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WO1990011278A1 - Composes de thiazole et leurs applications - Google Patents

Composes de thiazole et leurs applications Download PDF

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Publication number
WO1990011278A1
WO1990011278A1 PCT/JP1990/000385 JP9000385W WO9011278A1 WO 1990011278 A1 WO1990011278 A1 WO 1990011278A1 JP 9000385 W JP9000385 W JP 9000385W WO 9011278 A1 WO9011278 A1 WO 9011278A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
group
propionic acid
acid
thiazolyl
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/JP1990/000385
Other languages
English (en)
Japanese (ja)
Inventor
Tomokazu Goto
Tadashi Okano
Naoki Sugiyama
Fumihiko Akaboshi
Shinichiro Ono
Yoichiro Naito
Yasunari Yamaura
Chikara Fukaya
Kazumasa Yokoyama
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.)
Mitsubishi Tanabe Pharma Corp
GC Biopharma Corp
Original Assignee
Green Cross Corp Japan
Green Cross Corp Korea
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 Green Cross Corp Japan, Green Cross Corp Korea filed Critical Green Cross Corp Japan
Publication of WO1990011278A1 publication Critical patent/WO1990011278A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • 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
    • C07D277/24—Radicals substituted by oxygen atoms
    • 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
    • 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
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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

Definitions

  • the present invention relates to a novel compound having an anti-inflammatory effect and its use as a pharmaceutical.
  • the present invention has the general formula
  • R 1 and R 2 are the same or different, and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a nitro group, a trifluoromethyl group, a phenyl group, a substituted phenyl group, a pyridyl group.
  • lower ⁇ R 1 and R 2 may form one (CH 2 ) m — (m is 3 to 5) with a sil group, a hydroxyl group, a lower alkoxy group or a lower alkylthio group, and R 3 is a hydrogen atom or R 4 is a hydroxyl group, a lower alkoxy group, or N (R 7 ) (R 8 ) (R 7 and R 8 are the same or different and represent a hydrogen atom or a lower alkyl group);
  • thiazole compound (I) CH (R 3 ) C 0 R 4 only) or a lower alkylthio group] (hereinafter referred to as thiazole compound (I)) or a thiazole compound (I). It relates to pharmacologically acceptable salts.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a thiazole compound, a pharmaceutically acceptable salt thereof, and a carrier.
  • each group means the following.
  • the halogen atom include chlorine, bromine, fluorine, and iodine.
  • the lower alkyl group may be straight-chained or branched, and preferably has 1 to 4 carbon atoms, and specifically includes a methyl group, an ethyl group, Examples include an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, and a t-butyl group.
  • the lower alkenyl group may be linear or branched, and preferably has 2 to 4 carbon atoms, and specifically includes a vinyl group, an isopropenyl group, a 1-propenyl group, Aryl group, 1—methylol 1-butanol group, 2—methylenol 1—propenyl group, 1—methylaryl group, 2—methylaryl group, 1—butyr group, 2-butyr group, 3-butul group and the like.
  • the lower alkoxy group may be linear or branched, and preferably has 1 to 4 carbon atoms, and specific examples include a methoxy group, an ethoxy group, and a propoxy group.
  • the lower alkylthio group may be linear or branched and preferably has 1 to 4 carbon atoms, and specific examples include a methylthio group, an ethylthio group, and a propylthio group.
  • the lower alkoxycarbonyl group may be either straight-chain or branched, and preferably has 1 to 4 carbon atoms, and specifically includes a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxy group. And a carbonyl group.
  • the lower acyl group may be linear or branched and is preferably an alkanol group having 2 to 5 carbon atoms, specifically, an acetyl group, a propionyl group and a butyl group. And a valeryl group.
  • a substituted phenyl group is an amino group, a nitro group or a tri-substituted one or two substituents such as a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group and a lower alkyl group. Fluoromethyl group, etc. Is a furyl group substituted by one or two arbitrary positions.
  • the pyridyl group may be any of a 2-pyridyl group, a 3-pyridyl group and a 4-pyridyl group.
  • the substituted pyridyl group is a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group, an amino group in which one or two lower alkyl groups are substituted, a nitro group, a trifluoromethyl group.
  • viridyl groups having one or two substituents at any positions.
  • the compounds of the present invention include tautomers.
  • R 1 is a hydroxyl group
  • pharmacologically acceptable salts include alkali metal salts (such as sodium salts and potassium salts), alkaline earth metal salts (such as calcium salts), and organic amine salts (such as calcium salts). Pyridin salt and the like).
  • alkali metal salts such as sodium salts and potassium salts
