利培酮_MSDS_用途_密度_利培酮CAS号【106266-06-2】

Risperidone是 5-HT2 受体的阻断剂,P-糖蛋白 (P-Glycoprotein) 的抑制剂和 dopamine D2 受体的拮抗剂,其对 5-HT2A 和 dopamine D2 受体的 Ki 值分别为 4.8,5.9 nM。

[ 描述 ]:

Risperidone是 5-HT2 受体的阻断剂,P-糖蛋白 (P-Glycoprotein) 的抑制剂和 dopamine D2 受体的拮抗剂,其对 5-HT2A 和 dopamine D2 受体的 Ki 值分别为 4.8,5.9 nM。

[ 相关类别 ]:

信号通路 >> G 蛋白偶联受体/G 蛋白 >> 5-HT受体

信号通路 >> 神经信号通路 >> 5-HT受体

信号通路 >> G 蛋白偶联受体/G 蛋白 >> 多巴胺受体

信号通路 >> 神经信号通路 >> 多巴胺受体

信号通路 >> 跨膜转运 >> P-糖蛋白

研究领域 >> 神经疾病

[ 靶点 ]

5-HT2A Receptor:4.8 nM (Ki)

dopamine D2 receptor:5.9 nM (Ki)

P-Glycoprotein

[体外研究]

利培酮是5-羟色胺5-HT2受体阻断剂,P-糖蛋白抑制剂和有效的多巴胺D2受体拮抗剂,对于5-HT2A和多巴胺D2受体,Kis分别为4.8,5.9nM。利培酮剂量依赖性地抑制成熟DC中IL-12的释放,而IL-10的产生通过利培酮剂量依赖性地增加。高剂量的利培酮可以诱导成熟DC释放TNF-α[3]。

[体内研究]

在第一个实验中,发现作为年龄函数的利培酮治疗大鼠体重略微但显着较低。与第一个实验类似,在第二个运动实验中,在三个治疗组之间也观察到体重的年龄依赖性差异。在出生后第35,38和41天,用3.0mg/kg剂量的利培酮治疗的大鼠比载体治疗的大鼠重量更轻。第三次运动实验涉及较大的混合性窝,与使用的较小的单性窝相比较在前两个实验中。如前两个实验所述,在第三个实验中用利培酮治疗的大鼠以年龄依赖性方式获得较少的体重[4]。

[动物实验]

大鼠[4]使用总共211只Long-Evans大鼠（56只雌性和155只雄性）。在每个研究中，三组大致相等数量的大鼠接受1.0mg / kg利培酮，3.0mg / kg利培酮或用作利培酮溶液的载体作为对照。在第一个实验中，26个雄性大鼠（载体中n = 9和利培酮组3.0mg / kg; 1.0mg / kg利培酮组中n = 8）在出生后每天测试20分钟的运动活性。第49天，每天一直持续到出生后第53天。第二个实验确定早期利培酮治疗的运动效应是否持续到成年期。第三个实验确定了性别对年轻成年大鼠中早期利培酮的运动作用的影响。在该实验中，治疗60只雄性（每个治疗组n = 20）和56只雌性（载体中n = 19只大鼠和3.0mg / kg剂量组，1.0mg / kg剂量组中n = 18）大鼠。第四个实验评估了在给予早期利培酮的大鼠成年期间的逆转学习。对42只雄性大鼠（每个治疗组n = 14）进行治疗[4]。

[参考文献]

[1]. Nyberg S, et al. 5-HT2 and D2 dopamine receptor occupancy in the living human brain. A PET study with risperidone. Psychopharmacology (Berl). 1993;110(3):265-72.

[2]. Zhu HJ, et al. Risperidone and paliperidone inhibit p-glycoprotein activity in vitro. Neuropsychopharmacology. 2007 Apr;32(4):757-64.

[3]. Chen ML, et al. Risperidone modulates the cytokine and chemokine release of dendritic cells and induces TNF-α-directed cell apoptosis in neutrophils. Int Immunopharmacol. 2012 Jan;12(1):197-204.

