Sarpogrelate, 사르포그렐레이트염산염

Sarpogrelate, 사르포그렐레이트염산염

Sarpogrelate

135159-51-2,HYROCHLORIDE

125926-17-2 (free base)

5-HT 2a receptor antagonist

Useful for treating arterial occlusive disease and ischemic heart disease.

Sarpogrelate (Anplag, MCI-9042, LS-187,118) is a drug which acts as an antagonist at the5HT2A[1][2] and 5-HT2B[3] receptors. It blocks serotonin-induced platelet aggregation, and has applications in the treatment of many diseases including diabetes mellitus,[4][5] Buerger’s disease,[6] Raynaud’s disease,[7] coronary artery disease,[8] angina pectoris,[9] andatherosclerosis.[10]

사르포그렐레이트염산염

Sarpogrelate Hydrochloride

C24H31NO6& : 465.97

1-[2-(Dimethylamino)-1-[[2-[2-(3-methoxyphenyl)ethyl]phenoxy]methyl]ethyl hydrogen butanedioate hydrochloride [135159-51-2]

第十六改正日本薬局方(JP16)名称データベース 検索結果

詳細については第十六改正日本薬局方でご確認ください。

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検索キーワード:Sarpogrelate Hydrochloride
検索件数:1

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第十六改正日本薬局方　化学薬品等サルポグレラート塩酸塩 Sarpogrelate Hydrochloride 塩酸サルポグレラート C24H31NO6.HCl : 465.97 [135159-51-2] 本品は定量するとき，換算した脱水物に対し，サルポグレ ラート塩酸塩(C24H31NO6・HCl)98.5～101.0％を含む

Sarpogrelate hydrochloride tablets in 1993 Japan’s first listed under the tradename Anplag, is a 5-HT2 receptor blocker, can inhibit platelet aggregation, inhibition of vascular contraction, has antithrombotic effect and microcirculation. Ulcer indications for the improvement of their chronic arterial occlusive disease caused by pain, and cold ischemic various flu symptoms. -1_ {[2- (3-methoxyphenyl) phenoxy] methyl} succinic acid ethyl ester hydrochloride, the structural formula of sarpogrelate hydrochloride chemical name 2- (dimethylamino)

As follows:

  Journal of Medicinal Chemistry (J.Med.Chem, 1990,33: 1818-1823) published synthetic routes as follows:

  Sarpogrelate hydrochloride drug substance used in the preparation Sarpogrelate hydrochloride tablets needed to achieve acceptable purity, single hetero content must meet the corresponding requirements. US4485258 discloses a synthesis method of the first sarpogrelate hydrochloride, and recrystallized from acetone to obtain, but the experiments show that sarpogrelate hydrochloride poor solubility in acetone, acetone, hydrochloric acid is not suitable as a recrystallization solvent sarpogrelate. CN101239920A disclosed as acetonitrile, propionitrile, 1,4_ dioxane, tetrahydrofuran, dimethyl formamide, dimethyl acetamide, sulfolane, dimethyl sulfoxide or a mixture of more than two kinds thereof with methanol, ethanol, , acetone, ethyl acetate, diethyl ether, diisopropyl ether or the like can be used as the recrystallization solvent sarpogrelate hydrochloride, the purity of the product can reach 98%. And C2-C10 alkanes, C3-C10 ketones, C2-C10 carboxylic acid esters, Cl-ClO halogenated alkanes, aromatic hydrocarbons or aromatic derivative at room temperature to the reflux temperature of the hydrochloric acid solubility is small should not alone sarpogrelate as a recrystallization solvent, sarpogrelate hydrochloride, and water as a recrystallization solvent or an organic solvent, an aqueous 5% or more can not be obtained a high purity product. Existing literature does not mention the issue of a single impurity content control.

J Med Chem1990, 33,(6): PG 1818

The reaction of 2-hydroxy-3′-methoxybibenzyl (I) with epichlorohydrin (II) by means of NaH in DMF gives 2-(2,3-epoxypropoxy)-3′-methoxybibenzyl (III), which by reaction with dimethylamine in refluxing THF yields 2-[3-(dimethylamino)-2-hydroxypropoxy]-3′-methoxybibenzyl (IV). Finally, this compound is treated with succinic anhydride (V) in refluxing THF and with HCl in acetone.

