WO1994005274A1 - Inhibiteur de glycosylation - Google Patents

Inhibiteur de glycosylation Download PDF

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Publication number
WO1994005274A1
WO1994005274A1 PCT/JP1993/001249 JP9301249W WO9405274A1 WO 1994005274 A1 WO1994005274 A1 WO 1994005274A1 JP 9301249 W JP9301249 W JP 9301249W WO 9405274 A1 WO9405274 A1 WO 9405274A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
carbon atoms
diabetic
furosine
ascochlorin
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/JP1993/001249
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English (en)
Japanese (ja)
Inventor
Tomoyoshi Hosokawa
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.)
Immuno Japan Inc
Original Assignee
Immuno Japan Inc
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 Immuno Japan Inc filed Critical Immuno Japan Inc
Publication of WO1994005274A1 publication Critical patent/WO1994005274A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/12—Ketones
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a drug containing ascochlorin represented by the general formula (I) and one or more active ingredients thereof. More specifically, the present invention relates to a therapeutic agent for diabetic complications due to inhibition of gligation, in particular, diabetic neuropathy, diabetic nephropathy, and diabetic retinopathy.
  • diabetes The complications of diabetes are not characteristic of diabetes, but are high in macroangiopathies that occur at a high rate and microangiopathies characteristic of diabetes, i.e., diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy. Separated. It is even said that diabetes is not a terrible disease without complications, and the severity of diabetes cannot be described by variable blood sugar levels. Sakamoto questioned, "Can blood glucose control prevent diabetic complications?"
  • diabetic nephropathy has little involvement in tubular function, and No improvement in autonomic nervous function was observed in diabetic retinopathy.
  • diabetic retinopathy there was no improvement in a single dose of Insulin 1 and there were many cases of deterioration, and even in the insulin frequent injection group. He reported that there were more cases of worsening than improved cases (Takazo Kawamori, “History of Medicine”, 156, 1034, 1991).
  • countermeasures against diabetic complications are the most important issues in diabetes treatment, and development of preventive and therapeutic drugs for diabetic complications is expected.
  • microangiopatii is considered to be polyol.
  • Metabolism and gligation are considered important.
  • aldose reductase is activated under hyperglycemia and sorbitol accumulates in tissues and plays an important role in the development of diabetic neuropathy. Epeltatu is known.
  • no effective therapeutic agent has yet been developed for gligation inhibitors.
  • Glycation is also referred to as the Maillard reaction.
  • Glycated glycated protein is considered to be one of the causes of renal basement membrane thickening. It is believed to be an important cause. Daligation produces a Schiff base by a non-enzymatic binding reaction between a protein and a reducing sugar. Amadori rearranges to produce ketoamine. The reaction so far is considered the early stage of the Maillard reaction. This Amadori compound slowly repeats dehydration and rearrangement, and moves to the late stage of the Maillard reaction. Furosine is known as one of the acid hydrolysates of the early stage compounds, and pentosidine is known as one of the late stage compounds.
  • Furosine has been reported to significantly increase the tissue content of sciatic nerve, kidney, tendon, lens, etc. in diabetic patients and experimental diabetic model animals (Volgt. “Diabetes”, 31, 1123). , 1982, Shogo Masuda, "Diabetes", 34, 576, 1991). Bentocidin has been reported to increase the skin collagen and lens tissue content of diabetic patients (Monnier. Proc. Natl. Acad. Sci., 81, 583, 1984, Sel l. "J. CI inn. Invest.”, 85, 380, 1990).
  • a gligation inhibitor is considered to be useful as a prophylactic and therapeutic agent for diabetic complications, but no effective gligation inhibitor has been developed so far.
  • the present invention inhibits gligation and reduces the accumulation of glycated proteins in tissues, and is intended to be useful for the prevention and treatment of diabetic complications, specifically, diabetic neuropathy, diabetic nephropathy, and diabetic retinopathy. Stuff.
  • the present invention relates to a glycation inhibitor comprising an ascochlorin derivative represented by the general formula (I) as an active ingredient.
  • R is a hydrogen atom, — (C IntelH 2n ) — R ′ (n is an integer of 1 to 5, R ′ is a hydrogen atom or a group substituted by one of n carbon atoms COOR” Wherein R "represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms), or —CO R '''(R''' is a pyridyl group, an amino group substituted with 1 to 3 carbon atoms) Group, a phenyloxyalkyl group having a halogen atom in the nucleus or a phenyl group having an alkoxy group having 1 to 3 carbon atoms or an alkoxycarbonyl group having 1 to 3 carbon atoms in the nucleus) Is shown.
  • Ascochlorin is an antibiotic found by the present inventors in the product of the filamentous fungus Ascochytavisiae (see Patent No. 585252). Regarding its derivatives, the production method and blood sugar lowering action And Japanese Patent Publication No. 3-6138. The present inventor studied the inhibitory effect of glycation, which is deeply involved in diabetic complications, relatively independently of the hyperglycemic state, on linseed and its derivatives. Excellent gligation inhibitory action of the compound represented by the general formula (I) was found in in vivo and in vitro experiments.
  • R represents an alkyl group having 1 to 3 carbon atoms and the number of carbon atoms is 3, it may be any of an n-propyl group and an isopropyl group.
