托吡酯 | 97240-79-4

• 物质功能分类: 原料药 - 神经系统用药 - 抗癫痫及抗惊厥药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氧吡喃
• 中文名称: 托吡酯
• 中文别名: 2,3:4,5-双-0-(1-甲基亚乙基)-Β-吡喃果糖氨基磺酸酯；托佩马特；妥吡酯；妥泰,2,3:4,5-双-0-(1-甲基亚乙基)-β-吡喃果糖氨基磺酸酯；2,3,4,5-双-o-(1-甲基亚乙基)-β-d-吡喃果糖氨基磺酸酯；2,3,4,5-双-O-(1-甲基亚乙基)-Β-D-吡喃果糖氨基磺酸酯；妥泰
• 英文名称: topiramate
• 英文别名: TPM；2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate；Topamax；[(1R,2S,6S,9R)-4,4,11,11-tetramethyl-3,5,7,10,12-pentaoxatricyclo[7.3.0.02,6]dodecan-6-yl]methyl sulfamate
• CAS: 97240-79-4
• 化学式: C₁₂H₂₁NO₈S
• mdl: MFCD00865320
• 分子量: 339.367
• InChiKey: KJADKKWYZYXHBB-XBWDGYHZSA-N

物化性质

• 熔点：
  125°C
• 比旋光度：
  D23 -34.0° (c = 0.4 in methanol)
• 沸点：
  438.7±55.0 °C(Predicted)
• 密度：
  1.336±0.06 g/cm3(Predicted)
• 闪点：
  9℃
• 溶解度：
  二甲基亚砜：44 mg/mL
• LogP：
  2.970 (est)
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from ethyl acetate and benzene
• 味道：
  Bitter
• 蒸汽压力：
  7.0X10-8 mm Hg at 25 °C (est)
• 水溶性：
  -1.7
• 旋光度：
  Specific optical rotation = -34 deg/D (c = 0.4 in methanol)
• 碰撞截面：
  170.1 Ų [M+Na]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  -0.8
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  124
• 氢给体数：
  1
• 氢受体数：
  9

ADMET

代谢

托吡酯的代谢物不被认为具有活性。托吡酯的代谢特点包括葡萄糖醛酸化、羟基化和水解反应，这些反应导致产生六个次要代谢物。托吡酯的一些代谢物包括2,3-去异丙叉基托吡酯、4,5-去异丙叉基托吡酯、9-羟基托吡酯和10-羟基托吡酯。

The metabolites of topiramate are not known to be active. The metabolism of topiramate is characterized by reactions of glucuronidation, hydroxylation and hydrolysis that lead to the production of six minor metabolites. Some of topiramate's metabolites include 2,3-desisopropylidene topiramate, 4,5-desisopropylidene topiramate, 9-hydroxy topiramate, and 10-hydroxy topiramate.

来源:DrugBank

代谢

托吡酯在人体内不是广泛代谢的。已经确定了六种次要代谢物（通过羟基化、水解和葡萄糖醛酸化形成），其中没有一个构成超过给药剂量5%的部分。

Topiramate is not extensively metabolized. Six minor metabolites (formed by hydroxylation, hydrolysis, and glucuronidation) have been identified in humans, with none constituting more than 5% of an administered dose.

来源:Hazardous Substances Data Bank (HSDB)

代谢

2,3:4,5-双-O-(1-甲基乙基亚胺)-β-D-果糖磺酰胺（托吡酯，Topamax，TPM）的代谢和排泄在动物和人类中进行了研究。放射性标记的[14C] TPM通过口服给药给小鼠、大鼠、家兔、狗和人类。收集并分析了血浆、尿液和粪便样本。在这些样本中分离并鉴定了TPM及其总共12种代谢物。代谢物的形成包括TPM的7-或8-甲基上的异丙基亚胺的羟基化并随后重排，另一个异丙基亚胺的10-甲基上的羟基化，2,3-O-异丙基亚胺的水解，4,5-O-异丙基亚胺的水解，磺酰胺基团的裂解，葡萄糖醛酸结合和硫酸结合。在动物和人类的尿液中回收了大量未改变的TPM。在小鼠、雄性大鼠、家兔和狗中，TPM的主要代谢物似乎是通过2,3-O-异丙基亚胺基团的水解形成的。

