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Docosahexaenoic acid ethers and their application for treatment and prevention of cardiovascular diseases
Docosahexaenoic acid ethers and their application for treatment and prevention of cardiovascular diseases
IPC classes for russian patent Docosahexaenoic acid ethers and their application for treatment and prevention of cardiovascular diseases (RU 2451672):
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Method of synthesis of anticancer derivatives of (poly)aminoalkylaminoacetamide epipodofillotoxine Method of synthesis of anticancer derivatives of (poly)aminoalkylaminoacetamide epipodofillotoxine / 2450009
Invention refers to a new method for preparing anticancer preparations representing derivatives of (poly)aminoalkylaminoacetamide epipodofillotoxine of formula 1. The method implies a condensation stage of the compounds of formulae 4 and 6 in a polar aprotonic solvent without pre-protection of functional amine groups to produce a compound of formula 1, wherein in formulae 1, 4 and 6 R represents hydrogen atom or -(CH2)c-NH2, 2≤a, b, c≤5.
Carbocyclic and heterocyclic arylsulfones as γ-secretase inhibitors Carbocyclic and heterocyclic arylsulfones as γ-secretase inhibitors / 2448964
Claimed invention relates to compounds of formula (I) or to their pharmaceutically acceptable salts, in which X is selected from group, consisting of-C(R1)2-, -O-, -S-, -S(O2)-, -NR1-; each R1 is independently selected from group consisting of H and alkyl; each of R2, R3 and R4 is independently selected from group consisting of (1) H, (2) alkyl, (3) -OR5, (4) alkylene-OR5, (5) -alkylene-R6, (6) -C(O)O-alkyl, (7) - alkylene-C(O)O-alkyl, (8) -alkylene-R8, (9) -NHR5, (10) -N(R5)2, (11) alkenyl, (12) -NH-R8, (13) -NH-CH(C(O)O(C1-C6)alkyl)-alkylene-O-alkyleneR6, (14)-NHCH(C(O)O(C1-C6)aalkyl)-alkylene-OH, (15) -NH-C(O)-alkenyl and (16) -N(C1-C6alkyl)C(O)-alkenyl; or R2 and R3 or R2 and R4 or R3 and R4 together with atoms with which they are bound, form condensed 3-7-member cycloalkyl or heterocycloalkyl ring, which represents non-aromatic monocyclic ring system, which contains in ring from about 5 to about 7 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen or oxygen, and said condensed cycloalkyl or heterocycloalkyl ring is not substituted or is substituted with one or several groups L3 ; and on condition that if X represents -O-, and m equals 1, then, at least, one of R2, R3 or R4 is not H; each R5 is independently selected from group consisting of (1) H, (2) (C1-C6)alkyl, (3) hydroxy-substituted alkyl, (4) R6, (5) R7, (6) -C(O)-(C1-C6)alkyl, (7) -C(O)-(C1-C6)halogenalkyl, (8) -C(O)-R6, (9) -C(O)-R7, (10) -C(O)NH-(C1-C6)alkyl, (11) -C(O)N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (12) -S(O)2-(C1-C6)alkyl, (13) -S(O)2-(C1-C6)halogenalkyl, (14) -S(O)2-R6, (15) -S(O)2-R7, (16) -S(O)2-R8, (17) -alkylene-C(O)-(C1-C6)alkyl, (18) -alkylene-C(O)-(C1-C6)halogen-alkyl, (19) -alkylene-C(O)-R6, (20) -alkylene-C(O)-R7, (21) -alkylene-S(O)2-(C1-C6)alkyl, (22) -alkylene-S(O)2-(C1-C6)halogenalkyl, (23) -alkylene-S(O)2-R6, (24) -alkylene-S(O)2-R7, (25) -alkylene-S(O)2-R8, (26) -alkylene-NHC(O)-(C1-C6)alkyl, (27) -alkylene-NHC(O)-(C1-C6)halogenalkyl, (28) alkylene-NHC(O)-R6, (29) -alkylene-NHC(O)-R7, (30) -alkylene-NHS(O)2-(C1-C6)alkyl, (31) -alkylene-NHS(O)2-(C1-C6)halogenalkyl, (32) -alkylene-NHS(O)2-R6, (33) -alkylene-NHS(O)2-R7, (34) -alkylene-N(alkyl)C(O)-(C1-C6)alkyl, (35) -alkylene-N(alkyl)C(O)-(C1-C6)halogenalkyl, (36) -alkylene-N(alkyl)C(O)-R6, (37) -alkylene-N(alkyl)C(O)-R7, (38) -alkylene-N(alkyl)S(O)2-(C1-Ce)alkyl, (39) -alkylene-N(alkyl)S(O)2-(C1-C6)halogen-alkyl, (40)-alkylene-N(alkyl)S(O)2-R6, (41) -alkylene-N(alkyl)S(O)2-R7, (42) -alkylene-C(O)-NH-(C1-C6)alkyl, (43) -alkylene-C(O)-NHR6, (44) -alkylene-C(O)-NHR7, (45) -alkylene-S(O)2NH-(C1-C6)alkyl, (46) -alkylene-S(O)2NH-R6, (47) -alkylene-S(O)2NH-R7 , (48) -alkylene-C(O)-N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (49) -alkylene-C(O)-N(alkyl)-R6, (50) -alkylene-C(O)-N(alkylene)-R7, (51) -alkylene-S(O)2N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (52) -alkylene-S(O)2N(alkyl)-R6, (53) -alkylene-S(O)2N(alkyl)-R7, (54) -alkylene-OH, (55) -alkylene-OC(O)-NH-alkyl, (56) -alkylene-OC(O)NH-R8, (57) -alkylene-CN, (58) -R8, (59) -alkylene-SH, (60) -alkylene-S(O)2-NH-R8, (61) -alkylene-S(O)2-alkylene-R6, (62) substituted with halogen alkylene, (63) -C(O)OR8, (64) -C(O)O(C1-C6)alkyl, (65) -C(O)R8, (66) -C(O)-alkylene-O-(C1-C6)alkyl, (67) -C(O)NH2, (68) -alkylene-O-(C1-C6)alkyl, (69) -alkylene-R8, (70) -S(O)2-halogen(C1-C6)alkyl, (71) hydroxy-substituted halogen(C1-C6)alkyl, (72) -alkylene-NH2, (73) -alkylene-NH-S(O)2-R8, (74) -alkylene-NH-C(O)-R8, (75) -alkylene-NH-C(O)O-(C1-C6)alkyl, (76) -alkylene-O-C(O)-(C1-C6)alkyl, (77) -alkylene-O-S(O)2-(C1-C6)alkyl, (78) -alkylene-R6 , (79) -alkylene-R7, (80) -alkylene-NH-C(O)NH-(C1-C6)alkyl, (81) -alkylene-N(S(O)2 halogen(C1-C6)alkyl)2, and each -S(O)2 halogen(C1-C6)alkyl fragment is selected independently, (82) -alkylene-N((C1-C6)alkyl)S(O)2-R8 , (83) -alkylene-OC(O)-N(alkyl)2, and each alkyl is selected independently, (84) -alkylene-NH-(C1-C6)alkyl, (85) -C(O)-alkylene-C(O)O-(C1-C6)alkyl, (86) -C(O)-C(O)-O-(C1-C6)alkyl, (87) -C(O)-alkylene-R6, (88) -C(O)-NH-R8, (89) -C(O)-NH-R6, (90) -C(O)-NH-alkylene-R6, (91) -C(O)-alkylene-NH-S(O)2-halogen(C1-C6)alkyl, (92) -C(O)-alkylene-NH-C(O)-O-(C1-C6)alkyl, (93) -C(O)-alkylene-NH2, (94) -C(O)-alkylene-NH-S(O)2-R8, (95) -C(O)-alkylene-NH-S(O)2-(C1-C6)alkyl, (96) -C(O)-alkylene-NH-C(O)-(C1-C6)alkyl, (97) -C(O)-alkylene-N(S(O)2(C1-C6)alkyl)2, and each -S(O)2(C1-C6)alkyl fragment is elected independently, (98) -C(O)-alkylene-NH-C(O)-NH-(C1-C6)alkyl, (99) -alkylene-O-R6, (100) -alkylene-R7, (101) -C(O)OH, (102) -alkylene-N(S(O)2(C1-C6)alkyl)2, (103) -alkylene-C(O)-O-(C1-C6)alkyl, (104) halogenalkyl, (105) halogen, (106) -alkylene-C(O)-NH2, (107) =N-O-(C1-C6)alkyl, (108) =N-O-alkylene-R6, (109) =N-O-alkenyl, (110) -N-O-R6, (111) =N-NH-S(O)2-R6, (112) alkenyl, (113) =R8, (114) -O-C(O)-R9, (115) -O-C(O)-(C1-C6)alkyl, (116)-CN, R6 is selected from group consisting of unsubstituted (C6-C14)aryl, (C6-C14)aryl, substituted with one or several groups L1, unsubstituted (C5-C14)heteroaryl and (C5-C14)heteroaryl, which represents aromatic monocyclic or bicyclic system, which contains in ring from about 5 to about 9 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen or sulphur, one or in combination, substituted with one or several groups L1; R7 is selected from group consisting of unsubstituted heterocycloalkyl and heterocycloalkyl which represents non-aromatic monocyclic system, which contains in ring from about 4 to about 6 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen substituted with one or several groups L2; R8 is selected from group consisting of unsubstituted cycloalkyl and cycloalkyl substituted with one or several groups L2; A8 is selected from group consisting of (a) unsubstituted aryl, (b) aryl substituted with one or several groups L1; each group L1 is independently selected fron group consisting of halogen, alkyl, -CN, -CF3, -O-(C1-C6)alkyl, -O-(halogen(C1-C6)alkyl), -alkylen-OH (-CH2OH); each group L2 is independently selected from group consisting of (a) -OH, (b) alkyl, (c) alkyl substituted with one or several groups -OH and (d) piperidyl; each group L3 is independently selected from group consisting of -CN, =O, R5 , -OR5 ; =N-R5 and -N(R5)2; n equals 0, 1, 2 or 3; and m equals 0, 1 or 2; and on condition that in composition of substituent -OR5 fragment R5 and oxygen atom, which it is bound with, do not form group -O-O-; and on condition that in composition of substituents -OR5, =N-R5 and -NHR5 R5 are not -CH2OH, -CH2NH2, -CH2NH-alkyl, -CH2NH-aryl or -C(O)OH. Invention also relates to pharmaceutical composition, as well as to application of one or several compounds by one of ii. 1-125.
