US3405152A - Glycyrrhetinic acid esters and the method of preparation thereof - Google Patents
Glycyrrhetinic acid esters and the method of preparation thereof Download PDFInfo
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- US3405152A US3405152A US454566A US45456665A US3405152A US 3405152 A US3405152 A US 3405152A US 454566 A US454566 A US 454566A US 45456665 A US45456665 A US 45456665A US 3405152 A US3405152 A US 3405152A
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- stearyl
- glycyrrhetinic acid
- glycyrrhetinate
- oleyl
- acid
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- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical class C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 title description 33
- 238000002360 preparation method Methods 0.000 title description 10
- 238000000034 method Methods 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 description 23
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 18
- -1 oleyl halide Chemical class 0.000 description 17
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 description 14
- 229960003720 enoxolone Drugs 0.000 description 14
- 239000002253 acid Substances 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 241000700159 Rattus Species 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- WNIFXKPDILJURQ-JKPOUOEOSA-N octadecyl (2s,4as,6ar,6as,6br,8ar,10s,12as,14br)-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-3,4,5,6,6a,7,8,8a,10,11,12,14b-dodecahydro-1h-picene-2-carboxylate Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C)CC[C@@](C(=O)OCCCCCCCCCCCCCCCCCC)(C)C[C@H]5C4=CC(=O)[C@@H]3[C@]21C WNIFXKPDILJURQ-JKPOUOEOSA-N 0.000 description 7
- WNIFXKPDILJURQ-UHFFFAOYSA-N stearyl glycyrrhizinate Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=O)OCCCCCCCCCCCCCCCCCC)(C)CC5C4=CC(=O)C3C21C WNIFXKPDILJURQ-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 229920000742 Cotton Polymers 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 230000003110 anti-inflammatory effect Effects 0.000 description 6
- 239000008188 pellet Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- GLDOVTGHNKAZLK-UHFFFAOYSA-N n-octadecyl alcohol Natural products CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 229940055577 oleyl alcohol Drugs 0.000 description 3
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 3
- WSULSMOGMLRGKU-UHFFFAOYSA-N 1-bromooctadecane Chemical compound CCCCCCCCCCCCCCCCCCBr WSULSMOGMLRGKU-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- NZGKLLOWEPXNDG-SSCMEWPNSA-N (2s,4as,6ar,6as,6br,8ar,10s,12as,14br)-2,4a,6a,6b,9,9,12a-heptamethyl-10-octadecanoyloxy-13-oxo-3,4,5,6,6a,7,8,8a,10,11,12,14b-dodecahydro-1h-picene-2-carboxylic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](OC(=O)CCCCCCCCCCCCCCCCC)C1(C)C NZGKLLOWEPXNDG-SSCMEWPNSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- KUGRPPRAQNPSQD-UHFFFAOYSA-N OOOOO Chemical compound OOOOO KUGRPPRAQNPSQD-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 239000012374 esterification agent Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/63—Steroids; Derivatives thereof
Definitions
- R is selected from the class consisting of stearyl and oleyl groups, and R is selected from the class consisting of hydrogen, stearoyl and oleoyl groups.
- This invention relates to novel glycyrrhetinic acid esters and the methods of preparing thereof.
- glycyrrhetinic acid esters of the present invention not only had an anti-inflammatory effect much superior to that of glycyrrhetinic acid, but also that it excelled in its solubility in fats as well as its solubility in organic solvents.
- the product of this invention is suitable fo use in oil preparations, salves, emulsions and sticklike preparations and exhibits an excellent anti-phlogistic effect because of its good transcutaneous absorption. This is a characteristic which was not noted in the known glycyrrhetinic acid and its esters and is an unexpected result.
- the invention product could be used for the same purpose as the corticoidal hormones.
- a noteworthy characteristic of the invention product is the fact that side reactions such as were manifested in case of the corticoidal hormones, i.e., deposits of sugar and shrinkage of the adrenals, do not occur.
- the invention product has excellent uses as an anti-phlogistic agent because of its very low toxicity and absence of side reactions.
- these compounds (I) are prepared by reacting stearyl or oleyl halide with the compound (IV) in the presence of an alkaline catalyst such as an alkali bicarbonate, alkali carbonate, organic amines or other alkaline substances.
- an alkaline catalyst such as an alkali bicarbonate, alkali carbonate, organic amines or other alkaline substances.
- the compounds (I) can also be obtained by reacting stearyl or oleyl alcohol with the compound (IV) in the presence of an acid esterification accelerator such as hydrochloric acid, sulfuric acid and aromatic sulfonic acids.