[4]. Bardgett ME, et al. Adult rats treated with risperidone during development are hyperactive. Exp Clin Psychopharmacol. 2013 Jun;21(3):259-67.

[相关活性小分子]

[ 密度 ]:
1.4±0.1 g/cm3

[ 沸点 ]:
572.4±60.0 °C at 760 mmHg

[ 熔点 ]:
170°C

[ 分子式 ]:
C₂₃H₂₇FN₄O₂

[ 分子量 ]:
410.484

[ 闪点 ]:
300.0±32.9 °C

[ 精确质量 ]:
410.211792

[ PSA ]:
64.16000

[ LogP ]:
2.88

[ 外观性状 ]:
结晶固体

[ 蒸汽压 ]:
0.0±1.6 mmHg at 25°C

[ 折射率 ]:
1.677

[ 储存条件 ]:
Room temp

详细MSDS(安全技术说明书)

CHEMICAL IDENTIFICATION

RTECS NUMBER :: UV1164800

CHEMICAL NAME :: 4H-Pyrido(1,2-a)pyrimidin-4-one, 6,7,8,9-tetrahydro-3-(2-(4-(6-fluoro-1,2-benzisoxazol -3-yl)- 1-piperidinyl)ethyl)-2-methyl-

CAS REGISTRY NUMBER :: 106266-06-2

LAST UPDATED :: 199712

DATA ITEMS CITED :: 13

MOLECULAR FORMULA :: C23-H27-F-N4-O2

MOLECULAR WEIGHT :: 410.54

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Human - man

DOSE/DURATION :: 3428 ug/kg

TOXIC EFFECTS :: Behavioral - hallucinations, distorted perceptions Cardiac - EKG changes not diagnostic of specified effects Nutritional and Gross Metabolic - changes in sodium

REFERENCE :: AEMED3 Annals of Emergency Medicine. (American College of Emergency Physicians, 1125 Executive Circle, Irving, TX 75038) Volume(issue)/page/year: 22,1908,1993

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Human - man

DOSE/DURATION :: 429 ug/kg/15D-I

TOXIC EFFECTS :: Brain and Coverings - changes in surface EEG Behavioral - anorexia (human) Behavioral - alteration of operant conditioning

REFERENCE :: JCLPDE Journal of Clinical Psychiatry. (Physicians Postgraduate Press, Inc., POB 240008, Memphis, TN 38124) V.39- 1978- Volume(issue)/page/year: 58,323,1997

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Human - man

DOSE/DURATION :: 114 ug/kg/2D-I

TOXIC EFFECTS :: Behavioral - wakefulness Behavioral - euphoria Behavioral - excitement

REFERENCE :: AJPSAO American Journal of Psychiatry. (American Psychiatric Assoc., Circulation Dept., 1400 K St., NW, Washington, DC 20005) V.78- 1921- Volume(issue)/page/year: 153,1234,1996

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

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 56600 ug/kg

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

REFERENCE :: JPETAB Journal of Pharmacology and Experimental Therapeutics. (Williams & Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- Volume(issue)/page/year: 244,685,1988

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

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 98 mg/kg

TOXIC EFFECTS :: Sense Organs and Special Senses (Eye) - ptosis Behavioral - somnolence (general depressed activity) Lungs, Thorax, or Respiration - dyspnea

REFERENCE :: KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 27,2991,1993

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

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 34300 ug/kg

TOXIC EFFECTS :: Behavioral - tremor Behavioral - convulsions or effect on seizure threshold Nutritional and Gross Metabolic - body temperature decrease

REFERENCE :: KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 27,2991,1993

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

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 63100 ug/kg

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

REFERENCE :: JPETAB Journal of Pharmacology and Experimental Therapeutics. (Williams & Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- Volume(issue)/page/year: 244,685,1988

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

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 26900 ug/kg

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

REFERENCE :: JPETAB Journal of Pharmacology and Experimental Therapeutics. (Williams & Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- Volume(issue)/page/year: 244,685,1988

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

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 18300 ug/kg

TOXIC EFFECTS :: Behavioral - muscle weakness Lungs, Thorax, or Respiration - respiratory stimulation Gastrointestinal - hypermotility, diarrhea