Synergist for improvement of effectiveness of biological agents against colorado potato beetle Synergist for improvement of effectiveness of biological agents against colorado potato beetle / 2448464
Improvement of effectiveness of insecticidal preparation is achieved through the use in sublethal doses of a mixture of fluorinated usnic acid (FUA) of the formula and II obtained by the reaction of (+)-usnic acid with perfluoropropene as a synergist of such insecticides. The decline of the latent period of the disease and increased mortality rate of larvae of Colorado potato beetle is marked using FUA and entomopathogenic microorganisms of Beauveria bassiana, Metarhizium anisopliae and Bacillus thuringiensis. The mixed composition of FUA at a concentration of 0.03% with a suspension of conidia of the fungus Bauveria bassiana with a titer of 3×106 conidia/ml (in vitro) and 5×106 conidia/ml (in the field) has proved to be the best in all respects.
Method of producing optically active chromene oxide compound Method of producing optically active chromene oxide compound / 2448112
Invention relates to a method of producing an optically active chromene oxide compound of formula or formula where R5, R6, R7, R8, R9, R10 and A are as described in the claim, and the absolute configuration of carbon atoms, denoted by *, denotes (R) or (S), which includes asymmetric epoxidation of a chromene compound of formula or formula with an oxidant in a solvent using optically active titanium complexes of formula formula formula and formula where R1, R2, R3 and R4 are defined in the claim, as a catalyst for asymmetric oxidation of the optically active chromene compound with high enantioselectivity and high chemical output.
Novel condensed pyrrole derivatives Novel condensed pyrrole derivatives / 2434853
Invention relates to compounds of formula (1) (lb) in which A denotes a benzene ring; Ar denotes naphthalenyl which optionally contains 1-3 substitutes independently selected from a group comprising C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, hydroxy group, C1-C6alkoxy group, halogen, heteroalkyl, heteroalkoxy group, nitro group, cyano group, amino- and mono- or di- C1-C6alkyl-substuted amino group; R1 denotes hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy group, carboxy group, heteroalkyl, hydroxy group optionally substituted with heterocyclylcarbonyl-C1-C6alkyl or R1 denotes N(R')(R")-C1-C6alkyl or N(R')(R")-carbonyl- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, heteroalkyl, phenyl-C1-C6alkyl; or R1 denotes R'-CO-N(R")-C1-C6alkyl, R'-O-CO-N(R")- C1-C6alkyl- or R'-SO2-N(R")- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cyclalkyl, C3-C7cycloalkyl- C1-C6alkyl or optionally substituted phenyl; R2, R2' and R2" independently denote hydrogen, halogen, cyano group, C1-C6alkyl, halogenated C1-C6alkyl or C1-C6alkoxy group; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to use of compounds in any of claims 1-9, as well as to a pharmaceutical composition.
Antiarrhythmic compound precursors, synthesis processes and methods of application Antiarrhythmic compound precursors, synthesis processes and methods of application / 2422447
Invention refers to compounds of formula formula (1) formula (2) or to their hydrate, solvate, salt or tautomer form where R1 independently represents H or halogen; R2 represents H or --R10-NR11R12 where R10 represents C1-C6 alkylene; R11 and R12 independently represent H, C1-C4 alkyl; and R3 independently represents H or halogen. Besides, the invention covers methods of preparing the compounds of the present invention.
Synthesis of protease inhibitor precursor Synthesis of protease inhibitor precursor / 2421459
Invention relates to a compound of formula (I) or stereoisomer thereof, or salt thereof, as well as synthesis method thereof and intermediate compounds of formulae (II) and (III) used in this method.
Methods of producing (3r, 3as, 6ar) hexahydrofuro[2,3-b]furan-3-ol Methods of producing (3r, 3as, 6ar) hexahydrofuro[2,3-b]furan-3-ol / 2421458
Invention relates to methods of producing diastereoismerically pure (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol (6), as well as a novel intermediate compound (3aR,4S,6aS)-4-methoxytetrahydrofuro [3,4-b]furan-2-one (4) for use in said methods. More specifically, the invention relates to a stereo-selective method of producing diastereoisomerically pure (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol, as well as methods for crystallisation of (3aR,4S,6aS)-4-methoxytetrahydrofuro[3,4-b]furan-2-one and epimerisation of (3aR,4S,6aS)-4-methoxytetrahydrofuro[3,4-b]furan-2-one to (3aR,4S,6aS)-4- methoxytetrahydrofuro[3,4-b]furan-2-one.
Products of oxidative decomposition of atorvastatin calcium Products of oxidative decomposition of atorvastatin calcium / 2412191
Invention relates to products of oxidative decomposition of atorvastatin calcium, specifically to 4-[6-(4-fluorophenyl)-6-hydroxy-1b-isopropyl-6a-phenyl-1a-phenylcarbamoylhexahydro-1,2-dioxa- 5a-azacyclopropa [a]inden-3-yl]-3-(R)-hydroxybutyric acid, phenylamide 4-(4-fluorophenyl)-2,4-dihydroxy-2-isopropyl-5-phenyl-3,6-dioxabicyclo[3.1.0]hexane-1-carboxylic acid and 4-[1b-(4-fluorophenyl)-6-hydroxy-6-isopropyl-1a-phenyl-6a-phenylcarbamoylhexahydro-1,2-dioxa-5a-azacyclopropa [a]inden-3-yl]-3-(R)-hydroxybutyric acid. The invention also relates synthesis methods thereof, based on oxidation of an atorvastatin salt.
Method and device for preparing compositions rich in episesamin Method and device for preparing compositions rich in episesamin / 2408598
Sesamin or sesamin-containing composition undergoes epimerisation in such a way that a portion of the sesamin converts to episesamin. Episesamin is crystallised through recrystallisation. The device for producing sesamin has an isomerisation unit which has a mixing reservoir for mixing oil or fat containing sesamin or a sesamin-containing composition with an acid catalyst; a crystallisation unit having a crystallisation reservoir for carrying out recrystallisation; a liquid supply line which connects the mixing reservoir with the crystallisation reservoir.