  • alkaline earth metal salts such as calcium salts
  • organic amine salts such as calcium salts
  • Pyridin salt and the like The compound of the present invention is specifically produced by the following production method.
  • Reaction (i) is carried out in an organic solvent such as tetrahydrofuran or hexane for about 100 to 195 for about 0.5 to 2 hours.
  • organic solvent such as tetrahydrofuran or hexane
  • reaction (ii) is carried out in an organic solvent such as tetrahydrofuran for 100- 30 to 5 to 12 hours.
  • reaction (iii) is carried out in an organic solvent such as acetate for about 10 to 10 hours.
  • Reaction (iii) is performed under a hydrogen atmosphere, and acetic acid or the like is used as a solvent. The reaction is carried out at 60 to 80'C for about 10 to 20 hours.
  • Reaction (i) is carried out by adding concentrated hydrochloric acid to acidify, adding sodium nitrite, reacting at 12 to 2'C for about 10 to 60 minutes, and returning to neutrality.
  • reaction (ii) is carried out for about 10 to 60 minutes, and then for about 40 to 50'C for about 1 to 3 hours.
  • Reaction (iii) is carried out in an organic solvent such as dimethylformamide for about 80 to 100 hours and about 1 to 10 hours.
  • Reaction (iv) is preferably performed under a nitrogen atmosphere.
  • the reaction is carried out by heating and refluxing for about 1 to 5 hours in an organic solvent such as ethanol.
  • the thiazole compound (I) of the present invention and a pharmacologically acceptable salt thereof are novel compounds which have not been described in any literature, and are used in mammals such as humans, mice, rats, dogs, mice and rats. It is an industrially useful compound that has excellent pharmacological actions such as analgesic, anti-inflammatory and antipyretic effects, and is a pharmaceutical product such as an analgesic, anti-inflammatory and antipyretic.
  • the thiazole compound (I) and its pharmacologically acceptable salt can be formulated orally or parenterally (injection, rectum, skin) by itself or formulated by a conventional means with a carrier known per se. Administered to
  • Examples of the preparation include tablets, capsules, powders, syrups, suppositories, injections, and skin patches.
  • the dosage of the thiazole compound (I) and its pharmacologically acceptable salt varies depending on the condition, body weight, age, sex, administration route, etc., and is usually 1 to 100 nig, 1 to several times a day. It is administered in divided doses.
  • reaction solution was poured into 5% hydrochloric acid under ice cooling, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the ethyl acetate layer were combined, and the solvent was distilled off to obtain a reaction mixture.
  • the reaction mixture was subjected to silica gel column chromatography (eluent; Purification was carried out by using (formanol-methanol system), and 3.32 g of 1- (4-phenylthiazole-12-ecle) -13- (1-carboxyl) benzyl alcohol was obtained. Obtained at 63%.
  • Example 1 In the same manner as in Example (1), 2-(3-bromofuunyl) pulp bionic acid 4.172 g and 2-formyl 4- 4-phenylthiazole 3.48 5 g of the mixture, and then use the silica gel column chromatographic method. (Eluent; black-form-methanol system) to give a crude product of ⁇ - (4-1-phenylthiazole-2-yl) 13- (1-carboxyshetyl) benzyl alcohol. 3.306 g of the obtained crude benzyl alcohol 2.980 g was dissolved in ether 30 ⁇ in a solution of diazomethane in ether under ice-cooling (0.476). ramol /) 30 drops were dropped.
  • IRV Sl ⁇ cw- 1 3660-3130, 1726, 1225, 1198, 1167, 740, 694
  • IR ⁇ l x r cm- 1 3640-3275, 3275-2750, 1700, 1220, 736, 730, 705, 688
  • IRV Si ⁇ cm- 1 330Q, 3180, 2980 and 2940, 1720, 1620, 805, 700
  • Example 4 (1- (4-phenylthiazol-2-yl)-(1-methoxycarbonylethyl) benzylbenzyl alcohol obtained in Example 1 (1) was used in Example 2 (2 ) To give a hydrogenolysis reaction in the same manner as in) to give methyl 2-([4- (4-phenylthiazole-12-ylmethyl) phenyl] probionate in a yield of 73%.
  • Example 4 (1- (4-phenylthiazol-2-yl)-(1-methoxycarbonylethyl) benzylbenzyl alcohol obtained in Example 1 (1) was used in Example 2 (2 ) To give a hydrogenolysis reaction in the same manner as in) to give methyl 2-([4- (4-phenylthiazole-12-ylmethyl) phenyl] probionate in a yield of 73%.
  • Example 4 (1- (4-phenylthiazol-2-yl)-(1-methoxycarbonylethyl) benzylbenzyl
  • IRVS! ⁇ Cm- 1 1730, 1430, 1370, 1240, 1200, 1170,
  • IRV cm— 1 3200-2700, 1690, 1640, 1570, 1380, 1325,
  • IR 1 / il ⁇ cm- ' 3640-3280, 3200-2800, 1725, 1328, 1293, 1208, 872
  • IR cm ' 1 3150-2150, 1690, 1600, 1482, 1243, 1204.
  • IR or 1 3200-2200, 1900, 1705, 1593, 1540, 1398, 1240, 1220, 1141, 1098, 796
  • Example 13 In the same manner as in Example 9, 2-[[3-methyl-4- (2-thiazolyl) phenyl] propionic acid was prepared.
  • IR on— 1 3000-2500, 1705, 1450, 1340, 1305, 1225, 1155
  • IR cm— 1 3500-2300, 3080-2960, 2910, 1708, 1661, 1587, 1460, 1369, 1327, 1232, 1055: 932, 844, 800
  • Example 26 to 39 The following compounds of the present invention were prepared in a similar manner.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

