Modified fluorinated nucleoside analogues

FIELD: chemistry.

SUBSTANCE: present invention relates to (2'R)-2'-dezoxy-2'-fluoro-2'-C-methylnucleoside (β-D or (β-L) , where X represents O; R1 and R7 independently represent H; R3 represents hydrogen and R4 represents NH2; or its pharmaceutically acceptable salt. The invention also pertains to the method of producing the said compounds, which involves glycosylation of N4-benzoylcytosine with a compound of formula 1-4, where R represents methyl, Pg is chosen from C(O)Ph, CH2Ph or both Pg groups can be included in 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene); with further removal of protection of 3'-OPg and 5'-OPg and N-benzoyl of the obtained product.

EFFECT: invented compounds or their pharmaceutically acceptable salts are used as active ingredients against Flaviviridae family viruses in pharmaceutical compositions and liposomal pharmaceutical compositions.

4 cl, 9 tbl, 5 ex, 4 dwg

 

The text descriptions are given in facsimile form.

1. (2'R)-2'-deoxy-2'-fluoro-2'-C-metrocles (β-D or β-L) formula

where the base denotes cytosine formula

X denotes O;
R1and R7independently denote H;
R3denotes hydrogen and R4denotes NH2;
or its pharmaceutically acceptable salt.

2. Pharmaceutical composition with activity against viruses of the family Flaviviridae, containing an effective amount of the nucleoside according to claim 1 and a pharmaceutically acceptable carrier.

3. The method of producing nucleoside according to claim 1, including:
a) glycosylation of N4-benzoylthiophene compound of the formula

where R denotes methyl, Pg is selected from C(O)Ph, CH2Ph or both group Pg can be part of 1,3-(1,1,3,3-tetraisopropyldisiloxane); and
b) removing the protection of the 3'-OPg and 5'-OPg and N-benzoyl compound of the formula

where each Pg is a protecting group, as defined above.

4. Liposomal pharmaceutical composition with activity against viruses of the family Flaviviridae, containing an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: claimed invention relates to method of gemcitabine hydrochloride purification, which includes enriching gemcitabine hydrochloride with its p-anomer, according to which solution of gemcitabine hydrochloride in water is taken with ratio of water to gemcitabine hydrochloride from 3:1 to 12:1 (wt/vol); solution is processed with activated coal, activated coal being taken in amount from 0.1 to 10 wt % of gemcitabine hydrochloride amount in solution; activated coal is removed from solution with formation of filtered solution; concentration of gemcitabine hydrochloride in filtered solution is increased until ratio of filtered solution to gemcitabine hydrochloride equals from 1:1 to 1:5 (wt/vol), efficient for gemcitabine hydrochloride sedimentation; deposited gemcitabine hydrochloride is isolated; and in case admixture content in deposited gemcitabine hydrochloride is not reduced to required level, stages (a)-(e) are repeated. Claimed invention also relates to method of obtaining gemcitabine hydrochloride using claimed purification method.

EFFECT: creation of efficient method of gemcitabine hydrochloride purification.

5 cl, 1 tbl, 5 dwg, 8 ex

FIELD: medicine, pharmacology, bioorganic chemistry, pharmacy.

SUBSTANCE: invention relates to the effective using amount of β-L-2'-deoxynucleoside of the formula (I) or (II) used in manufacturing a medicinal agent used in treatment of hepatitis B, pharmaceutical compositions containing thereof, and methods for treatment of hepatitis B. Proposed agent shows the enhanced effectiveness in treatment of hepatitis B.

EFFECT: enhanced and valuable medicinal properties of agent.

83 cl, 6 tbl, 11 ex

FIELD: organic chemistry, biochemistry, medicine, virology.

SUBSTANCE: invention relates to derivatives of 2'=amino-2'-deoxynucleosides of the formula:

wherein R means hydrogen atom (H), alkyl, aminoalkyl; R1 means -(R2NR3) wherein R2 and/or R3 means H, -OH, -NH2, alkyl, benzyl under condition that R doesn't represent H or methyl when R2 and R3 mean H. Compounds elicit an antiviral activity with respect to measles and Marburg viruses exceeding that of ribavirin.