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http://www.google.com/patents/CN103242179A?cl=en

Specific embodiments

Example 1 Preparation of crude sarpogrelate hydrochloride [0019] Example

[0020] 1_ dimethylamino _3- [2- [2- (3_-methoxyphenyl) ethyl] phenoxy] -2-propanol hydrochloride A 250ml 13.7g plus a single-neck flask, then add water 25ml, and stirred to dissolve. With 20% aqueous sodium hydroxide to adjust PH value to 9_14, and extracted with 30ml of toluene, and the organic layer was concentrated to 50 ° C under reduced pressure until no liquid slipped 0 to give a brown oil. Of tetrahydrofuran was added 30g, and stirred to dissolve, butyryl anhydride 4.5g, was heated to reflux with stirring. After the reaction was refluxed for I~4 hours, the reaction was incubated at 40 ° C and concentrated to dryness under reduced pressure; the residue was added ethyl acetate 25g, After stirring to dissolve, the dropwise addition of saturated hydrogen chloride in ethyl acetate solution to adjust PH value to I below, was stirred 50~60min. Centrifugal filtration, was Sarpogrelate hydrochloride crude wet product. 45~55 ° C under reduced pressure (-0.08~-0.1MPa) the residue was dried to less than 0.5% of ethyl acetate to give the crude sarpogrelate hydrochloride 14.7g, yield 86%, HPLC purity 98.6%, largest single heteroatom content of 1.2 %.

Purification of the crude hydrochloride Sarpogrelate Example 2 [0021] Example

[0022] The crude product was sarpogrelate hydrochloride 5g, join butanone 20ml, heated with stirring until dissolved and refluxed 20~30min, cooling to 25~35 ° C, incubated with stirring 40~60min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55~65 ° C and dried under reduced pressure to 24h, to give sarpogrelate hydrochloride 4.6g, yield 92%, HPLC purity of 99.9% and a maximum content of 0.04%, a single hybrid.

Example 3 Purification of the crude hydrochloride Sarpogrelate [0023] Example

[0024] The crude product was sarpogrelate hydrochloride 5g, join butanone 30ml, heated with stirring until dissolved and refluxed 20~30min, cooling to 25~35 ° C, incubated with stirring 40~60min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55~65 ° C and dried under reduced pressure to 24h, to give 4.55 sarpogrelate hydrochloride, yield 91%, HPLC purity 99.7%, largest single matter content of 0.05%.

Example 4 Purification of the crude hydrochloride Sarpogrelate [0025] Example

[0026] The crude product was sarpogrelate hydrochloride 5g, join butanone 40ml, heated with stirring until dissolved and refluxed 20~30min, cooling to 25~35 ° C, incubated with stirring 40~60min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55~65 ° C and dried under reduced pressure to 24h, to give sarpogrelate hydrochloride 4.5g, yield 90%, HPLC purity 99.8%, largest single matter content 0.05%.

Example 5 Purification of the crude hydrochloride Sarpogrelate [0027] Example

[0028] The crude product was sarpogrelate hydrochloride 5g, join butanone 20ml, heated with stirring until dissolved and refluxed 20~30min, cooled slowly with stirring to room temperature, at -10 ° c~o ° c stand for crystallization, filtration, The filter cake was rinsed with a small amount of methyl ethyl ketone to give a white fluffy solid, 55~65 ° C and dried under reduced pressure to 24h, to give the hydrochloride sarpogrelate 4.62g, yield 92.4%, HPLC purity 99.2%, largest single matter content of 0.09%.

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WO-2015008973 NEW PATENT

Method for preparing crystalline form II of sarpogrelate hydrochloride is claimed.  Represents first filing from Dae He Chemical on sarpogrelate, which was developed and launched by Mitsubishi Tanabe Pharma.

