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利拉萘酯

利拉萘酯用途

Liranaftate是鲨烯环氧化酶抑制剂,有抗真菌活性。

利拉萘酯名称

[ CAS 号 ]:
88678-31-3

[ 中文名 ]:
利拉萘酯

[ 英文名 ]:
Liranaftate

[中文别名 ]:

利拉柰酯

[英文别名 ]:

Liranaftatum
Liranaftate
M-732
piritetrate
Liranaftato
Zefnart
Liranaftate (JAN)

利拉萘酯生物活性

[ 描述 ]:

Liranaftate是鲨烯环氧化酶抑制剂,有抗真菌活性。

[ 相关类别 ]:

信号通路 >> 抗感染 >> 真菌

研究领域 >> 感染

[参考文献]

[1]. Oku, Y., et al., [Fungicidal activity of liranaftate against Trichophyton rubrum]. Nihon Ishinkin Gakkai Zasshi, 2002. 43(3): p. 181-7.

[2]. Oku, Y., N. Takahashi, and K. Yokoyama, [Fungicidal activity of liranaftate against dermatophytes]. Nihon Ishinkin Gakkai Zasshi, 2009. 50(1): p. 9-13.

[相关活性小分子]

利拉萘酯物理化学性质

[ 密度 ]:
1.2±0.1 g/cm3

[ 沸点 ]:
462.5±55.0 °C at 760 mmHg

[ 熔点 ]:
98.5-99.5ºC

[ 分子式 ]:
C₁₈H₂₀N₂O₂S

[ 分子量 ]:
328.429

[ 闪点 ]:
233.5±31.5 °C

[ 精确质量 ]:
328.124542

[ PSA ]:
66.68000

[ LogP ]:
5.20

[ 外观性状 ]:
白色结晶固体

[ 蒸汽压 ]:
0.0±1.1 mmHg at 25°C

[ 折射率 ]:
1.642

[ 储存条件 ]:
-20°C Freezer

利拉萘酯毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :: FD3890000

CHEMICAL NAME :: Carbamothioic acid, (6-methoxy-2-pyridinyl)methyl-, O-(5,6,7,8-tetrahydro-2- naphthalenyl) ester

CAS REGISTRY NUMBER :: 88678-31-3

LAST UPDATED :: 199312

DATA ITEMS CITED :: 12

MOLECULAR FORMULA :: C18-H20-N2-O2-S

MOLECULAR WEIGHT :: 328.46

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: >2 gm/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,281,1993

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: >2 gm/kg

TOXIC EFFECTS :: Liver - other changes Blood - changes in spleen Nutritional and Gross Metabolic - weight loss or decreased weight gain

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,281,1993

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: >2 gm/kg

TOXIC EFFECTS :: Skin and Appendages - dermatitis, other (after systemic exposure)

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,281,1993

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >2 gm/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,281,1993

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >2 gm/kg

TOXIC EFFECTS :: Lungs, Thorax, or Respiration - respiratory depression Liver - other changes Skin and Appendages - hair

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,281,1993

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >2 gm/kg

TOXIC EFFECTS :: Skin and Appendages - dermatitis, other (after systemic exposure)

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,281,1993

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: >2 gm/kg

TOXIC EFFECTS :: Skin and Appendages - dermatitis, other (after systemic exposure)

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,281,1993 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 5824 mg/kg/26W-I

TOXIC EFFECTS :: Blood - changes in serum composition (e.g. TP, bilirubin, cholesterol) Blood - changes in leukocyte (WBC) count Biochemical - Metabolism (Intermediary) - lipids including transport

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,287,1993

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 819 mg/kg/26W-I

TOXIC EFFECTS :: Endocrine - changes in thymus weight Biochemical - Metabolism (Intermediary) - other proteins Related to Chronic Data - changes in prostate weight

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,287,1993 ** REPRODUCTIVE DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Subcutaneous

DOSE :: 3300 mg/kg

SEX/DURATION :: female 7-17 day(s) after conception

TOXIC EFFECTS :: Reproductive - Specific Developmental Abnormalities - musculoskeletal system

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,376,1993

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Subcutaneous

DOSE :: 7800 mg/kg

SEX/DURATION :: female 17-21 day(s) after conception lactating female 21 day(s) post-birth

TOXIC EFFECTS :: Reproductive - Maternal Effects - other effects Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain) Liver - changes in liver weight

