GB2144746A - Diastereoisomers of glycyrrhetinic acid derivatives - Google Patents
Diastereoisomers of glycyrrhetinic acid derivatives Download PDFInfo
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- GB2144746A GB2144746A GB08418700A GB8418700A GB2144746A GB 2144746 A GB2144746 A GB 2144746A GB 08418700 A GB08418700 A GB 08418700A GB 8418700 A GB8418700 A GB 8418700A GB 2144746 A GB2144746 A GB 2144746A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Virology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Communicable Diseases (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The diastereoisomers of formula (II) are new and have anti viral activity: <IMAGE> wherein -COOR1 and -COOR2, which can be the same or different, are free, salified or esterified carboxylic acid groups.
Description
SPECIFICATION
Diastereoisomers of glycyrrhetinic acid derivatives
The present invention is concerned with new and pharmaceutically useful diastereoisomers of certain derivatives of glycyrrhetinic acid.
In our British Patent Specification No. 1,387,499, we have described and claimed derivatives of glycyrrhetinic acid of the general formula:
wherein R is a hydrogen atom or an alkyl radical and R' is also a hydrogen atom or an alkyl radical and the salts of those compounds in which R and/or R' is a hydrogen atom. This Specification also states that the compounds in question possess valuable pharmaceutical properties and, in particular, have a good anti-inflammatory action.
Subsequently, it was discovered that several derivatives of glycyrrhetinic acid, including those of general formula (I), are very useful for the treatment of viral infections and of diseases which result from viral infections.
The compounds of general formula (I) derived from cyclohexane-1 ,2-dicarboxylic acid exist as a mixture of diastereoisomers due to the chirality of ring carbon atoms C1 and C2 of the cyclohexane-1 ,2-dicarboxylic acid attached to C-3 position of the glycyrrhetinic acid.
As a result of further investigations, we have now found that antiviral activity is far greater in one diastereoisomer than in the other. Thus, by way of example, in one series of experiments, one diastereoisomer of the disodium salt of mono-(18ss-glyCyrrhet-3-yl)-cis-cyclohexane-1,2-dicarboxylic acid, namely 3ss-(cis-2S-carboxycyclohexane-1 S-carbonyloxy)-1 1 -oxo-1 8ss-olean-12-en-30-oic acid disodium salt, was found to have an antiviral activity against HSV-2 strain HG52 which was about 50 times greater than the antiviral activity of the other diastereoisomer, namely, 3p-(cis-2B-carboxycyclohexane-1 R-carbonyloxy)-1 1- oxo-18P-olean-l 2-en-30-oic acid disodium salt.
Thus, according to the present invention, there are provided diastereoisomers of the general formula:
wherein -COOR1 and -COOR2, which can be the same or different, are free, salified or esterified carboxylic acid groups.
Insofar as -COOR1 and -COOR2 are esterified carboxylic acid groups, R1 and R2 are preferably aliphatic hydrocarbon radicals containing up to 6 carbon atoms, which can be straight-chained or branched, saturated or unsaturated and substituted or unsubstituted.
For the preparation of the new compounds acording to the present invention of general formula (II), there can be used 1 8a- or 18p-glycyrrhetinic acid or an ester thereof which is reacted either with commerciallyavailable cis-cyclohexane-1 ,2-dicarboxylic acid anhydride to give a mixture of diastereoisomers which are separated in known manner, for example, by fractional crystallisation, or with an appropriate isomer of clyclohexane-1 ,2-dicarboxylic acid anhydride.
Insofar as the diastereoisomers obtained contain free carboxylic acid groups, they can be salified or esterified in known manner. Esterification is preferably carried out by reaction with an appropriate diazo compound, for example with diazomethane when it is desired to obtain a methyl ester, or an appropriate alcohol and sulphuric acid.
The present invention also provides pharmaceutical compositions containing at least one of the new compounds, in admixture with a solid or liquid pharmaceutical diluent or carrier.