The metabolism and excretion of 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate (TOPAMAX, topiramate, TPM) have been investigated in animals and humans. Radiolabeled [14C] TPM was orally administered to mice, rats, rabbits, dogs and humans. Plasma, urine and fecal samples were collected and analyzed. TPM and a total of 12 metabolites were isolated and identified in these samples. Metabolites were formed by hydroxylation at the 7- or 8-methyl of an isopropylidene of TPM followed by rearrangement, hydroxylation at the 10-methyl of the other isopropylidene, hydrolysis at the 2,3-O-isopropylidene, hydrolysis at the 4,5-O-isopropylidene, cleavage at the sulfamate group, glucuronide conjugation and sulfate conjugation. A large percentage of unchanged TPM was recovered in animal and human urine. The most dominant metabolite of TPM in mice, male rats, rabbits and dogs appeared to be formed by the hydrolysis of the 2,3-O-isopropylidene group.

来源:Hazardous Substances Data Bank (HSDB)

代谢

未广泛代谢，70%的剂量以原形在尿液中排出。另外30%通过肝脏代谢成六种代谢物（通过羟基化、水解和葡萄糖醛酸化形成），其中任何一种都不超过给药剂量的5%。有证据表明托吡酯存在肾小管重吸收。 消除途径：托吡酯未广泛代谢，主要以其原形通过尿液排出（约占总给药剂量的70%）。 半衰期：19至23小时。重复给药后，缓释制剂的平均消除半衰期为31小时。

Not extensively metabolized, 70% of the dose is eliminated unchanged in the urine. The other 30% is metabolized hepatically to six metabolites (formed by hydroxylation, hydrolysis, and glucuronidation), none of which constitute more than 5% of an administered dose. There is evidence of renal tubular reabsorption of topiramate. Route of Elimination: Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Half Life: 19 to 23 hours. The mean elimination half-life was 31 hours following repeat administration of the extended-release formulation.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

托吡酯的确切作用机制尚不清楚。然而，研究表明托吡酯以时间依赖性的方式阻断由神经元的持续去极化引发的重复动作电位，这表明了一种状态依赖性的钠通道阻断作用。托吡酯还能增强某些亚型的γ-氨基丁酸（GABA）神经递质在GABA_A受体（控制一个完整的氯离子通道）上的活性，表明可能通过增强GABA的活性来实现作用机制。托吡酯还展示了对抗AMPA/海人藻酸亚型的谷氨酸兴奋性氨基酸受体的作用。它还抑制碳酸酐酶（特别是同工酶II和IV），但这种作用较弱，不太可能与它的抗惊厥作用相关。

The precise mechanism of action of topiramate is not known. However, studies have shown that topiramate blocks the action potentials elicited repetitively by a sustained depolarization of the neurons in a time-dependent manner, suggesting a state-dependent sodium channel blocking action. Topiramate also augments the activity of the neurotransmitter gamma-aminobutyrate (GABA) at some subtypes of the GABA_A receptor (controls an integral chloride channel), indicating a possible mechanism through potentiation of the activity of GABA. Topiramate also demonstrates antagonism of the AMPA/kainate subtype of the glutamate excitatory amino acid receptor. It also inhibits carbonic anhydrase (particularly isozymes II and IV), but this action is weak and unlikely to be related to its anticonvulsant actions.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

