依那普利 | 75847-73-3

• 物质功能分类: 原料药 - 循环系统用药 - 抗高血压病药
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 依那普利
• 中文别名: 苯酯丙脯酸；(S)-1-(N-(1-(乙氧羰基)-3-苯丙基)-L-丙氨酰基)-L-脯氨酸
• 英文名称: enalapril
• 英文别名: (2S)-1-[(2S)-2-[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]azaniumyl]propanoyl]pyrrolidine-2-carboxylate
• CAS: 75847-73-3
• 化学式: C₂₀H₂₈N₂O₅
• mdl: MFCD00133304
• 分子量: 376.453
• InChiKey: GBXSMTUPTTWBMN-XIRDDKMYSA-N

物化性质

• 熔点：
  142-147℃
• 沸点：
  582.4±50.0 °C(Predicted)
• 密度：
  1.204±0.06 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜
• 物理描述：
  Solid
• 蒸汽压力：
  1.06X10-12 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions. /Enalapril maleate/
• Caco2细胞的药物渗透性：
  -5.64
• 解离常数：
  pKa1 = 3 (carboxylic acid); pKa2 = 5.4 (secondary amine), at 25 °C
• 碰撞截面：
  187.2 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  27
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  95.9
• 氢给体数：
  2
• 氢受体数：
  6

ADMET

代谢

大约60%的吸收剂量通过肝酯酶介导的去酯化作用广泛水解为依那普利拉。在人体内，未观察到超出生物激活至依那普利拉的代谢。

About 60% of the absorbed dose is extensively hydrolyzed to enalaprilat via de-esterification mediated by hepatic esterases. In humans, metabolism beyond bioactivation to enalaprilat is not observed.

来源:DrugBank

代谢

大约60%的依那普利剂量被广泛水解为依那普利拉，主要在肝脏通过酯酶进行。大约20%在首次通过肝脏时似乎被水解；这种水解在人类血浆中似乎并不发生。依那普利拉是一种比依那普利更强的血管紧张素转换酶抑制剂。在人类、大鼠或狗中没有发现依那普利其他代谢物的证据。然而，在恒河猴的尿液中发现了依那普利拉的脱丙基代谢物，占依那普利马来酸盐口服剂量的13%。在严重肝功能损害的患者中，依那普利水解为依那普利拉可能会延迟和/或受损，但药物的药效动力学效果似乎并没有显著改变。

About 60% of an absorbed dose of enalapril is extensively hydrolyzed to enalaprilat, principally in the liver via esterases. About 20% appears to be hydrolyzed on first pass through the liver; this hydrolysis does not appear to occur in plasma in humans. Enalaprilat is a more potent angiotensin converting enzyme inhibitor than enalapril. There is no evidence of other metabolites of enalapril in humans, rats, or dogs. However, a despropyl metabolite of enalaprilat was identified in urine in rhesus monkeys, accounting for 13% of an oral dose of enalapril maleate. Hydrolysis of enalapril to enalaprilat may be delayed and/or impaired in patients with severe hepatic impairment, but the pharmacodynamic effects of the drug do not appear to be significantly altered.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：依那普利是血管紧张素转换酶抑制剂和抗高血压药。人类研究：依那普利过量会产生主要延伸药物作为血管紧张素转换酶抑制剂药理效果的影响。在2名患者中，急性摄入300-440毫克依那普利马来酸盐后10-15小时内，血浆血管紧张素酶活性被完全抑制。依那普利过量的最可能表现是低血压，这可能是深度的，也可能伴随昏迷。急性过量后，低血压效果的开始和持续时间可能会延长。还可能发生肾功能不全，包括急性肾衰竭、高钾血症和低钠血症。在怀孕的第二和第三个月使用作用于肾素-血管紧张素系统的药物会降低胎儿肾功能，并增加胎儿和新生儿发病率和死亡。导致的少羊水可以与胎儿肺发育不良和骨骼畸形有关。潜在的新生儿不良反应包括头骨发育不良、无尿、低血压、肾衰竭和死亡。当发现怀孕时，尽快停止使用依那普利马来酸盐片。动物研究：当依那普利以高达90毫克/千克/天的剂量给予雄性和雌性大鼠106周，或以高达90和180毫克/千克/天的剂量分别给予雄性和雌性小鼠94周时，没有肿瘤发生的证据。在使用高达90毫克/千克/天依那普利的雄性和雌性大鼠的生殖性能上没有不良影响。依那普利马来酸盐或活性二酸在Ames微生物突变试验中无论有无代谢激活均不具有突变性。依那普利在以下遗传毒性研究中也为阴性：rec-分析，以大肠杆菌为反向突变分析，以培养的哺乳动物细胞为姐妹染色单体交换，以小鼠为微核试验，以及在体内使用小鼠骨髓的细胞遗传学研究。

