WO1997003058A1 - Derives de 4-alkylthiazoline - Google Patents

Derives de 4-alkylthiazoline Download PDF

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Publication number
WO1997003058A1
WO1997003058A1 PCT/JP1996/001862 JP9601862W WO9703058A1 WO 1997003058 A1 WO1997003058 A1 WO 1997003058A1 JP 9601862 W JP9601862 W JP 9601862W WO 9703058 A1 WO9703058 A1 WO 9703058A1
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WO
WIPO (PCT)
Prior art keywords
group
methyl
thiazoline
compound
carbon atoms
Prior art date
Application number
PCT/JP1996/001862
Other languages
English (en)
Japanese (ja)
Inventor
Masakazu Sato
Akira Manaka
Keiko Takahashi
Yutaka Kawashima
Katsuo Hatayama
Original Assignee
Taisho 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
Application filed by Taisho Pharmaceutical Co., Ltd. filed Critical Taisho Pharmaceutical Co., Ltd.
Priority to AU63189/96A priority Critical patent/AU6318996A/en
Publication of WO1997003058A1 publication Critical patent/WO1997003058A1/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
    • C07D277/32—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

Definitions

  • the present invention relates to a novel thiazoline derivative having a platelet aggregation inhibitory action.
  • platelet aggregation is caused by the expression of a binding site of fibrinogen on the platelet membrane glycoprotein GPbZma complex by stimulation of various platelet aggregation-inducing substances. Therefore, a compound having an antagonistic effect on the fibrinogen receptor may have a platelet aggregation inhibitory effect.
  • thiazoline derivative having an effect of inhibiting platelet aggregation by having an antagonistic action on fibrinogen receptor
  • An object of the present invention is to provide a compound having an excellent platelet aggregation inhibitory action and exhibiting more favorable oral activity.
  • R 11 and R 12 are each a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, and a cycloalkyl group having 4 to 8 carbon atoms.
  • R 2 1 and R 22 each represent a hydrogen atom or a C 1 -C 6 alkyl group, m and n represents an integer of 1 to 3,
  • A is methylene, carbonylation Le group , Ethylenedioxymethylene group, oxygen atom, sulfur atom, sulfinyl group, sulfonyl group or formula
  • R 31 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a formyl group, an alkanoinole group having 2 to 7 carbon atoms, a phenyl group, or ⁇ an alkyl group having 1 to 6 carbon atoms.
  • R 2 represents an alkyl group having 2 to 6 carbon atoms, an alkyl group having 3 to 6 carbon atoms or a phenyl group
  • R 3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • R 4 represents an alkynole group having 1 to 4 carbon atoms. ] The thiazoline derivative represented by these, and its salt.
  • the “alkyl group” used as itself or as a part of a certain group is a straight-chain or branched one, and examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, and a propyl group.
  • Those having 1 to 6 carbon atoms include those described above, as well as pentyl group, isopentyl group, hexyl group and 2-methyl group. And a pentyl group.
  • cycloalkyl group having 4 to 8 carbon atoms refers to a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
  • Halogen atoms are fluorine, chlorine and bromine atoms.
  • An aralkyl group is an alkyl group having 1 to 3 carbon atoms, the terminal of which is substituted by an aryl group (eg, phenyl, naphthyl, toluyl, etc.), such as benzyl, phenethyl, naphthylmethyl. And the like.
  • Pharmaceutically acceptable salts of the compounds of formula (I) include salts with alkali metals, alkaline earth metals, ammonium, alkylammonium and the like, or mineral acids, carboxylic acids, sulfonic acids and the like. Salt. They include, for example, sodium, potassium, calcium, ammonium, aluminum, triethylammonium, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, monomethyl sulfate.