  • R ′ is —CO R ′ ′′ and R ′ ′′ is a pyridyl group
  • the substitution position of CO on the pyridyl ring may be any of the 2-, 3-, and 4-positions .
  • R ′ ′′ is an amino group substituted with an alkyl group having 1 to 3 carbon atoms, it may be either monoalkyl-substituted or alkyl-substituted.
  • R ′ ′′ has 3 carbon atoms
  • n— Either a propyl group or an isopropyl group may be used.
  • R ''' is a phenoxyalkyl group having a halogen atom in the nucleus
  • the halogen atom is selected from F, C1, B and I, and the number of halogen substituents is 1 to 3.
  • the position of the substituent may be any position.
  • the alkyl group in the phenoxyalkyl group has 1 to 5 carbon atoms, and may be linear or branched.
  • R ′ ′ ′ is a phenyl group having an alkoxy group having 1 to 3 carbon atoms or an alkoxycarbonyl group having 1 to 3 carbon atoms in the nucleus
  • R ′ ′ ′ is a phenyl group having an alkoxy group having 1 to 3 carbon atoms or an alkoxycarbonyl group having 1 to 3 carbon atoms in the nucleus
  • the number of carbon atoms is 3
  • an n-propyl group Or the isopropyl group, and the substitution position of the alkoxy group or the alkoxycarbonyl group on the phenyl ring may be any.
  • Representative compounds among the compounds represented by the general formula (I) are shown below.
  • a ketoamine of the present invention a reaction solution containing bovine serum albumin and glucose was used as an in vitro experiment. Ascochlorin and its derivative were added and cultured for a long period of time, and the amount of furosine was measured, and as an in ViVo experiment, ascochlorin derivative 410-carboxymethylascochlorin was added to streptozotocin glycourea rats. AS-6) was administered for 1 month, and the amount of furosine in each tissue was measured.
  • ascochlorin and its derivatives were added to a reaction solution containing ribose, arginine, and lysine, and cultured for 4 or 8 days, and the amount of pentosidine was measured.
  • ascochlorin and its derivatives inhibited the production of furosine and pentosidine, and showed an inhibitory effect on the gligation reaction. This will prevent ascochlorin and its derivatives against diabetic complications such as diabetic neuropathy, diabetic nephropathy, and diabetic retinopathy. A therapeutic effect is expected.
  • the dose of the medicament of the present invention varies depending on the type of disease state, symptoms, etc., for example, 5 to 100 mg per adult per day for injection, 30 to 3000 mg for oral administration, 50 to 50 mg for suppositories.
  • the goal can be achieved with 100 Omg.
  • the compound of the present invention may be used alone, but it is usually neutralized with water and dissolved in water, or mixed with a suspension, excipient or other adjuvant for parenteral administration. It is preferable to formulate a dosage form suitable for oral administration.
  • Preferred preparations include, for example, injections, powders, granules, tablets, dragees, pills, capsules, suppositories, and the like.
  • preparations may be prepared in a conventional manner, for example, as an excipient or adjuvant, lactose, sucrose, various starches, glucose, cellulose, methylcellulose, carboxymethylcellulose, magnesium stearate, lauryl sulfate, talc, vegetable oil , Lecithin and a mixture of two or more of these.
  • furosine When measured at 280 nm at a flow rate of 1 m1 in and 7 ml of phosphoric acid as a solvent, furosine was detected at 4.2 minutes after injection, and the amount of furosine was indicated by its area (S. Tadashi, Diabetes, 28, 1 1 19, 19 85) o
  • Pentosidine was quantified by adding ascochlorin and its derivative to a reaction solution containing ribose, arginine, and lysine, and culturing for 4 or 8 days. After completion of the reaction, 101 was injected into a high performance liquid chromatograph. The measurement instrument, column, and solvent were the same as those for the furosine determination, and the detection was measured by fluorescence (EXc. 335 nm, Em. 385 nm). Pentosidine was detected 14 minutes after injection, and the amount of bentosidine was indicated by its area (Gradhee. J. Biol. Chem. 266, 1 1649, 1991).
  • S TZ 55m strebutozotocin (S TZ) on wister rat g / kg intravenously, and at the same time, the animals were fed a 0.1% AS-6 mixed feed for 1 month, and furin was measured in blood and tissues. The results are shown in Table 4.
  • 41-Methylascocrine oral administration improved the subjective symptoms of neurosis over time, and "symptoms" decreased from 12 to 2 after 12 weeks.
  • the compound represented by the general formula (I) exhibits an excellent glycation reaction inhibitory action, it is a prophylactic or therapeutic drug for diabetic complications such as diabetic neuropathy, diabetic nephropathy and diabetic retinopathy.
  • diabetic complications such as diabetic neuropathy, diabetic nephropathy and diabetic retinopathy.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Urology & Nephrology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Un inhibiteur de glycosylation contient au moins un membre choisi parmi ascochlorine et ses dérivés représentés, en tant qu'ingrédients actifs, par la formule générale (I), où R représente hydrogène, -(CnH2n)-R' (où n représente un nombre entier de 1 à 5; R' représente hydrogène ou COOR'' substitué sur l'un ou l'autre des n atomes de carbone; et R'' représente hydrogène ou C1-C3 alkyle), ou -COR''' (où R''' représente pyridyle, amino substitué par un groupe C1-C3, phénoxyalkyle halogéné sur le cycle benzène, ou phényle substitué par C1-C3 alkoxy ou C1-C3 alkoxycarbonyl). Les composés (I) permettent de prévenir ou traiter différentes complications du diabète comme la névrose, la néphopathie et la rétinopathie diabétiques.
PCT/JP1993/001249 1992-09-10 1993-09-03 Inhibiteur de glycosylation Ceased WO1994005274A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP4242051A JPH0816057B2 (ja) 1992-09-10 1992-09-10 グリケイション阻害剤
JP4/242051 1992-09-10

