group comprising surfactants, solid and liquid diluents; composition for invertebrate insect controlling containing biologically effective amount of formula I and at least one additional biologically active compound or agent. Also disclosed are method for insect controlling as well as intermediates such as benzoxazinone and parasolocarboxylic acid derivatives.

EFFECT: compounds with insecticide activity, useful in insect controlling.

20 cl, 16 tbl, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

Up!