  • R 3 is a hydrogen atom, preferably compounds wherein R 4 is a methyl group, furthermore R 3 is a hydrogen atom, R 4 is a methyl group, R 2 Is most preferred.
  • the compound of the present invention can be produced, for example, by the following method.
  • the compound of the formula (c) is prepared by the method described in WO 94/02472, pp. 3-4 [alkylation of the thiazoline ring at the 3-position of the compound of the formula ( ⁇ ), hydrolysis at the 5-position and amide Formula (f)
  • R 2 and R 4 have the same meanings as described above, and R 7 represents R 3 other than a hydrogen atom.
  • the compound of the formula (f) can also be produced by converting the substituent at the 5-position of the thiazoline ring, if necessary, using the method described in JP-A-8-99966. Can be built.
  • the compound of formula (f) is reacted with hydrogen sulfide using, for example, a base as a catalyst, or with Na BH 2 S 3 to obtain the compound of formula (g).
  • R 2 , R 4 , R 7 and R 8 are as defined above, or a salt thereof.
  • R 11 and R 12 are as defined above, or a compound represented by the formula (j):
  • the compound of the present invention wherein R 3 is a hydrogen atom or a salt thereof
  • the compound is obtained by hydrolyzing the ester moiety from the compound of the present invention wherein R 3 is an alkyl group having 1 to 6 carbon atoms.
  • General methods such as alkali treatment, mineral acid treatment, and organic acid treatment can be used for ester hydrolysis.
  • the compounds of the present invention in which R 3 is an alkyl group having 1 to 6 carbon atoms can be mutually exchanged by, for example, an acid-catalyzed transesterification reaction.
  • examples of the base include sodium carbonate, carbonated lime, sodium hydrogencarbonate, hydrogenated limestone, sodium hydroxide, hydroxylated limestone, gymnyl sodium, hydrogenated sodium, sodium amide, Alkali metal salts such as tertiary potassium, amines such as triethylamine, diisopropylethylamine and pyridine, sodium acetate, potassium acetate and the like can be used, and mineral acids include, for example, hydrochloric acid and hydrogen bromide.
  • Acids, hydroiodic acid, nitric acid, sulfuric acid, etc., and organic acids include, for example, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like.
  • Reaction solvents include water, methanol, ethanol, isopropyl alcohol, alcohols such as tert-butyl alcohol, ethers such as dioxane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide, pyridine, methylene chloride, chloroform, acetone.
  • a solvent inert to the reaction such as acetic acid or acetic acid, can be used.
  • the compound of formula (I) thus obtained can be used for fibrinogen, fibronectin, vonvig, on the blood fibrinogen receptor (Gp ⁇ b / ma). It inhibits the binding of various adhesive proteins such as LeBrand factor, and has an inhibitory effect on platelet aggregation and adhesion.
  • the compound of the present invention can be used as an agent for preventing and treating ischemic diseases such as thrombosis, cerebral infarction and myocardial infarction, and diseases such as arteriosclerosis.
  • ischemic diseases such as thrombosis, cerebral infarction and myocardial infarction, and diseases such as arteriosclerosis.
  • the compounds of the formula (I) are added with customary extenders, binders, disintegrants, pH regulators, solubilizers, etc. and, according to conventional formulation techniques, into tablets, pills, capsules, It can be prepared into granules, powders, solutions, emulsions, suspensions and the like.
