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WO1990006920A1 - Derive de vinylthiazole et antagoniste de leucotriene le contenant en tant qu'ingredient actif - Google Patents

Derive de vinylthiazole et antagoniste de leucotriene le contenant en tant qu'ingredient actif Download PDF

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Publication number
WO1990006920A1
WO1990006920A1 PCT/JP1989/001273 JP8901273W WO9006920A1 WO 1990006920 A1 WO1990006920 A1 WO 1990006920A1 JP 8901273 W JP8901273 W JP 8901273W WO 9006920 A1 WO9006920 A1 WO 9006920A1
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WO
WIPO (PCT)
Prior art keywords
group
carbon atoms
hydrogen atom
atom
active ingredient
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Application number
PCT/JP1989/001273
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English (en)
Japanese (ja)
Inventor
Yoshio Hayashi
Tomei Oguri
Rikizo Furuya
Masaki Shinoda
Harumi Nouka
Noboru Yamada
Original Assignee
Mitsubishi Kasei Corporation
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
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Application filed by Mitsubishi Kasei Corporation filed Critical Mitsubishi Kasei Corporation
Publication of WO1990006920A1 publication Critical patent/WO1990006920A1/fr

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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
    • C07D277/22—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2

Definitions

  • the present invention relates to a specific vinyl thiazole derivative and a pharmaceutically acceptable salt thereof, and an oral icotriene antagonist containing the compound as an active ingredient.
  • Disodium chromoglycate [The Merck Index, 9th edition, 2585 (1976)] and tranilast [Nihon Pharmaceutical Journal, 74, 699 (1978)] are representative drugs belonging to the former.
  • the latter include drugs that antagonize histamine, which is one of the mediators of the allergic reaction, such as diphenhydramine, chlorfeniramine, astemizol, terfenadine, and clemastine. are well known.
  • R 1 represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms
  • R 2 and R 3 each independently represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, It may have an alkoxyl radical or a substituent.
  • n represents an integer of 2 to 5. It has been found that the thiazole derivative represented by ⁇ and a pharmaceutically acceptable salt thereof have a leukotriene antagonistic activity (Japanese Patent Application Laid-Open No. 62-142168). IC 50 values are Atsuta in about 10 ⁇ 5 ⁇ in in vitro.
  • the present inventors have searched for a compound that has a stronger leukotriene anti-action and is effective as a therapeutic agent for various diseases caused by oral triene, and as a result, the present invention relates to a novel compound having an X-substituted carboxyl group.
  • the present inventors have found that a vinylthiazole derivative has an excellent leukotriene antagonistic effect, and have completed the present invention.
  • the present invention has the following general formula (I):
  • R 1 represents a hydrogen atom or a straight-chain or branched alkyl group having 1 to 5 carbon atoms
  • R 2 and R 3 each independently represent a hydrogen atom, a carbon atom having 1 to 5 carbon atoms.
  • the forces R 2 and R 3 representing a phenyl group or a phenylalkyl group which may have a substituent on the benzene ring are not simultaneously hydrogen atoms.
  • R 2 and R 3 may be combined to form a cyclopentane ring or a cyclohexene ring.
  • R 4 and R 5 each independently represent a hydrogen atom, a linear or branched alkyl group having 1 to 5 carbon atoms, or a phenyl group which may have a substituent;
  • the range of the compound included in the general formula (I) is not limited by the following specific examples.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 may be a straight-chain or branched alkyl group having 1 to 5 carbon atoms, such as a methyl group, Ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl Group, t-butyl group, n-pentyl group, i-pentyl group, t-pentyl group and the like.
  • Examples of the phenyl group which may have a substituent and the phenylalkyl group which may have a substituent on a benzene ring which may be included in R 2 and R 3 include phenyl, benzyl and phenylethyl.
  • Group, phenylpropyl group, phenylbutyl group, etc., and the substituent on the benzene ring is a lower alkyl group such as methyl group, ethyl group, n-propyl group; chlorine atom, bromine atom, fluorine atom, etc.
  • a lower alkoxy group such as a methoxy group, an ethoxy group or an n-propoxy group; a lower alkoxycarbonyl group such as a methoxycarbonyl group or an ethoxycarbonyl group; a carbonyl group; a hydroxy group; Amino groups; cyano groups; lower acetylamino groups such as acetylamino, propionylamino and the like.
  • Examples of the alkoxy group of rice A 1 to 5 include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy.