The foilowing Examples are given for the purpose of illustrating the present invention:
Example 1 3P-lcis-2S-Carboxycyclohexane- 1S-carbonyloxyJ- I 1-oxo- 18p-olean- 12-en-30-oic acid
a) 100 g. of the disodium salt of mono-(glycyrrhet-3-yl)-cis-cyclohexane-1,2-dicarboxylic acid (obtained in conventional manner by reacting 18ss-glycyrrhetinic acid with cis-cyclohexane-1,2-dicarboxylic acid anhydride, followed by neutralisation with sodium hydroxide) were dissolved, with heating, in 600 ml.
acetone/water (1/1 v/v) and the solution filtered. Acetone was added to the hot filtrate until a faint cloudiness persisted, 280 ml. acetone being required for this purpose. The solution was allowed to cool to ambient temperature and the solid obtained was filtered off, washed with acetone/water (85/15 v/v) and then with acetone and dried in a vacuum at 60"C. The yield was 40 g.
A high pressure liquid chromatogram run on a 25 cm x 4 mm. Spherisorb ODS 10CL column using the solvent system methanol/0.1 M phosphate buffer (pH 7) (75/25/v/v) showed that the solid contained 95% of the slower running isomer.
The solid was dissolved, with heating, in 300 ml. acetone/water (1/1 v/v) and acetone was added to the hot solution until a faint cloudiness persisted, 90 ml. of acetone being required for this purpose. The solution was allowed to cool to ambient temperature and the solid was filtered off, washed with acetone/water (85/15 v/v), then with acetone and dried to constant weight in a vacuum at 600C. The yield was 22.6 g.
A high pressure liquid chromatogram run as above showed less than 1% of the faster running isomer. A thin layer chromatogram using n-butanol/0.88 ammonia (5/1 v/v) showed no impurities.
An infra-red absorption spectrum (Nujol mull) showed major bands atvmax = 1710 (ester), 1650 (enone), 1560 (broad,CO2Na) cm-1. The material had a melting point of > 360 C. and an optical rotation of [ex]2D0 = +118" f- 2" (1% in methanol/0.2% sodium carbonate solution.
The corresponding free acid had a melting point of 295 - 297"C. (decomp.). The infra-red absorption spectrum (Nujol mull) had majorbandsatvmax = 1740-1700 (acids + ester), 1660 (enone) cm-'.
b) 3 g. of the free diastereoisomeric diacid were mixed with 30 ml. methanol and sufficient dichloromethane was added to give a clear solution to which was added an excess of ethereal diazomethane. After a few minutes, a little acetic was added to destroy excess diazomethane, a clear solution being obtained. This was then concentrated on a hot plate until crystallisation commenced and then left to cool to ambient temperature. The crystalline solid was filtered off, washed with methanol and dried to constant weight in a vacuum oven at 80"C. The yield was 3.1 6 g of the dimethyl ester of the diastereoisomeric diacid.
The product had a melting point of 197 - 198"C. and the infra-red absorption spectrum (Nujol mull) had major bands at vmaX = 1740 (C-3 and side chain esters), 1710 (C-30 ester) and 1655 (enone) cm-'. The NMR spectrum (CDCl3) supported the structure.
Examination of the product by thin layer chromatography using petroleum ether (b.p. 60-800C,)/ dichloromethane/acetone (6/3/1 v/v/v) indicated that the product had a degree of purity of > 99%.
c) 1 g. of the free diastereoisomeric diacid was suspended in 20 ml. dry toluene and 0.6 ml. oxalyl chloride was added. The resultant mixture was magnetically stirred under anhydrous conditions at ambient temperature for 1 hour. After this time, the reaction mixture was still a suspension. A further 0.6 ml. oxalyl chloride was added and the reaction mixture was left to stir overnight. The clear solution was rotary evaporated and the residue dried in a vacuum oven to constant weight. There was obtained 1.07 g. of the di-acid chloride.
1.07 g. of the di-acid chloride was added to a mixture of 2 ml. anhydrous pyridine and 0.8 ml. hexan-l-ol.
The resultant mixture was refluxed in an oil bath at 140"C. under anhydrous conditions for 2 hours. Athin layer chromatogram (petroleum ether 60-80/dichloromethane/acetone; 6:3:1 v/v/v) indicated that the reaction was 95% complete. The reaction mixture was refluxed for a further hour and then left to cool. The reaction mixture was poured into ice/concentrated hydrochloric acid and extracted twice with ethyl acetate.
The ethyl acetate phase was then washed with distilled water until the washings were neutral, dried over anhydrous sodium sulphate, filtered and rotary evaporated to dryness. There was obtained 1.35 g. of the di-n-hexyl ester of the diastereoisomeric di-acid.
