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WO1992010176A1 - Agent therapeutique contre les maladies du foie - Google Patents

Agent therapeutique contre les maladies du foie Download PDF

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Publication number
WO1992010176A1
WO1992010176A1 PCT/JP1991/001700 JP9101700W WO9210176A1 WO 1992010176 A1 WO1992010176 A1 WO 1992010176A1 JP 9101700 W JP9101700 W JP 9101700W WO 9210176 A1 WO9210176 A1 WO 9210176A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
therapeutic agent
acid derivative
liver disease
malonic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1991/001700
Other languages
English (en)
Japanese (ja)
Inventor
Susumu Otomo
Shohei Higuchi
Iwao Arai
Michihiro Ohnaka
Shugo Matsuno
Mari Misawa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zeon Corp
Taisho Pharmaceutical Co Ltd
Original Assignee
Taisho Pharmaceutical Co Ltd
Nippon Zeon Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Taisho Pharmaceutical Co Ltd, Nippon Zeon Co Ltd filed Critical Taisho Pharmaceutical Co Ltd
Publication of WO1992010176A1 publication Critical patent/WO1992010176A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin

Definitions

  • the present invention relates to a therapeutic agent for liver disease. More specifically, the present invention relates to a therapeutic agent for a liver disease of a highly active mammal, particularly a human, comprising a malonic acid derivative as an active ingredient.
  • liver In the liver of humans and other mammals, complex and diverse chemical reactions, such as detoxification, sugar metabolism, protein metabolism, lipid metabolism, bile production and secretion, hormonal regulation, blood coagulation prothrombin formation, liver Cell regeneration and storage of various vital components (fat, carbohydrate, protein, and vitamin) are being carried out.
  • the liver which has these complex physiological functions, is sometimes acutely or chronically damaged by alcohol, malnutrition, viral infection, and various factors of chemical toxins, resulting in hepatic necrosis and fat. It causes hepatic and biliary disorders and cirrhosis.
  • Glycyrrhizin is known as a drug widely used for the treatment and prevention of these diseases, but this glycyrrhizin is effective for liver damage, cirrhosis, hepatitis, liver protection after surgery, etc. However, its efficacy was observed only by intravenous administration, and no efficacy was demonstrated by oral administration. There is a restriction that.
  • liver diseases that can be orally administered have been proposed.
  • any of these conventional drugs useful for oral administration have a desired physiological level. At present, it has no activity.
  • the present invention has been made in view of such circumstances, and has been developed to provide a new drug that is more active than the conventionally proposed therapeutic agent for liver disease and is effective for treating liver disease in mammals, particularly humans. It is intended to provide.
  • the present invention solves the above-mentioned problem by providing a formula (I)
  • a in the formula represents a hydrogen atom, a lower chain aliphatic group, a cycloaliphatic group, an aromatic ring group or a heterocyclic group, and when A is other than a hydrogen atom, it may have a substituent.
  • malonic acid derivative represented by A therapeutic agent for liver disease.
  • Examples of the lower-chain aliphatic group of A include a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isopropyl group, a tert-lipyl group, a vinyl group, and a butyl group.
  • Examples thereof include lower alkenyl groups such as benzyl group, butenyl group and crotyl group, and lower alkynyl groups such as 1-propynyl group, propargyl group and butynyl group. Of these, a lower alkyl group and a lower alkenyl group are preferred.
  • Examples of the cycloaliphatic group for A include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl and the like. .
  • Examples of the aromatic ring group of A include a phenyl group, a naphthyl group, a tetrahydronaphthyl group, an indanyl group and the like. Of these, a phenyl group and a tetrahydronaphthyl group are preferred.
  • heterocyclic group of A examples include pyrrolidinyl, pyridyl, pyrimidyl, imidazolyl, benzoimidazolyl, triazolyl, benzotriazolyl, oxazolyl, Examples include a benzoxazolyl group, an oxazinyl group, a thiazolyl group, a benzothiazolyl group, and a thiazinyl group. Of these, a thiazolyl group and a benzothiazolyl group are preferred.
  • A when A is other than a hydrogen atom, it has a substituent May be.
  • substituents include halogen atoms such as chlorine, bromine, iodine, and fluorine atoms, lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl groups, methoxy, ethoxy, isopropoxy, butoxy, and the like.
  • Lower alkoxy groups such as isobutoxy group, chloromethyl, chloroethyl, bromomethyl, dichloromethyl, fluoromethyl, trifluoromethyl, chlorofluoroethyl, halogenated alkyl groups such as methoxymethyl group, methylenedioxy, ethylenedioxy, petylenedioxy Examples thereof include a lower alkylenedioxy group such as a group.