- an acid esterification accelerator such as hydrochloric acid, sulfuric acid and aromatic sulfonic acids.
- a compound such as of the following Formula VI (this compound is comprehended by the compound having the aforsaid Formula I) can also be prepared by 3 reacting a glycyrrhetinic acid ester having the following Formula V with stearyl or oleyl halide.
- R has the meaning as hereinbefore defined and R"" is selected from the class consisting of stearoyl and oleoyl groups.
- FIGS. 1-4 being those of the invention compounds obtained in Examples 1-4, respectively, whereas FIG. is that of glycyrrhetinic acid presented as a control.
- EXAMPLE 2 Preparation of stearyl glycyrrhetinate Thirty cc. of chloroform are added to 30 g. of stearyl alcohol and dissolved. In this solution are suspended 4.7 g. of glycyrrhetinic acid, followed by passing anhydrous hydrochloric acid gas therethrough for 4 hours. After allowing to stand overnight, the mixture is heated on a water bath and the hydrochloric acid gas and chloroform are distilled off. This is followed by distilling off of the excess stearyl alcohol on an oil bath at reduced pressure. When the residual product is recrystallized from ethanol, 2.6 g. of colorless, flaky crystals having a melting point of ll61l8 C. are obtained.
- the infrared absorption spectrum curve of this product is as shown in FIG. 3 and the results of an elementary analysis and calculated values are as follows.
- EXAMPLE 5 This example illustrates the pharmacological test of the invention chemical substances.
- Stearyl glycyrrhetinate (a compound of Formula I wherein the R and R therein are a stearyl group and hydrogen, respectively).
- Oleyl glycyrrhetinate (a compound of Formula I wherein the R and R therein are an oleyl group and hydrogen, respectively).
- Stearyl 3-stearoyloxyglycyrrhetinate (a compound of Formula I wherein the R and R therein are stearyl group and a stearoyl group, respectively).
- the anti-inflammatory effect was tested by means of animal experiments using the following procedures.
- Rat foot test [H. Selye, Brit. Med. Jour. 2, 1129 (1949)]: The test drug is injected hypodermically into rats daily 'for 7 days. On the last day, 0.1 ml. of
- a glycyrrhetinic acid ester represented by the generic formula wherein R is selected from the class consisting of stearyl and oleyl groups, and R is selected from the class consisting of hydrogen, stearoyl and oleoyl groups.
- Stearyl glycyrrhetinate having the formula 4.
- Oleyl glycyrrhetinate having the formula 5 1130 OH;
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Birds (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Oct. 8, 1968 TAKEQ UEDA I 3,405,152
GLYCYRRHETINIC ACID ESTERS AND THE METHOD OF PREPARATION THEREOF Filed May 10, 1965 5 Sheets-Sheet 1 Fig 0: OOOOO O. q-mrONNc\|--.
WA\ /ENUMBER mm") LLI WAVENUMBER (Cm' Oct. 8, 1968 TAKEO UEDA GLYCYRRHETINIC ACID ESTERS AND THE METHOD OF PREPARATION THEREOF 3 Sheets-Sheet 2 Filed May 10, 1965 WAVENUMBER .(Cm"') -oow 89 0o -ooE com -091 8m oom. so o8 com 88 00mm 00mm Oowm -Oowm WAVENUMBER 1cm") Oct. 8, 1968' TAKEO UEDA GLYCYRRHETINIC ACID ESTERS AND THE METHOD OF PREPARATION THEREOF 5 Sheets-Sheet 5 Filed May 10, 1965 0 -89 -oo og -82 -83 -89 699. -oot -89 -82 88 8% -ooww -oomm 68m WAVENUMBER ((Zm") United States Patent fice 3,405,152 Patented Oct. 8, 1968 ABSTRACT OF THE DISCLOSURE Novel glycyrrhetinic acid esters represented by the formula:
wherein R is selected from the class consisting of stearyl and oleyl groups, and R is selected from the class consisting of hydrogen, stearoyl and oleoyl groups.
This invention relates to novel glycyrrhetinic acid esters and the methods of preparing thereof.
These compounds have a generic Formula I such as follows:
(I) COOR (11) H30 oooH in which two foregoing formulas R" is an alkanoyl group of not more than 4 carbon atoms and R' is an alkyl group of not more than 4 carbon atoms in their respective formulas.
The anti-inflammatory effect of these compounds however is only equal to, if not less than, that of glycyrrhetinic acid.