A thin layer chromatogram, run as above, indicated that the product was of 95% purity.
25 g. Silica gel (Merck 7734) were packed into a column. The column was eluted with a solvent mixture of petroleum ether 60-80)dichloromethane/acetone (6:3:1 v/v/v) and then a solution of 1.35 g of the dihexyl ester in the same solvent mixture was applied to the column, whereafter the column was then topped up with the same solvent mixture. A 25 ml. fraction was first collected and discarded. 10 ml. fractions were then collected and spotted on thin layer chromatography plates. The pure fractions were combined and rotary evaporated to dryness. There was obtained 0.88 g. of the purified dihexyl ester.
A thin layer chromatogram (petroleum ether 60-80/dichloromethane/acetone; 6:3:1 v/v/v) indicated that the product was of 99% purity.
0.88 g. of the dihexyl ester was dissolved in 8 ml. petroleum ether 60-80 and left in a deep-freeze for 1 week. The crystalline product obtained was filtered through a cold sintered glass funnel, washed with a small quantity of methanol and dried in a vacuum desiccator to constant weight. Yield 0.56 g.
A thin layer chromatogram, run as above, indicated that the product was of greater than 99% purity. The material had a melting point of 118 - 121"C. and the infra-red spectrum had major bands at: -vmax = 1710-1730 (esters), 1660 (enone) cm-1.
Example 2 3a-(cis-2S-Carboxycyc/ohexane- l S-carbonyloxyJ- 1 1-oxo- 18p-o/ean- 12-en-30-oic acid
a) 23.5 g.18a-Clycyrrhetinic acid, 17.6 g. cis-l ,2-cyclohexane-dicarboxylic anhydride and 28.2 ml.
anhydrous pyridine were heated under reflux for 4 hours at an oil bath temperature of 140 - 1 600C. After this time, thin layer chromatography indicated that the reaction was approximately 90% complete. To the cooled reaction mixture was added 352.5 ml. acetone and, while magnetically stirring the solution, there was added a solution of 42.3 ml concentrated hydrochloric acid in 112 ml. distilled water at ambient temperature.
The resultant precipitate was filtered off, washed with 70% aqueous acetone and then with distilled water until the washings were neutral and dried in a vacuum oven at 100"C. The yield was 28.28 g.
28.28 g. of the above di-acid were slurried with 84.8 ml. acetone and a solution of 3.64 g. sodium hydroxide in 84.8 ml. distilled water was added slowly, with stirring, until the pH was 9. The reaction mixture was still a suspension so it was warmed on a hot water-bath. This gave no change so a further 24 ml. distilled water were added and the mixture re-warmed. The slightly cloudy solution was hot filtered and, with continued heating, acetone was added until the solution became cloudy. This was then left to cool at 40C.
The precipitated solid was filtered off, washed with acetone/water (85:15 v/v) and then with acetone and dried in a vacuum oven to constant weight. The yield of the disodium salt of the diacid was 17.60 g.
The above disodium salt was dissolved in 106 ml. hot aqueous acetone (1:1 v/v) 6 x volume), filtered and, with continued heating, acetone was added until the mixture became cloudy, whereafter it was cooled at 40C.
The crystalline solid obtained was filtered off, washed with about 50 ml. acetone/water (85:15 v/v) and then with acetone. The product was dried in a vacuum oven to constant weight, the yield being 12.05 g. HPLC indicated that the diastereoisomer was of 97.5% purity.
Two further recrystallisations of the disodium salt using the above conditions gave 6.95 g. of white crystals.
HPLC, using a 75:25 v/v methanol/0.1 M phosphate buffer (pH 7) solvent mixture, indicated that the material contained > 99% of the desired diastereoisomer.
The material had a melting point of > 360 C. and the infra-red absorption spectrum had major bands at vmax = 1710 (ester), 1660 (enone), 1570 (CO2Na) cm-1. The pH of a 10% aqueous solution of the disodium salt was 8.6.
0.5 g. of the disodiu m salt was converted to the corresponding diacid by treating an aqueous solution thereof with dilute hydrochloric acid. The resulting precipitate was filtered off, washed with water until the washings were neutral and dried to constant weight in a vacuum oven at 100"C. The yield was 0.29 g.