EFFECT: valuable properties of compounds.

4 tbl, 2 dwg, 18 ex

The invention relates to a derivative of gemcitabine formula (I), where R1, R2, R3independently selected from hydrogen and C18and C20saturated and monounsaturated acyl groups, provided that R1, R2, R3can't all be hydrogen

The invention relates to the chemistry of nucleosides, in particular to an improved method for the preparation of 3'-azido-2',3'-dideoxythymidine (azidothymidine, AZT), used in medicine as an antiviral drug for the treatment of patients suffering from acquired immunodeficiency syndrome (AIDS)

The invention relates to a method for obtaining enriched beta-anomer nucleoside of the formula I, where T is fluorine and R is the corresponding nucleoside described in paragraph 1 of the formula
The invention relates to the synthesis of nucleosides and relates to an improved method for the preparation of 3'-azido-2',3'-dideoxythymidine with the ability to suppress the reproduction of human immunodeficiency virus and finds application in medical practice for the treatment of AIDS

The invention relates to new compounds of formula I Nu-O-Fa, where O is oxygen, Nu is a nucleoside or nucleoside analogue, including such nitrogen base, as adenine, Esenin, cytosine, uracil, thymine; Fa - acyl monounsaturated C18YPD C20-9-fatty acids, which fatty acid etherification hydroxyl group in 5-position of the sugar portion of the nucleoside or nucleoside analog, or a hydroxyl group, an acyclic chain of an analogue of the nucleoside

The invention relates to the chemistry of nucleosides, in particular to the compounds used in medicine as anti-viral drugs for the treatment of diseases caused by, for example, human immunodeficiency virus (HIV), myeloblastosis birds (VMP)

The invention relates to the field of organic chemistry and Virology and applies to new nucleoside analogues containing the carbohydrate components of the 3-oximino-2-deoxyribofuranosyl, 3 Allexinno-2-deoxyribofuranosyl (acyl= acetyl, propionyl, isobutyryl, pivaloyl, benzoyl and other) or a 3-methoxyimino-2-deoxyribofuranosyl possessing antiviral activity of a broad spectrum of activity against the human immunodeficiency viruses (HIV), herpes simplex (HSV) and hepatitis B (VHB), which can find application in medicine

FIELD: pharmacology.

SUBSTANCE: claimed invention relates to pyrazole derivatives, which are represented by general formula (I), as well as theirpharmacologically acceptable salts, which have inhibiting activity against human SGLT1, to pharmacological composition, inhibitor of human SGLT1 and based on them medications, to their application for producing pharmacologic composition and to intermediate compounds for their obtaining. where R1 represents H, hydroxy(C2-6)alkyl group, one of Q and T represents group, which is presented by general formula: or group, which is presented by general formula while another presents C1-6alkyl group; R2 represents hydrogen atom, C1-6alkyl group or group of formula: -A-R8, where A represents oxygen atom, and R8 represents C6hetherocycloalkyl group, containing oxygen atom as heteroatom; X represents simple bond or oxygen atom, Y represents C1-6alkylene group or C2-6alkylene group; Z represents carbonyl group or sulphonyl group; R4 and R5 are similar or different, and each represents hydrogen atom or C1-6alkyl group, which can have similar or different 1-3 substituents, selected from substituents (i) Values of sunstituents (i) are iven in invention formula.

EFFECT: obtaining of pyrazole derivatives and based on them medications.

28 cl, 3 tbl, 197 ex

FIELD: biology.

SUBSTANCE: present invention relates to biotechnology, more specifically to obtaining nucleoside-5'-triphosphates, labelled with phosphorous-32 (phosphorous-33) in the alpha-position, and can be used for analysis in molecular biology, genetics and medical biochemistry. The method is realised through treatment of labelled nucleosidephosphate in a buffer solution with a mixture of deoxyribonucleoside monophosphate kinase of bacteriophage T5 and pyruvate kinase with subsequent chromatographic purification of the target product.

EFFECT: simple method of obtaining nucleoside-5'-triphosphates and stable output of the target product.