REFERENCE :: KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 27,2991,1993

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

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 14100 ug/kg

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

REFERENCE :: JPETAB Journal of Pharmacology and Experimental Therapeutics. (Williams & Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- Volume(issue)/page/year: 244,685,1988 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 228 mg/kg/13W-I

TOXIC EFFECTS :: Blood - pigmented or nucleated red blood cells Blood - changes in erythrocyte (RBC) count Nutritional and Gross Metabolic - weight loss or decreased weight gain

REFERENCE :: KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 27,2991,1993

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 2738 mg/kg/1Y-C

TOXIC EFFECTS :: Kidney, Ureter, Bladder - other changes Endocrine - other changes Nutritional and Gross Metabolic - weight loss or decreased weight gain

REFERENCE :: KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 27,2991,1993 ** REPRODUCTIVE DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 110 mg/kg

SEX/DURATION :: female 8-18 day(s) after conception

TOXIC EFFECTS :: Reproductive - Maternal Effects - other effects Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Specific Developmental Abnormalities - musculoskeletal system

REFERENCE :: KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 27,3023,1993

[ 符号 ]:

GHS02, GHS06, GHS08

[ 信号词 ]:
Danger

[ 危害声明 ]:
H225-H301 + H311 + H331-H370

[ 警示性声明 ]:
P210-P260-P280-P301 + P310-P311

[ 个人防护装备 ]:
Eyeshields;Faceshields;Gloves;type P2 (EN 143) respirator cartridges

[ 危害码 (欧洲) ]:
T: Toxic;

[ 风险声明 (欧洲) ]:
R25

[ 安全声明 (欧洲) ]:
S28-S36-S45

[ 危险品运输编码 ]:
3249

[ RTECS号 ]:
UV1164800

[ 包装等级 ]:
II

[ 危险类别 ]:
6.1(a)

[ 海关编码 ]:
2934999090

详细合成路线

利培酮上游产品

利培酮下游产品

1. 4-甲酰氯-1-乙酰基哌啶和间二氟苯在三氯化铝催化下,进行酰化,再用盐酸水解脱去哌啶环上的乙酰基,和羟胺反应后再碱催化环合,得到苯并异噁唑衍生物.4.4份该异噁唑衍生物、5.3份3-氯乙基-2-甲基-4H-吡啶并[1,2-α]嘧啶-4-酮盐酸盐、8份碳酸钠和0.1份碘化钾,在二甲基甲酰胺中,于85-90℃加热,得利培酮,收率46%.

2. 1-乙氧甲酰基-4-哌啶甲酸的制备

在反应瓶中加入4-哌啶甲酸12.9g(0.1mol)、水90ml和Na2CO310.6g(0.1mol),搅拌溶解,再加入THF90ml和氯甲酸乙酯10.8g(0.1mol)混合液,于室温下搅拌反应2h.减压蒸除溶剂,加入水150ml,用浓盐酸调节pH2至2,用二氯甲烷(100ml×3)提取,无水Na2SO4干燥,过滤,滤液减压蒸除溶剂,剩余物加石油醚20ml, 搅拌析晶,抽滤,干燥,得白色固体18.4g,收率91.5%,mp68.5~69.8 ºC.

3. 1-乙氧甲酰基-4-哌啶甲酰氯的制备

在反应瓶中加入上步制备的化合物18.4g(0.092mol)和二氯亚砜19.5g(31.94g,0.268mol),室温下搅拌反应6h. 减压蒸除过量的二氯亚砜,得色油状物1-乙氧甲酰基-4-哌啶甲酰氯20.0g, 收率99.3%.

4. 2,4-二氟苯基-(1-乙氧甲酰基-4-哌啶基)甲酮的制备

在反应瓶中加入无水三氯化铝12.1g(0.091mol) 和上步制备的化合物1-乙氧甲酰基-4-哌啶甲酰氯20.0g(0.091mol),搅拌均匀后,慢慢滴加1,3-二氟苯36g(0.365mol),滴毕,加热回流反应2h.冷至室温,减压蒸除1.3-二氟苯,缓慢倒入200g冰水中,二氯甲烷(200×3)提取,并有机层,无水NaSO4干燥.过滤,滤液减压蒸出二氯甲烷,剩余物干燥,得浅黄色油状物2,4-二氟苯基-(1-乙氧甲酰基-4-哌啶基)甲酮19.6g,收率72.5%.