Novel floroglucin derivatives, possessing activity with respect to selectin ligand Novel floroglucin derivatives, possessing activity with respect to selectin ligand / 2418584
Claimed invention relates to chemical-pharmaceutical industry. Pharmaceutical compositions including, at least, one compound of formula where -X- represents, for instance, group of formula and Y represents, for instance, group of formula or its pharmaceutically acceptable salts, esters or amides, or pro-drugs and pharmaceutically acceptable carrier, which is acceptable in therapy, can be applied for modulation in vitro and in vivo processes of binding, mediated by binding of E-, P- or L- selectin.
Propane-1,3-dion derivative or salt Propane-1,3-dion derivative or salt / 2404973
Invention refers to a compound of formula I where A represents an optionally substituted aryl or heteroaryl, B - a benzene or thiophene cycle, C - a benzene or aliphatic hydrocarbon cycle, while values of other radicals are disclosed in the description. The compound according to the present invention, and the based pharmaceutical compositions exhibit a strong antagonistic effect in relation to GnRH receptor that makes them applicable for treatment of GnRH-related diseases, particularly prostate cancer, benign prostatic hyperplasia, breast cancer, endometriosis and/or uterine fibroid tumour.
Substituted acrylamide derivative and pharmaceutical composition based on said derivative Substituted acrylamide derivative and pharmaceutical composition based on said derivative / 2404966
In formula (I') , R5 is any group selected from a group comprising C1-C6 alkoxy group, which can be substituted with one group selected from a group of β substitutes, phenyloxy group which can be substituted with one group selected from a group of γ substitutes, C1-C6 halogenalkoxy group and C3-C6 cycloalkyloxy group; R6 is a substitute in a benzene ring which is selected from a group of α substitutes; R7 is a hydrogen atom, C1-C6 halogenalkyl group, C1-C6 hydroxyalkyl group which can be substituted with a hydroxy-protective group, C1-C6 alkyl group which can be substituted with one group selected from a group of β substitutes, or a phenyl group which can be substituted with one hydroxy group; m equals 1; n equals 1 or 2; numbers in each benzene ring denote the number of the position of each substitute; the group of substitutes includes hydroxyl groups, nitro groups, cyano groups, C1-C6 dialkylamino groups, acetamide groups, halogen atoms, C1-C6 alkyl groups, which can be substituted with one group selected from a group of β substitutes, C1-C6 halogen alkyl groups, C3-C10 cycloalkyl groups, 6-member heterocyclic groups with an N atom or O atom as a heteroatom, C3-C6 cycloalkenyl groups, phenyl group which can be substituted with one group selected from a group of γ substitutes, 5-6-member heteroaryl groups with 1-3 N atoms as heteroatoms which can be substituted wit one or more groups selected from a group of γ substitutes, C1-C6 alkoxy groups, C1-C6 halogenalkoxy groups, C3-C10 cycloalkoxy groups, phenyloxy group, C1-C6 alkylthio groups, C1-C6 halogenalkylthio groups, C1-C6 alkylsulphonyl groups and C1-C6 alkylcarbonyl groups; the group of β substitutes includes C1-C6 alkoxycarbonyl groups, C3-C10 cycloalkyl groups which can be substituted with one group selected from a group of γ substitutes, C3-C6 cycloalkenyl groups, C6-C10 aryl groups which can be substituted with one or more groups selected from a group of γ substitutes, 5-6-member heteroaryl groups with one N, O or S heteroatom, 9-member heteroaryl groups with two heteroatoms selected from N and S, C1-C6 alkoxy group and C6-C10 aryloxy group; and the group of γ substitutes include cyano groups, C1-C6 dialkylamino groups, C1-C6 cyclic amino groups, halogen atoms, C1-C6 alkyl groups, C3-C10 cycloalkyl grous, C1-C6 halogenalkyl groups, C1-C6 alkoxy groups and C1-C6 alkylenedioxy groups. The invention also relates to compounds or pharmaceutically acceptable salts thereof, selected from: 4-(2-cyclopropylethoxy)-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide, 4-(2-cyclopropylethoxy)-N-(2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide, 4-(2-cyclopropylethoxy)-N-(2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}-vinyl)-benzamide. Other compounds are given in the formula of invention. The invention also relates to a pharmaceutical composition which can inhibit bone resorption, which contains the disclosed compound, to use of the disclosed compound as a medicinal agent for inhibiting bone resorption, for preparing a medicinal agent for lowering concentration of calcium in the blood, for preparing a medicinal agent for inhibiting reduction of bone mass, to a medicinal agent for inhibiting bone resorption in form of the disclosed compound, to a method of inhibiting bone resorption, a method of lowering concentration of calcium in the blood, a method of inhibiting reduction of bond mass, involving addition of an effective amount of the disclosed compound.
Condensed bicyclic carboxamide derivatives used as cxcr2 inhibitors for treating inflammations Condensed bicyclic carboxamide derivatives used as cxcr2 inhibitors for treating inflammations / 2404962
Disclosed compounds can be used as a medicinal agent having CXCR2 inhibiting properties. In formula I , X denotes -CR3=CR4-, -CR5=N-, -N=CR6-, -NR7- or -S-; R3, R4, R5 and R6 independently denote hydrogen, F, CI, Br, I; R7 denotes hydrogen; Y1, Y2, Y3 and Y4 independently denote -CR8- or nitrogen, provided that at least two of Y1, Y2, Y3 and Y4 denote -CR8-; where R8 denotes hydrogen, F, CI, Br, I; A denotes a cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms; a bicyclic partially saturated 9-member cycloalkyl; a bicyclic partially saturated 9-10-member heterocycle in which two atoms in the ring are oxygen atoms; phenyl; naphthyl; a 5-6-member heteroaryl in which 1-3 atoms in the ring are oxygen, sulphur and nitrogen atoms; a 9-10-member bicyclic heteroaryl in which 1-3 atoms in the ring are nitrogen, oxygen and sulphur atoms; a 6-member heterocycle in which one atom in the ring is a nitrogen atom and which can be unsubstituted or substituted with alkyl having 1, 2, 3 or 4 carbon atoms, -C(O)CH3, -C(O)CH2CH3, -C(O)cyclopropyl, -C(O)CF3 and -C(O)OC(CH3)3; where phenyl, heterocyclic or heteroaryl radical is substituted with 1, 2 or 3 radicals selected from a group consisting of F, O, Br, I, OH, CN, NO2, SCF3, SF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; cycloalkyl having 3, 4, 5 or 6 carbon atoms; alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -S-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -NR9R10, C(O)R44, S(O)SR47, -(CH2)k-phenyl, 5-6-member heteroaryl, in which 1-3 atoms in the ring are nitrogen and sulphur atoms; where the phenyl radical may be substituted with F, CI, Br, I; R9 is an alkyl having 1, 2, 3 or 4 carbon atoms; R10 is an alkyl having 1, 2, 3 or 4 carbon atoms; R44 is an alkyl having 1, 2, 3 or 4 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; alkoxy