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WO2001094326A1 - Nouveaux derives de thiazolidinedione et utilisation de ceux-ci comme medicament - Google Patents

Nouveaux derives de thiazolidinedione et utilisation de ceux-ci comme medicament Download PDF

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Publication number
WO2001094326A1
WO2001094326A1 PCT/JP2001/004469 JP0104469W WO0194326A1 WO 2001094326 A1 WO2001094326 A1 WO 2001094326A1 JP 0104469 W JP0104469 W JP 0104469W WO 0194326 A1 WO0194326 A1 WO 0194326A1
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WO
WIPO (PCT)
Prior art keywords
group
chymase
disease
pharmaceutically acceptable
acceptable salt
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/JP2001/004469
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English (en)
Japanese (ja)
Inventor
Yusuke Sakai
Jun Inoue
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.)
Senju Pharmaceutical Co Ltd
Original Assignee
Senju Pharmaceutical 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
Priority claimed from JP2000170977A external-priority patent/JP2004123536A/ja
Priority claimed from JP2000318511A external-priority patent/JP2004123538A/ja
Application filed by Senju Pharmaceutical Co Ltd filed Critical Senju Pharmaceutical Co Ltd
Priority to AU2001258854A priority Critical patent/AU2001258854A1/en
Publication of WO2001094326A1 publication Critical patent/WO2001094326A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to novel thiazolidinediene derivatives and pharmaceutical uses thereof. These derivatives have chymase inhibitory activity and are useful for the prevention and treatment of various diseases involving chymase.
  • Chymase is one of the neutral serine proteases (about 30 kD), but it is an enzyme that converts angiotensin I to angiotensin 11 in tissues ["Biol. Chem. , 265, 22348 (1990)], it is considered to be involved in the development of heart and circulatory system diseases caused by Anji Taishin 11.
  • chymase has been shown to activate collagen from collagenase to active collagenase, limit the degradation of extracellular matrix, trombin and IG, and promote the release of histamine from mast cells. Biochem. 103, 820 (1988)], chymase is considered to be involved in allergic or inflammatory diseases.
  • chimase in ocular tissues has not yet been fully elucidated, it is involved in regulation of ocular inflammation and allergy, ocular circulation (eye blood flow, aqueous humor circulation) and ciliary muscle. it seems to do. From the above-mentioned widespread action of chymase in vivo, inhibitors of such enzymes are expected to be useful as preventive and therapeutic agents for various diseases.
  • chymase inhibitors conventionally, imidazolidine derivatives (W09604248), acetate amide derivatives (W09809949), triazine sulfone derivatives (JP-A-10-245384), and hydantoin derivatives (JP-A-9-31061) ), Quinazoline derivatives (W09711941), phenol ester derivatives (JP-A-10-87567), thiazine derivatives (EP 0713876), heterocyclic amide compounds (W09633974, WI9818794), peptide compounds (Proc. Natl. Acad ScI. USA, Vol. 92, p. 6738, (1995)], but these compounds have not yet been put to practical use.
  • the present inventors have conducted research for the purpose of developing a novel thiazolidinediene derivative having a chymase inhibitory action.
  • An object of the present invention is to provide a novel thiazolidinedione derivative having an excellent chimase inhibitory action. It is another object of the present invention to provide a method for preventing and treating diseases associated with chimase. Disclosure of the invention
  • the present inventors have conducted intensive studies to achieve the above object, and as a result, have created a novel thiazolidinedione derivative having an excellent chymase inhibitory action, and have further studied to complete the present invention.
  • A represents a carbonyl group or a sulfonyl group
  • R 1 represents a hydrogen or a benzene ring
  • R 2 represents an optionally substituted benzene ring
  • R 3 represents an aromatic hydrocarbon group.
  • A represents a carbonyl group
  • R 1 represents hydrogen
  • a chymase inhibitor comprising the thiazolidinediene derivative or the pharmaceutically acceptable salt thereof according to the above 1 to 3,
  • the medicament according to the above 4 which is a prophylactic or therapeutic agent for a disease associated with chymase.
  • the substituent which may be substituted on the benzene ring represented by is halogen (chlorine, bromine, fluorine, etc.), hydroxyl group, carboxyl group, Examples thereof include an alkyl group which may have a group, an alkoxy group which may have a substituent, and an aromatic ring group which may have a substituent.
  • alkyl group which may be substituted on the benzene ring examples include a linear or branched alkyl group having 1 to 9 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and an isobutyl group.
  • Examples of the substituent which the alkyl group may have include an aryl group such as a phenyl group and a naphthyl group, and a phenyl group is preferable. These aryl groups may further have a substituent such as halogen (chlorine, bromine, fluorine, etc.).
  • Examples of the alkoxy group which may be substituted on the benzene ring include a linear or branched alkoxy group having 1 to 10 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a methoxy group.
  • Examples include a butyloxy group, an octyloxy group, a nonyloxy group, and a decyloxy group, and preferred are alkoxy groups having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group.
  • substituent which the alkoxy group may have include an aryl group such as a phenyl group and a naphthyl group, and a phenyl group is preferable. These aryl groups may further have a substituent such as halogen (chlorine, bromine, fluorine, etc.).
  • aromatic ring groups may be further substituted with a halogen (eg, chlorine, bromine, fluorine, etc.), a hydroxyl group, an alkyl group, an alkoxy group, or the like.