  • the lower alkoxy group of R bonded to the carbonyl group is a methoxy, ethoxy, propoxy, isopropoxy, butoxy, or isobutoxy group having 1 to 4 carbon atoms, and the halogenated phenyl group is chlorine, bromine, or iodine.
  • the halogenated phenyl group is chlorine, bromine, or iodine.
  • Examples of the lower alkyl group of R 2 constituting the ester bond include a methyl, ethyl, propyl, isopropyl, butyl, isoptyl and tertiary butyl group having 1 to 4 carbon atoms.
  • malonic acid derivative As an active ingredient used in the therapeutic agent for liver disease of the present invention, Specific examples of the malonic acid derivative include, for example, the following compounds when classified according to the characteristics of the above A.
  • Jetyl normal propyl urea mino methylene malonate Jetil tertiary butyl hydrazino dimethylene malonate
  • Jetil 4 Promoenilua Mino Methylene Malonet
  • Zinolmarbro pill 2 eodofenylamino melamine malonate
  • Jetil 2 methyl diaminoaminomethylamine ronate
  • Jetil 4 methylenilaminomethylmalonate
  • Jetil 4 methyl phenyl hydrazino methylene malonate
  • Jetil 4 Trifluoremyl phenylamine amino lemmalonete
  • Jetil 1 (5, 6, 7, 8 — Tetrahydronaftyl) hydra dinomethylenmalonate
  • Jetyl 5 Indanylaminomethylenmalonate, () A: Heterocyclic group
  • Diisopro pill 2 oxazoli rua Net
  • Getyl 2 thiazinylaminomethylenemalonate, 1—perfluorophenylcarbonyl 1—ethoxycarbonyl-2-yl (2-pyrimidinyl) amine
  • Such malonic acid derivatives are, for example, getyl 2-benzo Thiazolyl amino methylene manage and getyl 2 monobenzothiazolyl hydrazinomethylene malonate are useful as active ingredients of therapeutic agents for liver diseases.
  • the malonic acid derivative represented by the formula (I) according to the present invention is known in the art. It can be manufactured by any method including the method described above. For example, the expression ( ⁇ )
  • (X is a group having a reactivity such as an alkoxy group).
  • This reaction is carried out without solvent or in the presence of an inert solvent.
  • the inert solvent include aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and chlorobenzene, dimethylformamide, dimethylsulfoxide, and ethanol. it can.
  • the compound represented by the formula (I) has extremely low toxicity to human mammals.
  • the compound represented by the formula (I) is useful for the treatment of various disease models experimentally created by administration of drugs such as carbon tetrachloride, D-galactosamine, ⁇ -naphthyl isocyanate, and etyonin.
  • drugs such as carbon tetrachloride, D-galactosamine, ⁇ -naphthyl isocyanate, and etyonin.
  • the therapeutic agent of the present invention can be used as a compound represented by the formula (I) in an amount of 0.1 to 30 nigZ 1 ⁇ body weight Z day 1 to 3 per day when administered orally to an adult. Administer in divided doses. This dose can be adjusted appropriately according to the patient's age, weight, and symptoms.
  • the therapeutic agent of the present invention is obtained by adding a conventional carrier to the compound represented by the formula (I) by a conventional method, and preparing a solid preparation for oral administration such as tablets, granules, powders and capsules, a liquid preparation and a suspension. It can be used by preparing it into a liquid preparation for oral administration or parenteral administration such as a turbidity agent, an emulsion or an injection.
  • Carriers that can be used to prepare solid preparations for oral administration include excipients such as lactose, glucose, crystalline cellulose, mannitol, corn starch, sugar, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl. Binders such as cellulose, polyvinyl alcohol, gelatin, and gum arabic; wetting agents such as glycerin and ethylene glycol; corn starch, potato starch, calcium carboxymethyl cellulose, low substitution degree Disintegrants such as hydroxypropylcellulose, lubricants such as calcium stearate, magnesium stearate, talc, polyethylene glycol, hydrogenated oil, etc., and other surfactants and coloring agents as required Use of seasonings, etc. It can be.
  • excipients such as lactose, glucose, crystalline cellulose, mannitol, corn starch, sugar, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl. Binders such as cellulose, polyviny
  • Diluents that can be used to prepare liquid preparations for oral administration include: Water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, tragacanth, etc.Use dissolution aids, buffers, preservatives, fragrances, coloring agents, seasonings, etc. as necessary. be able to.
  • Compound (1) 200 g, microcrystalline cellulose 40 g, and corn starch 40 g were mixed to form a uniform mixed powder, and 15 g of hydroxypropyl cellulose was used as a binder, and wet processing was performed. Granules were prepared by a granulation method.
  • This mixed powder was filled into a No. 1 hard strength tablet at a dose of 300 mg per capsule to obtain a capsule.
  • Compound (6) 200 g
  • mannitol 300 g
  • corn starch 450 g
  • Granules were prepared by a wet granulation method as granules to obtain granules.