having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms; R47 is an alkyl having 1, 2, 3 or 4 carbon atoms; k equals 0, 1, 2 or 3; s equals 1 or 2; B is -O-C(R11R12), -C≡C-, -CR52=CR53-, -C(R13R14)C(R15R16), -NR17-C(R18R19); R11, R12, R13, R14, R15, R16, R17, R18, R19, R52, R53 independently denote hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; D is C(O)OH, C(O)NHR21 or C(=NR58)NHR22; R21 and R22 independently denote hydrogen, -SO2-alkyl having 1, 2, 3 or 4 carbon atoms, -SO2-phenyl; R58 is OH; R1 and R2 independently denote an alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where the alkyl radicals are unsubstituted or substituted with 1 radical selected from a group consisting of F, Cl, Br, I, phenyl substituted with OH; or R1 and R2, taken together with a carbon atom with which they are bonded form a 3-, 4-, 5- or 6-member carbocycle. The invention also relates to use of formula I compounds in preparing a medicinal agent which has CXCR2 inhibiting properties, to a medicinal agent which containing an effective amount of the disclosed compound and having CXCR2 inhibiting properties, as well as to use of formula II compounds (formula and values of radicals are given in the formula of invention) in preparing a medicinal agent having CXCR2 inhibiting properties.
Amide derivatives carrying cyclopropylaminocarbonyl substitute, suitable as cytokine inhibitors Amide derivatives carrying cyclopropylaminocarbonyl substitute, suitable as cytokine inhibitors / 2382028
Invention relates to novel compounds of formula , where Qa is phenyl or heteroaryl, and Qa can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; R1 and R2 are each independently selected from hydrogen and (1-6C)alkyl; Qb is phenyl or heteroaryl, and Qb can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, (1-6C)alkylthio, (1-6C)alkylsulfinyl and (1-6C)alkylsulfonyl; where any of the substitutes Qa and Qb defined above, containing a CH2 group which is bonded to 2 carbon atoms, or a CH3 group bonded to a carbon atom, can possibly carry on each of the said CH2 or CH3 group one or more substitutes selected from hydroxy, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; where heteroaryl is an aromatic 5- or 6-member monocyclic ring which can contain up to three heteroatoms selected from oxygen, nitrogen and sulphur, and can be condensed with a benzene ring or a five-member nitrogen-containing ring containing 2 nitrogen atoms; as well as pharmaceutically acceptable salts thereof. The invention also relates to a method of producing formula I compounds, a pharmaceutical composition and use of these compounds for treating conditions mediated by effect of TNF cytokines.
Phenyl derivatives as ppar agonists Phenyl derivatives as ppar agonists / 2374230
Invention relates to compounds of formula and to their pharmaceutically acceptable salts or esters, where X1 is O, S, CH2; R1 is hydrogen; R2 is hydrogen or C1-C7alkyl, R3 is hydrogen or C1-C7alkyl; R4 and R8 are independently hydrogen, C1-C7alkyl, C1-C7alkoxy-C1-C7alkyl, fluoroC1-C7alkyl; R5, R6 and R7 are independently hydrogen, C1-C7alkyl, halogen, fluoroC1-C7alkyl; and one or R5, R6 and R7 represents , where X2 is S, O, NR9, (CH2)PNR9CO or (CH2)PCONR9, R9 is hydrogen, C1-C7alkyl; one or two of Y1, Y 2, Y3 and Y4 is N, and the rest represent C-R12 R10 is C1-C7alkyl, C3-C7 cycloalkyl; R11 is hydrogen; R12 in each case is independently selected from hydrogen, C1-C7alkyl, C3-C7 cycloalkyl, fluoroC1-C7 alkyl, C1-C7alkoxy-C1-C7alkyl, hydroxyC1-C7alkyl, di-C1-C7alkylamino-C1-C7alkyl; R13 is phenyl or heteroaryl, which is a 6-member aromatic ring, containing nitrogen as a heteroatom, which can be substituted with a CF3 group, lower fluroalkoxy group or halogen; m=0 or 1, n=0, 1, 2, and p=0, 1 or 2, and the sum of m, n and p=1, 2, 3 or 4; under the condition that, there are no formula I compounds, where X1 is O, R2 and R3 are hydrogen; R6 is , X2 is O or S, and m=0. The invention also relates to pharmaceutical compositions containing such compounds, with agonistic activity towards PPARδ and/or PPARα.
Benzannealed compounds as ppar activators Benzannealed compounds as ppar activators / 2367654
Invention refers to compounds of formula I and its pharmaceutically acceptable salts and esters where X1 stands for O or CH2; R1 stands for hydrogen; R2 stands for hydrogen or C1-C7-alkyl, or if X1 stands for CH2, R2 stands for hydrogen, C1-C7-alkyl or C1-C7-alkoxygroup; R3 stands for hydrogen or C1-C7-alkyl; R4 and R5 or R5 and R6 are bound and form a ring together with carbon atoms whereto attached, and R4 and R5 or R5 and R6 simultaneously stand for -CH=CH-CH=CH- or -(CH2)P- where p is equal to 4; and R4 and R6 are included in a ring structure as specified above, or independently stand for hydrogen; R7 and R8 stand for hydrogen; and one of R6 and R7 stands for where X2 stands for O or NR9; R9 stands for C1-C7-alkyl; one or two of Y1, Y2, Y3 and Y4 stand for N, and the others stand for C-R12; R10 stands for hydrogen, C1-C7-alkyl; R11 stands for hydrogen, C1-C7-alkyl; R12 independently in each case are chosen from the group including hydrogen, C1-C7-alkyl, C3-substituted with CF3; and n is equal to 0 or 1.
Compounds for treatment of metabolic diseases Compounds for treatment of metabolic diseases / 2341513
Novel compounds of formulas , , , , , , (designation of all groups are given in invention formula) are used for treatment of different metabolic diseases, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver, cachexia, obesity, atherosclerosis and arteriosclerosis.
Substituted aryl ketones Substituted aryl ketones / 2339615
In novel substituted aryl ketones of formula (I) Z stands for groupings and A1, A2, A3, R1, R2, R3, R4, R5, R6, R7, X and Y and m are such as given in formula of invention. In substituted aryl carboxylic acid of formula (II) and derivative of aryl carboxylic acid of formula (III) A1, A2, A3, R1, R2, X and Y are such as given in item 1 of invention formula, R12 stands for allyl, which are intermediate products. Also described is means to fight undesirable plants based on formula (I) compound.
Production method of α -racemate of 1-(2-piperidyl)-1,2-ethandiol Production method of α -racemate of 1-(2-piperidyl)-1,2-ethandiol / 2334740
Invention refers to production method of α-racemate of 1-(2-piridyl)-1,2-ethandiol: catalytic reducing (1RS)-1-(2-piridyl)-1,2-ethandiol distinctive in that nickel aluminium alloy is used as catalyst, while reduced at atmospheric active hydrogen pressure generated by reaction (1RS)-1-(2-piridyl)-1,2-ethandiol with sodium hydroxide in aqueous medium, resulted in and β-racemates of 1-(2-piperidyl)-1,2-ethandiol and their subsequent diethyl ether fractional crystallisation to produce end product applied as raw product for medical product synthesis, such as Ethoxadrol, Dexoxadrol, Levoxadrol, Dioxadrol.
Heterocyclic compounds as crth2 receptor antagonists Heterocyclic compounds as crth2 receptor antagonists / 2451019
Invention relates to a compound of formula I:

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to a compound ether of docosahexanoic acid and an alcohol, its production method and a pharmaceutical composition applied as a medication for prevention and treatment of cardiovascular diseases. The said alcohol is selected from pentanol with formula: and inositol with formula . The compound ether production method consists in transetherification of docosahexanoic acid ethyl ether with one of the said alcohols.

EFFECT: development of a pharmaceutical composition applied as a medication for production for cardiovascular diseases treatment and prevention.

10 cl, 5 tbl, 1 dwg, 5 ex

 

The present invention relates to esters of docosahexaenoic acid (DHA) with alcohols selected from vitamins or provitamins groups, such as nicotinebuy alcohol (B3), panthenol (B5) or Inositol (V7), or isosorbide or isosorbide of Mononitrate, and, in particular, pyridine-3-ylmethylphosphonate, and their application as pharmaceuticals for the treatment and prevention of cardiovascular diseases.

Polyunsaturated fatty acids omega-3, particularly EPA (eicosapentaenoic acid) and DHA, preferably purified and concentrated in the form of ethyl ester, known due to their potential application for the treatment of some cardiovascular diseases and to modulate the relevant risk factors. In particular, they are known for the treatment of hyperlipidemia, hypercholesterolemia and hypertension. Clinical trials conducted with drugs, containing a high concentration of ethyl ester of EPA and DHA, on patients suffering from myocardial infarction, showed their effectiveness in reducing mortality and, in particular, sudden death. These results were attributed partly stabilizing effect on the cell membrane of ventricular cardiomyocytes, which prevent the occurrence of malignant arrhythmias in the presence of ischemic myocytes, as observed in the patient is in after a heart attack or in experimental models, that reproduce such conditions.

In addition, according to patent application WO 2004/047835 it is also known that ethyl esters of DHA and EPA can be used to prevent atrial fibrillation. However, unexpectedly, the authors of this application have found that DHA and EPA have different effects on atrial fibrillation: DHA has a much greater effect on atrial fibrillation than EPA. Thus, for the treatment of atrial fibrillation and, of course, for treatment of most cardiovascular disease is more preferable to use one DHA and not a mixture of DHA and EPA.

B vitamins comprise water-soluble molecules belonging to diverse chemical classes, but all of which have as a primary function the ability to control the activity of enzymes in the metabolism process in the body. These vitamins are thiamine (B1), Riboflavin (B2), Niacin (EOI), Pantothenic acid (B5), pyridoxine (B6), Biotin (B8), folic acid (B9) and cyanocobalamin (B12).

Vitamins and provitamins groups have the benefits associated with their function. In particular, nicotinebuy alcohol is an alcohol derived from nicotinic acid (vitamin EOI). In the body it is rapidly converted to nicotinic acid.

Nicotinic acid, also known as Niacin, p is ecstasy a water-soluble b vitamin, which can be synthesized from tryptophan. However, the effective therapeutic dose for the reduction of cholesterol and lipids is higher than the number produced by the body. Thus, it is proved that the oral Supplement is essential to reduce the levels of cholesterol and/or triglycerides.

With regard to mechanism of action, suggest that nicotinic acid inhibits the release of free fatty acids from adipose tissue, resulting in reduced delivery of fatty acids to the liver. Because less fatty acids will tarifitsirovatsja in triglycerides, less will be included in the low-density lipoprotein (LDL), thereby reducing the levels of LDL cholesterol. Also noticed that nicotinic acid significantly increases the levels of HDL cholesterol, most likely through inhibition of the catabolism of HDL cholesterol.

In particular, nicotinic acid has a strong peripheral vasodilating effect. Thus, intravenous injection nicotineamide alcohol after its conversion to nicotinic acid leads to vasodilation favorable for lowering blood pressure.

Nicotinic acid is widely used in therapy to reduce levels of cholesterol and lipids.

It was also shown that nicotinic acid can be Ob is Diana with inhibitors of HMG-CoA-reductase (hydroxymethylglutaryl-coenzyme A-reductase), such as statins, for example, in cases where the reduction of cholesterol by these inhibitors HMG-CoA reductase inhibitor is not sufficient. This combination can be useful when seeking benefits from the effects of each connection, in particular, reduction of LDL cholesterol with statins and cholesterol HDL nicotinic acid. In addition, nicotinic acid suitable for the treatment of mixed dyslipidemia and, thus, are able to influence levels of both cholesterol and triglycerides.

Panthenol is an alcohol derivative of Pantothenic acid, more commonly known as vitamin B5. In the body panthenol is converted into Pantothenic acid. Pantothenic acid then becomes an important part of the connection of coenzyme a, which is of particular interest in cellular metabolism. Indeed, he is involved in the metabolism of lipids, carbohydrates and proteins. Panthenol is also involved in the formation of acetylcholine and adrenal steroids. It also plays a role in detoxification of foreign bodies and in resistance to infection.

Inositol (vitamin B7) mobilizes fats by preventing their accumulation. He also possesses anxiolytic effect, it stimulates the nervous system and liver, and it reduces the level of cholesterol in the blood. He is involved in the increased activity of the serotonin system, the control to which ncentratio intracellular calcium, maintaining the potential of the cell membrane and the Assembly of the cytoskeleton.

Isosorbide in particular isosorbide Mononitrate is a powerful peripheral vasodilator.

Unexpectedly, the inventors have found that esters of docosahexaenoic acid (DHA) with alcohols selected from vitamins or provitamins groups, such as nicotinebuy alcohol (B3), panthenol (B5) and Inositol (V7), or isosorbide or isosorbide-Mononitrate, in particular, pyridine-3-iletileceginden (ester of docosahexaenoic acid (DHA) with nicotinoyl alcohol), also have significant activity against cardiovascular disease.

Thus, the present invention relates to a complex ether, docosahexaenoic acid with an alcohol selected from vitamins or provitamins group, preferably consisting of:

- nicotineamide alcohol of the following formula:

,

- panthenol following formula:

- Inositol following formula:

or isosorbide following formula:

or isosorbide-Mononitrate the following formula:

Preferably ester of the present invention is a pyridine-3-iletild azahexane following General formula (1):

The present invention also relates to a process for the preparation of ester of docosahexaenoic acid according to the present invention, in particular, pyridine-3-ylmethylphosphonate (1), by transesterification of the ethyl ester of docosahexaenoic acid with an alcohol selected from the group comprising nicotinebuy alcohol, panthenol, isosorbide, isosorbide Mononitrate and Inositol, preferably with nicotinoyl alcohol.

Transesterification can be carried out by methods well-known to specialists in this field of technology.

Preferably, the transesterification of the present invention is carried out in the presence of a catalyst. Preferably, this catalyst is a carbonate of an alkali metal or carbonate of alkaline earth metal, preferably K2CO3. Preferably, the molar ratio of the carbonate of an alkali metal or carbonate of alkaline earth metal to ethyl ether DHA is in the range from 1/1 to 6/1. Preferably, the molar ratio of alcohol to ethyl ether DHA is in the range from 1/1 to 6/1, even more preferably, the molar ratio nicotineamide alcohol to ethyl ether DHA is in the range from 1/1 to 6/1. Preferably, the reaction of transesterification is carried out in a solvent, predpochtitelnye from dioxane or tetrahydrofuran (THF); preferably, the selected THF. Preferably, THF Tegaserod by ozonation nitrogen. Even more preferably, the reaction mixture is heated under reflux, preferably for at least 14 hours.

In another specific embodiment of the invention the catalyst for the transesterification of the present invention is a lipase, preferably a lipase from Candida antarctica. In particular, the lipase is immobilized form. Preferably, the lipase is a Novozyme®, sold by Novo Nordisk (Novo Nordisk). Preferably, the reaction proceeds in the absence of solvent or in a solvent such as 2-methyl-2-butanol or acetonitrile, preferably in the absence of solvent in the case nicotineamide alcohol and solvent in the case of panthenol. Preferably, in the case of Inositol used solvent is an ionic polar solvent such as 1-butyl-3-methylimidazole tetrafluoroborate (BF4) or 1-butyl-3-methylimidazole C(CN)2. Preferably, the reaction proceeds at temperatures above room temperature, preferably at 60°C.

Preferably, the ethanol is removed during the reaction, preferably under vacuum or by ozonation nitrogen, more preferably, by means of ozonation nitrogen. In this way increase Corot conversion, accelerate the reaction and remove the parasitic reaction of hydrolysis.

Preferably, the molar ratio of alcohol to ethyl ether DHA is between 1 and 5, preferably between 1.5 and 4.5.

Preferably, the reaction is carried out for from 1 hour to 100 hours, preferably from 1 hour to 72 hours, preferably from 1 hour to 48 hours, even more preferably from 1 hour to 3 hours.