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WO1994005274A1 true WO1994005274A1 (fr) 1994-03-17

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5420334A (en) * 1994-04-04 1995-05-30 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO2000035867A1 (fr) * 1998-12-14 2000-06-22 Nuclear Receptor Research Limited Nouveaux ligands d'un recepteur nucleaire
WO2000053563A1 (fr) * 1999-03-11 2000-09-14 Nuclear Receptor Research Limited Nouveaux ligands de recepteurs nucleaires ppar
WO2003063849A1 (fr) * 2002-01-31 2003-08-07 Arigen, Inc. Composition pharmaceutique destinee au diagnostic, a la prevention ou au traitement d'un syndrome multifactoriel
WO2017119515A1 (fr) * 2016-01-05 2017-07-13 Nrl Pharma, Inc. Dérivé d'ascochlorine et son utilisation comme activateur d'ampk
WO2018216821A1 (fr) * 2017-05-23 2018-11-29 Nrl Pharma, Inc. Utilisation d'un dérivé d'ascochlorine pour une polythérapie
WO2019053159A1 (fr) * 2017-09-15 2019-03-21 Nestec S.A. Composés méroterpénoïdes destinés à être utilisés dans la prévention et le traitement d'un trouble neurologique
US11298358B2 (en) 2017-05-18 2022-04-12 Tatsuo Hoshino Combination therapy using ascochlorin derivative