  • a powder was prepared by uniformly mixing 400 g of the compound (9) and 1500 g of lactose, and the powder was divided into 100 mg each to obtain a powder.
  • Test Example 1 1 CR male mice (7 weeks old, weighing about 30 g) were tested in groups of 8 to 10 mice. The test drug was prepared at a concentration of 1 OmgZnii by suspending the sample in 5% Arabia gum solution.
  • test drug (10 nilZkg body weight) was orally administered to each group of animals (100 iu / kg body weight), and after standing for 60 minutes, a 0.3% carbon tetrachloride oil solution (10 ml Zkg body weight) was orally administered.
  • a 0.3% carbon tetrachloride oil solution (10 ml Zkg body weight) was orally administered.
  • 1% OmlZkg body weight of a 5% arabia gum solution was orally administered to animals in a separate group, and the GPT value of the serum was measured according to the treatment described above.
  • the hepatoprotective effect was determined based on the rate of inhibition of serum GPT in the control group that increased.
  • test drug 1 OmlZkg body weight was orally administered to a separate group of animals (3 OmgZkg body weight) in the same manner as in Test Example 1 except that the test drug was prepared so that the sample concentration was 3 mgZml. In the same manner, the serum GPT value was measured.
  • 1% OmlZkg body weight of a 5% arabia gum solution was orally administered to animals in a separate group, and the GPT value of the serum was measured according to the treatment described above.
  • the hepatoprotective effect was determined based on the rate of inhibition of serum GPT in the control group that increased.
  • the test was conducted with 6 rats of a male Wister line (8 weeks old, weighing about 200 g) in one group.
  • the test sample was suspended in 5% Arabia gum solution to prepare a test drug with a concentration of 10 mgZml.
  • Test drug 5 mlZkg body weight was orally administered to each group of animals (10 OmiZkg body weight), left for 60 minutes and then 10% tetrachloride 5 ml Zkg body weight of carbon oil solution was orally administered.
  • the hepatoprotective effect was determined based on the rate of inhibition of serum GPT in the control group that increased.
  • test drug was prepared at a concentration of 2 O mgZmi by suspending the sample in a 5% arabia gum solution.
  • Test drug 5 ml ZJcg body weight was orally administered to each group of animals (10 O mgZkg body weight), and after standing for 30 minutes, D-galactosamine solubilized in purified water and adjusted to pH 7.0 was added. It was intraperitoneally administered to give 300 mg / kg body weight. After standing for 24 hours, the animals were bled under ether anesthesia, centrifuged, and the GPT value of the serum was measured with a fully automatic biochemical analyzer (Hitachi 710).
  • the hepatoprotective effect was determined based on the rate of inhibition of serum GPT in the control group that increased.
  • test drug so that the concentration of the sample is 10 mg / ml. Except for the test drug, 5 mlZkg body weight is orally administered to each animal in a separate group in the same manner as in Test Example 4 except that the test drug concentration is 10 mg / ml (5 OmgZkg body weight). Thereafter, the same treatment was performed, and the GPT value of the serum was measured.
  • the hepatoprotective effect was determined by the rate of inhibition of serum GPT in the control group that increased. Destroyed- ⁇ rz GPT Uvi iv Jrtb GP Ding up
  • ICR mice Ten ICR mice (5 weeks old, weighing about 25 g) were provided for the test as a group.
  • a specimen containing Compound 16 and Compound 13 was prepared in a 5% arabia gum solution, and 500 mg / kg of the specimen was orally administered to the animals, and the presence or absence of death for 14 days after the administration was observed.
  • the compounds of the present invention represented by formula (I) are useful for treating acute or chronic liver diseases in humans caused by various causes, such as fatty liver, alcoholic hepatitis, toxic liver injury, and depression. It has an excellent effect on the treatment of blood liver, cholestatic liver injury or cirrhosis which is the terminal image thereof, and the therapeutic agent of the present invention containing a compound represented by the formula (I) as an active ingredient has been described above. It can be used as a therapeutic agent for liver diseases.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Agent thérapeutique contre les maladies du foie, contenant un dérivé de l'acide malonique représenté par la formule générale (I) en tant qu'ingrédient actif. Dans la formule, A représente hydrogène, ou un groupe aliphatique inférieur, cycloaliphatique, aromatique ou hétérocyclique éventuellement substitué; R1 représente alcoxy inférieur ou phényle halogéné; R2 représente alkyle inférieur; n vaut 0 ou 1.
PCT/JP1991/001700 1990-12-07 1991-12-07 Agent therapeutique contre les maladies du foie Ceased WO1992010176A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2/400918 1990-12-07
JP40091890 1990-12-07