In another specific embodiment of the method according to the present invention, the reaction of transesterification takes place in an anhydrous solvent, in nebosvodom solvent in the presence of the separator, such as, for example, lithium chloride, MgCl2or silica gel, or without solvent in a dry atmosphere. So remove the parasitic reaction of hydrolysis.

Preferably, the reaction of transesterification occurs with pure ethyl ester of docosahexaenoic acid (at least 95%purity, commercially available purified by methods well known to experts in the art, from a mixture of ethyl esters of fatty acids) or with a mixture containing at least 70 mol.% ethyl ester of DHA. When used DHA ethyl ester is a mixture, it is advisable to clean the obtained ester after reaction of transesterification.

The present invention also relates to pharmaceutical compositions containing the th ester of docosahexaenoic acid according to the present invention, in particular, pyridine-3-iletileceginden, and at least one pharmaceutically acceptable excipient.

The pharmaceutical compositions of the present invention can be prepared in the form of preparations for the introduction of mammals, including humans. Doses vary depending on the modes of treatment and diseases that are treated. These compositions are prepared in such a way as to introduce oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal route. In this case, the active ingredient can be entered to animals or humans in the form of dosage forms in a single dose or in a mixture with standard pharmaceutical carriers. Suitable dosage forms per dose include forms for administration by mouth, such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions, forms for sublinguales and oral administration, forms for subcutaneous, local, intramuscular, intravenous, intranasal or intraocular administration and forms for rectal administration.

When a solid composition is prepared in tablet form, then the primary active ingredient is mixed with a pharmaceutical carrier, such as gelatin, starch, lactose, magnesium stearate, talc, Arabic gum, silicon dioxide and the and analogues. Tablets can be coated with sucrose or other suitable substances, or they can be processed in such a manner that it can be slowed or delayed activity and so as to continuously release a specified amount of the active ingredient.

The drug is in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and then rashes resulting mixture into soft or hard gelatin capsules.

A preparation in syrup or elixir may contain the active ingredient in combination with a sweetener, an antiseptic agent, and a flavoring and an appropriate dye.

Powders or granules, which can be dispersed in water, may contain the active ingredient mixed with dispersing agents, wetting agents or suspendresume agents, as well as with taste-aromaticheskimi agents or sweeteners.

Suppositories which are prepared with binders agents that melt at rectal temperature, such as cocoa butter or polyethylene glycol, for example, are used for rectal administration.

For parenteral (intravenous, intramuscular, etc.), intranasal, or intraocular injection are aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing Pharm is ecologicheski compatible dispersing agents and/or moisturizing agents.

The active ingredient may also be prepared in the form of microcapsules, possibly with one or more additives.

Preferably, the pharmaceutical composition of the present invention is intended for administration orally or by injection, preferably intravenously, in the case of treatment of post-infarction state.

The pharmaceutical composition of the present invention may contain other active ingredients that provide complementary or possibly a synergistic effect. Preferably, the pharmaceutical composition does not contain a complex ester EPA.

The present invention also relates to the complex ether docosahexaenoic acid according to the present invention, in particular, pyridine-3-ylmethylphosphonate, or pharmaceutical compositions of the present invention, for use as pharmaceuticals.

The present invention also relates to the complex ether docosahexaenoic acid according to the present invention, in particular, pyridine-3-ylmethylphosphonate, or pharmaceutical compositions of the present invention, for use as a drug for prevention and/or treatment of cardiovascular diseases, preferably related to heart rhythm (preferably the rhythm disturbance or breach of conduct is tis), preferably selected from the atrial and/or ventricular arrhythmia, tachycardia and/or fibrillation; for the prevention and/or treatment of diseases caused by defects in the electrical conduction in myocardial cells; for the prevention and/or treatment of multiple risk factors for cardiovascular diseases, preferably selected from hypertriglyceridemia, hypercholesterolemia, hypertension, hyperlipidemia, dyslipidemia, preferably mixed dyslipidemia, and/or factor VII hyperactivity in blood coagulation; for the treatment and/or primary or secondary prevention of cardiovascular disease resulting from arrhythmias, such as atrial and/or ventricular arrhythmia, tachycardia, atrial and/or defects in the conductivity caused by myocardial infarction, preferably sudden death; and/or for the treatment of post-infarction state.

Disruptions include, in particular, defects sinus-atrial node, such as sinus tachycardia; atrial arrhythmia, such as atrial extrasystoles, regular atrial tachycardia or atrial fibrillation; nodal tachycardia, such as paroxysmal nodal tachycardia or syndrome Wolff-Parkinson-white; or ventricular arrhythmias, such as premature contraction of the ventricles, tachycard what I ventricles or ventricular fibrillation.

Conduction disorders include, in particular, bradycardia.

Thus, the present invention relates to a complex ether, docosahexaenoic acid according to the present invention, in particular, pyridine-3-ylmethylphosphonate, or pharmaceutical compositions of the present invention, for use as a drug for prevention and/or treatment of atrial fibrillation.

Without being bound by theory, believe that the ester of docosahexaenoic acid according to the present invention, in particular pyridine-3-iletileceginden, releases in the body alcohol and DHA, in particular nicotinebuy alcohol and DHA in the case of pyridine-3-ylmethylphosphonate, thanks esterase activity. Thus, an ester of docosahexaenoic acid according to the present invention, apparently, has the same activity in the form of a mixture of DHA and alcohol. Thus, if the alcohol is a vitamin or provitamin group, an ester of docosahexaenoic acid according to the present invention will have the same effect as the mixture of DHA and vitamin or provitamin group C. it also follows that in the case of pyridine-3-ylmethylphosphonate nicotinebuy alcohol is converted in the body to nicotinic acid. Thus, pyridine-3-iletileceginden of the present invention, VI is the Imam, has the same activity as the mixture of DHA and nicotinic acid. The advantage of the vasodilator effect of nicotinic acid is the most satisfactory distribution of DHA on the periphery, in particular, in the case of intravenous injection pyridine-3-ylmethylphosphonate, after transformation nicotineamide alcohol nicotinic acid.

The invention will be better understood with reference to graphic materials and examples which follow.

Figure 1 presents the dependence of the consumption of DHA-EE (ethyl ester of docosahexaenoic acid) in the percentage of time for examples 3.1 (open tube), 3.2 (under vacuum) and 3.3 (when bubbling with nitrogen during the reaction of transesterification in the presence of 200 mg of Novozyme® at 60°C with a ratio of alcohol to ether complex, is equal to 3.

The following examples are given as examples and not limiting the invention.

Example 1: Synthesis of pyridine-3-ylmethylphosphonate using the K2CO3

1 g (2.8 mmol) of ethyldimethylamine (purity more than 95%; supplied by the company Interchim) was placed in 5 ml of THF, degassed by ozonation nitrogen in the presence of 1.53 g (11 mmol) of powdered K2CO3and 1.06 ml (10.9 mmol) nicotineamide alcohol (purity more than 98%; supplied by the firm Acros). The reaction mixture is heated under reflux for 7 h and then add the keys from 0.76 g (5.5 mmol) of K 2CO3and the heating continued for 7 hours

After cooling, the reaction mixture is poured into water and then extracted with ethyl acetate. The organic phase is dried over MgSO4, filtered and then concentrated to dryness. The resulting residue is purified using flash chromatography on silica gel (CH2Cl2→the gradient of CH2Cl2/ethyl acetate, 90/10, for 15 min). Produce a clear oil (0.84 g, yield 71%).

TLC (thin layer chromatography) on silica gel 60 F 254 Merck, CH2Cl2/AcOEt, 90/10, Rf=0.35 in.

Example 2: Synthesis of pyridine-3-ylmethylphosphonate using lipase

All reactions carried out in a reactor with periodic stirring (magnetic stirring) at the optimum temperature for each enzyme.

The materials used are:

a mixture of ethyl esters enriched up to 70% DHA ethyl ester (DHA-EE) (sold by the company Croda Chemical Ltd.), referred to below as "70%of the ester mixture of DHA-EE";

- Novozyme®, immobilizovannaya form of lipase from Candida antarctica, sold by the company Novo Nordisk;

- nicotinebuy alcohol.

