What Is the Difference Between Enalapril and Captopril?

Trendopril is an angiotensin-converting enzyme inhibitor, which plays a role after being converted into Trendopril in vivo. It has a high affinity for ACE, and is a potent and long-acting ACE mechanism agent. It is mainly used in the treatment of arterial hypertension, and has certain effects on other types of hypertension. Also treats congestive heart failure and myocardial infarction

Chinese name: Trandolipril
Chinese alias: Thandolipril

English alias: Gopten, Odrik
details: Pharmacological action

Basic information ^[1]

Chinese name

Chinese alias: Trendopril; Quandomolipril; Trans-Donate; Trans-Dopril;

Chemical name: (2S, 3aR, 7aS) -1-[(2S) -2-[[(1S) -1-ethoxyformyl-3-phenyl-propyl] amino] propionyl] -2, 3,3a, 4,5,6,7,7a-octahydroindole-2-carboxylic acid;

Or (3R.7S) -1- [N- [1 (S) -ethoxycarbonyl] -3-phenylpropyl]-(S) -alanyloctahydroindole-2 (S) -carboxylic acid;

English name:

(2S, 3aR, 7aS) -1-[(2S) -2-[[(2S) -1-ethoxy-1-oxo-4-phenylbutan-2-yl] amino] propanoyl] -2,3,3a, 4,5,6,7,7a-octahydroindole-2-carboxylic acid

CAS number: 87679-37-6

Molecular formula: C ₂₄ H ₃₄ N ₂ O ₅

Structural formula:

Molecular weight: 430.553700

Exact mass: 430.24700

PSA: 95.94000

LogP: 3.10210

Physical and chemical properties

Appearance and properties: white powder

Density: 1.181 g / cm3

Melting point: 122-123 ° C

Boiling point: 626ºC at 760 mmHg

Flash point: 332.4ºC

Refractive index: 1.549

[1] Syndropril synthesis route [1]

1. Preparation of 3-chloro-N-levulinic acid methyl ester

Into a reaction flask, add 181 g of 3-chloroalanine methyl ester hydrochloride (91.04 mol), 163.9 g (2.08 mol) of acetyl chloride and 1500 ml of anhydrous toluene, stir and heat to reflux, and reflux for 5 h until the reaction mixture becomes a clear solution. After the reaction, the reaction solution was concentrated to dryness, and the residue was recrystallized from a mixed solvent of ethyl acetate / petroleum ether to obtain 170 g of 3-chloro-N-levulinic acid methyl ester with a yield of 91% and mp 104 ° C.

2. Preparation of 3- (2-oxocyclohexyl) -N-levulinic acid methyl ester

Add 160 g (0.89 mol) of the compound 3-chloro-N-levulinic acid methyl ester prepared in the previous step, 171.9 g (1.12 mol) of 1-pyrrolylcyclohexane, and 1200 ml of anhydrous DMF into the reaction flask. The mixture was left at 20 ~ 25ºC for 3 days. The reaction solution was concentrated under high vacuum. After adding 600 ml of water to the residue, it was adjusted to pH 2 with concentrated hydrochloric acid. The aqueous layer was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous Na2SO4. , Filtered, and the filtrate was concentrated to obtain an oily crude 3- (2-oxocyclohexyl) -N-levulinic acid methyl ester 220 g, with a yield of> 100%, which was directly used in the next reaction.

3. Preparation of 3,3a, 4,5,6,7-2H-hexahydroindole-2-carboxylic acid hydrochloride

Add 220 g (about 0.90 mol) (crude) of 3- (2-oxocyclohexyl) -N-acetoalanine methyl ester prepared in the previous step to the reaction flask, and 1000 ml of 2 mol / L hydrochloric acid. The reaction mixture was stirred and refluxed for 2H. The reaction mixture was extracted with ethyl acetate, and the aqueous phase was concentrated. The residual amount of water was added to toluene three times and removed by vacuum azeotropic distillation to obtain a yellow oil 3, 3a, 4, 5, 6, 7-2H. -210g of hexahydroindole-2-carboxylic acid hydrochloride, yield> 100%, the product can be crystallized and solidified by cooling and standing.

4. Preparation of DL-2, 3, 7a-octahydroindole-2-carboxylic acid

Add the compound 3,3a, 4,5,6,7-2H-hexahydroindole-2-carboxylic acid hydrochloride 128g (about 0.63mol), 700ml glacial acetic acid and Pd / C (10%) 4g, replace the air in the bottle 3 times with N2 under stirring, and replace the N2 with H2, hydrogenate the reaction at room temperature under H2 pressure. After the reaction is completed, the catalyst is filtered off, the filtrate is concentrated to dryness, and the residue is heated to dissolve 500ml ethanol After cooling the solution to -20ºC, the isomers of the compounds DL-2, 3, 7a-octahydroindole-2-carboxylic acid (2, 3, 7-octahydroindolecarboxylic acid) were precipitated. The concentrated solution was crystallized with isopropanol and filtered to obtain colorless crystals DL-2, 3, 7a-octahydroindole-2-carboxylic acid 280g, mp280ºC.