前瞻性研究表明，长期使用托吡酯治疗的患者中，不到1%的人血清转氨酶水平会升高。临床上明显的托吡酯肝毒性相当罕见，通常发生在接受多种其他抗惊厥药物的患者中。托吡酯通过CYP 3A4代谢，可能会增加丙戊酸或其他抗惊厥药物肝毒性的风险。一种独特的综合征是在长期丙戊酸治疗中添加（或增加剂量）托吡酯后2到3周内出现乏力、虚弱、血清转氨酶显著升高和血氨升高。虽然丙戊酸单独可以引起类似的综合征，但与单独使用丙戊酸相比，联合使用时似乎更常见（约1%），而单独使用丙戊酸时约为0.1%。这种综合征具有雷耶综合症的特征（高氨血症、低血糖、快速逆转损伤），在许多情况下，它是由急性病毒性疾病引起的。托吡酯本身很少与临床上明显的肝损伤有关，损伤的临床特征和过程尚未明确。托吡酯尚未与抗惊厥药物超敏反应综合症病例有关联，被认为是该综合症患者的安全替代品。

Prospective studies suggest that less than 1% of subjects develop elevations in serum aminotransferase levels during long term topiramate therapy. Clinically apparent hepatotoxicity from topiramate is quite rare and usually arises in patients receiving multiple other anticonvulsants. Topiramate is metabolized by CYP 3A4 and may increase the risk of valproate or other anticonvulsant hepatotoxicity. A distinctive syndrome is the development of lethargy, weakness with marked serum aminotransferase elevations and hyperammonemia arising within 2 to 3 weeks of the addition (or dose increase) of topiramate to long term valproate therapy. While valproate alone can cause a similar syndrome, it appears much more common (~1%) with the combination than with valproate alone (~0.1%). This syndrome has several features suggestive of Reye syndrome (hyperammonemia, hypoglycemia, rapid reversal of injury) and in many instances is preceded by a acute viral illness. Topiramate by itself has only rarely been linked to clinically apparent liver injury and the clinical features and course of injury have not been well defined. Topiramate has not been linked to cases of the anticonvulsant hypersensitivity syndrome and is considered a safe alternative in patients with that syndrome.

来源:LiverTox

毒理性

• 药物性肝损伤

托吡酯

Compound:topiramate

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：较少的药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

在400毫克剂量的临床试验中，托吡酯在1.8-4.3小时内达到最大浓度，范围在1.73-28.7微克/毫升。食物虽然会延迟达到峰值浓度的时间，但并未显著影响吸收程度。在肌酐清除率正常的患者中，稳态浓度在4天内达到。与托吡酯溶液相比，片剂形式的托吡酯的生物利用度约为80%。

After a 400mg dose in one clinical trial, topiramate reached maximal concentrations within 1.8-4.3 hours and ranged from 1.73-28.7 ug/mL. Food did not significantly affect the extent of absorption, despite delaying time to peak concentration. In patients with normal creatinine clearance, steady state concentrations are reached within 4 days. The bioavailability of topiramate in tablet form is about 80% compared to a topiramate solution.

来源:DrugBank

吸收、分配和排泄

• 消除途径

托吡酯主要通过肾脏消除。大约70-80%的消除剂量在尿液中以原形存在。

Topiramate is mainly eliminated through the kidneys. About 70-80% of the eliminated dose is found unchanged in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

托吡酯的平均表观分布容积在给予100mg至1200mg剂量时，范围从0.6-0.8 L/kg。托吡酯容易穿过血脑屏障。

The mean apparent volume of distribution of topiramate ranges from 0.6-0.8 L/kg when doses of 100mg to 1200mg are given. Topiramate readily crosses the blood-brain barrier.

来源:DrugBank

吸收、分配和排泄

• 清除

根据一项药代动力学研究，托吡酯的平均口服血浆清除率范围在22-36 mL/min，而肾清除率为17-18 mL/min。美国食品药品监督管理局（FDA）对托吡酯的标签说明，成年人的类似口服血浆清除率大约为20至30 mL/min。

The mean oral plasma clearance of topiramate ranges from 22-36 mL/min while the renal clearance is 17-18 mL/min, according to one pharmacokinetic study. The FDA label for topiramate indicates a similar oral plasma clearance of approximately 20 to 30 mL/min in adults.

