Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • 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
  • A61P39/00—General protective or antinoxious agents
  • A61P39/02—Antidotes
• • 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

Definitions

• the present invention relates to a method for directly synthesizing glycyrrhetinic acid using glycyrrhizic acid, and further relates to a 11-deoxy-18 a-glycyrrhetinic acid ester compound and a preparation method thereof, and a medicament containing 11-deoxy-18 ⁇ -glycyrrhetinate Compositions, and their use in the treatment of liver damage and inflammation.
• Glycyrrhiza uralensis is the root and stem of leguminous licorice. Its main pharmacological active substance is glycyrrhi zic ac id and its glycorrhetinic acid (Glycyrrhet inic ac id). Modern research shows that glycyrrhetinic acid has many effects such as anti-inflammatory, anti-ulcer, anti-virus (hepatitis virus, HIV, etc.), blood fat reduction, and prevention and treatment of tumors.
• Glycyrrhetinic acid is structurally similar to hydrocortisone, and many clinical trials have demonstrated that glycyrrhetinic acid has anti-inflammatory effectiveness.
• Zaki rov's study found that 3-amino-11-deoxyglycyrrhetinic acid showed significant anti-inflammatory activity against aseptic arthritis in various animals.
• Toyoshima et al. prepared 11-deoxyglycyrrhetinic acid cis-butenedioate and its salt as an anti-inflammatory agent, and also as an anti-ulcer agent and an immunomodulator, see US 4,448,788. It is well documented that salts of glycyrrhetinic acid such as sodium glycyrrhetinate have an anti-inflammatory effect.
• glycyrrhetinic acid and its derivatives have aldosterol (DCA) activity, which is often accompanied by side effects in clinical use.
• DCA aldosterol
• glycyrrhetinic acid preparation can cause sodium retention, high blood pressure and low potassium alkaline poisoning.
• John S. Baran et al. found that 11-deoxyglycyrrhetinic acid is essentially free of aldosterol activity and has no such side effects (John S. Baran et al. Journa l of Medi c ina l Chemi s try, 1974, Vol.17, (2) P184-191).
• glycyrrhetinic acid is mainly prepared by glycyrrhizic acid, and then the structure of glycyrrhetinic acid is chemically modified and modified.
• the inventors have found that the glycyrrhetinic acid or its salt derivative directly produces a glycyrrhetinic acid derivative derivative method, which requires only one step of reaction, and does not need to obtain glycyrrhetinic acid first, and then is modified, and the method uses a low temperature. No need for high pressure, high yield, low cost, suitable for industrial production.
• the present inventors further obtained 11-position deoxygenated glycyrrhetinic acid ester, specifically 11-deoxy-18 a-glycyrrhetinate, on the basis of monolithic synthesis of glycyrrhetinic acid derivatives.
• These 11-deoxy-18 a-glycyrrhetinates have anti-inflammatory and anti-ulcer activities, and also have activity for treating liver damage; and have a reduced side effect, good fat solubility, and high absorption and utilization of the human body.
• the present invention relates to a compound of the formula II, that is, 11-deoxy-18 a-glycyrrhetinate, a process for the preparation thereof, and a composition formed by mixing the same with a pharmaceutical carrier, and the above substances for treating inflammation, ulcers and liver damage, etc. Application of the field.
• the present invention also relates to a method for synthesizing a glycyrrhetinate derivative.
• ⁇ is 11, a linear or branched dC 18 alkyl formyl group, a linear or branched dC 18 alkenyl formyl group or an aryl formyl group; and R 2 is a linear or branched dC 18 alkoxy group.
• a aryl or aryloxy group, the 18 position is an alpha configuration or a beta configuration.
• it is H, a linear or branched C "C 6 alkyl formyl group or a linear or branched C "CJ thiol formyl group, more preferably H;
• R 2 is preferably a linear or branched C "C 6 alkoxy group, more preferably an ethoxy group;
• the 18 position is preferably in the alpha configuration.
• a preferred compound of the formula of the invention is 11-deoxy-18 alpha-glycyrrhetic acid ethyl ester.