  • the compound of formula (I) can be administered to adult patients in 1 to 10 OmgZ days in several divided doses. This dosage can be adjusted appropriately according to the type of disease, the age, weight, and symptoms of the patient.
  • Test example Oral administration of guinea pig eXViv0 platelet aggregation inhibitory action
  • PPP platelet poor plasma
  • PRP platelet poor plasma
  • the platelet aggregation measurement is based on the method of Born [Born, GVR, Nature, Vol. 194, pp. 927 (1962)], and adenosine diphosphate (Sigma: hereinafter referred to as ADP) as an aggregation-inducing substance.
  • Table 2 shows a list of the compounds synthesized in this example.
  • Example 2 The same operation as in Example 1 (2) was carried out using the 2-amino-4-cyclopropylthiazo-1-yl 5-carbonate methyl hydrochloride obtained in (1) as a raw material, and performing the same operation as in Example 1 (2).
  • Example 3 The same operation as in Example 1 (3) was carried out using 2- (4-cyanobenzoinoleamino) -14-cyclopropylthiazo-1-yl 5-carboxylate obtained in (2) as a raw material.
  • carboxamide as a raw material and performing the same operation as in Example 1 (6)
  • N— (2-methoxycarbonylethyl) —2— [4- (methylthioimidyl) benzoylimino] —3 —Methyl-4-cyclopropyl-3H-thiazoline-5_carboxamide ′ methyl sulfate was obtained.
  • Example 2 Using 2-ethylamino-4-isopropylthiazol-5-carboxylate obtained in (1) as a raw material, the same operation as in Example 1 (2) was carried out to give 2- (4-cyano). Benzoinoleamino) -4-ethylthiazol-1-ethyl 5-carboxylate was obtained.
  • N- (2-Methoxycarbonylethyl) obtained in Example 9 (6) 2- [4- (methylthioimidoyl) benzoylimino] -13-methyl-14-isopropyl-3H-thiazoline-5-carboxamide
  • methylsulfate Using methylsulfate as a raw material, the same operation as in Example 2 was carried out to give N- (2-methoxycarbonylethyl) —2- ⁇ 4-[[4- (pyridine-1-yl) pidazine One 1-yl] Imidyl) Benzo (LUMINO) —3-Methyl-4-isopropyl-3H-thiazoline-15-canoleboxamide “methyl sulfate (Compound 10) was obtained.
  • Example 9 (1) Using ethyl 3-oxoenanoate as a raw material, the same operation as in Example 9 (1) was carried out to obtain 2-ethylamino-4-n-butylthiazolyl-5-potassium ethyl ester.
  • carboxamide as a raw material, the same operation as in Example 1 (5) was carried out to give N— (2-methoxycarbonylethyl) -12- (4-thiocarbamoylbenzoylimino) —3-methyl-4- n-Butyl-3H-thiazoline-5-carboxamide was obtained.
  • Example 13 N— (2-Methoxycarbonylethyl) —2- [4- (methylthioimidoyl) benzoylimino] —3-Methyl-4_n_butyl-3H-thiazoline-5-canoleboxami obtained in (6) Heat a mixture of de-methyl sulfate (1 g), 11- (pyridin-1-yl) piperazine (0.42 g), acetic acid (0.15 ml), and methanol (10 ml) under reflux. The mixture was stirred for 2 hours.
  • Example 9 (1) Using ethyl benzoyl acetate as a raw material, the same operation as in Example 9 (1) was carried out to obtain ethyl 2-amino-4-phenylthiazol-5-carboxylate. Melting point 166 ⁇ 168 ° C
  • Example 3 The same operation as in Example 1 (3) was carried out, using 2- (4-cyanobenzoylamino) 1-4-phenylthiazole-5-potassium ruethyl acrylate obtained in (2) as a raw material.
  • the reaction yielded 2- (4-cyanobenzoinoleimino) -13-methyl-14-phenyl-13H-thiazoline-5-ethyl ethyl ribonate.
  • carboxamide as a raw material and performing the same operation as in Example 1 (6), N- (2-methoxycarbonylethyl) -12_ [4- (methylthioimidoyl) benzoylimino] -13-methyl-4-phenyl (2) 3H-thiazoline-1-5-carboxamide methyl sulfate was obtained.