  • substituents which may be substituted on the benzene ring may be substituted at any of 2-, 3- and 4-positions. Further, it may have two or more same or different substituents, and the two or more substituents may be 2, 3-, 2, 4, 1, 2, 5-, 2, 6-, 3,4-, 3,5-disubstituted, 2,3,4-mono, 2,4,6-, 2,3,5-trisubstituted, 2,3,4,5-tetrasubstituted Or 2, 3, 4, 5, 6-pentasubstituted form.
  • a 3,4-disubstituted product is used. Specifically, for example, a 3-ethoxy-14-pentyloxyphenyl group and the like can be mentioned.
  • the aromatic hydrocarbon group represented by R 3 is preferably a group having 6 to 18 carbon atoms, for example, a phenyl group, a naphthyl group, an anthryl group, a phenanthrenyl group, Examples thereof include a naphthacenyl group and a triphenylenyl group, preferably a naphthyl group, and more preferably a 1-naphthyl group or a 2-naphthyl group.
  • the compound of the present invention includes, for example, 5- (3-ethoxy-4-pentyloxyphenyl) -1,3- (2-naphthyl) -1,1,3-thiazolidine-2,4-dione, 5- (3 —Ethoxy 1 4-pentyl xyphenyl) 1 3— (1—Naphthoyl) 1,1,3-thiazolidine—2,4-dione, 5— (3-ethoxy—4_pentyl xy phenyl) 1-3 benzoyl—1,3 _Thiazolidine-1 2,4-diene, 5,5-diphenyl-3- (2-naphthyl) _1,3-Thiazolidine-2,4 dione, 5,5-diphenyl-3- (1 Naphthyl) _ 1,3-thiazolidin -2,4 diene, 5,5-diphenyl-3-(2-naphthylsulfonyl) -1,1,
  • the compound represented by the general formula (I) of the present invention can be produced, for example, by the following production method or according to the method.
  • X represents an octagen atom (chlorine, bromine, fluorine, etc.), and A and R 3 have the same meanings as in the description of the formula (I).
  • R ′ and R 2 are the same as those in the formula (I).
  • the compound represented by (I) can be produced.
  • a reaction can be carried out in a reaction solvent, in an organic solvent and in the presence / absence of an organic base.
  • the reaction solvent that can be used in this reaction include anhydrous methylene chloride, chloroform, N, N-dimethylformamide, benzene, toluene, ethylbenzene, cyclohexane, hexane, heptane, getyl ether, terephthalic acid
  • Conventional solvents that do not adversely affect the reaction such as trihydrofuran (hereinafter sometimes referred to as THF), or a mixed solvent thereof may be used.
  • THF trihydrofuran
  • Preferred is THF or a mixed solvent of THF and N, N-dimethylformamide.
  • Inorganic bases that can be used in this reaction include alkali metal hydrides such as sodium hydride, alkali metal carbonates such as potassium carbonate, and alkali metal bicarbonates such as sodium hydrogen carbonate.
  • Organic bases that can be used in this reaction include trialkylamines such as triethylamine and diisopropylethylamine, pyridine, lutidine, picoline, 4-dimethylaminopyridine and the like. Particularly preferred base used is sodium hydride.
  • Such inorganic and organic bases are preferably used in a ratio of 0.5 to 1.5 mol per 1 mol of the thiazolidinediene derivative represented by the formula (III).
  • the reaction temperature is usually in a range from under cooling to under heating, and preferably in a range from ⁇ 10 ° C. to 30 ° C.
  • Examples of the pharmaceutically acceptable salt of the compound represented by the general formula (I) thus obtained include, for example, alkali metal salts such as sodium salt and potassium salt, and calcium salts.
  • Alkaline earth metal salts such as sodium salt, magnesium salt, etc.
  • salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and acetate, citrate, toluene sulfone
  • Examples thereof include salts with organic acids such as acid salts, but are not limited thereto.
  • the present invention includes various solvates and polymorphs of the compound represented by the general formula (I), and prodrugs thereof.
  • the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof (hereinafter may be abbreviated as the compound of the present invention) has chymase inhibitory activity, so Diseases involving chymase in blood animals (eg monkeys, dogs, cats, cats, guinea pigs, rats), eg heart and cardiovascular diseases (restenosis after vascular injury due to percutaneous transluminal coronary angioplasty, hypertension) Prevention and treatment of diseases, arteriosclerosis, myocardial infarction, cardiac hypertrophy, cardiac insufficiency, diabetic and non-diabetic renal disorders, peripheral circulatory disorders, etc.
  • so Diseases involving chymase in blood animals eg monkeys, dogs, cats, cats, guinea pigs, rats
  • eg heart and cardiovascular diseases restenosis after vascular injury due to percutaneous transluminal coronary angioplasty, hypertension
  • Prevention and treatment of diseases arteriosclerosis, myocardial
  • Macular degeneration Macular degeneration, ischemic optic neuropathy, iridocyclitis, retinal artery occlusion, retinal vein occlusion, diabetic retinopathy, retinal disease Choroidal disease secondary to alteration, and glaucoma
  • It is also used as a regulator of ciliary muscle contraction and relaxation to improve myopia and asthenopia, etc. It is also used for the whole body (e.g., gastrointestinal tract inflammation such as nephritis, hepatitis, pneumonia, and inflammation, atopy, arthritis, rheumatism) and ocular localization.
  • gastrointestinal tract inflammation such as nephritis, hepatitis, pneumonia, and inflammation, atopy, arthritis, rheumatism
  • ocular localization e.g., gastrointestinal tract inflammation such as nephritis, hepatitis, pneumonia, and inflammation, atopy, arthritis, rheumatism
  • It can be appropriately used orally or parent
  • Examples of the form of the preparation of the compound of the present invention include solid preparations such as tablets, granules, powders, capsules and ointments and liquid preparations such as injections and eye drops. Any of the preparations can be appropriately prepared by a known method.