• the present invention also provides a method of synthesizing a compound of formula I I:
• the 11 position of the compound of formula I below is subjected to deoxygenation reduction to give the corresponding compound of formula I I which is hydrogen. If necessary, the 3 hydroxyl groups can be further esterified to obtain the corresponding compound of formula I I.
• R 2 is straight or branched (ds alkoxy or aryloxy, and position 18 is in the alpha or beta configuration.
• Deoxygenation reduction uses methods of reduction well known to those skilled in the art including, but not limited to, gram Method of reduction by Cl e ⁇ ens en, catalytic hydrogenation, etc.
• the Cle ⁇ ens en reduction method uses amorphine and hydrochloric acid to reduce the carbonyl group at position 11 to a methylene group.
• the solvent may be tetrahydrofuran, 1,4-dioxane or the like; the catalytic hydrogenation method may use a conventional catalyst such as platinum, palladium or an oxide thereof, and the solvent may be, for example, methanol, ethanol, 1,4-dioxane, Tetrahydrofuran, etc.
• the hydroxyesterification can be carried out by using a carboxylic acid or a carboxylic acid anhydride, and the reaction is carried out in an inert organic solvent such as 1,4-dioxane or tetrahydrofuran, and the temperature of the reaction is selected depending on the carboxylic acid or carboxylic anhydride used.
• R 2 is defined as above, including:
• the licorice of the formula I is prepared by reacting an alkyl alcohol or an aromatic alcohol (R 2 H) with one or more of glycyrrhizic acid, glycyrrhizic acid or glycyrrhizic acid in the presence of a dehydrating agent such as an acid chloride or concentrated sulfuric acid. Lower ester. Among them, glycyrrhizinate can be enumerated as potassium, sodium, ammonium, calcium or magnesium salt of glycyrrhizic acid.
• Glycyrrhizic acid, glycyrrhizic acid or glycyrrhizic acid derivatives can be purchased directly, or can be obtained as a salt or a derivative by extracting glycyrrhizic acid from licorice. Among them, 18 ⁇ - glycyrrhizic acid can be obtained by catalytic isomerization of natural glycyrrhizic acid base by the method of ZL02111693.
• the acid chloride may be oxalyl chloride, acetyl chloride or chloroformyl chloride, and the acyl chloride may be leucoyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride.
• the amount of the acid is preferably used in an amount of 0. 5-5 moles.
• the reaction is carried out in a solvent, or the alcohol participating in the reaction is used as a solvent, and the reaction solvent is a solvent capable of dissolving glycyrrhizic acid, glycyrrhizinate and/or glycyrrhizic acid derivative, such as N. , N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, and the like.
• the alkyl alcohol is a lower alcohol, it is preferred to directly use the alcohol participating in the reaction as a solvent.
• the preparation method of the glycyrrhetinic acid ester of the formula I comprises: adding glycyrrhizic acid, glycyrrhizic acid or glycyrrhizic acid derivative to anhydrous ethanol, adding concentrated sulfuric acid or acid chloride, heating under reflux, cooling, crystallizing out Solid, filtered, refined with ethanol/water, dried to give the target compound; or added glycyrrhizic acid or glycyrrhizinate to anhydrous methanol, added with acetyl chloride, heated to reflux, cooled, crystallized solid, filtered, purified with ethanol/water , dry, to obtain the target compound.
• linear or branched dC 18 alkyl refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, which is bonded to the remainder of the molecule by a single bond.
• the alkyl group has
• the alkyl group may be unsubstituted or substituted by one or more substituents selected from the group consisting of a halogen and a hydroxyl group.
• substituents selected from the group consisting of a halogen and a hydroxyl group.
• unsubstituted alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, neopentyl , n-hexyl, 2-methylhexyl and the like.
• linear or branched dC 18 -glycol refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, which contains at least one unsaturated bond through a single bond and a molecule. The rest of the connection.