Publications (1)

Publication Number Publication Date
WO1992010176A1 true WO1992010176A1 (fr) 1992-06-25

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PCT/JP1991/001700 Ceased WO1992010176A1 (fr) 1990-12-07 1991-12-07 Agent therapeutique contre les maladies du foie

Country Status (1)

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WO (1) WO1992010176A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0741320A1 (fr) * 1995-05-04 1996-11-06 Du Pont De Nemours (Deutschland) Gmbh Matériau photothermographique d'enregistrement sensible à la lumière à gradation élevée

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6144866A (ja) * 1984-07-18 1986-03-04 バイエル・アクチエンゲゼルシヤフト キノロン−及びナフチリドン−カルボン酸の製造方法
JPS61282365A (ja) * 1985-06-07 1986-12-12 バイエル・アクチエンゲゼルシヤフト １−アリ−ル−４−シアノ−５−ハロゲノピラゾ−ル類
JPS63165367A (ja) * 1986-12-17 1988-07-08 バイエル・アクチエンゲゼルシヤフト 置換ピラゾリン−５−オン誘導体およびその用途
JPH0158163B2 (fr) * 1982-06-16 1989-12-11 Daiichi Seiyaku Kk

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0158163B2 (fr) * 1982-06-16 1989-12-11 Daiichi Seiyaku Kk
JPS6144866A (ja) * 1984-07-18 1986-03-04 バイエル・アクチエンゲゼルシヤフト キノロン−及びナフチリドン−カルボン酸の製造方法
JPS61282365A (ja) * 1985-06-07 1986-12-12 バイエル・アクチエンゲゼルシヤフト １−アリ−ル−４−シアノ−５−ハロゲノピラゾ−ル類
JPS63165367A (ja) * 1986-12-17 1988-07-08 バイエル・アクチエンゲゼルシヤフト 置換ピラゾリン−５−オン誘導体およびその用途

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0741320A1 (fr) * 1995-05-04 1996-11-06 Du Pont De Nemours (Deutschland) Gmbh Matériau photothermographique d'enregistrement sensible à la lumière à gradation élevée

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