The diacid had a melting point of 303 - 305"C. and the infra-red spectrum had major bands at vmax = 1705-1725 (CO2H + ester), 1665 (enone) cm-l. The NMR spectrum (d5 pyridine) supported the expected structure.
b) 40 ml. dry methanol and 1 ml. concentrated sulphuric acid were added to 2 g. of the disodium salt and the resultant mixture was refluxed on a hot water bath for 7 hours. After this time, a thin layer chromatogram (petroleum ether 60-80/dichloromethane/acetone; 6:3:1 v/v/v) indicated that the reaction was incomplete.
0.4 ml. Concentrated sulphuric acid was added to the reaction mixture and the solution was refluxed for a further 4 hours, after which time a thin layer chromatogram showed the reaction to be 95% complete.
The cooled reaction mixture was poured into ice/water and extracted with ethyl acetate. This procedure was repeated and the ethyl acetate extracts were combined, washed with water until the washings were neutral and dried over anhydrous sodium sulphate. The dried ethyl acetate solution was then filtered and rotary evaporated to dryness. The yield was 1.66 g.
The above product was dissolved in methanol/dichloromethane (2:1 v/v) and concentrated on a hot plate until crystallisation commenced. The crystalline solid filtered off, washed with methanol and dried in a vacuum oven at800C. until a constant weight was reached. The yield was 1.36 9. A thin layerchromatogram showed the product to be of > 99% purity.
The infra-red spectrum had major bands at vmax = 1740 (ester), 1710 (esters) and 1655 (enone) cm-'.
The material had a melting point of 235 - 237"C. Gas chromatography (1' 1% OV-17 column at 305"C.) showed the product to be of 99% purity and contained less than 1% of the corresponding 18ss compound. A nuclear magnetic resonance spectrum (CDC13) supported the expected structure.
c) The diacid chloride was prepared in a manner analogous to that described in Example 1 c) but the final working up was different.
The clear solution was rotary evaporated to about half of its original volume. Dry toluence was added and the same process repeated. This was carried out until no oxalyl chloride remained. The final solution was concentrated to 10 ml. and placed in the deep-freeze for 15 minutes. The crystalline solid obtained was filtered off and washed with a small quantity of dry toluence. The product was used for the next stage without drying.
The di-n-hexyl ester was prepared in a manner analogous to that described in Example 1 c), the yield being 0.83g.
Athin Iayerchromatogram (petroleum ether60-80/dichloromethane/acetone; 6:3:1 v/v/v) indicated that the product was of greater than 99% purity.
0.63 g. of the dihexyl ester was dissolved in 7 ml. petroleum ether and left in a deep-freeze for 3 weeks. The crystalline product obtained was filtered off, washed with methanol and dried in a vacuum oven at 40"C. to constant weight. The yield was 416 mg.
The material had a melting point of 99 - 101 C. and the infra-red spectrum had major bands at vmax = 1700-1720 (esters), 1660 (enone) cm-1.
Claims (7)
1. Compounds of the general formula :
wherein -COOR1 and -COOR2, which can be the same or different, are free, salified or esterified carboxylic acid groups.
2. 3ss-(cis-2S-Carboxycyclohexane-1 S-carbonyloxy)-1 1 -oxo-1 8p-olean-1 2-en-30-oic acid and the disodium salt, dimethyl ester and di-n-hexyl ester thereof.
3. 3ss-(cis-2S-Carboxycyciohexane-1 S-carbonyloxy)-1 1 -oxo-1 8a-olean-1 2-en-30-oic acid and the disodium salt, dimethyl ester and di-n-hexyl ester thereof.
4. Process for the preparation of compounds according to claim 1,wherein 1 8 or 18ss-glycyrrhetinic acid or an ester thereof is either reacted with cis-cyclohexane-1 ,2-dicarboxylic acid anhydride to give a mixture of diastereoisomers which is then separated in known manner or is reacted with an appropriate isomer of cyclohexane-1 ,2-dicarboxylic acid anhydride, whereafter, if desired, free carboxylic acid groups in the product obtained are salified or esterified in known manner.
5. Process according to claim 4 for the preparation of compounds according to claim 1, substantially as hereinbefore described and exemplified.