I found that the glycyrrhetinic acid esters of the present invention not only had an anti-inflammatory effect much superior to that of glycyrrhetinic acid, but also that it excelled in its solubility in fats as well as its solubility in organic solvents.
Thus, the product of this invention is suitable fo use in oil preparations, salves, emulsions and sticklike preparations and exhibits an excellent anti-phlogistic effect because of its good transcutaneous absorption. This is a characteristic which was not noted in the known glycyrrhetinic acid and its esters and is an unexpected result.
Further, it was found that the invention product could be used for the same purpose as the corticoidal hormones. And in this case, a noteworthy characteristic of the invention product is the fact that side reactions such as were manifested in case of the corticoidal hormones, i.e., deposits of sugar and shrinkage of the adrenals, do not occur. In other words, the invention product has excellent uses as an anti-phlogistic agent because of its very low toxicity and absence of side reactions.
These compounds (I) of the present invention are prepared by reacting an esterification agent with a compound having the following Formula IV:
(IV) C O OH wherein R has the meaning hereinbefore defined.
For example, these compounds (I) are prepared by reacting stearyl or oleyl halide with the compound (IV) in the presence of an alkaline catalyst such as an alkali bicarbonate, alkali carbonate, organic amines or other alkaline substances.
Further, the compounds (I) can also be obtained by reacting stearyl or oleyl alcohol with the compound (IV) in the presence of an acid esterification accelerator such as hydrochloric acid, sulfuric acid and aromatic sulfonic acids.
Further, a compound such as of the following Formula VI (this compound is comprehended by the compound having the aforsaid Formula I) can also be prepared by 3 reacting a glycyrrhetinic acid ester having the following Formula V with stearyl or oleyl halide.
in which two foregoing formulas R has the meaning as hereinbefore defined and R"" is selected from the class consisting of stearoyl and oleoyl groups.
The accompanying drawings are in all cases infrared spectrum curves, FIGS. 1-4 being those of the invention compounds obtained in Examples 1-4, respectively, whereas FIG. is that of glycyrrhetinic acid presented as a control.
The following examples are given to illustrate the invention further, it being understood however that these examples are not in limitation of the invention.
EXAMPLE 1 Preparation of stearyl glycyrrhetinate A mixture of 2.35 g. of glycyrrehetinic acid, 1.67 g. of stearyl bromide and 0.5 g. of potassium bicarbonate is heated under reflux for hours in 30 cc. of anhydrous ethanol. After completion of the reaction, the reaction mixture is filtered and concentrated. Then when the crystals deposited after cooling are recrystallized from anhydrous ethanol, 2.88 g. of colorless, flaky crystals having a melting point of 116-1 18 C. are obtained. The infrared absorption spectrum curve of these crystals are as shown in FIG. 1, and the elementary analysis results and calculated values (as C H O are as follows.
Calculated values: C:79.72%, H=11.43%. Experimental values: C=79.58%, H=11.25%.
EXAMPLE 2 Preparation of stearyl glycyrrhetinate Thirty cc. of chloroform are added to 30 g. of stearyl alcohol and dissolved. In this solution are suspended 4.7 g. of glycyrrhetinic acid, followed by passing anhydrous hydrochloric acid gas therethrough for 4 hours. After allowing to stand overnight, the mixture is heated on a water bath and the hydrochloric acid gas and chloroform are distilled off. This is followed by distilling off of the excess stearyl alcohol on an oil bath at reduced pressure. When the residual product is recrystallized from ethanol, 2.6 g. of colorless, flaky crystals having a melting point of ll61l8 C. are obtained.
The infrared absorption spectrum curve of these crystals are as shown in FIG. 2.
4 EXAMPLE 3 Preparation of oleyl glycyrrhetinate 4.7 g. of glycyrrhetinic acid are suspended in 20 cc. of oleyl alcohol, following which anhydrous hydrochloric acid gas is passed therethrough for 2 hours. After allowing this suspension to stand overnight, it is heated on a water bath, followed by reducing the pressure to eliminate the hydrochloric acid gas. This is followed by heating over an oil bath at reduced pressure to distill off the excess oleyl alcohol to thereby obtain a jelly-like residual product. This product is, dissolved in benzene and, after purifying by passing through a column of alumina, the benzene is distilled off completely. The yield is 6.1 g.
The infrared absorption spectrum curve of this product is as shown in FIG. 3 and the results of an elementary analysis and calculated values are as follows.
Calculated values: C=79.29%, H=11.09%. Experimental values: C=79.64%, H=10.88%.