The reaction mixture is either:

environment without solvent, which is used only for substrates;

or

- organic environment using different solvents.

The solvents used in the organic medium, are Soboh is:

- 2-methyl-2-butanol (MW), moderately polar solvent, which makes possible a joint solubilization of hydrophobic compounds, such as esters of polyunsaturated fatty acids and hydrophilic compounds, such as nicotinebuy alcohol; or

- acetonitrile, for the same reasons that MV.

The reaction conditions shown in the following table 1:

Table 1
The reaction conditions tested for the transesterification 70%of the energy esters of DHA-EE with nicotinoyl alcohol
Alcohol Wednesday [70%esters of DHA-EE] (M) [Alcohol] Total volume (ml) The molar ratio of alcohol/ester
Nicotinebuy alcohol Organic (MW and acetonitrile) 0,43 0,64 12 1,5
Without solvent 1,5 4,5 3,5 3

For each the conditions incubated with 200 mg Novozyme® at 60°C. Reactions in MW conducted in the open air (in the hood), tested at 60°C with 200 mg Novozyme®.

Regular sample volume of 500 ál take before completion of the reactions. The reaction process is quenched by centrifugation for 5 minutes at 13,000 rpm, making it possible to remove immobilizovannogo enzyme from the medium. All samples stored at 4°C until analysis.

Control reactions without enzyme control reactions without cosubstrate (nicotinebuy alcohol) was performed in parallel.

Tests conducted using two HPLC (using the apparatus Agilent 1100 series) in accordance with the following parameters:

Method 1

- Bond column SB-C18 (4.6 mm×25 cm)

- Temperature: 40°C

- Flow rate: 1 ml/min

- Eluent: 0.02% methanol/acetic acid

- Detection: refractometry

- Running time: 15 minutes

Method 2

- Bond column SB-C18 (4.6 mm×25 cm)

- Temperature: 40°C

- Flow rate: 3 ml/min

- Eluent: 50/50 acetonitrile/acetone

- Detection: refractometry

- Running time: 15 minutes

The samples taken during the various reactions, diluted in advance to a concentration of less than 100 mm in a mixture of 0.02% methanol/acetic acid in the case of methods 1 and in acetone in the case of method 2.

Results and discussion

Two products appear during the reaction of transesterification. The first eluted with 4,15 mine is Oh and corresponds to the product of the hydrolysis of ester, and the second eluted with 4,85 minutes under analytical conditions. Last connection corresponds to the product of transesterification between 70%-tion esters of DHA-EE and nicotinoyl alcohol. Here it is expected only one product, because nicotinebuy alcohol has only one primary hydroxyl.

The relative conversion obtained at different reaction conditions shown in the following table 2:

Table 2
The relative conversion obtained during the transesterification 70%of the energy ethyl esters of DHA-EE with nicotinoyl alcohol (*: in this case, the tube is left open to allow evaporation of the ethanol produced during the reaction)
The reaction conditions The relative conversion of DHA-EE DHA-nicotinebuy alcohol
Acetonitrile 31% after 72 h
MV 47% after 48 h
MV outdoors* 60% after 118 h
Without solvent 11% after 72 h
Without dissolve the I outdoors* 100% after 72 h

The speed of conversion is higher when the reaction is carried out in the open air; the resulting ethanol, which shifts the equilibrium of the reaction toward the synthesis of DHA-nicotineamide alcohol is evaporated. These reactions of transesterification accompanied by strong blackening of the reaction mixture.

The products of hydrolysis appear preferably, when the solvent of the reaction using MV. However, weak hydrolysis reaction is also present in the environment without solvent. Thus, it follows that water is also used in nikotinova alcohol or the environment humidity causes this parasitic reaction.

Demonstrated the feasibility of reactions of transesterification 70%of the energy esters of DHA-EE with nicotinoyl alcohol, such reactions showed a preferential rate of conversion of close to 90% or higher, in particular when the ethanol produced during the reaction, is removed from the reaction mixture. However, the parasitic reaction of hydrolysis due to the presence of water in the used solvents and/or environmental humidity prevents these syntheses.

Thus, it seems interesting to try to avoid the observed parasitic hydrolysis. For example, you could use a completely anhydrous solvents. The can is about to carry out these similar reactions in the presence of the separator (lithium chloride, MgCl2or silica gel, for example) to eliminate any possibility of hydrolysis.

For the reaction of synthesis of ester nicotinebuy alcohol-DHA, the ethanol produced during the reaction, apparently, is the element that limits the reaction. Remove shift the equilibrium of the reaction toward the synthesis of the considered esters. Thus, it is advisable to optimize the removal, especially when carrying out the synthesis under reduced pressure. This makes possible the rapid evaporation of ethanol and, thus, increase the reaction rate.

Example 3, Synthesis of pyridine-3-ylmethylphosphonate using lipase; optimization of transesterification; evaporation of the ethanol produced during the reaction, and the removal of oxidative darkening

The reaction is similar to the reaction of example 2 was carried out using the same initial products (nicotinebuy alcohol, 70%of the ester mixture of DHA-EE, Novozyme®) in the absence of solvent at 60°C in the presence of 200 mg of Novozyme® with a ratio of alcohol to ether complex, is equal to 3. Used reactor is the same as the reactor of example 2, and analysis methods are the same.

Example 3.1

The only difference in comparison with example 2 is that the reaction is carried out in an open tank (open vial).

The results (Figure 1):

The reaction is relateively is "slow", occupying a total of approximately 80 hours. Oxidative Browning is present. "Strong" parasitic hydrolysis is present.

Example 3.2

The only difference in comparison with example 2 is that the reaction is carried out under vacuum.

The results (Figure 1):

Observed acceleration of the reaction compared to example 3.1, but it remains slow, occupying a total of approximately 48 hours.

In addition, oxidative darkening and parasitic hydrolysis is stored.

Example 3.3

The only difference in comparison with example 2 is that the reaction was carried out while bubbling with nitrogen.

The results (Figure 1):

There is a very significant acceleration of the reaction, which is in total less than 3 hours due to the immediate removal of the ethanol produced during the reaction, and improved mix.

The lack of oxidative darkening.

Parasitic hydrolysis greatly reduced.

Example 4: Synthesis of ester DHA with panthenol using lipase

Experimental and analytical conditions are the same as in example 2, except for the following differences:

The reaction conditions shown in the following table 3:

Table 3
The reaction conditions tested in respect of transesterification 70%of the energy esters of DHA-EE with panthenol
Alcohol Wednesday [70%esters of DHA-EE] (M) [Alcohol] Total volume (ml) The molar ratio of alcohol/ester
Panthenol Organic (MW and acetonitrile) 0,43 1,28 12 3

Results and discussion

Two species elute with a 3.9 minutes and 4,14 minutes in the analytical conditions. Panthenol has two primary alcohol. Thus, one would assume the production of several products (maximum of three). However, for control without cosubstrate (panthenol) peak appears at 4,14 minutes. The specified peak, therefore, will correspond to the hydrolysis of ethyl ether, associated with the presence of water in the used solvent. This reaction occurs only in the presence of the enzyme.

Therefore, only the first peak corresponds to the synthesis of ester of panthenol-DHA.

The relative conversion obtained at different reaction conditions shown in the following table 4:

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Table 4
The relative conversion obtained during the transesterification 70%of the energy ethyl esters of DHA-EE with panthenol (*: in this case, the tube is left open to allow evaporation of the ethanol produced during the reaction)
The reaction conditions The relative conversion of DHA-EE DHA-panthenol
Acetonitrile 68% after 136 h
MV 76% after 115 h
MV outdoors* 88% after 96 h

From this it follows that the relative conversion of 70%of the energy esters of DHA-EE is increased when the reaction is carried out outdoors. Indeed, under this condition, the ethanol produced during the reaction is evaporated. The equilibrium of this reaction is thus shifted towards the synthesis of esters of panthenol-DHA. Moreover, these values of conversion, of course, underestimated due to the common evaporation MV solvent (effect concentration environment). These reactions of transesterification is also accompanied by strong blackening of the reaction mixture.