5. Preparation of DL-2, 3, 7a-octahydroindole-2-carboxylic acid benzyl ester hydrochloride

Add 14ml benzyl alcohol (14.58g, 134.84mmol) and thionyl chloride (SOCl2) 1.41ml (2.29g, 19.27mmol) to the reaction flask and cool to -5ºC ~ 0ºC, then add the previous step at -10ºC ~ 0ºC with stirring. 1.4 g (8.28 mmol) of the prepared compound DL-2, 3, 7a-octahydroindole-2-carboxylic acid. After the addition was completed, the mixture was stirred and reacted at 0 ° C for 1 h. The mixture was allowed to stand overnight at 20-25 ° C. The reaction was reacted at 50 ° C The benzyl alcohol (benzyl alcohol) in the solution was distilled off under high vacuum. The residue was crushed and ground with diisopropyl ether and filtered to obtain DL-2, 3, 7a-octahydroindole-2-carboxylic acid benzyl ester hydrochloride. 2.5g of salt, yield> 100%, the product is colorless crystal (still crude), mp154ºC. It can be used directly in the next step.

6. Preparation of N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl-2, 3, 7a-indolin-2-carboxylic acid benzyl ester

Add 2.16 g (7.74 mmol) of N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanine and 8.6 ml of anhydrous DMF to the reaction flask, stir and suspend, and add 1-hydroxyl to the suspension 1.06 g (7.85 mol) of benzotriazole, the compound DL-2, 3, 7a-octahydroindole-2-carboxylic acid benzyl ester hydrochloride 2.2 g (7.45 mol) and N-ethyl prepared in the previous step 1.08ml of phthaloline, stir and mix, and then add 1.7g of dicyclohexylcarbodiimide (DCC) (control the internal temperature to 0ºC when DCC is added). After the addition, stir the reaction at 20 ~ 25ºC for 3.5h. The reaction mixture is ethyl acetate. Diluted in 200ml, filtered off the dicyclohexyl urea produced, and concentrated the filtrate under reduced pressure to evaporate the solvent. The residue was dissolved in diethyl ether, and the solution was washed twice with saturated aqueous NaHCO3 solution, dried over anhydrous Na2SO4, filtered, and the residue after the filtrate was concentrated was used Separation and purification on silica gel column [eluent: ethyl acetate / cyclohexane], after treatment, two parts of pale yellow oil (ratio 1: 1), each containing the target compound N- (1S-ethoxycarbonyl- 3-phenylpropyl) -S-alanyl-2, 3, 7a-octahydroindole-2-carboxylic acid benzyl isomer [ie (2R, 3R, 7S) -N- (1S- (Ethoxycarbonyl-3-phenylpropyl) -S-alanyl-2, 3, 7a-indolin-2-carboxylic acid benzyl ester and (2 S, 3S, 7R) -N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl-2, 3, 7a-octahydroindole-2-carboxylic acid benzyl ester.

7. (2S, 3R, 7S) -1-[(2S) -2-[[(1S) -1- (ethoxycarbonyl) -3-phenylpropyl] amino] -1-oxopropyl] Synthesis of octahydro-1H-indole-2-carboxylic acid (Trendopril)

Add (2S, 3S, 7R) N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl-2, 3, 7a-octahydroindole-2-carboxylic acid to the hydrogenation reaction flask 1.7 g (3.26 mol) of benzyl ester, 60 ml of absolute ethanol, and 200 mg of 10% Pd / C catalyst, replace the air in the bottle 3 times with N2 #Replace N2 3 times with H2, and react with H2 at 25ºC under normal pressure for 2 h (under stirring) After the reaction, the catalyst was filtered off, and the filtrate was concentrated to evaporate the solvent to obtain a colorless foam (2S, 3R, 7S) -1-[(2S) -2-[[(1S) -1- (ethoxycarbonyl) 3-Phenylpropyl] amino] -1-oxopropyl] octahydro-1H-indole-2-carboxylic acid (Trendopril) 1.2 g, yield 85.7% (this foamy object Colorless amorphous powder can be obtained as the hydrochloride). ^[1]