EXAMPLE 4 Preparation of stearyl-stearoyloxyglycyrrhetinate 1.48 g. of 3-stearoyloxyglycyrrhetinic acid are dissolved in 20 cc. of anhydrous ethanol, following which 0.67 g. of stearyl bromide and 0.15 g. of anhydrous sodium carbonate are added. The mixture is then refluxed for 5 hours on a water bath. After completion of the reaction, the reaction mixture is filtered While hot and the filtrate is concentrated followed by addition of a small amount of water. The crystals deposited after cooling are separated by filtration. When these crystals are recrystallized from ethanol, 1.64 g. of colorless crystals are obtained.
The infrared absorption spectrum curve of these crystals is as shown in FIG. 4, and the results of an elementary analysis and calculated values (as C H O are as follows.
Calculated values: C=79.94%, H=1l.99%. Experimental values: C=79.77%, H=1l.86%.
EXAMPLE 5 This example illustrates the pharmacological test of the invention chemical substances.
The materials of the experiment The following compounds were used in the experiment.
( 1) Stearyl glycyrrhetinate (a compound of Formula I wherein the R and R therein are a stearyl group and hydrogen, respectively).
(2) Oleyl glycyrrhetinate (a compound of Formula I wherein the R and R therein are an oleyl group and hydrogen, respectively).
(3) Stearyl 3-stearoyloxyglycyrrhetinate (a compound of Formula I wherein the R and R therein are stearyl group and a stearoyl group, respectively).
(4) 3-acetoxyglycyrrhetinic acid.
(5) 3-lauroyloxyglycyrrhetinic acid.
(6) 3-palmitoyloxyglycyrrhetinic acid.
(7) Lauryl glycyrrhetinate.
(8) Cetyl glycyrrhetinate.
The procedures of the experiment Male rats of the Wistar weighing about 150 grams are administered by the hypodermic injection of glycyrrhetinic acid and the derivatives thereof daily for 7 successive days. The dose administered is millimole/Z mL/kg. as a 1% Tween sesame oil suspension.
The anti-inflammatory effect was tested by means of animal experiments using the following procedures.
(1) Rat foot test [H. Selye, Brit. Med. Jour. 2, 1129 (1949)]: The test drug is injected hypodermically into rats daily 'for 7 days. On the last day, 0.1 ml. of
from Table II, the following compounds have the belowindicated rates.
solution of physiological saline in formalin is injected Percent into the tendinous membrane of the sole of the back feet Stearyl glycynrhetinate 40.1 of the rats. The extent of the increase in the swelling of 5 Oleyl glycyrrhetinate 35.1 the feet after the lapse of 1, 2, and 3 hours are measured Stearyl 3-stearoyloxyglycyrrhetinate 43.2 and the difference in the average value of the increase when these are compared with the inhibition rate of the Swenmg P P 1 feet between f F Ff and glycyrrhetinic acid, letting 1.00 be the rate of the latter, treated rats are indicated as the rate of inhibition. h follo i ratios are b i d (2) The cotton pellet method [R. Meier et al., Experi- 10 Times mented, 6, 469' (1959)]: Four dental cotton pellets of s l l h ti 2,78 about 5 mg. are weighed and then each is transplanted to Oleyl glycyrrhetinate 2.44 the axillae and inguinal regions of a rat, following which Stearyl 3-stearoyloxyglycyrrhetinate 3.00
TABLE I Swelling of Foot Inhibition N 0. Drugs rate, per- Inhibition Increase Difference cent ratio of increase 1 Control 27510.21 2.. Glyeyrrhetinie acid 2 3010.19 0.451003 16.3 1.00 3.-
3-aeetoxyglyeyrrhetinie aeid 2 4210. 03310.02 12.0 0.73 4.. 3-lauroyloxygiyeyrrhetinic acid... 2 7210.17 0.0310. 01 1. 1 0.07 5.. 3-pahnitoyloxyglyeyn'hetinio acid 2 6210.22 0.151001 5.5 0.34 6 2 2010.16 0. 5510.03 20.0 1.22 7 2 1010.16 06510.04 23.6 1.44 8 1 7210.12 1. 0310. 09 37.5 2.30 9.. Oleyl glycyrrhetinate 1 7410.14 1.0110. 09 36.7 2. 10 Stearyl 3-stearoyloxyglycyrrhetinate 1 5410.10 1. 2110. 10 44.0 2. 69
TABLE II Weight of Cotton Pellet N0. Drugs Inhibition Inhibition Increase Difference rate, perratio of increase cent Control 8. 9510. 72 Glyeyrrhetinic acid 7 6610. 71 1. 2910. 08 14.4 1.00 3-aeetoxyglyeyrrhetinie aeid.... 8 1210.70 0 8310.06 9.2 0. 64 3 1anroyloxyglycyrrhetime aeid.... 8 5210.68 0 4310.03 4.7 0.33 3-palmitoyloxyglyeyrrhetinic acid.. 8.4710. 74 0 4810. 03 5.3 0.37 Lauryl glycyrrhetinate....' 7. 2610. 49 1 691011 18.8 1.31 Cetyl glyeyrrhetinate. 7. 1010. 53 1 8510. 0Q 20. 6 1. 43 Stearyl glycyrrhetinate. 5. 3610. 28 3 5910. 29 40. 1 2. 78 Oleyl glyeyrrhetinate- 5.8010. 36 3. 1510. 21 35. 1 2. 44 Stearyl 3stearoyloxyglycyrrhetinate 5. 0810. 41 3. 8710. 31 43. 2 3. 00
Results of the experiments The results obtained in the rat foot and cotton pellet tests are shown in Tables I and II, respectively.