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,402,1993

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Subcutaneous

DOSE :: 6500 mg/kg

SEX/DURATION :: female 6-18 day(s) after conception

TOXIC EFFECTS :: Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Effects on Embryo or Fetus - fetal death

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,422,1993

利拉萘酯安全信息

[ RTECS号 ]:
FD3890000

利拉萘酯制备

主要有四种合成路线和方法:其一是将5,6,7,8-四氢-2-萘酚与N-(6-甲氧基-2-吡啶基)-N-甲基硫代氨基甲酰氯缩合;其二是6-甲氧基-2-甲氨基吡啶与5,6,7,8-四氢-2-萘氧硫酰氯缩合;其三是将N-(6-甲氧基-2-吡啶基)-N-甲基二硫代氨基甲酸钠与2-(2,4-二硝基苯氧基)-5,6,7,8-四氢萘缩合;其四是将中间体N-(6-甲氧基-2-吡啶基)-N-甲基二硫代氨基甲酸-2,4-二硝基苯酯与5,6,7,8-四氢-2-萘酚缩合.推荐方法二的合成方法和路线.

(1).6-甲氧基-2-甲氨基吡啶的制备

在1L的不锈钢高压釜中加入2,6-二氯吡啶270g(1.82mol)、30%甲胺水溶液567g(含甲胺170g)(5.48mol),密闭高压釜,开搅拌升温至135~140 ºC反应3 ~4h,反应过程中釜内压力约为0.8~1.3Mpa.反应毕,冷至60 ºC,加入48%的溶液92ml,加热至100 ºC保持2h.以便除去过量的甲胺(可回收甲胺98%).再将其冷至50 ºC以下,将混合物转移至2L分液漏斗,用苯(270ml*3)提取,合并有机层,用饱和食盐水洗涤,无水Na2SO4干燥,过滤,滤液浓缩除苯,冷至50 ºC加入140ml无水甲醇,得6-氯-2-甲氨基吡啶的甲醇溶液.

在1L高压釜加入6-氯-2-甲氨基吡啶的甲醇溶液和新鲜制备的甲醇钠187g(3.46mol),密闭反应釜#搅拌升温至145~150ºC,保温反应4h(釜内压力大约为1MPa).反应毕,冷至50ºC,加水430ml,剩余物用氯仿(100ml×4)提取,合并氯仿层,减压蒸除氯仿,得油状物6-甲氧基-2-甲氨基吡啶213g,收率84%左右,无需进一步纯化,直接用于下步反应.

(2)5,6,7,8-四氢-2-萘氧硫酰氯的制备

在反应瓶中加入硫光气(纯度95%)12.7g(0.105mol),四氯化碳75ml,搅拌,冰水浴冷却到5 ºC

以下,于1.5~2h内滴加5,6,7,8-四氢-2-萘酚[14.8g(0.100mol)]的NaOH(2mol/L,50ml)溶液,控制滴加过程温度5~6 ºC,滴毕,继续搅拌反应5~15h(用HPLC跟踪,5,6,7,8-四氢-2-萘酚消失,则反

应达终点).反应毕,将反应混合液用水洗,分相,有机相减压蒸除溶剂,得粗品21.5g,进行真空蒸馏,收集106~112 ºC/39.996Pa馏分,得精制品5,6,7,8-四氢-2-萘氧硫酰氯 18g油状物,收率79.5%(中真空蒸馏收率84%).

(3)利拉萘酯的合成

在反应瓶中加粗制6-甲氧基-2-甲氨基吡啶 19.6g(折合0.128mol)、异丙醇250ml、水100ml、无水K2CO3 29.4g,

于室温下1~1.5h内滴加5,6,7,8-四氢-2-萘氧硫酰氯 41.9g(0.128mol)的异丙醇100ml的溶液.滴毕,继续在室温搅拌反应4~5h,当反应瓶产生多量结晶沉淀时反应终了(一般反应5~6h).加水500ml,充分搅拌则析出大量结晶,过滤,滤饼水洗至中性,抽干,干燥,得粗品50g,用无水乙醇200ml重结晶,过滤,滤饼用少量冰冷乙醇洗涤,抽干,干燥得利拉萘酯 31g,收率73.7%,mp97~99 ºC,纯度99.5~99.8%(HPLC法)。(注意：5,6,7,8-四氢-2-萘酚按文献[27,28]制备.)