• the base has from 1 to 18 carbon atoms, preferably from 1 to 6 carbon atoms.
• the alkenyl group may be unsubstituted or substituted by one or more substituents selected from the group consisting of a steroid, a hydroxy group or a carboxy group.
• unsubstituted alkenyl groups include, but are not limited to, ethenyl, propenyl, propyl-2-yl, n-butenyl, isobutenyl, n-pentyl, 2-methylbutanyl, n-hexyl, 2-Methylhexyl and so on.
• aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a fully conjugated ⁇ -electron system having from 6 to 14 carbon atoms, preferably from 6 to 12 carbon atoms, most It preferably has 6 carbon atoms.
• the aryl group may be unsubstituted or substituted with one or more selected from the group consisting of an alkyl group, an aryl group, an aralkyl group, an amine group, a halogen group, and a hydroxyl group. Examples of the unsubstituted aryl group include, but are not limited to, a phenyl group, a tea group, and an anthracenyl group.
• the invention also provides a compound of formula II and a composition comprising the compound of formula II in the treatment of inflammation, ulceration Use of one or more of ulcers and liver damage.
• the compounds of the formula II of the present invention may be administered alone, and are of course generally in the form of a pharmaceutical preparation comprising at least one of the compounds of the formula II as an active ingredient, and further comprising one or more pharmaceutically acceptable carriers. These carriers vary depending on the mode of administration.
• Formulations comprising a compound of the invention may be administered topically or systemically, including orally, rectally, nasally, sublingually, dermally, vaginally, and the like.
• Oral compositions can be solid, gel or liquid.
• solid preparations include, but are not limited to, tablets, capsules, granules, and bulk powders. These preparations may optionally contain a binder, a diluent, a disintegrant, a lubricant, a glidant, a sweetener, and/or a flavoring agent and the like.
• the invention also provides a veterinary composition
• a veterinary composition comprising at least one of the above active ingredients and at least one veterinary carrier, the veterinary carrier being a material for administration to cattle, horses, sheep, cats, dogs, horses, rabbits or other animals, for veterinary use
• Solid, liquid or gaseous materials which are compatible with the active ingredients are acceptable in the art, and these veterinary compositions can be administered by oral and parenteral routes and the like.
• the present inventors synthesized a glycyrrhetinic acid ester by a single method, and in particular, synthesized 11-deoxy-18 ⁇ - glycyrrhetinic acid ester.
• 11-deoxy-18 ⁇ -glycyrrhetinic acid has anti-inflammatory and anti-ulcer activity; it can be used for treating liver damage, inhibiting hepatocyte necrosis and protecting liver damage, and has the prospect of treating liver disease; especially for acute liver injury and drugs Hepatic injury has a therapeutic effect, and has low side effects, good fat solubility, easy absorption, and high absorption.
• the bioavailability is high, and the enzyme-reducing effect is obvious.
• Example 6 demonstrates that the compound of formula II of the present invention has an anti-inflammatory effect.
• Examples 7 and 8 demonstrate that the compounds of formula I I of the present invention have an effect of treating drug-induced liver damage.
• Tables 1 and 2 show that the compound of the formula II of the present invention, especially a preferred compound, is effective against liver damage caused by D-Ga In, can effectively inhibit the elevation of serum transaminase, and is superior to glycyrrhizin and diammonium glycyrrhizinate, especially It is better for oral administration.
• Table 3 and Table 4 show that the compound of the formula II of the present invention, especially the preferred compound, is effective for liver damage caused by TAA, can effectively inhibit the elevation of serum transaminase, and is superior to diammonium glycyrrhizinate, which can inhibit hepatocyte necrosis, and is excellent. In the diammonium glycyrrhizinate.