When the anti-inflammatory effect of the several compounds, as obtained by the rat foot test, is indicated by means of the inhibition rate, as is apparent from Table I, the following compounds have the rates as indicated below:
Percent Stearyl glycyrrhetinate 37.5 Oleyl glycyrrhetinate 36.7 Stearyl 3-stea-royloxyglycyrrhetin-ate 44 When these are compared with the inhibition rate of glycyrrhetinic acid, letting 1.00 be the rate of the latter, the following ratios are obtained.
Times Stearyl glycyrrhetinate 2.3 Oleyl glycyrrhetinate 2.25 Stearyl 3-stearoyloxyglycyrrhetinate 2.69
Next, when the anti-inflammatory effect of the several compounds, as obtained by the cotton pellet test, is indicated by means of the inhibition rate, as is apparent As described above, the results of the rat foot test and the cotton pellet test show a similar tendency, it being shown that stearyl glycynrhetinate, oleyl glycyrrhetinate and stearyl 3-stearoyloxyglycyrrhetinate of the present invention, in all cases, have a much more potent antiinflammatory effect than the reference compound glycyrrhetinic acid. The other compounds manifested results which were only equal to, if not less, than glycyrrhetinic acid. Hence, it can be said that the compounds of the presentinvention are novel anti-inflammatory agents whose effect is much more potent than the known glycyrrhetinic acid.
I claim:
1. A glycyrrhetinic acid ester represented by the generic formula wherein R is selected from the class consisting of stearyl and oleyl groups, and R is selected from the class consisting of hydrogen, stearoyl and oleoyl groups.
7 s 2. Stearyl glycyrrhetinate having the formula 4. Stearyl 3-stearoy1oxyglycy1=rhetinate having the H30 0 0001 11,, formula 0=/\ CH3 i CH3 0- CH3 011i cm 10 I i 110- V 3 UnllaaCO-O HaC on; x 3. Oleyl glycyrrhetinate having the formula 5 1130 OH;
H C 0000 H 3 ls N References Cited FOREIGN PATENTS 20 894,265 4/1962 Great Britain.
0- OTHER REFERENCES C11; Brewster: Organic Chemistry (1948), pp. 218-20.
EV 25 HENRY R. JILES, Primary Exam e H10 on:
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2691364 | 1964-05-14 | ||
| JP4842664 | 1964-08-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3405152A true US3405152A (en) | 1968-10-08 |
Family
ID=26364768
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US454566A Expired - Lifetime US3405152A (en) | 1964-05-14 | 1965-05-10 | Glycyrrhetinic acid esters and the method of preparation thereof |
Country Status (2)
| Country | Link |
|---|---|
| US (1) | US3405152A (en) |
| GB (1) | GB1046566A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10232774B4 (en) * | 2002-07-18 | 2004-07-15 | Cognis Deutschland Gmbh & Co. Kg | Cosmetic preparations with antibacterial properties |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB894265A (en) * | 1960-03-04 | 1962-04-18 | Biorex Laboratories Ltd | Glycyrrhetinic acid esters |
-
1965
- 1965-05-10 US US454566A patent/US3405152A/en not_active Expired - Lifetime
- 1965-05-12 GB GB20087/65A patent/GB1046566A/en not_active Expired
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB894265A (en) * | 1960-03-04 | 1962-04-18 | Biorex Laboratories Ltd | Glycyrrhetinic acid esters |
Also Published As
| Publication number | Publication date |
|---|---|
| GB1046566A (en) | 1966-10-26 |
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