Composés de thiazole et leurs sels acceptables en pharmacologie, présentant d'excellentes propriétés analgésiques, anti-inflammatoires et antipyrétiques, représentés par la formule générale (I), dans laquelle R1 et R2 représentent chacun indépendamment hydrogène, alkyle, alcényle, nitro, CF¿3?, phényle substitué, pyridyle, pyridyle substitué, carboxyle, alkoxycarbonyle, -CONR?5R6 (où R5 et R6¿ représentent chacun hydrogène ou alkyle), acyle, hydroxy, alkoxy ou thioalkyle, ou alors R1 et R2 sont combinés entre eux pour former -(CH¿2?)m- (où m est compris entre 3 et 5); R?3¿ représente hydrogène ou alkyle; R4 représente hydroxy, alkoxy ou -NR?7R8 (où R7 et R8¿ représentent chacun hydrogène ou alkyle); X représente carbonyle ou -(CH¿2?)n- (où n vaut 0 ou 1); et Y représente hydrogène, halogène, alkyle, nitro, CF3, -NR?9R10 (où R9 et R10¿ représentent chacun hydrogène ou alkyle), hydroxy (uniquement lorsque la position de X est para par rapport au groupe CHR3COR4), alkoxy (uniquement lorsque la position de X est para par rapport au groupe CHR3COR4), ou alkylthio.
PCT/JP1990/000385 1989-03-24 1990-03-22 Composes de thiazole et leurs applications Ceased WO1990011278A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP7224489 1989-03-24
JP1/72244 1989-03-24
JP20545889 1989-08-08
JP1/205458 1989-08-08

Publications (1)

Publication Number Publication Date
WO1990011278A1 true WO1990011278A1 (fr) 1990-10-04

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ID=26413384

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1990/000385 Ceased WO1990011278A1 (fr) 1989-03-24 1990-03-22 Composes de thiazole et leurs applications

Country Status (1)

Country Link
WO (1) WO1990011278A1 (fr)

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS47784A (fr) * 1970-06-12 1972-01-14
JPS5069075A (fr) * 1973-10-24 1975-06-09
JPS5466674A (en) * 1977-11-08 1979-05-29 Hisamitsu Pharmaceut Co Inc Novel phenylacetic acid derivative
JPS55133366A (en) * 1979-04-05 1980-10-17 Otsuka Pharmaceut Factory Inc Thiazole derivative
JPS5925380A (ja) * 1982-06-30 1984-02-09 Hisamitsu Pharmaceut Co Inc 新規なフエニル酢酸誘導体
JPS5925381A (ja) * 1982-06-30 1984-02-09 Hisamitsu Pharmaceut Co Inc 新規なフエニル酢酸誘導体
JPS59155355A (ja) * 1983-02-21 1984-09-04 Shionogi & Co Ltd ４−チアゾリルオキシ−および４−チアゾリルチオ−フエニル酢酸誘導体の新規製造法
JPS61100575A (ja) * 1984-10-19 1986-05-19 Dai Ichi Seiyaku Co Ltd チアゾ−ル誘導体
JPS62142168A (ja) * 1985-10-16 1987-06-25 Mitsubishi Chem Ind Ltd チアゾ−ル誘導体及びそれを有効成分とするロイコトリエンきつ抗剤
JPS6339868A (ja) * 1986-08-04 1988-02-20 Otsuka Pharmaceut Factory Inc ジ低級アルキルフエノ−ル誘導体

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS47784A (fr) * 1970-06-12 1972-01-14
JPS5069075A (fr) * 1973-10-24 1975-06-09
JPS5466674A (en) * 1977-11-08 1979-05-29 Hisamitsu Pharmaceut Co Inc Novel phenylacetic acid derivative
JPS55133366A (en) * 1979-04-05 1980-10-17 Otsuka Pharmaceut Factory Inc Thiazole derivative
JPS5925380A (ja) * 1982-06-30 1984-02-09 Hisamitsu Pharmaceut Co Inc 新規なフエニル酢酸誘導体
JPS5925381A (ja) * 1982-06-30 1984-02-09 Hisamitsu Pharmaceut Co Inc 新規なフエニル酢酸誘導体
JPS59155355A (ja) * 1983-02-21 1984-09-04 Shionogi & Co Ltd ４−チアゾリルオキシ−および４−チアゾリルチオ−フエニル酢酸誘導体の新規製造法
JPS61100575A (ja) * 1984-10-19 1986-05-19 Dai Ichi Seiyaku Co Ltd チアゾ−ル誘導体
JPS62142168A (ja) * 1985-10-16 1987-06-25 Mitsubishi Chem Ind Ltd チアゾ−ル誘導体及びそれを有効成分とするロイコトリエンきつ抗剤
JPS6339868A (ja) * 1986-08-04 1988-02-20 Otsuka Pharmaceut Factory Inc ジ低級アルキルフエノ−ル誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, No. 65:15362g. *

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