来源:DrugBank

吸收、分配和排泄

托吡酯的吸收是快速的。片剂剂型的生物利用度约为80%，与溶液相比。食物不会影响托吡酯的生物利用度。

Absorption /of topiramate is/ rapid. The bioavailability of the tablet dosage form is about 80% as compared with that from a solution. Food does not effect the bioavailability of topiramate.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S26,S36
• 危险类别码：
  R36/37/38
• WGK Germany：
  3
• 海关编码：
  29350090
• 危险品运输编号：
  UN1230 - class 3 - PG 2 - Methanol, solution
• RTECS号：
  LS7083000
• 危险标志：
  GHS07
• 危险性描述：
  H315,H319,H335
• 危险性防范说明：
  P261,P305 + P351 + P338
• 储存条件：
  存放在0至10℃的环境中；请避免加热。

SDS

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SECTION 1: Identification of the substance/mixture and of the company/undertaking
Product identifiers
Product name : Topiramate
REACH No. : A registration number is not available for this substance as the substance
or its uses are exempted from registration, the annual tonnage does not
require a registration or the registration is envisaged for a later
registration deadline.
CAS-No. : 97240-79-4
Relevant identified uses of the substance or mixture and uses advised against
Identified uses : Laboratory chemicals, Manufacture of substances

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SECTION 2: Hazards identification
Classification of the substance or mixture
Classification according to Regulation (EC) No 1272/2008
Skin irritation (Category 2), H315
Eye irritation (Category 2), H319
Specific target organ toxicity - single exposure (Category 3), H335
For the full text of the H-Statements mentioned in this Section, see Section 16.
Classification according to EU Directives 67/548/EEC or 1999/45/EC
Xi Irritant R36/37/38
For the full text of the R-phrases mentioned in this Section, see Section 16.
Label elements
Labelling according Regulation (EC) No 1272/2008
Pictogram
Signal word Warning
Hazard statement(s)
H315 Causes skin irritation.
H319 Causes serious eye irritation.
H335 May cause respiratory irritation.
Precautionary statement(s)
P261 Avoid breathing dust/ fume/ gas/ mist/ vapours/ spray.
P305 + P351 + P338 IF IN EYES: Rinse cautiously with water for several minutes. Remove
contact lenses, if present and easy to do. Continue rinsing.
Supplemental Hazard none
Statements
Other hazards - none

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SECTION 3: Composition/information on ingredients
Substances
Synonyms : 2,3:4,5-Bis-O-(1-methylethylidene)-36-D-fructo-pyranose sulfamate
Topamax
McN 4853
RWJ 17021
Formula : C12H21NO8S
Molecular Weight : 339,36 g/mol
CAS-No. : 97240-79-4
Hazardous ingredients according to Regulation (EC) No 1272/2008
Component Classification Concentration
Topiramate
CAS-No. 97240-79-4 Skin Irrit. 2; Eye Irrit. 2; STOT <= 100 %
SE 3; H315, H319, H335
Hazardous ingredients according to Directive 1999/45/EC
Component Classification Concentration
Topiramate
CAS-No. 97240-79-4 Xi, R36/37/38 <= 100 %
For the full text of the H-Statements and R-Phrases mentioned in this Section, see Section 16

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SECTION 4: First aid measures
Description of first aid measures
General advice
Consult a physician. Show this safety data sheet to the doctor in attendance.
If inhaled
If breathed in, move person into fresh air. If not breathing, give artificial respiration. Consult a physician.
In case of skin contact
Wash off with soap and plenty of water. Consult a physician.
In case of eye contact
Rinse thoroughly with plenty of water for at least 15 minutes and consult a physician.
If swallowed
Never give anything by mouth to an unconscious person. Rinse mouth with water. Consult a physician.
Most important symptoms and effects, both acute and delayed
The most important known symptoms and effects are described in the labelling (see section 2.2) and/or in
section 11
Indication of any immediate medical attention and special treatment needed
no data available

