PHOSPHONATE DERIVATES OF BETULIN COMPOUNDS WITH ANTIVIRAL ACTIVITY, METHOD FOR THEIR PREPARATION AND THEIR APPLICATION
The invention relates to the phosphonate derivatives of the 3-carboxyacylbetulinic acid with antiviral activity, of formula 1A or of formula 1B, wherein:R is an alkyl group (C<sub>1</sub>-C<sub>4</sub>),R<sub>1</sub>is an alkyl group (C<sub>1</sub>-C<sub>4</sub>),R<sub>2</sub>is a hydroxyl or carbonyl or acetyloxy or carboxyacyloxy group,R<sub>3</sub>is an acetyloxymethyl or hydroxymethyl or carboxyl group.The invention also relates to a method of preparing the derivatives of formula 1A, where there are following steps: (a) compound of formula 2A, wherein: R is an alkyl group (C<sub>1</sub>-C<sub>4</sub>), and R<sub>1</sub>is an alkyl group (C<sub>1</sub>-C<sub>4</sub>), is subjected to alkaline hydrolysis in the presence of an aqueous solution of a metal hydroxide, in an organic solvent or in a mixture of organic solvents, resulting in 30-phosphonate of 3-acetylbetulin; (b) the product of step (a) is reacted with the Jones reagent taken in an amount of 1 to 4 ml per 1 mmol of the product of step (a), in at least 10 ml of an organic solvent per 1 mmol of the product of step (a), resulting in 30-phosphonate of 3-acetylbetulinic acid; (c) the product of step (b) is subjected to alkaline hydrolysis in the presence of an aqueous solution of a metal hydroxide in an organic solvent, resulting in 30-phosphonate of betulinic acid; (d) the product of step (c) is reacted with a dicarboxylic acid anhydride or with a dicarboxylic acid, at a molar ratio of between 1:1 to 1:10, for at least 30 minutes.The invention also relates to a method of preparing the derivatives of formula 1B, where there are following steps: (a) compound of formula 2B, wherein R is an alkyl group (C<sub>1</sub>-C<sub>4</sub>), and R<sub>1</sub>is an alkyl group (C<sub>1</sub>-C<sub>4</sub>), is reacted with the Jones reagent taken in an amount of 2 to 6 ml per 1 mmol of the compound of formula 2B, resulting in 29-phosphonate of betulonic acid; (b) the product of step (a) is reduced by sodium or lithium borohydride, resulting in 29-phosphonate of betulinic acid; (c) the product of step (b) is reacted with a dicarboxylic acid anhydride or with a dicarboxylic acid, at a molar ratio of between 1:2.5 to 1:10, for at least 30 minutes.The invention also relates to the use of phosphonate derivatives of 3-carboxyacylbetulinic acid with antiviral activity, of formula 1A or 1B (wherein: R is an alkyl group (C<sub>1</sub>-C<sub>4</sub>), R<sub>1</sub>is an alkyl group (C<sub>1</sub>-C<sub>4</sub>), R<sub>2</sub>is a hydroxyl or carbonyl or acetyloxy or carboxyacyloxy group, R<sub>3</sub>is an acetyloxymethyl or hydroxymethyl or carboxyl group) in the manufacture of pharmaceutical agents for suppressing HIV-1 replication..
Medienart: |
Patent |
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Erscheinungsjahr: |
2019 |
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Erschienen: |
2019 |
Enthalten in: |
Europäisches Patentamt - (2019) vom: 04. Dez. Zur Gesamtaufnahme - year:2019 |
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Sprache: |
Englisch |
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Beteiligte Personen: |
BORYCZKA STANISLAW [VerfasserIn] |
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Links: |
Volltext [kostenfrei] |
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Anmerkungen: |
Source: www.epo.org (no modifications made), First posted: 2019-12-04, Last update posted on www.tib.eu: 2022-04-30, Last updated: 2023-02-09 |
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Patentnummer: |
EP3575310 |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
EPA004084667 |
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245 | 1 | 0 | |a PHOSPHONATE DERIVATES OF BETULIN COMPOUNDS WITH ANTIVIRAL ACTIVITY, METHOD FOR THEIR PREPARATION AND THEIR APPLICATION |
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520 | |a The invention relates to the phosphonate derivatives of the 3-carboxyacylbetulinic acid with antiviral activity, of formula 1A or of formula 1B, wherein:R is an alkyl group (C<sub>1</sub>-C<sub>4</sub>),R<sub>1</sub>is an alkyl group (C<sub>1</sub>-C<sub>4</sub>),R<sub>2</sub>is a hydroxyl or carbonyl or acetyloxy or carboxyacyloxy group,R<sub>3</sub>is an acetyloxymethyl or hydroxymethyl or carboxyl group.The invention also relates to a method of preparing the derivatives of formula 1A, where there are following steps: (a) compound of formula 2A, wherein: R is an alkyl group (C<sub>1</sub>-C<sub>4</sub>), and R<sub>1</sub>is an alkyl group (C<sub>1</sub>-C<sub>4</sub>), is subjected to alkaline hydrolysis in the presence of an aqueous solution of a metal hydroxide, in an organic solvent or in a mixture of organic solvents, resulting in 30-phosphonate of 3-acetylbetulin; (b) the product of step (a) is reacted with the Jones reagent taken in an amount of 1 to 4 ml per 1 mmol of the product of step (a), in at least 10 ml of an organic solvent per 1 mmol of the product of step (a), resulting in 30-phosphonate of 3-acetylbetulinic acid; (c) the product of step (b) is subjected to alkaline hydrolysis in the presence of an aqueous solution of a metal hydroxide in an organic solvent, resulting in 30-phosphonate of betulinic acid; (d) the product of step (c) is reacted with a dicarboxylic acid anhydride or with a dicarboxylic acid, at a molar ratio of between 1:1 to 1:10, for at least 30 minutes.The invention also relates to a method of preparing the derivatives of formula 1B, where there are following steps: (a) compound of formula 2B, wherein R is an alkyl group (C<sub>1</sub>-C<sub>4</sub>), and R<sub>1</sub>is an alkyl group (C<sub>1</sub>-C<sub>4</sub>), is reacted with the Jones reagent taken in an amount of 2 to 6 ml per 1 mmol of the compound of formula 2B, resulting in 29-phosphonate of betulonic acid; (b) the product of step (a) is reduced by sodium or lithium borohydride, resulting in 29-phosphonate of betulinic acid; (c) the product of step (b) is reacted with a dicarboxylic acid anhydride or with a dicarboxylic acid, at a molar ratio of between 1:2.5 to 1:10, for at least 30 minutes.The invention also relates to the use of phosphonate derivatives of 3-carboxyacylbetulinic acid with antiviral activity, of formula 1A or 1B (wherein: R is an alkyl group (C<sub>1</sub>-C<sub>4</sub>), R<sub>1</sub>is an alkyl group (C<sub>1</sub>-C<sub>4</sub>), R<sub>2</sub>is a hydroxyl or carbonyl or acetyloxy or carboxyacyloxy group, R<sub>3</sub>is an acetyloxymethyl or hydroxymethyl or carboxyl group) in the manufacture of pharmaceutical agents for suppressing HIV-1 replication. | ||
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