IDENTIFICATION AND USE: Enalapril is angiotensin-converting enzyme inhibitor and antihypertensive agent. HUMAN STUDIES: Overdosage of enalapril produces effects that are mainly extensions of the drug's pharmacologic effects as an angiotension converting enzyme inhibitor. Plasma angiotension enzyme activity was completely suppressed within 10-15 hr after acute ingestion of 300-440 mg of enalapril maleate in 2 patients. The most likely manifestation of enalapril overdosage is hypotension, which may be profound and also maybe accompanied by stupor. Onset and duration of the hypotensive effect may be prolonged following acute overdosage. Renal dysfunction, including acute renal failure, hyperkalemia, and hyponatremia may also occur. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue enalapril maleate tablets as soon as possible. ANIMAL STUDIES: There was no evidence of a tumorigenic effect when enalapril was administered for 106 weeks to male and female rats at doses up to 90 mg/kg/day or for 94 weeks to male and female mice at doses up to 90 and 180 mg/kg/day, respectively. There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril. Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with Escherichia coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

像其他ACE抑制剂一样，依那普利与血清转氨酶升高的低发生率有关（

Enalapril, like other ACE inhibitors, has been associated with a low rate of serum aminotransferase elevations (

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：依那普利

Compound:enalapril

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：低药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重等级：7

Severity Grade:7

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服给药后，依那普利在1小时内达到血浆峰浓度（Cmax），而依那普利拉的Cmax出现在给药后三到四小时。稳态在第四天剂量时达到，重复给药没有积累。然而，在肌酐清除率小于30 mL/min的患者中可能会出现依那普利拉的积累。食物摄入对药物吸收的影响最小。口服给药后，大约60%的依那普利被吸收。以静脉注射依那普利拉作为参照标准时，依那普利的生物利用度平均约为40%。

Following oral administration, the peak plasma concentrations (Cmax) of enalapril is achieved within 1 hour post dosing while the Cmax of enalaprilat occurs at three to four hours post dosing. The steady-state is achieved by the fourth daily dose and there is no accumulation with repeated dosing. However, accumulation of enalaprilat may occur in patients with creatinine clearance less than 30 mL/min. Food intake is reported to have a minimal effect on drug absorption. Following oral administration, about 60% of enalapril was absorbed. Bioavailability of enalapril averaged about 40% when intravenous enalaprilat was used as a reference standard.

来源:DrugBank

吸收、分配和排泄

• 消除途径

恩纳普利主要通过肾脏排泄，大约94%的总剂量以恩纳普利酸或未改变的母体化合物的形式通过尿液或粪便排出。大约61%和33%的总剂量可以在尿液和粪便中分别回收。在尿液中，大约40%的回收剂量以恩纳普利酸的形式存在。

Enalapril is mainly eliminated through renal excretion, where approximately 94% of the total dose is excreted via urine or feces as either enalaprilat or unchanged parent compound. About 61% and 33% of the total dose can be recovered in the urine and feces, respectively. In the urine, about 40% of the recovered dose is in the form of enalaprilat.

来源:DrugBank

吸收、分配和排泄

• 分布容积

分布容积尚未确定。尽管在治疗剂量下，穿越血脑屏障的情况尚未得到证实，但试验表明，enalaprilat可渗透大多数组织，尤其是肾脏和血管组织。在犬类研究中，enalapril和enalaprilat穿越血脑屏障的能力较差。极小量的药物会渗透进乳汁，但会发生显著的胎儿转移。该药物在大鼠和仓鼠中穿越胎盘屏障。

The volume of distribution of enalapril has not been established. Enalaprilat is shown to penetrate into most tissuesm, in particular the kidneys and vascular tissuem, although penetration of the blood-brain barrier has not been demonstrated after administration at therapeutic doses. In dog studies, enalapril and enalaprilat cross the blood-brain barrier poorly. Minimal penetration occurs into breast milk but significant fetal transfer occurs. The drug crosses the placental barrier in rats and hamsters.