  • These preparations contain commonly used excipients (starch, pudose, fructose, sucrose, calcium phosphate, etc.), binders (starch, acacia, gelatin solution, sodium alginate, carmellose solution, etc.), disintegrants (starch, Calcium carbonate, crystalline cellulose, etc.), Lubricants (stearic acid, magnesium stearate, talc, etc.), Absorption promoters (thin glycolic acid, acetic acid, prillic acid, etc.), Buffering agents (boric acid, boric acid) Sand, sodium acetate, citrate buffer, phosphate buffer, etc.), surfactants (sodium lauryl sulfate, polysorbate 80, poly Oxyethylene hydrogenated castor oil, etc.), solubilizers (sodium lauryl sulfate, sodium benzoate, ethylenediamine, potassium iodide, etc.), preservatives (benzalcodium chloride, parabens, chlorobut
  • PH adjusters hydrochloric acid, citric acid, sodium hydroxide, etc.
  • the dosage depends on the type of disease to be treated, the type of compound used, the age, weight, symptom of the patient and the dosage form thereof. For example, in the case of oral administration, it is better to administer to an adult patient several times a day, about 1 mg to 100 mg per dose. In the case of injections, it is recommended to administer about 0.1 mg to 3 Omg to adult patients once a day.
  • the compound of the present invention when used as a topical ophthalmic dosage form for ocular circulatory disorders, may be used in an amount of about 0.01 w / v% to 1.1 w / v. %, Preferably about 0.05 w / v% to 0.5 w / v%, one to several drops at a time, about 1 to 8 times a day. Even if the disease is local to the eye, it may be administered systemically for the purpose of efficiently reaching the compound to the inner eye such as the retina.
  • the compound of the present invention may be used alone or in an appropriate combination of two or more of the compounds of the present invention, if necessary.
  • the compound of the present invention may be used in an appropriate combination of a chymase-inhibiting component not included in the present invention, another component having the same medicinal properties as the present invention, and other medicinal components, as long as the object of the present invention is not contradicted. it can.
  • Example 2 The same operation as in Example 1 was carried out except that 1-naphthoyl chloride was used instead of 2-naphthoyl chloride, to give the title compound (compound 2) as white crystals (yield 61).
  • Example 3 The same operation as in Example 1 was carried out except that benzoyl chloride was used instead of 2-naphthoyl chloride, to give the title compound (compound 3) as white crystals (yield 9%).
  • Chymase inhibitory activity was measured according to the method of Kato et al. (J. Biochem., 103, 820 (1988)). That is, 2.5 ⁇ L of the test substance dissolved in dimethyl sulfoxide (hereinafter referred to as DMSO) was added to a solution prepared with HEPES buffer so that the enzyme activity of recombinant human chymase (JP-A-10-87567) was 2.3 Units. L, and incubated at 30 ° C for 5 minutes, and added 125 L of 0.6 mM Suc-AIa-AIa-Pro-Phe-MCA (manufactured by Peptide Research Laboratories) / Tris buffer as a substrate. The reaction solution was used.
  • DMSO dimethyl sulfoxide
  • reaction solution was set in a multiwell plate reader CYT0FLU0R Series 4000 (manufactured by Perceptive Biosystems), and the change in fluorescence intensity was measured over time at 30 ° C for 30 minutes (excitation wavelength 360 nm, detection wavelength 450 nm),
  • Control was performed using DMS02.5ALL containing no test substance, and treated and measured in the same manner. Planck added HEP ESS buffer instead of chymase solution, treated similarly, and measured.
  • the chymase inhibition rate (%) was calculated from the change in fluorescence intensity based on the slope of the approximate straight line of the test substance (S), the slope of the approximate straight line of the control (C), the slope of the approximate straight line of Planck of the test substance (Bs), and the control.
  • the slope (Be) of the Planck approximate straight line was calculated from the following equation.
  • Inhibition rate (%) [1 _ (S—Bs) / (C—Bc)] X 100
  • 50% inhibition concentration (IC 5D ) was calculated from the chymase inhibitory activity determined by this method. The results are shown in Table 1. This result indicates that the compound represented by the general formula (I) of the present invention has chymase inhibitory activity.
  • Tablets were formed by a conventional method using the above ingredients as a material for one tablet.
  • the tablets may be coated with a sugar coating and a film (eg, technical cellulose).
  • a film eg, technical cellulose.
  • the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof has excellent chymase inhibitory activity, and therefore has various chymase-related diseases such as systemic and local ocular circulatory system. It is useful as a prophylactic / therapeutic agent for diseases, inflammatory and allergic diseases, and as a regulator of ciliary muscle contraction tone.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Ophthalmology & Optometry (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des nouveaux composés de formule générale (I) ou des sels acceptables sur le plan pharmaceutique de ceux-ci, présentant une activité inhibitrice de la chymase et pouvant être utilisés comme médicaments préventifs et thérapeutiques pour des allergies et des maladies inflammatoires, telles que le glaucome, etc. (Dans la formule (I), A désigne un carbonyle ou un suflonyle; R1 désigne un hydrogène ou un noyau benzénique; R2 désigne un noyau benzénique éventuellement substitué; et R3 désigne un groupe hydrocarbone aromatique).
PCT/JP2001/004469 2000-06-07 2001-05-28 Nouveaux derives de thiazolidinedione et utilisation de ceux-ci comme medicament Ceased WO2001094326A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001258854A AU2001258854A1 (en) 2000-06-07 2001-05-28 Novel thiazolidinedione derivatives and use thereof as drugs