5. 2,4-二氟苯基-(4-哌啶基)甲酮盐酸盐的制备

在反应瓶中加入上步制备的化合物2,4-二氟苯基-(1-乙氧甲酰基-4-哌啶基)甲酮19.6g(0.066mol)和浓盐酸70ml,搅拌回流反应15h.冷却至室温,用二氯甲烷(300ml×3)洗涤反应液.分出水层,减压蒸出水,加入异丙醇30ml,搅拌后过滤,滤饼干燥,得白色固体2,4-二氟苯基-(4-哌啶基)甲酮盐酸盐13.2g,收率76.5%,mp204.5~206.3 ºC.

6. 2,4-二氟苯基-(4-哌啶基)甲酮肟的制备

在反应瓶中加入上步制备的化合物2,4-二氟苯基-(4-哌啶基)甲酮盐酸盐13.2g(0.050mol)、盐酸羟胺10.5g(0.151mol)和95%(积分数)乙醇100ml搅拌下加入三乙胺13.9g(0.1mol),加热至回流,搅拌回流反应3h. 反应毕,冷至室温,析出固体,抽滤,滤饼干燥,得白色固体2,4-二氟苯基-(4-哌啶基)甲酮肟11.4g,收率82.4%,mp256.8~258.4 ºC(分解).

7. 6-氟-3-(4-哌啶基)-1,2-苯并异唑盐酸盐的制备

在反应瓶中加入KOH11.5g(0.206mol)和水35ml,搅拌溶解,再加入乙醇40ml和上步制备的化合物2,4-二氟苯基-(4-哌啶基)甲酮肟11.4g(0.041mol),搅拌回流反应4h.冷却至室温,减压蒸除溶剂,剩余物加水120ml,用甲苯(800ml×3)提取,合并提取液,水洗涤,无水Na2SO4干燥,过滤,滤液减压蒸除甲苯,剩余物干燥,得灰白色固体8.7g.将其用正己烷重结晶,得白色固体7.6g,收率84.2%.将其用甲醇76ml溶解,搅拌下滴加饱和氯化氢的甲醇溶液,滴至pH3,析出白色固体,过滤,得白色固体6-氟-3-(4-哌啶基)-1,2-苯并异唑盐酸盐7.7g,收率73.2%,mp1686~170.4 ºC.

8. 3-[2-[4-(6-氟-1,2-苯并异唑-3-基)-1-哌啶基]乙基]-6,7,8,9-四氢-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮(利培酮) 的合成

在反应瓶中加入上步制备的化合物6-氟-3-(4-哌啶基)-1,2-苯并异唑盐酸盐7.7g(0.030mol)、碘化钾1.2g(0.007mol)、无水Na2CO3 12.7g(0.120mol)、3-(2-氯乙基)-6,7,8,9-四氢-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮6.8g(0.030mol)和DMF130ml,搅拌加热至90 ºC,在该温度下保温搅拌反应10h. 冷却至室温#倒入350ml冰水中,静置,抽滤,滤饼用水洗涤,抽干,干燥,得浅黄色固体10g,将其用乙醇/水重结晶,得白色固体3-[2-[4-(6-氟-1,2-苯并异唑-3-基)-1-哌啶基]乙基]-6,7,8,9-四氢-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮(利培酮)8.6g,收率69.9%,mp168.7~170.3 ºC.

[ 海关编码 ]: 2934999090

[ 中文概述 ]:
2934999090. 其他杂环化合物. 增值税率:17.0%. 退税率:13.0%. 监管条件:无. 最惠国关税:6.5%. 普通关税:20.0%

[ 申报要素 ]: 品名, 成分含量, 用途

[ Summary ]:
2934999090. other heterocyclic compounds. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%

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