4 ex

FIELD: medicine.

SUBSTANCE: invention relates to method of obtaining gemcitabine hydrochloride, characterised by the following: 2,2-dimethyl-[1,3]-dioxolane-4-carbaldehyde is subjected to interaction with ethyl bromodifluoracetate in presence of zinc in organic solvent medium processing reaction mixture with ultrasound for 5-60 minutes, obtained ethyl 3-hydroxy-2,2-difluoro-3-[2,2-dimethyl-[1,3]dioxolane-4-yl]propionate is subjected to hydrolysis and cyclisation by means of ion-exchange resin in water-alcohol medium obtaining (4R,5R)-4-hydroxy-5-hydroxymethyl-3,3-difluorodihydrofuran-2(3H)-on, which is processed with solution of trimethylchlorosilane in dichloromethane obtaining (4R,5R)-4-trimethylsilyloxy-5-((trimethylsilyloxy)methyl)-3,3-difluorodihydrofuran-2(3H)-on, which is subjected to reduction by means of lithium diisopropylalumohydride in organic solvent medium at cooling to -70°C obtaining (4R,5R)-2-hydroxy-4-(trimethylsilyloxy)-5-((thrimethylsilyloxy)methyl)-3,3-difluorotetrahydrofurane, which is converted into (4R,5R)-2-methylsulphonyloxy-4-(trimethylsilyloxy)-5-((trimethylsilyloxy)methyl)-3,3-difluorotetrahydrofurane by processing with methane sulphonylchloride in solvent medium at cold, obtained (4R,5R)-2-methylsulphonyloxy-4-(trimethylsilyloxy)-5-((trimethylsilyloxy)methyl)-3,3- difluorotetrahydrofurane after optic isomer separation is processed with bis-trimethylsilylacetylcytozine in water-free dichlorethane and boil with trifluoromethane sulphonyloxymethylsilane with further cooling and separation of obtained gemcitabine in form of base or hydrochloride, as well as method of gemcitabine hydrochloride purification by its re-crystallisation from water solution with processing with ultrasound.

EFFECT: invention results in increase of ratio 3-(R)-hydroxy-isomer to 3(S)-hydroxy-isomer.

6 cl, 2 dwg, 4 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: invention refers to derivatives of olivomycin I antibiotic of aureolic acid group with anticancer activity by structural formula as follows, where R5 represents hydrogen, C3-C10-cycloalkyl or C1-C4-alkyl with straight or branched hydrocarbon chain, optionally substituted with one or more hydroxyls. Additionally, invention concerns method of production of the specified derivatives, consisting in selective modification of 2'-carbonyl group of olivomycin 1 by reaction with aminooxyacetic acid, followed by amidation reaction of produced intermediate 2'-(carboxymethoxime)olivomycin 1 and related amines condensing agent added.

EFFECT: method of production of antibiotic derivatives with anticancer activity.

2 cl, 5 tbl, 6 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: invention refers to method of 6-O-[β-D-(2,3,4,6-tetra-O-acetyl)glucopyranosyl]-d,1-α-tocopherol (1) or 6-O-[β-D-(2,3,4,6-tetra-O- acetyl)galactopyranosyl]-d,1-α-tocopherol (2), consisting in interaction of α-tocopherol and α- or β-anomer of related D-gluco- or D-galactopyranose pentaacetates with added catalyst systems: BF3·OEt2 ionic liquid [bmim]PF6 at mole ratio α-tocopherol:sugar pentaacetate: BF3·OEt2:[bmim]PF6 = 1:1:2.5:0.3-5, in methylene chloride within 3 h at room temperature.

EFFECT: given compounds are precursors of related deacetylated glycosides with observed antiallergic and anti-inflammatory activity.