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1150034C (zh) 1998-08-24 2004-05-19 黑川清 羰基压力改善剂和腹膜透析液
JP4195840B2 (ja) * 2003-07-18 2008-12-17 アークレイ株式会社 メイラード反応阻害剤
JP4553569B2 (ja) * 2003-10-06 2010-09-29 アリジェン製薬株式会社 フェノール系誘導体を有効成分とするクリプトスポリジウム症の予防・治療剤

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0074628A2 (fr) * 1981-09-10 1983-03-23 Chugai Seiyaku Kabushiki Kaisha Dérivés de l'ascochlorin, procédé pour leur préparation et compositions pharmaceutiques les contenant
JPH03291220A (ja) * 1990-04-09 1991-12-20 Chugai Pharmaceut Co Ltd アスコクロリン誘導体を有効成分とするＣａ代謝異常改善剤

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5869860A (ja) * 1981-10-23 1983-04-26 Chugai Pharmaceut Co Ltd アスコクロリン誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0074628A2 (fr) * 1981-09-10 1983-03-23 Chugai Seiyaku Kabushiki Kaisha Dérivés de l'ascochlorin, procédé pour leur préparation et compositions pharmaceutiques les contenant
JPH03291220A (ja) * 1990-04-09 1991-12-20 Chugai Pharmaceut Co Ltd アスコクロリン誘導体を有効成分とするＣａ代謝異常改善剤

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 106, No. 19, Abstract No. 149241u; & ARTERIALSCLEROSIS, Vol. 14, No. 3, p. 609-17, (1986). *
CHEMICAL ABSTRACTS, Vol. 98, No. 9, Abstract No. 65305w; & AGRIC. BIOL. CHEM., Vol. 46, No. 11, p. 2865-9. *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5420334A (en) * 1994-04-04 1995-05-30 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO2000035867A1 (fr) * 1998-12-14 2000-06-22 Nuclear Receptor Research Limited Nouveaux ligands d'un recepteur nucleaire
US6605639B1 (en) 1998-12-14 2003-08-12 Nuclear Receptor Research, Ltd. Ligands of nuclear receptor
WO2000053563A1 (fr) * 1999-03-11 2000-09-14 Nuclear Receptor Research Limited Nouveaux ligands de recepteurs nucleaires ppar
WO2003063849A1 (fr) * 2002-01-31 2003-08-07 Arigen, Inc. Composition pharmaceutique destinee au diagnostic, a la prevention ou au traitement d'un syndrome multifactoriel
WO2017119515A1 (fr) * 2016-01-05 2017-07-13 Nrl Pharma, Inc. Dérivé d'ascochlorine et son utilisation comme activateur d'ampk
US10968186B2 (en) 2016-01-05 2021-04-06 Tatsuo Hoshino Ascochlorin derivative and use thereof as AMPK activator
US11298358B2 (en) 2017-05-18 2022-04-12 Tatsuo Hoshino Combination therapy using ascochlorin derivative
WO2018216821A1 (fr) * 2017-05-23 2018-11-29 Nrl Pharma, Inc. Utilisation d'un dérivé d'ascochlorine pour une polythérapie
WO2019053159A1 (fr) * 2017-09-15 2019-03-21 Nestec S.A. Composés méroterpénoïdes destinés à être utilisés dans la prévention et le traitement d'un trouble neurologique
US11510890B2 (en) 2017-09-15 2022-11-29 Societe Des Produits Nestle S.A. Meroterpenoid compounds for use in the prevention and treatment of a neurological disorder

Also Published As

Publication number Publication date
JPH06305959A (ja) 1994-11-01
JPH0816057B2 (ja) 1996-02-21

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