  • Example 17 N- (2-Methoxycarbonylethyl) 1-2- [4- (methylthioimidoyl) benzoylimino] -13-methyl-4-4-phenyl-3H-thiazoline-1-5- obtained in (6) Using carboxamide methyl sulfate as a raw material, the same operation as in Example 14 was carried out to obtain N— (2-methoxycarbonylethyl) —2— ⁇ 4 — ⁇ [4- (pyridine-1-yl) [Piperazinyl] imidoyl) benzoylimino ⁇ -3-Methyl-4-1-phenyl-3H-thiazoline-5-carboxamide methyl sulfate (Compound 18) was obtained.
  • Example 17 N- (2-Methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -13-methyl-4-4-phenyl-3H-thiazoline-1-5- obtained in (6)
  • a mixture of carboxamide methyl sulfate (1 g), 1-ethylpyrazine (0.28 g), acetic acid (0.14 ml), and methanol (10 ml) was stirred with heating under reflux for 2 hours.
  • the reaction mixture was concentrated under reduced pressure to obtain an oily crude product. This was washed by a decantation method using toluene.
  • Example 17 N— (2-Methoxycarbonylethyl) —2- [4- (methylthioimidoyl) benzoylimino] —3-Methyl-4-phenyl-3H—thiazoline—5-canolepoxamide obtained in (6) Using methyl sulfate and 4-fluorobenzylamine as raw materials, the same operation as in Example 14 was carried out to obtain N- (2-methoxycarbonylylethyl) -12- ⁇ 4- [N- (4-fluorobenzyl)]. Amidino] benzoylimino ⁇ —3-methyl-4-phenyl-3H-thiazoline-5-carboxamide acetate (Compound 21) was obtained.
  • Example 17 N— (2-Methoxycarbonylethyl) —2— [4- (methylthioimidoyl) benzoylimino] —3-Methyl-4-Phenyl-3 Obtained in (6) A mixture of H-thiazoline-5-carboxamide methyl sulfate (1 g), 4-fluoroaniline (0.2 g), and methanol (10 ml) was stirred under heating and reflux for 2 hours.
  • Example 17 N- (2-Methoxycarbonylethyl) —2- [4- (methylthioimidyl) benzoylimino] -13-methyl-4-1-phenyl-3H-thiazoline-5-carboxamide methyl obtained in 7 (6) Using sulfate and 41-anisidine as raw materials, the same operation as in Example 22 was carried out to obtain N- (2-methoxycarbonylethyl) —2- ⁇ 4-1- [N— (4-methoxyphenyl). Amidino] benzoylimino) 1-3-methyl-4-phenyl_3H-thiazoline-5-carboxamide'methyl sulfate (Compound 23) was obtained.
  • reaction mixture was allowed to cool to room temperature, and the precipitated crystals were collected by filtration, washed with acetone, and N- (2-t-butoxycarbonylethyl) —2- [4- (methylthioimidyl) benzoylimino] — 3-Methyl-4-isopropyl-1-H-thiazoline-5-carboxamide hydroiodide was obtained.
  • Example 29 (3) Using the compound obtained in Example 29 (3) and 4-anisidine as raw materials, the same operation as in Example 29 (4) was performed to obtain N— (2-t-butoxycarbonylethyl) 1-2— ⁇ 4- [N- (4-Methoxyphenyl) amidino] benzilimino ⁇ -13-methyl-4-isopropyl-13H-thiazoline-5-carboxamide hydroiodide (Compound 32) was obtained.
  • Example 29 N- (2-t-butoxycarbonylethyl) obtained in (3) —2- [4- (methylthioimidoyl) benzoylimino] —3-methyl-4-isopropyl- 3 H-thiazoline-5 _Carboxamide 'Hydroiodide 1 g (1.58 mmol) n-Butylamine 0.173 g (2.37 mmol) and acetone 10 ml mixture are stirred under heating and reflux for 5 hours did.
  • Example 29 N_ (2-t-butoxycarbonylethyl) 1-2- [4- (methylthioimidoyl) benzoylimino] —3-methyl-4--4-isopropyl-3H-thiazoline-5-carboxamide obtained in (3) ⁇
  • the following compounds were obtained in the same manner as in Example 31, except that the hydroiodide and the corresponding amine were used as raw materials.
  • Example 29 N— (2-t-butoxycarbonylethyl) obtained in (3) —2- [4- (methylthioimidoyl) benzoylimino] -13-methyl-4-isopropyl-3H-thiazoline _ 5 _
  • Carboxamide 'hydroiodide 0.8 g (l. 26 mmo 1), dimethylamine hydrochloride 0.16 g (1.90 mmo l), sodium acetate
  • 0.16 g (l. 9 Ommo 1) of thorium, lm 1 of methanol and 9 m 1 of acetone was stirred for 1 hour while heating under reflux.
  • Example 35 The same operations as in Example 35 were carried out using Compounds 32 to 46 as raw materials, to obtain the following compounds.