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SECTION 5: Firefighting measures
Extinguishing media
Suitable extinguishing media
Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.
Special hazards arising from the substance or mixture
Carbon oxides, nitrogen oxides (NOx), Sulphur oxides
Advice for firefighters
Wear self contained breathing apparatus for fire fighting if necessary.
Further information
no data available

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SECTION 6: Accidental release measures
Personal precautions, protective equipment and emergency procedures
Use personal protective equipment. Avoid dust formation. Avoid breathing vapours, mist or gas. Ensure
adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust.
For personal protection see section 8.
Environmental precautions
Do not let product enter drains.
Methods and materials for containment and cleaning up
Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed
containers for disposal.
Reference to other sections
For disposal see section 13.

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SECTION 7: Handling and storage
Precautions for safe handling
Avoid contact with skin and eyes. Avoid formation of dust and aerosols.
Provide appropriate exhaust ventilation at places where dust is formed.
For precautions see section 2.2.
Conditions for safe storage, including any incompatibilities
Store in cool place. Keep container tightly closed in a dry and well-ventilated place.
Recommended storage temperature: 2 - 8 °C
Specific end use(s)
Apart from the uses mentioned in section 1.2 no other specific uses are stipulated

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SECTION 8: Exposure controls/personal protection
Control parameters
Components with workplace control parameters
Exposure controls
Appropriate engineering controls
Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and
at the end of workday.
Personal protective equipment
Eye/face protection
Safety glasses with side-shields conforming to EN166 Use equipment for eye protection tested
and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).
Skin protection
Handle with gloves. Gloves must be inspected prior to use. Use proper glove removal technique
(without touching glove's outer surface) to avoid skin contact with this product. Dispose of
contaminated gloves after use in accordance with applicable laws and good laboratory practices.
Wash and dry hands.
The selected protective gloves have to satisfy the specifications of EU Directive 89/686/EEC and
the standard EN 374 derived from it.
Body Protection
impervious clothing, The type of protective equipment must be selected according to the
concentration and amount of the dangerous substance at the specific workplace.
Respiratory protection
For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher
level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges.
Use respirators and components tested and approved under appropriate government standards
such as NIOSH (US) or CEN (EU).
Control of environmental exposure
Do not let product enter drains.

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SECTION 9: Physical and chemical properties
Information on basic physical and chemical properties
a) Appearance Form: solid
b) Odour no data available
c) Odour Threshold no data available
d) pH no data available
e) Melting point/freezing no data available
point
f) Initial boiling point and no data available
boiling range
g) Flash point no data available
h) Evapouration rate no data available
i) Flammability (solid, gas) no data available
j) Upper/lower no data available
flammability or
explosive limits
k) Vapour pressure no data available
l) Vapour density no data available
m) Relative density no data available
n) Water solubility no data available
o) Partition coefficient: n- no data available
octanol/water
p) Auto-ignition no data available
temperature
q) Decomposition no data available
temperature
r) Viscosity no data available
s) Explosive properties no data available
t) Oxidizing properties no data available
Other safety information
no data available

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SECTION 10: Stability and reactivity
Reactivity
no data available
Chemical stability
Stable under recommended storage conditions.
Possibility of hazardous reactions
no data available
Conditions to avoid
no data available
Incompatible materials
Strong oxidizing agents
Hazardous decomposition products
Other decomposition products - no data available
In the event of fire: see section 5

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SECTION 11: Toxicological information
Information on toxicological effects
Acute toxicity
no data available
LD50 Intraperitoneal - rat - > 1.500 mg/kg
Skin corrosion/irritation
no data available
Serious eye damage/eye irritation
no data available
Respiratory or skin sensitisation
no data available
Germ cell mutagenicity
no data available
Carcinogenicity
IARC: No component of this product present at levels greater than or equal to 0.1% is identified as
probable, possible or confirmed human carcinogen by IARC.
Reproductive toxicity
no data available
Specific target organ toxicity - single exposure
Inhalation - May cause respiratory irritation.
Specific target organ toxicity - repeated exposure
no data available
Aspiration hazard
no data available
Additional Information
RTECS: LS7083000
To the best of our knowledge, the chemical, physical, and toxicological properties have not been
thoroughly investigated.