来源:DrugBank

吸收、分配和排泄

• 清除

在健康男性志愿者口服给药后，肾清除率大约为158 ± 47 mL/min。据报道，恩纳普利和恩纳普利拉在给药后4小时内在血浆中检测不到。

Following oral administration in healthy male volunteers, the renal clearance was approximately 158 ± 47 mL/min. It is reported that enalapril and enalaprilat are undetectable in the plasma by 4 hours post-dosing.

来源:DrugBank

吸收、分配和排泄

静脉注射依那普利0.50 mg/kg、口服安慰剂以及口服依那普利三种不同剂量（0.50、1.00和2.00 mg/kg）的药代动力学和药效学在7匹健康马匹中进行了分析。对依那普利及其活性代谢物依那普利拉的血清浓度进行了药代动力学分析。测定了血管紧张素转换酶（ACE）活性、血清尿素氮（SUN）、肌酐和电解质，并监测了血压以进行药效学分析。静脉注射依那普利后，依那普利和依那普利拉的消除半衰期分别为0.67小时和2.76小时。口服给药后，所有马匹的依那普利浓度均低于定量限（10 ng/mL），7匹马中有4匹马匹的依那普利拉浓度低于定量限。从基线开始的平均最大ACE抑制率分别为静脉注射依那普利0.50 mg/kg的88.38%，安慰剂的3.24%，口服依那普利0.50 mg/kg的21.69%，1.00 mg/kg的26.11%，和2.00 mg/kg的30.19%。在实验期间，血压、SUN、肌酐和电解质保持不变。

Pharmacokinetic and pharmacodynamic of IV enalapril at 0.50 mg/kg, PO placebo and PO enalapril at three different doses (0.50, 1.00 and 2.00 mg/kg) were analyzed in 7 healthy horses. Serum concentrations of enalapril and enalaprilat were determined for pharmacokinetic analysis. Angiotensin-converting enzyme (ACE) activity, serum ureic nitrogen (SUN), creatinine and electrolytes were measured, and blood pressure was monitored for pharmacodynamic analysis. The elimination half-lives of enalapril and enalaprilat were 0.67 and 2.76 hr respectively after IV enalapril. Enalapril concentrations after PO administrations were below the limit of quantification (10 ng/mL) in all horses and enalaprilat concentrations were below the limit of quantification in 4 of the 7 horses. Maximum mean ACE inhibitions from baseline were 88.38, 3.24, 21.69, 26.11 and 30.19% for IV enalapril at 0.50 mg/kg, placebo and PO enalapril at 0.50, 1.00 and 2.00 mg/kg, respectively. Blood pressures, SUN, creatinine and electrolytes remained unchanged during the experiments.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S22,S24/25
• WGK Germany：
  3
• 危险品运输编号：
  OTH
• 危险标志：
  GHS07,GHS08
• 危险性描述：
  H317,H361
• 危险性防范说明：
  P280
• 储存条件：
  室温

SDS

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Section 1. IDENTIFICATION OF THE SUBSTANCE/MIXTURE
Product identifiers
Product name : Enalapril
: CDS020548
CAS-No. : 75847-73-3

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Section 2. HAZARDS IDENTIFICATION
Classification of the substance or mixture
Classification according to Regulation (EC) No 1272/2008 [EU-GHS/CLP]
Skin sensitization (Category 1)
Reproductive toxicity (Category 2)
Classification according to EU Directives 67/548/EEC or 1999/45/EC
May cause sensitization by skin contact. Possible risk of impaired fertility. Possible risk of harm to the
unborn child.
Label elements
Labelling according Regulation (EC) No 1272/2008 [CLP]
Pictogram
Signal word Warning
Hazard statement(s)
May cause an allergic skin reaction.
Suspected of damaging fertility or the unborn child.
Precautionary statement(s)
Wear protective gloves.
Supplemental Hazard none
Statements
According to European Directive 67/548/EEC as amended.
Hazard symbol(s)
R-phrase(s)
R43 May cause sensitization by skin contact.
R62 Possible risk of impaired fertility.
R63 Possible risk of harm to the unborn child.
S-phrase(s)
S22 Do not breathe dust.
S26 In case of contact with eyes, rinse immediately with plenty of water and
seek medical advice.
S36 Wear suitable protective clothing.
Other hazards - none

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Section 3. COMPOSITION/INFORMATION ON INGREDIENTS
Substances
: (S)-(−)-1-[N-(1-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-Lproline
Synonyms
Formula : C20H28N2O5
Molecular Weight : 376,45 g/mol
Component Concentration
(S)-(−)-1-[N-(1-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-Lproline
CAS-No. 75847-73-3 -