1 cl, 8 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: invention refers to method of 6-O-[β-D-(2,3,4,6-tetra-O-acetyl)glucopyranosyl]-d,1-α-tocopherol (1) or 6-O-[β-D-(2,3,4,6-tetra-O- acetyl)galactopyranosyl]-d,1-α-tocopherol (2), consisting in interaction of α-tocopherol and α- or β-anomer of related D-gluco- or D-galactopyranose pentaacetates with added catalyst systems: BF3·OEt2 ionic liquid [bmim]PF6 at mole ratio α-tocopherol:sugar pentaacetate: BF3·OEt2:[bmim]PF6 = 1:1:2.5:0.3-5, in methylene chloride within 3 h at room temperature.

EFFECT: given compounds are precursors of related deacetylated glycosides with observed antiallergic and anti-inflammatory activity.

1 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention concerns crystalline azithromycin L-malate monohydrate of formula (I) with high stability, solubility and non-hygroscopicity. Also invention concerns pharmaceutical composition for microbe infection treatment, based on compound of the formula (I), and method of obtaining compound of the formula (I), involving: a) interaction of azithromycin with malic acid in aqueous organic solvent, or b) recrystallisation of water-free azithromycin L-malate from aqueous organic solvent.

EFFECT: obtaining crystalline azithromycin L-malate monohydrate of formula (I) with high stability, solubility and non-hygroscopicity.

15 cl, 7 tbl, 7 dwg, 18 ex

FIELD: chemistry.

SUBSTANCE: invention concerns method of obtaining natural and modified deoxy- and ribooligonucleotide 5'-triphosphate salts, involving monophosphation of initial reagent, protected natural or modified oligonucleotide of deoxy- or ribo- range in the form of 0.1-0.5 M solution, in pyridine by double or triple excess of phosphor oxychloride for 10-15 minutes; further processing of activated oligonucleotide derivative by tenfold to fifteenfold excess of pyrophosphate bis-tributylammonium salt solution in acetonitryl and 20-fold excess of tert-amine; reacting mix maturing for 15-30 minutes, followed by degradation of intermediary oligonucleotide trimetaphosphate derivative by triethylammonium bicarbonate buffer, purification of target product by reverse-phase chromatography (RPC), removal of protection groups from functional oligonucleotide groups, and second purification of target product by RPC. Target product output after purification comprises 45-95%. Purity grade of obtained compounds by the data of high-precision electronic liquid chromatography and nuclear magnetic resonance spectrography is over 95%.

EFFECT: obtaining compounds applicable in biological molecular and genetic engineering research.

2 cl, 1 dwg, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to ester lipids of halogenated adenine nucleotides with formula I, which can be used in treating cancerous diseases. (I), where R1 - C1-C20-alkyl, can be substituted with C1-C6-alkoxyl radical, C1-C6-alkylmercaptan radical, C1-C6-alkylsulfenyl or C1-C6-alkylsulfonyl groups, R2 - C1-C20-alkyl, which can be substituted with C1-C6-alkoxyl radical, C1-C6-alkylmercaptan radical or C1-C6-alkylsulfonyl group, R3 - amino group, X - sulphur atom, sulfenyl or sulfonyl group, Y - oxygen atom.

EFFECT: obtaining new biologically active compounds.

3 cl, 9 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of 1-α-halogen-2,2-difluoro-2-deoxy-D-ribofuranose of the general formula (I) in solid state, where R1 is benzoyl or ; R2 is hydrogen; and X is CI, Br or I; which can be applied as intermediates in stereoselective method of gemcitabine obtainment. In addition, invention claims stereoselective method of obtaining compounds of the general formula (I), including stages of: (i) recovery of 1-oxoribose of formula to obtain lactol of formula ; (ii) interaction of compound of formula (III) with halogen phosphate compound of formula in the presence of a base to obtain 1-phosphatefuranose derivative of formula ; and (iii) interaction of compound of formula (V) (also included in the claim) with halogen source, with further recrystallisation of obtained product; where R1, R2 and X are the same as indicated above while R3 is phenyl.

EFFECT: efficient method of obtaining derivatives of the abovementioned agent.

11 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention claims novel compounds with inhibition effect on HCV (hepatitis C virus) protease, and methods of obtaining the claimed compounds.

EFFECT: pharmaceutical compositions including these compounds, and methods of compound application in treatment of HCV protease related diseases.

23 cl, 5 tbl, 39 ex

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