  • the alkoxycarbonyl group having 2 to 6 carbon atoms includes methoxycarbonyl group, ethoxycarbonyl group, and n-propoxy group. Reporto, nil group, i-propoxycarbonyl group, n-butoxycarbonyl group, t-butoxycarbonyl group, n-pentyloxycarbonyl group and i-pentyloxycarbonyl group, and the like.
  • acetyl group examples include an acetyl group, a propionyl group, an n-butyryl group, an i-butyryl group, an n-pentanoyl group and an i_pentanoyl group, and an acetylamino group having 2 to 5 carbon atoms.
  • the group examples include an acetylamino group, a propionylamino group, an n-butylylamino group, an i-butyrylamino group, and an n-pentanoylamino group.
  • Examples of the substituent of the substituted phenyl group which may be included in R 4 and R 5 include a halogen atom such as a chlorine atom, a bromine atom and a fluorine atom; a hydroxyl group; a methoxy group, an ethoxy group and an n-propoxy group.
  • a lower alkoxy group such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group and an n-butyl group; a lower alkoxy carboxy group such as a methoxycarbyl group and an ethoxycarbonyl group; A carboxyl group; an amino group; a nitro group; a cyano group; an acetylamino group such as an acetylamino group and a propionylamino group;
  • the vinylthiazole derivative of the present invention is not limited to a specific isomer, but includes all geometric isomers, optical isomers, and mixtures thereof, for example, racemates.
  • the vinylthiazole derivative of the present invention can be synthesized by various methods. For example, it can be synthesized by a synthesis route shown in the following reaction formula-1. Reaction formula-:
  • the vinylthiazole derivative ( la) by reacting the benzaldehyde derivative (II) with 0.8 to 2 equivalents of the 2-methylthiazole derivative (III) and 0.5 to 2 equivalents of the lower fatty acid anhydride to cause a dehydration condensation reaction, the vinylthiazole derivative ( la).
  • Acetic anhydride, propionic anhydride, n-butyric anhydride and the like are used as lower fatty acid anhydrides, and high boiling solvents such as xylene, dimethyl sulfoxide and dimethylformamide can be used as reaction solvents, but none.
  • the reaction may be performed with a solvent.
  • the reaction temperature is room temperature to 250 ° C, preferably 110 to 180 ° C.
  • the vinylthiazole derivative ( Ia) can be converted into a vinylthiazole derivative (Ib ) by hydrolyzing the ester product by a conventional method.
  • This hydrolysis step can be easily carried out in an aqueous organic solvent such as aqueous ethanol using an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, at a temperature within the range of o ° c to the boiling point of the solvent. Can be.
  • the compound (I) of the present invention has a remarkable leukotriene antagonistic action. That is, when the compound of the present invention was tested in vitro for antagonism to SRS using isolated guinea pig ileum, it was found that the compound of the present invention had selective antagonism to SRS even at low concentrations. found. Therefore, the compound of the present invention is useful for various diseases caused by leukotriene, for example, allergic diseases such as asthma, cerebral edema caused by cerebral ischemia, cerebral vasospasm, or angina caused by reduced coronary blood flow. Etc. are effective for prevention and / or treatment.
  • the leukotriene antagonist of the present invention comprises, as an active ingredient, a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, as a solid or liquid pharmaceutical carrier or diluent, that is, an excipient. Included with excipients such as excipients and stabilizers.
  • preferred salts are pharmaceutically acceptable non-toxic salts such as alkali metal salts and alkaline earth metal salts, for example, sodium salts and potassium salts. Examples include um salt, magnesium salt, calcium salt, and aluminum salt.
  • lower alkylamines eg, triethylamine] salts
  • hydroxy lower alkylamines eg, 2-hydroxylethylamine, bis- (2-hydroxylethyl) amine, tris ( Hydroxy Methyl) amino acid or N-methyl-D-glucamine] salt
  • cycloalkylamine for example, dicyclohexylamine] salt
  • benzylamine eg, N, N'-dibenzylethylenediamine
  • Suitable non-toxic amine salts such as salts and dibenzylamine salts are likewise preferred.
  • preferred salts include hydrochloride, methanesulfonate, hydrobromide, sulfate, phosphate, fumarate, and succinic acid.
  • Non-toxic salts such as salts. Since these salts are water-soluble, they are most suitable for use as injections.
  • the ratio of the therapeutically active ingredient to the carrier ingredient may be varied between 1% and 90% by weight.
  • the oral triene antagonist may be administered orally in the form of granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions or liquids.