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SECTION 12: Ecological information
Toxicity
no data available
Persistence and degradability
no data available
Bioaccumulative potential
no data available
Mobility in soil
no data available
Results of PBT and vPvB assessment
PBT/vPvB assessment not available as chemical safety assessment not required/not conducted
Other adverse effects
no data available

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SECTION 13: Disposal considerations
Waste treatment methods
Product
Offer surplus and non-recyclable solutions to a licensed disposal company. Dissolve or mix the material
with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber.
Contaminated packaging
Dispose of as unused product.

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SECTION 14: Transport information
UN number
ADR/RID: - IMDG: - IATA: -
UN proper shipping name
ADR/RID: Not dangerous goods
IMDG: Not dangerous goods
IATA: Not dangerous goods
Transport hazard class(es)
ADR/RID: - IMDG: - IATA: -
Packaging group
ADR/RID: - IMDG: - IATA: -
Environmental hazards
ADR/RID: no IMDG Marine pollutant: no IATA: no
Special precautions for user
no data available

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SECTION 15 - REGULATORY INFORMATION
N/A

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

以下是关于托吡酯（Topiramate）的关键信息总结：

化学性质

• 外观：白色细粉末晶体

用途

• 抗惊厥药
• 抗癫痫药

用法用量

• 成人剂量：

  • 起始剂量25mg，qd（每天一次）
  • 第1周每晚服50mg
  • 第2周早晚各服50mg
  • 第3周早晨服50mg，晚上服100mg
  • 第4周早晚各服100mg
  • 第5周早晨服100mg，晚上服150mg
  • 第6周早晚各服150mg
  • 第7周早晨服150mg，晚上服200mg
  • 第8周早晚各服200mg
  • 维持量400mg/d

• 儿童剂量（2～16岁）：

  • 每日5～9mg/kg，分2次服用

临床评价

• 单独使用或联合其他抗癫痫药物治疗癫痫患者的效果明显优于卡马西平。

不良反应与注意事项

• 最常见不良反应：中枢神经系统相关症状（如共济失调、注意力受损等）
• 其他不良反应：焦虑、抑郁、肾石症风险增加

注意事项

1. 逐渐停药以减少发作频率增高的可能性。
2. 致畸作用：动物实验表明其具有致畸性，需注意。
3. 急性过量处理：立即采用胃管胃排空或诱发呕吐胃排空法解救；必要时可用血液透析。
4. 药物相互作用：
   • 与苯妥英同用时监测苯妥英血浆浓度
   • 苯妥英和卡马西平可降低本品的血药浓度
   • 注意地高辛、氢氯噻嗪等药物的影响

驾驶和操作机器风险

• 可能存在共济失调、头晕等症状，需谨慎驾驶或操作复杂机械。

总结来说，托吡酯是一种有效的抗癫痫药物，在使用过程中需要注意剂量调整以及可能出现的不良反应。

反应信息

• 作为反应物：
  描述：

  托吡酯 在 吡啶 、 磺酰氯 、 氨 作用下， 以 四氢呋喃 为溶剂， -60.0~20.0 ℃ 、165.48 kPa 条件下， 反应 0.67h， 生成 N-sulfamoyl-2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate
  参考文献：
  名称：

  [EN] NOVEL SUBSTITUTED SULFAMATE ANTICONVULSANT DERIVATIVES
  [FR] NOUVEAUX DERIVÉS ANTICONVULSIFS À SUBSTITUTION SULFAMATE

  摘要：

  公开号：

  WO2003097656A3
• 作为产物：
  描述：

  果糖 在 吡啶 、 硫酸 、 磺酰胺 作用下， 以 5,5-dimethyl-1,3-cyclohexadiene 为溶剂， 生成 托吡酯
  参考文献：
  名称：