References

1. Pertz H, Elz S. In-vitro pharmacology of sarpogrelate and the enantiomers of its major metabolite: 5-HT2A receptor specificity, stereoselectivity and modulation of ritanserin-induced depression of 5-HT contractions in rat tail artery. Journal of Pharmacy and Pharmacology. 1995 Apr;47(4):310-6. PMID 7791029
2. Nishio H, Inoue A, Nakata Y. Binding affinity of sarpogrelate, a new antiplatelet agent, and its metabolite for serotonin receptor subtypes. Archives Internationales de Pharmacodynamie et de Therapie. 1996 Mar-Apr;331(2):189-202. PMID 8937629
3. Muntasir HA, Hossain M, Bhuiyan MA, Komiyama T, Nakamura T, Ozaki M, Nagatomo T. Identification of a key amino acid of the human 5-HT(2B) serotonin receptor important for sarpogrelate binding. Journal of Pharmacological Sciences. 2007 Jul;104(3):274-7. PMID 17609583
4. Pietraszek MH, Takada Y, Taminato A, Yoshimi T, Watanabe I, Takada A. The effect of MCI-9042 on serotonin-induced platelet aggregation in type 2 diabetes mellitus.Thrombosis Research. 1993 Apr 15;70(2):131-8. PMID 8322284
5. Ogawa S, Takeuchi K, Sugimura K, Sato C, Fukuda M, Lee R, Ito S, Sato T. The 5-HT2 receptor antagonist sarpogrelate reduces urinary and plasma levels of thromboxane A2 and urinary albumin excretion in non-insulin-dependent diabetes mellitus patients.Clinical and Experimental Pharmacology and Physiology. 1999 May-Jun;26(5-6):461-4. PMID 10386239
6. Rydzewski A, Urano T, Hachiya T, Kaneko H, Baba S, Takada Y, Takada A. The effect of a 5HT2 receptor antagonist sarpogrelate (MCI-9042) treatment on platelet function in Buerger’s disease. Thrombosis Research. 1996 Dec 15;84(6):445-52. PMID 8987165
7. Igarashi M, Okuda T, Oh-i T, Koga M. Changes in plasma serotonin concentration and acceleration plethysmograms in patients with Raynaud’s phenomenon after long-term treatment with a 5-HT2 receptor antagonist. Journal of Dermatology. 2000 Oct;27(10):643-50. PMID 11092268
8. Satomura K, Takase B, Hamabe A, Ashida K, Hosaka H, Ohsuzu F, Kurita A. Sarpogrelate, a specific 5HT2-receptor antagonist, improves the coronary microcirculation in coronary artery disease. Clinical Cardiology. 2002 Jan;25(1):28-32. PMID 11808836
9. Kinugawa T, Fujita M, Lee JD, Nakajima H, Hanada H, Miyamoto S. Effectiveness of a novel serotonin blocker, sarpogrelate, for patients with angina pectoris. American Heart Journal. 2002 Aug;144(2):E1. PMID 12177659
10. Hayashi T, Sumi D, Matsui-Hirai H, Fukatsu A, Arockia Rani P J, Kano H, Tsunekawa T, Iguchi A. Sarpogrelate HCl, a selective 5-HT2A antagonist, retards the progression of atherosclerosis through a novel mechanism. Atherosclerosis. 2003 May;168(1):23-31. PMID 12732383

SARPOGRELATE

SYSTEMATIC (IUPAC) NAME
4-[2-(dimethylamino)-1-({2-[2-(3-methoxyphenyl)ethyl]phenoxy}methyl)ethoxy]-4-oxobutanoic acid
CLINICAL DATA
AHFS/DRUGS.COM	International Drug Names
LEGAL STATUS	?
IDENTIFIERS
CAS NUMBER	125926-17-2
ATC CODE	None
PUBCHEM	CID 5160
IUPHAR LIGAND	210
CHEMSPIDER	4976
UNII	19P708E787
CHEMBL	CHEMBL52939
SYNONYMS	Sarpogrelate, (-)-4-[1-dimethylamino-3-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]propan-2-yl]oxy-4-oxobutanoic acid
CHEMICAL DATA
FORMULA	C24H31NO6
MOLECULAR MASS	429.506 g/mol

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