  • it may be administered intravenously, intramuscularly or subcutaneously as an injection. It can also be used in the form of suppositories, nasal drops, eye drops or inhalants, and used as a topical preparation for rectal, nasal, ocular and pulmonary administration. In addition, it may be used as a powder for injection and prepared at the time of use.
  • Pharmaceutical organic or inorganic, solid or liquid carriers or diluents suitable for oral, enteral, parenteral or topical administration can be used to prepare the leukotriene antagonists of the present invention.
  • Liquid preparations for oral administration ie emulsions, syrups, suspensions, liquids And the like include commonly used inert diluents such as water or vegetable oil.
  • the formulation may contain, in addition to the inert diluent, adjuvants such as wetting agents, suspending aids, sweetening agents, flavoring agents, coloring agents or preservatives.
  • Liquid preparations may be included in capsules of absorbable substances such as gelatin.
  • Solvents or suspending agents used in the preparation of parenteral administration preparations include, for example, water, propylene glycol, polyethylene glycol Benzyl alcohol, ethyl oleate, lecithin and the like.
  • Bases used for suppositories include, for example, potato fat, emulsifying potato, laurin fat, witepsol and the like.
  • the preparation method of the preparation may be a conventional method.
  • the clinical dose when used by oral administration, is, for adults, the compound of the present invention for an adult generally in a daily dose of 0.01 to ⁇ OOOmg, preferably 0.01 to: LOOmg. It is more preferable to increase or decrease as appropriate according to the condition, symptom, presence or absence of simultaneous treatment, and the like.
  • the daily dose of the leukotriene antagonist may be administered once a day, divided into two or three times a day at appropriate intervals, or may be administered intermittently.
  • the compound of the present invention When used as an injection, the compound of the present invention is preferably administered continuously or intermittently to adults in a single dose of 0.001 to 100 mg. [Best Mode for Carrying Out the Invention]
  • IRJ infrared absorption spectrum
  • TLC in layer chromatography
  • NMR J nuclear magnetic resonance spectrum
  • the ratio of the solvent described in the column of separation indicates the volume ratio
  • the solvent in the brackets of ⁇ TLC '' indicates the developing solvent
  • ⁇ IRj is measured by the KBr tablet method unless otherwise specified.
  • the unit is cnr 1 , "The solvent in the katakana of NMR J indicates the measuring solvent, and the unit is s ppm.
  • Me, Et, and Pli represent a methyl group, an ethyl group, and a phenyl group, respectively, and 0, m, and p in the column of the substitution position in the tables represent ortho positions, respectively. , Meta position and para position.
  • Table 1 shows that Compound Nos. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 15, 16, 18, 19, 20, 21, and 22 As a result, the title compound was obtained.
  • the terminal ileum of a male Hartley guinea pig weighing 200 to 450 g was excised, the lumen was washed, and the ileum was placed in a 5 ml tissue bath containing a tie solution containing the following components. I installed it.
  • the ingredients are 136 mM sodium chloride, 2.7 mM chloride chloride, 11.9 mM sodium bicarbonate, 1.05 mM magnesium chloride, 1.8 mM calcium chloride, 0.4 mM sodium dihydrogen phosphate.
  • the glucose is 5.6 mM.
  • the temperature of the solution in the bath was maintained at 37 ° C, and aeration was performed with 95% oxygen / 5% carbon dioxide.
  • test drug concentration IC 50
  • results of the aforementioned SHS antagonist with FPL-55712 are also shown in the table.
  • a male Hartley guinea pig weighing 350-500 g was anaesthetized with an airway by a modified method of Konzett-Roessler using an artificial respirator of the herb type under urea under anesthesia. The resistance was measured. LTD 4 0.1 ⁇ : L.0 u g / kg against the increased airway resistance due to intravenous administration of body weight, and shows suppression rate by oral administration of test drug calculated result of () in Table 4.
  • Test compound ⁇ J J "Kanaguchi ⁇ ill half Compound No. Dose (mg / kg body weight) (%)
  • the vinylthiazole derivative of the present invention can be used as a leukotriene antagonist as a leukotriene antagonist, for example, in various diseases involving leukotriene, such as argygic diseases such as asthma, cerebral edema due to cerebral ischemia, cerebral vasospasm or coronary blood flow. It can be used as a preventive and therapeutic agent for angina pectoris due to decrease.
  • diseases involving leukotriene such as asthma, cerebral edema due to cerebral ischemia, cerebral vasospasm or coronary blood flow. It can be used as a preventive and therapeutic agent for angina pectoris due to decrease.