• the method for synthesizing the cartridge of the present invention directly uses glycyrrhizic acid or a derivative thereof as a starting material, and obtains glycyrrhetinic acid ester by a method of high yield in a tube and a high yield, thereby obtaining a deoxygenated glycyrrhetinic acid ester at position 11. Conducive to The full utilization of natural resources licorice reduces waste of resources.
• the reagents used in the specific examples below are all analytically pure reagents.
• Method 1 10 g of 18 ⁇ -glycyrrhizic acid was added to 100 ml of anhydrous methanol, 5 ml of acetyl chloride was added, and the mixture was heated under reflux for 2 hours, and 100 ml of water was added thereto, and the mixture was cooled to crystallize the solid, which was filtered, purified by ethyl alcohol/water, and dried to give the title compound. , yield 82%.
• Test methods 60 male ICR mice were randomly divided into 6 groups, 10 in each group: model group, compound glycyrrhizin injection group (6Qmg/kg), compound glycyrrhizin gavage group (24Qmg/kg), 11 - Deoxy-18 oc-glycyrrhetinic acid ethyl ester high dose group (240 mg/kg), middle dose group (120 mg/kg), low dose group (60 mg/kg). Each group was intraperitoneally or intragastrically administered in a volume of 10 ml/kg for 6 consecutive days. The model group was given an equal amount of 0.5% CMC_Na by gavage. The results are shown in the following table: Table 1. Therapeutic effect of 11-deoxy-18 ⁇ - glycyrrhetinic acid ethyl ester on D-Galn acute liver injury model mice. Dosing ALT AST
• mice 60 ICR male mice were randomly divided into 6 groups, 10 in each group: model group, diammonium glycyrrhizinate raw material group (24Qmg/kg), diammonium glycyrrhizinate injection group (60mg/kg), 11_deoxygenation - 18 ⁇ _ glycyrrhetinic acid ethyl ester high dose group (240 mg / kg), medium dose (120 mg / kg), low dose group (60 mg / kg), continuous administration for 7 days, model group IG given an equal amount of 0.5 %CMC-Na.
• Table 2 Therapeutic effect of 11-deoxy-18-glycyrrhetinic acid ethyl ester on D-Galn acute liver injury model mice Dose administration ALT AST group N
• mice 50 ICR male mice were randomly divided into 5 groups, 10 in each group: model group, diammonium glycyrrhizinate group (240 mg/kg), 11-deoxy-18 ⁇ -glycyrrhetinic acid ethyl ester high dose group (240 mg/kg)
• model group diammonium glycyrrhizinate group (240 mg/kg)
• 11-deoxy-18 ⁇ -glycyrrhetinic acid ethyl ester high dose group 240 mg/kg
• the model group IG was given an equal amount of 0.5% CMC_Na. The results are as follows:
• Example 6 Anti-inflammatory effect of 11-deoxy-18 ⁇ -glycyrrhetinic acid ethyl ester Injection of carrageenan in rats' ankles caused swelling and observed the anti-inflammatory effects of the drug. among them:
• Inflammatory agent carrageenan
• Test substance 11-deoxy-18 ⁇ glycyrrhetinic acid ethyl ester was formulated to a desired concentration with 1% CMC-Na;
• Positive drug indomethacin, formulated with 1% CMC-Na to the desired concentration;
• the 50 rats were randomly divided into 5 groups, each of 10, respectively, model group, positive group (administered indomethacin 10mg / kg), test drug dose groups (30, 60, 120mg / kg ) 0
• Each group of animals was administered continuously for 3 days.
• the left hind paw volume of the rats before administration was measured by micropipette measurement.
• the drug or CMC-Na was administered by intragastric administration.
• the freshly prepared carrageenan was aspirated with a 0.25 ml syringe, and the needle was injected into the left hind paw of the rat with 0.05 needle/paw, and then placed at 1, 3, respectively.
• the left hind paw volume of the rats was measured twice in the same way, and the average value was taken, so that the difference in the volume of the foot before and after the inflammation was the degree of swelling.
• Measurement data i ⁇ s indicates that the experimental data of each group was compared using the t-test of two sample means.
• P ⁇ 0.05 or P ⁇ 0.01 was considered to be statistically significant.
• 11-Deoxy-18-glycyrrhetinic acid ethyl ester provided by the Chinese Medicine Laboratory of the R&D Center of Jiangsu Zhengda Tianqing Pharmaceutical Co., Ltd. Biphenyl diester dropping pills: produced by Beijing Union Pharmaceutical Factory.