Prodem who has Staropoli feasibility reactions of transesterification 70%of the energy esters of DHA-EE with panthenol, and such reactions showed a preferential rate of conversion of close to 90% or higher, in particular when the ethanol produced during the reaction, is removed from the reaction mixture. However, the parasitic reaction of hydrolysis due to the presence of water in the used solvents and/or environmental humidity prevents these syntheses.

Thus, it seems interesting to try to avoid the observed parasitic hydrolysis. For example, you could use a completely anhydrous solvents. You can also perform these same reactions in the presence of the separator (lithium chloride, MgCl2or silica gel, for example) to eliminate any possibility of hydrolysis.

For the reaction of synthesis of ester of panthenol-DHA, the ethanol produced during the reaction, apparently, is the element that limits the reaction. Remove shift the equilibrium of the reaction toward the synthesis of the considered esters. Thus, it is advisable to optimize the removal, especially when carrying out the synthesis under reduced pressure. This makes possible the rapid evaporation of ethanol and, thus, increase the reaction rate.

Example 5: Comparative results of the actions of EPA and DHA on ultrafast flow of potassium and, thus, atrial fibrillation

Cardiac action potential, not only is em a main electric unit excitable cells of the heart and means the activity of several types of ion channels, responsible for various phases of the action potential. Different types of action potentials correspond to different regions of the heart, thus providing a consistent and coordinated activity in these areas. For this reason, potassium channels Kv 1.5 encoded gene KCNA5, are only expressed in atrial tissue and are responsible for ultrafast flow of potassium (IKur), which is involved in repolarization of atrial action potential. This vysokomineralizovannaya expression of Kv 1.5 is actually a target of choice for the treatment of atrial fibrillation, pathology, in which there are changes in the atrial action potentials.

Thus, investigated the effects of DHA and EPA at IKur.For this purpose human isoforms channel 1.5 Kv (hKv 1.5) endured a stable manner in the cells of SOME 293 (embryonic kidney human), and the flow resulting from the activity of these channels was investigated using the method of the patch-clamp (patch-clamp) on a cell.

Materials and methods

Maintenance of cell lines

Cells of SOME 293-hKv 1.5 grown in standard conditions (37°C incubator with 95% O2and 5% CO2in the cups Falcon up to 80%confluently. They are then transferred and cultured in 35-mm Petri dishes containing the following culture medium: DMEM (Invitrogen); 10% fetal bovine serum (Invitroen); a mixture of 100 units/ml penicillin, 100 μg/ml streptomycin and 0.25 mg/ml glutamine (Invitrogen); and 1.25 mg/ml Geneticin® selective antibiotic.

Electrophysiology

IKurexplore using the method of the patch-clamp on a cell at ambient temperature (19-22°C). Environment for pipetting contains: 125 mm K-aspartate, 20 mm KCl, 10 mm EGTA, 5 mm HEPES, 5 mm MD-ATP, 1 mm MgCl2pH of 7.3 (KOH). Extracellular environment contains: 140 mm NaCl, 20 mm HEPES, 5 mm D(+)-glucose, 5 mm KCl, 2 mm CaCl2, 1 mm MgCl2, pH 7.4 (NaOH).

IKurinduce every 15 seconds using a 300 MS +60 mV depolarizing pulse from -80 mV holding potential with subsequent -50 mV repolarization. The amplitude of the peak flow set based on the maximum flow obtained during the first 100 MS depolarizing impulse.

The amplitude of the flow at the end of the pulse is determined during the last 20 MS depolarizing impulse.

Reagents

DHA and EPA are delivered by the company Sigma. The original solutions (10 mm) was prepared in ethanol and the final concentration of the solvent is 0.25%.

Results

The results are shown in the following table 5.

Table 5
The percentage inhibition of IKurwith the help of DHA and EPA at various concentrations
DHA
Peak IKur The end of the pulse IKur n
Concentration Average SEM Average SEM
1 micron 8,2 6,3 the 10.1 5,8 5
3.2 mm 10,9 6,9 14,5 6,5 5
of 5.6 microns 15,4 4,8 33,7 7,8 6
10 µm 22,6 4,0 78,0 4,2 6
25 microns to 58.1 13,6 8,5 3,4 5
SEM - standard error of the mean
EPA
Peak IKur The end of the pulse IKur n
Concentration Average SEM Average SEM
1 micron 14,6 1,7 14,9 1,9 5
3.2 mm 16,1 3,1 to 19.9 4,4 5
10 µm of 17.5 6,4 36,6 7,2 10
25 microns of 5.4 6,8 61,6 7,3 5

EPA slightly reduces the peak amplitude of IKur(maximum inhibition of 17.5±6,4%, n=10, p<0.05 at 10 μm) and the amplitude of the flow at the end of the pulse (61,6±7,3%, n=5, p<0.05 at 25 microns).

DHA inhibited the peak amplitude of IKurthe maximum at 58.1±13,6% (n=5, p<0.005 percent) and the amplitude of the flow at the end of the pulse at 86,5±3,4% (n=5, p<0,005) at 25 ám.

Conclusion

These results demonstrate that the use of DHA inhibits stronger than EPA, and dependent on the concentration of the way ultrafast flow of potassium (IKurin the human channels 1.5 Kv, transfected into cells SOME 293. DHA acts preferably on stream at the end of the pulse, which implies that the effect on the activation of Kv channels 1.5. Moreover, this effect is accompanied by a decrease in peak IKur(in contrast to what is observed for EPA), the potentiation of inhibition IKurwith DHA.

These effects on the IKurindicate a beneficial effect of DHA on atrial fibrillation.

1. Ester of docosahexaenoic acid with an alcohol selected from the group consisting of:
panthenol formula:
and
isosorbide formula:
.

2. Ester of docosahexaenoic acid according to claim 1 with panthenol.

3. A method of obtaining a complex ester of docosahexaenoic acid according to claim 1, comprising the transesterification of ethyl ether docosahexaen the OIC acid with alcohol, selected from the group consisting of panthenol and isosorbide.

4. The method according to claim 3, where the specified process is carried out in the presence of a catalyst.

5. The method according to claim 4, where the catalyst is a lipase, preferably a lipase from Candida antarctica.

6. The method according to claim 5, where the ethanol is removed during the reaction, preferably by means of ozonation nitrogen.

7. The method according to claim 5 or 6, where the reaction proceeds in an anhydrous solvent or without solvent in a dry atmosphere.

8. Pharmaceutical composition for use as a drug for prevention and/or treatment of cardiovascular diseases associated with heart rhythm, for the prevention and/or treatment of diseases caused by defects in the electrical conductivity in the cells of the myocardium, for the prevention and/or treatment of multiple risk factors for cardiovascular disease, selected from hypertriglyceridemia, hypertension, hyperlipidemia and dyslipidemia, for treatment and/or primary or secondary prevention of cardiovascular disease, which is the result of disturbances of heart rhythm and/or for the treatment of postinfarction state containing an ester of docosahexaenoic acid according to claim 1 and at least one pharmaceutically acceptable excipient.

9. Ester of docosahexaenoic acid according to claim 1 applied for who I am as a drug for prevention and/or treatment of cardiovascular diseases, associated with the heart rhythm, for the prevention and/or treatment of diseases caused by defects in the electrical conductivity in the cells of the myocardium, for the prevention and/or treatment of multiple risk factors for cardiovascular disease, selected from hypertriglyceridemia, hypertension, hyperlipidemia and dyslipidemia, for treatment and/or primary or secondary prevention of cardiovascular disease, which is the result of disturbances of heart rhythm and/or for the treatment of post-infarction state.

10. Ester of docosahexaenoic acid according to claim 1 or the pharmaceutical composition of claim 8 for use as a drug for prevention and/or treatment of atrial fibrillation.

 
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