6. Compounds according to claim 1, whenever prepared by the process according to claim 4 or 5.
7. Pharmaceutical compositions containing at least one compound according to claim 1 in admixture with a solid or liquid pharmaceutical diluent or carrier.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB838321715A GB8321715D0 (en) | 1983-08-12 | 1983-08-12 | Diastereoisomers of glycyrrhetinic acid derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8418700D0 GB8418700D0 (en) | 1984-08-30 |
| GB2144746A true GB2144746A (en) | 1985-03-13 |
| GB2144746B GB2144746B (en) | 1986-11-05 |
Family
ID=10547194
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB838321715A Pending GB8321715D0 (en) | 1983-08-12 | 1983-08-12 | Diastereoisomers of glycyrrhetinic acid derivatives |
| GB08418700A Expired GB2144746B (en) | 1983-08-12 | 1984-07-23 | Diastereoisomers of glycyrrhetinic acid derivatives |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB838321715A Pending GB8321715D0 (en) | 1983-08-12 | 1983-08-12 | Diastereoisomers of glycyrrhetinic acid derivatives |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS6058942A (en) |
| DE (1) | DE3429590A1 (en) |
| FR (1) | FR2550537B1 (en) |
| GB (2) | GB8321715D0 (en) |
| IT (1) | IT1179033B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007105015A2 (en) * | 2006-03-10 | 2007-09-20 | York Pharma Plc | DERIVATIVES OF 18ß-GLYCYRRHETINIC ACID |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5519008A (en) * | 1992-09-10 | 1996-05-21 | Glycomed Incorporated | Derivatives of triterpenoid acids as inhibitors of cell-adhesion molecules ELAM-1 (E-selectin) and LECAM-1 (L-selectin) |
| US5527890A (en) * | 1993-04-16 | 1996-06-18 | Glycomed Incorporated | Derivatives of triterpenoid acids and uses thereof |
| CN103588849A (en) * | 2012-08-14 | 2014-02-19 | 江苏汉邦科技有限公司 | Preparation method for glycyrrhetinic acid |
| CN104004046A (en) * | 2014-05-27 | 2014-08-27 | 普凡生生物科技(北京)有限公司 | Preparation method of acetyl glycyrrhetinic acid |
| CN104004047A (en) * | 2014-05-27 | 2014-08-27 | 普凡生生物科技(北京)有限公司 | Preparation method of glycyrrhetinic acid |
| CN104387439B (en) * | 2014-10-31 | 2017-02-01 | 中国农业大学 | Method for preparing glycyrrhizic acid derivatives by carrying out subcritical hydrolysis reaction |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1022968A (en) * | 1964-05-07 | 1966-03-16 | Biorex Laboratories Ltd | New acyl derivatives of glycyrrhetinic acid |
| GB1387499A (en) * | 1972-09-06 | 1975-03-19 | Biorex Laboratories Ltd | Derivatives of glycyrrhetinic acid |
-
1983
- 1983-08-12 GB GB838321715A patent/GB8321715D0/en active Pending
-
1984
- 1984-07-23 GB GB08418700A patent/GB2144746B/en not_active Expired
- 1984-08-08 JP JP59166293A patent/JPS6058942A/en active Pending
- 1984-08-08 IT IT67795/84A patent/IT1179033B/en active
- 1984-08-10 DE DE19843429590 patent/DE3429590A1/en not_active Withdrawn
- 1984-08-10 FR FR848412656A patent/FR2550537B1/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007105015A2 (en) * | 2006-03-10 | 2007-09-20 | York Pharma Plc | DERIVATIVES OF 18ß-GLYCYRRHETINIC ACID |
| WO2007105015A3 (en) * | 2006-03-10 | 2008-03-27 | York Pharma Plc | DERIVATIVES OF 18ß-GLYCYRRHETINIC ACID |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2144746B (en) | 1986-11-05 |
| IT1179033B (en) | 1987-09-16 |
| GB8418700D0 (en) | 1984-08-30 |
| IT8467795A0 (en) | 1984-08-08 |
| FR2550537A1 (en) | 1985-02-15 |
| JPS6058942A (en) | 1985-04-05 |
| GB8321715D0 (en) | 1983-09-14 |
| DE3429590A1 (en) | 1985-02-28 |
| IT8467795A1 (en) | 1986-02-08 |
| FR2550537B1 (en) | 1989-03-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19940723 |