• the daily dose was 45 mg as a positive control.
• the drugs were formulated to the appropriate concentration with physiological saline according to the experimental requirements.
• Kunming mice were purchased from the Experimental Animal Center of China Pharmaceutical University. The volume of the mouse drug solution was 0.25 ml/10 g.
• mice 60 males, randomly divided into six groups according to body weight: normal control group, model control group, bifendate control group, each dose of 11-deoxy-18 ⁇ glycyrrhetinic acid ethyl ester group (240, 120, 60 mg/kg) o
• each group of the mice was injected with BCG 5 x 107 live bacteria once per tail.
• the animals in each group were given normal saline (normal control group and model group) or test drugs for 7 consecutive days.
• 10 ⁇ g of LPS was injected into the tail vein of each mouse except the normal group.
• the normal control group was injected with the same amount of normal saline twice in the same manner. After the model was established, the animals were fasted, and after free drinking for 12 hours, blood was taken from the eyelids, and the serum was separated by centrifugation at 2500 rpm for 15 minutes to measure serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
• ALT serum alanine aminotransferase
• AST aspartate aminotransferase
• the compound of the formula II of the present invention particularly 11-deoxy-18 ⁇ glycyrrhetinic acid, has a good liver-lowering enzyme-lowering effect and can effectively treat hepatocyte damage caused by immune factors.
• Example 8 Protective effect of the compound of formula II of the present invention on liver injury induced by acetaminophen in mice
• mice Sixty mice were randomly divided into 6 groups: normal control group; biphenyl diester group (positive drug group); model control group; each dose of 11-deoxy-18 ⁇ glycyrrhetinic acid ethyl ester group (240, 120, 60 mg) /ml); After each group of animals for adaptive feeding for 3 days, each group of animals were administered intragastrically for 10 days (once a day), normal control group and model group were given normal saline, each 0. 2ml / only. After the last administration for 6 hours, except for the normal control group In addition, the other groups were intraperitoneally injected with 4Q0 mg*kg-l acetaminophen.
• the liver damage caused by acetaminophen is mainly caused by the large amount of acetaminophen being metabolized in the body by the P450 enzyme system to produce excessive N-acetic acid-p-benzoquinone imine (NAPQI), which leads to the depletion of intrahepatic glutathione (GSH).
• NAPQI forms a covalent bond with hepatocyte macromolecules (such as proteins), causing hepatocyte necrosis.
• the experimental results show that the compound of the formula II of the present invention, especially 11-deoxy-18 alpha glycyrrhetinic acid ethyl ester, can reduce AST, ALT, and effectively protect liver cell damage caused by acetaminophen, and can be used for treating liver damage caused by drugs.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Epidemiology (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Toxicology (AREA)
• Gastroenterology & Hepatology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Steroid Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (5)

Applications Claiming Priority (2)

Publications (1)

Family

ID=43225035

Family Applications (1)

Country Status (7)

Cited By (1)

Families Citing this family (4)

Citations (2)

Family Cites Families (6)

• 2009
  • 2009-05-31 CN CN200910027345A patent/CN101899081B/zh active Active
• 2010
  • 2010-05-28 RU RU2011148301/04A patent/RU2522455C2/ru not_active IP Right Cessation
  • 2010-05-28 JP JP2012513459A patent/JP5658238B2/ja not_active Expired - Fee Related
  • 2010-05-28 US US13/375,332 patent/US20120172438A1/en not_active Abandoned
  • 2010-05-28 WO PCT/CN2010/073339 patent/WO2010139253A1/zh not_active Ceased
  • 2010-05-28 AU AU2010256187A patent/AU2010256187B2/en not_active Ceased
• 2011
  • 2011-12-22 ZA ZA2011/09483A patent/ZA201109483B/en unknown

Patent Citations (2)

Non-Patent Citations (3)

Also Published As

Similar Documents

Legal Events