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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
Flush eyes with water as a precaution.
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
hematopoiesis, renal damage, varation of retinal blood vessels, pruritus, taste disturbance, Exerts a potent
hypotensive action
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)
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 vapors, mist or gas. Ensure
adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust.
Environmental precautions
Prevent further leakage or spillage if safe to do so. 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.
Conditions for safe storage, including any incompatibilities
Store in cool place. Keep container tightly closed in a dry and well-ventilated place.
Specific end use(s)
no data available

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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
Face shield and safety glasses 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
Complete suit protecting against chemicals, The type of protective equipment must be selected
according to the concentration and amount of the dangerous substance at the specific workplace.
Respiratory protection
Where risk assessment shows air-purifying respirators are appropriate use a full-face particle
respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering
controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use
respirators and components tested and approved under appropriate government standards such
as NIOSH (US) or CEN (EU).

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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 not applicable
h) Evaporation 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
no data available
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

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Section 11. TOXICOLOGICAL INFORMATION
Information on toxicological effects
Acute toxicity
LD50 Oral - rat - 2.973 mg/kg
LD50 Oral - mouse - 3.507 mg/kg
LD50 Subcutaneous - rat - 1.418 mg/kg
LD50 Intravenous - rat - 849 mg/kg
LD50 Intravenous - mouse - 859 mg/kg
LD50 Subcutaneous - mouse - 1.160 mg/kg
Skin corrosion/irritation
no data available
Serious eye damage/eye irritation
no data available
Respiratory or skin sensitization
May cause sensitization by skin contact.
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
Suspected human reproductive toxicant
Specific target organ toxicity - single exposure
no data available
Specific target organ toxicity - repeated exposure
no data available
Aspiration hazard
no data available
Potential health effects
Inhalation May be harmful if inhaled. May cause respiratory tract irritation.
Ingestion May be harmful if swallowed.
Skin May be harmful if absorbed through skin. May cause skin irritation.
Eyes May cause eye irritation.
Signs and Symptoms of Exposure
hematopoiesis, renal damage, varation of retinal blood vessels, pruritus, taste disturbance, Exerts a potent
hypotensive action
Additional Information
RTECS: TW3665500

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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
no data available
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
This safety datasheet complies with the requirements of Regulation (EC) No. 1907/2006.
Safety, health and environmental regulations/legislation specific for the substance or mixture
no data available
Chemical Safety Assessment

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

马来酸依那普利的主要信息

化学名称与结构： 马来酸依那普利 (Enalapril Maleate) 的化学式为 C20H28N2O5·C4H4O4，具有一个α-氧代苯丁酸乙酯和L-丙氨酰-L-脯氨酸二肽通过缩合反应形成的骨架结构。其天然形式是白色针状结晶或结晶性粉末。

物理性质：

• 无臭无味。
• 易溶于水，微溶于乙腈。
• 熔点为143～144.5℃。
• 母体依那普利的旋光度 ([α]D25) -42.2°（C=1, 甲醇）。
• pH值约为2.6，pKa1 = 3.0，pKa2 (25°C) = 5.4。

药理作用：

• ACE抑制剂：作为血管紧张素转化酶的抑制剂，能减少血管紧张素Ⅱ的生成，从而扩张外周血管、降低血压。
• 治疗高血压：适用于原发性、肾性高血压及恶性高血压等。同时可用于充血性心力衰竭和对其他药物无效或不能耐受的患者。

制备方法

马来酸依那普利主要通过两种方法制备：

1. 缩合法：

   • α-氧代苯丁酸乙酯与L-丙氨酰-L-脯氨酸二肽在4A分子筛催化下生成Schiff’s碱，再用氰硼氢化钠还原得到依那普利。
   • 该方法进一步可与马来酸形成盐。

2. 一步法：

   • α-溴代苯丁酸乙酯和L-丙氨酰-L-脯氨酸二肽在DMF、TEA条件下直接缩合，一步即可获得依那普利。

3. 替代合成路径：

   • 该方法涉及从苯出发制备β-苯甲酰丙烯酸及其衍生物的步骤。
     • 苯丁酸乙酯的制备。
     • 耦合反应生成所需二肽片段。
     • 氢化还原和其它后处理操作。