  The first general protocol forN-monoalkylation of sulfamate esters: benign synthesis ofN-alkyl Topiramate (anticonvulsant drug) derivatives

  摘要：

  A novel protocol for the highly selective N-monoalkylation of the sulfamate ester moiety has been developed. This reaction proceeded efficiently using alkyl halides, benzyl halides and -halo ketones as the electrophile in the presence of KF-Al2O3 as a cost-effective and robust catalyst. This approach provides new access to N-monoalkylated Topiramate (anticonvulsant drug) derivatives which are potentially of great importance in medicinal chemistry.

  DOI：

  10.1080/17415993.2015.1069294

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• [EN] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
  申请人：GALLEON PHARMACEUTICALS INC

  公开号：WO2009151744A1

  公开（公告）日：2009-12-17

  The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.

  本发明涉及基于巯基和S-亚硝基巯基的SNO化合物及其衍生物，以及它们在治疗正常呼吸控制缺失方面的用途，包括治疗与睡眠、肥胖、某些药物和其他医疗状况相关的呼吸暂停和低通气。
• [EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
  申请人：ASTRAZENECA AB

  公开号：WO2016055858A1

  公开（公告）日：2016-04-14

  The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.

  本申请涉及式(I)、(Ia)或(Ib)的化合物及其药物组合物/制剂。本申请进一步涉及治疗或预防与Αβ相关的病理学，如唐氏综合症，β-淀粉样蛋白血管病，如但不限于脑淀粉样蛋白血管病或遗传性脑出血，与认知损害相关的疾病，如但不限于MCI（“轻度认知损害”），阿尔茨海默病，记忆丧失，与阿尔茨海默病相关的注意力缺陷症状，与疾病如阿尔茨海默病或痴呆症相关的神经退行性疾病，包括混合性血管性和退行性起源的痴呆，早老性痴呆，老年性痴呆和与帕金森病相关的痴呆的方法。
• NOVEL GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME
  申请人：Ryono Denis E.

  公开号：US20080009465A1

  公开（公告）日：2008-01-10

  Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure wherein is a heteroaryl ring; R 4 is —(CH 2 ) n -Z-(CH 2 ) m —PO(OR 7 )(OR 8 ), —(CH 2 ) n Z-(CH 2 ) m —PO(OR 7 )R g , —(CH 2 ) n -Z-(CH 2 ) m —OPO(OR 7 )R g , —(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10 ), or —(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10 ); R 5 and R 6 are independently selected from H, alkyl and halogen; Y is R 7 (CH 2 ) s or is absent; and X, n, Z, m, R 4 , R 5 , R 6 , R 7 , and s are as defined herein; or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.

  提供了磷酸酯和磷酸酯激活剂，因此在治疗糖尿病和相关疾病方面非常有用，并具有以下结构： 其中 是杂环芳基环； R 4 为—(CH 2 ) n -Z-(CH 2 ) m —PO(OR 7 )(OR 8 )、—(CH 2 ) n Z-(CH 2 ) m —PO(OR 7 )R g 、—(CH 2 ) n -Z-(CH 2 ) m —OPO(OR 7 )R g 、—(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10) 或—(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10) ； R 5 和R 6 分别选择自H、烷基和卤素； Y为R 7 (CH 2 ) s 或不存在；以及 X、n、Z、m、R 4 、R 5 、R 6 、R 7 和s如本文所定义；或其药用盐。 还提供了一种利用上述化合物治疗糖尿病和相关疾病的方法。
• [EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2016089721A1

  公开（公告）日：2016-06-09

  The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及甲基噁唑化合物，其为促进睡眠的受体拮抗剂。本发明还涉及所述化合物在潜在治疗或预防涉及促进睡眠的神经和精神疾病和疾病中的用途。本发明还涉及包含这些化合物的组合物。本发明还涉及这些组合物在潜在预防或治疗涉及促进睡眠的疾病中的用途。