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2000-170977 2000-06-07
JP2000170977A JP2004123536A (ja) 2000-06-07 2000-06-07 フェニルチアゾリジンジオン誘導体およびその医薬用途
JP2000-318511 2000-10-18
JP2000318511A JP2004123538A (ja) 2000-10-18 2000-10-18 ジフェニルチアゾリジンジオン誘導体およびその医薬用途

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WO2001094326A1 true WO2001094326A1 (fr) 2001-12-13

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PCT/JP2001/004469 Ceased WO2001094326A1 (fr) 2000-06-07 2001-05-28 Nouveaux derives de thiazolidinedione et utilisation de ceux-ci comme medicament

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AU (1) AU2001258854A1 (fr)
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0045165A1 (fr) * 1980-07-28 1982-02-03 Ono Pharmaceutical Co., Ltd. Dérivés de rhodanine, leur préparation et inhibiteurs aldose-réductase qui les contiennent
WO2000006594A1 (fr) * 1998-07-28 2000-02-10 Santen Pharmaceutical Co., Ltd. Nouveaux derives de thiazolidine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0045165A1 (fr) * 1980-07-28 1982-02-03 Ono Pharmaceutical Co., Ltd. Dérivés de rhodanine, leur préparation et inhibiteurs aldose-réductase qui les contiennent
WO2000006594A1 (fr) * 1998-07-28 2000-02-10 Santen Pharmaceutical Co., Ltd. Nouveaux derives de thiazolidine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SCHULTE K.E. ET AL.: "Oxazolidindion-derivative und 4-(piperidyl-(4'))-antipyrine als potentiell entzuendungshemmende substanzen", ARCH. PHARM., vol. 313, 1980, WEINHEIM, pages 229 - 237, XP002941755 *

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