用途

马来酸依那普利是一种有效的血管紧张素转化酶抑制剂，广泛用于治疗高血压及充血性心力衰竭。此外，它也被用作复方药物成分之一（如Vaseretic），以提高疗效。

总之，通过上述不同的合成路径可以制备出高质量的马来酸依那普利，并且这种化合物在临床应用中表现出良好的效果。

反应信息

• 作为反应物：
  描述：

  依那普利 以 sodium hydroxide 为溶剂， 生成 enalaprilic acid
  参考文献：
  名称：

  Method for analyzing isomers of enalapril and enalaprilat

  摘要：

  本发明涉及一种分析依那普利酯盐和依那普利酸盐的退化产物的方法，它们是强效的血管紧张素转换酶抑制剂。

  公开号：

  US05670655A1
• 作为产物：
  描述：

  N-<(1S)-1-(Ethoxycarbonyl)-3-phenylpropyl>-L-alanyl-L-proline Benzylester 在 palladium on activated charcoal 氢气 作用下， 以 乙醇 为溶剂， 反应 2.0h， 生成 依那普利
  参考文献：
  名称：

  Studies on Angiotensin Converting Enzyme Inhibitors. V. The Diastereoselective Synthesis of 2-Oxoimidazolidine Derivatives.

  摘要：

  建立了一种具有二面体选择性的imidapril（1）合成方法，该药物正在进行临床研究，作为一种基于其血管紧张素转化酶（ACE）抑制活性的抗高血压药物。将(2S)-2-amino-4-phenylbutyric acid ester（12）与3-((2R)-2-甲基或甲苯磺酰氧丙酰)-2-氧代咪唑烷衍生物（11）通过SN2方式进行N-烷基化，选择性地生成叔丁基(4S)-3-[(2S)-2-[N-[(1S)-1-乙氧基碳酰基)-3-苯基丙基]氨基]丙酰]-1-甲基-2-氧代咪唑烷-4-羧酸酯（13），该化合物是1的前体。作为替代，合成了苄基(2S)-2-[N-(1S)-1-(乙氧基碳酰基)-3-苯基丙基]氨基]丙酸酯（15），这是13的关键构件。该程序也应用于enalapril的合成。

  DOI：

  10.1248/cpb.39.1374
• 作为试剂：
  描述：

  L-丙氨酰基-L-脯氨酸 、 2-氧代-4-苯基丁酸乙酯 、 、 氢气 、 sodium hydroxide 在 镍 乙醇 、 水 、 乙酸乙酯 、 氯化钠 、 Sodium sulfate-III 、 desired product 、 依那普利 、 maleate salt 作用下， 以 乙醇 、 乙酸乙酯 、 水 为溶剂， 25.0 ℃ 、50.28 MPa 条件下， 反应 4.0h， 以to afford 5.2 g的产率得到Amprace
  参考文献：
  名称：

  Amino acid derivatives as antihypertensives

  摘要：

  本发明公开了制备羧基烷基二肽衍生物及其相关化合物的方法，这些化合物可用作血管紧张素转换酶（ACE）抑制剂和降压剂，并且与另一种降压剂和/或利尿剂化合物结合在一起的药物组合物中含有这些羧基烷基二肽化合物。

  公开号：

  US04472380A1

文献信息

• DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20160221965A1

  公开（公告）日：2016-08-04

  The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.

  本申请涉及新颖的2,5-二取代6-(三氟甲基)嘧啶-4(3H)-酮衍生物，其制备方法，其单独或与其他药物联合用于治疗和/或预防疾病，以及用于制备治疗和/或预防疾病的药物，特别是用于治疗和/或预防心血管、肾脏、炎症和纤维化疾病。
• [EN] SULFONYL COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN<br/>[FR] COMPOSÉS DE SULFONYLE QUI INTERAGISSENT AVEC LA PROTÉINE RÉGULATRICE DE LA GLUCOKINASE
  申请人：AMGEN INC

  公开号：WO2013123444A1

  公开（公告）日：2013-08-22

  The present invention relates to sulfonyl compounds that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.

  本发明涉及与葡萄糖激酶调节蛋白相互作用的磺酰基化合物。此外，本发明涉及使用这些化合物或其药学上可接受的盐治疗2型糖尿病和其他涉及葡萄糖激酶调节蛋白的疾病和/或症状的方法，以及含有这些化合物或其药学上可接受的盐的药物组合物。
• SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
  申请人：BLUM Andreas

  公开号：US20140135309A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I wherein Ar, R 1 and R 2 are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及公式I的新型磺酰胺取代的喹唑啉衍生物，其中Ar、R1和R2如本文所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。
• [EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2014072244A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及一种新型的配方(I)的磺酰胺取代喹唑啉衍生物，其中Ar、R1和R2如描述和声明中所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。
• 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。