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

Abstract

Dérivé de vinylthiazole représenté par la formule générale (I), ses sels acceptables en pharmacologie, et antagoniste de leucotriène le contenant en tant qu'ingrédient actif. Dans la formule (I) R' représente un atome d'hydrogène ou un groupe alkyle comportant de 1 à 5 C; R2 et R3 représentent chacun un atome d'hydrogène, un groupe alkyle comportant de 1 à 5 C, un groupe phényle pouvant être substitué, ou un groupe phénylalkyle pouvant être substitué sur le noyau benzénique, à condition que R2 et R3 ne représentent pas en même temps des atomes d'hydrogène, ou alors R2 et R3 peuvent être combinés l'un avec l'autre pour former un noyau cyclopentane ou cyclohexane; R4 et R5 représentent chacun un atome d'hydrogène, un groupe alkyle comportant de 1 à 5 C ou un groupe phényle pouvant être substitué, ou alors R4 et R5 sont combinés l'un avec l'autre pour former un groupe butadiénylène, (a) où R?6, R7, R8 et R9¿ représentent chacun un atome d'hydrogène, un atome d'halogène, un alkyle comportant de 1 à 5 C, un alcoxy comportant de 1 à 5 C, carboxyle, un alcoxycarbonyle comportant de 2 à 6 C, un acyle comportant de 2 à 5 C, amino, cyano, un groupe nitro ou acylamino comportant de 2 à 5 C; n est un nombre entier compris entre 0 et 5.
PCT/JP1989/001273 1988-12-22 1989-12-18 Derive de vinylthiazole et antagoniste de leucotriene le contenant en tant qu'ingredient actif WO1990006920A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP63/324470 1988-12-22
JP63324470A JPH02169584A (ja) 1988-12-22 1988-12-22 ビニルチアゾール誘導体およびそれを有効成分とする薬剤

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5296495A (en) * 1991-08-16 1994-03-22 Fujisawa Pharmaceutical Co., Ltd. Thiazolylbenzofuran derivatives and pharmaceutical composition comprising the same
WO2002100812A1 (fr) * 2001-04-20 2002-12-19 Eisai Co., Ltd. Dérivé de l'acide carboxylique et son sel
US7371777B2 (en) 2001-08-17 2008-05-13 Eisai Co., Ltd. Cyclic compound and PPAR agonist

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0219436A2 (fr) * 1985-10-16 1987-04-22 Mitsubishi Kasei Corporation Dérivés thiazoliques et antagoniste leucotrinique comprenant la même chose comme les ingrédients effectifs
EP0287471A2 (fr) * 1987-04-16 1988-10-19 Mitsubishi Kasei Corporation Dérivés de carboxystyrène et médicaments les contenant comme substance active

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0219436A2 (fr) * 1985-10-16 1987-04-22 Mitsubishi Kasei Corporation Dérivés thiazoliques et antagoniste leucotrinique comprenant la même chose comme les ingrédients effectifs
EP0287471A2 (fr) * 1987-04-16 1988-10-19 Mitsubishi Kasei Corporation Dérivés de carboxystyrène et médicaments les contenant comme substance active

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5296495A (en) * 1991-08-16 1994-03-22 Fujisawa Pharmaceutical Co., Ltd. Thiazolylbenzofuran derivatives and pharmaceutical composition comprising the same
WO2002100812A1 (fr) * 2001-04-20 2002-12-19 Eisai Co., Ltd. Dérivé de l'acide carboxylique et son sel
US7544835B2 (en) 2001-04-20 2009-06-09 Eisai R&D Management Co., Ltd. Carboxylic acid derivative and salt thereof
US7371777B2 (en) 2001-08-17 2008-05-13 Eisai Co., Ltd. Cyclic compound and PPAR agonist

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