Abstract

L'invention a pour but d'obtenir des composés ayant un excellent effet d'inhibition de l'agglutination plaquettaire et une bonne activité perorale. A cet effet, l'invention a pour objet des dérivés de thiazoline représentés par la formule générale (I) et des sels de ceux-ci, formule dans laquelle R1 est représenté par la formule (II), où R?11 et R12¿ représentent chacun hydrogène, alkyle, alcoxy-carbonyle, cycloalkyle, phényle éventuellement substitué ou aralkyle éventuellement substitué; ou par la formule (III), dans laquelle R?21 et R22¿ représentent chacun hydrogène ou allyle; m et n représentent chacun un nombre entier de 1 à 3; et A représente méthylène, carbonyle, éthylènedioxyméthylène, oxygène, soufre, sulfinyle, sulfonyle; ou par la formule (IV); ou bien représente une imidazolin-2-yle; R2 représente hydrogène ou alkyle; et R4 représente alkyle.
PCT/JP1996/001862 1995-07-07 1996-07-05 Derives de 4-alkylthiazoline WO1997003058A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU63189/96A AU6318996A (en) 1995-07-07 1996-07-05 4-alkylthiazoline derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP7/171893 1995-07-07
JP17189395 1995-07-07

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WO1997003058A1 true WO1997003058A1 (fr) 1997-01-30

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006137527A1 (fr) 2005-06-23 2006-12-28 Kyowa Hakko Kogyo Co., Ltd. Dérivé du thiazole
JP2009541367A (ja) * 2006-06-27 2009-11-26 インスティテュート オブ ファーマコロジー アンド トキシコロジー アカデミー オブ ミリタリー メディカル サイエンシス ピーエルエイ ２，４，５−三置換チアゾール化合物、それを含有する医薬組成物、並びにその調製及び医学的使用
US7718808B2 (en) 2003-12-26 2010-05-18 Kyowa Hakko Kirin Co., Ltd. Thiazole derivatives

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994002472A1 (fr) * 1992-07-15 1994-02-03 Taisho Pharmaceutical Co., Ltd. Derive de thiazoline
JPH07206860A (ja) * 1994-01-14 1995-08-08 Taisho Pharmaceut Co Ltd チアゾリン誘導体
JPH07242647A (ja) * 1994-01-14 1995-09-19 Taisho Pharmaceut Co Ltd チアゾリン誘導体
JPH07242626A (ja) * 1993-11-25 1995-09-19 Lab Del Dr Esteve Sa 胃酸分泌抑制剤及び抗潰瘍剤
JPH07242645A (ja) * 1994-01-14 1995-09-19 Taisho Pharmaceut Co Ltd ３−アリールチアゾリン誘導体
WO1995034543A1 (fr) * 1994-06-13 1995-12-21 Taisho Pharmaceutical Co., Ltd. Derive de thiazoline
JPH0859641A (ja) * 1994-08-24 1996-03-05 Taisho Pharmaceut Co Ltd ２−シクロアルキルチアゾリン誘導体
JPH0881450A (ja) * 1994-09-09 1996-03-26 Taisho Pharmaceut Co Ltd チアゾリン誘導体

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994002472A1 (fr) * 1992-07-15 1994-02-03 Taisho Pharmaceutical Co., Ltd. Derive de thiazoline
JPH07242626A (ja) * 1993-11-25 1995-09-19 Lab Del Dr Esteve Sa 胃酸分泌抑制剤及び抗潰瘍剤
JPH07206860A (ja) * 1994-01-14 1995-08-08 Taisho Pharmaceut Co Ltd チアゾリン誘導体
JPH07242647A (ja) * 1994-01-14 1995-09-19 Taisho Pharmaceut Co Ltd チアゾリン誘導体
JPH07242645A (ja) * 1994-01-14 1995-09-19 Taisho Pharmaceut Co Ltd ３−アリールチアゾリン誘導体
WO1995034543A1 (fr) * 1994-06-13 1995-12-21 Taisho Pharmaceutical Co., Ltd. Derive de thiazoline
JPH0859641A (ja) * 1994-08-24 1996-03-05 Taisho Pharmaceut Co Ltd ２−シクロアルキルチアゾリン誘導体
JPH0881450A (ja) * 1994-09-09 1996-03-26 Taisho Pharmaceut Co Ltd チアゾリン誘導体

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7718808B2 (en) 2003-12-26 2010-05-18 Kyowa Hakko Kirin Co., Ltd. Thiazole derivatives
US7880013B2 (en) 2003-12-26 2011-02-01 Kyowa Hakko Kirin Co., Ltd. Thiazole derivatives
US8420827B2 (en) 2003-12-26 2013-04-16 Kyowa Hakko Kirin Co., Ltd. Thiazole derivatives
US8889718B2 (en) 2003-12-26 2014-11-18 Kyowa Hakko Kirin Co., Ltd. Thiazole derivatives
EP3002283A1 (fr) 2003-12-26 2016-04-06 Kyowa Hakko Kirin Co., Ltd. Dérivés de thiazole
WO2006137527A1 (fr) 2005-06-23 2006-12-28 Kyowa Hakko Kogyo Co., Ltd. Dérivé du thiazole
JP2009541367A (ja) * 2006-06-27 2009-11-26 インスティテュート オブ ファーマコロジー アンド トキシコロジー アカデミー オブ ミリタリー メディカル サイエンシス ピーエルエイ ２，４，５−三置換チアゾール化合物、それを含有する医薬組成物、並びにその調製及び医学的使用

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