[2,3] Trendopril Trendopril related drug label information [2,3]

use

This product is a non-mercapto angiotensin-converting enzyme inhibitor.It is an ethyl ester prodrug formed by trandolapril (Trandola-Prilat), which is hydrolyzed by liver enzymes to activity in the body. The metabolite group doxorubic acid exerts a pharmacological effect. This product has a high affinity for ACE, and has a stronger ACE inhibitory effect than quinapril, enalapril and captopril. Those with normal blood pressure and hypertension take a single oral dose of 2mg of this product, and can inhibit ACE activity by 85% -100% within 2-4 hours; it can increase the total and active plasma renin levels, and plasma aldosterone levels usually decrease, so that Effectively reduce blood pressure with little or no effect on heart rate, cardiac output, and stroke volume. This product is mainly used for the treatment of arterial hypertension. It also has a certain effect on other types of hypertension, and it has rapid onset of action, long duration of action, and few adverse reactions. Clinically, it can also treat congestive heart failure and myocardial infarction.

Indication

This product is suitable for the treatment of various degrees of hypertension, with an effective rate of 60% to 70%, which is equivalent to atenolol or nifedipine sustained-release preparations. It is characterized in that the effect can be maintained for more than 48 hours after the last dose without blood pressure rebound after drug withdrawal. Blood pressure fluctuations were small when administered once a day. Currently used as second to third line medicine for the treatment of hypertension.

Dosage form

Capsule: 2mg / capsule.

Tablets: 0.5 mg / tablet, 1 mg / tablet, 2 mg / tablet.

Dosage

1. Oral, 0.5 to 2 mg each time, once a day. Up to 4mg per day.

2. Quandopril is not affected by food and can be taken before or after meals.

3. When treating hypertension, the single dose is 2mg daily. After 2 to 4 weeks of treatment, the dose can be doubled if necessary. The elderly do not need to adjust the dose for those with renal insufficiency.

4. For those who have previously used diuretics, the dose should start from 0.5mg.

5. In patients with renal failure, if the creatinine clearance is <30ml / min, the dose should be started at 0.5mg / d. If necessary, it can be increased to a single dose of 1 mg per day.

Pharmacological action

Trendopril is a new type of long-acting carboxyl-containing (COO) type ACE, which is 2.3 to 10 times stronger than enalapril. It is active by itself and the hydrolyzed active product Trandolaprilat after absorption, but the active product acts as the original drug. 7 times.

Trendopril maintains a long-lasting antihypertensive effect by inhibiting angiotensin-converting enzyme (ACE), and can inhibit angiotensin-induced blood pressure response, reduce cardiac hypertrophy, and reduce left ventricular weight and blood vessels in the right ventricle. Angiotensin (AGT) concentration, but has no effect on plasma AGTE concentration.

Experiments have shown that trandolapril has a blood pressure-lowering effect that is directly proportional to the dose within the effective dose range of 0.5 to 2 mg, and can be effective as long as a low threshold dose is given. Its effect is much stronger than EnalaPril.

Pharmacokinetics

The oral absorption rate of this product is 40% to 50%, and the absorption is not affected by diet. The peak time is about 1 hour, and the plasma protein binding rate is 80%. After absorption of this product, it is hydrolyzed into cluster dopril in the liver. The peak time of the latter is 6 hours, and the plasma protein binding rate is 94%. The original drug is cleared in the body quickly, and the elimination half-life is only 0.7h; however, the elimination of trandolapril is slow, and the elimination half-life can be as long as 24h at steady state. Trendopril is mainly excreted through urine and feces, and the clearance of those with impaired renal function slows down.

Healthy volunteers took 1 mg (10 cases) or 2 mg (8 cases) of this product orally every day, and reached steady-state blood concentration on the 4th day. The blood concentration at the steady-state blood concentration of trondopril acid does not seem to be related to the administered dose, because they were both 2.1 ng / ml on average in the 1 mg / d group or the 2 mg / d group. The half-life of effective cumulative concentration was 16h (1mg / d group) and 24h (2mg / d group). AUC ₀ _to _{24 h} after the first and 10th administration were 2.02 (1 mg / d group) and 1.9 (2 mg / d group), respectively. Renal function has an effect on the metabolism of trandolapril.

1. Absolute bioavailability.

Oral 2mg trandolapril capsules have an absorption of 40% to 60% of the same dose given intravenously.

2. Distributing oral 2mg Quandopril.

It is known by isotope measurement that the ratio of Trendopril in plasma is about 80%, and its plasma concentration is 0.1 to 1.000 ng / ml. The ratio of Trandolaprilat in plasma is 94%, and the plasma concentration is low, only 0.04ng / m1; the rate of binding of Trandolaprilate to proteins: 82 for albumin %, Glycoprotein 18%, and lipoprotein and IgG were zero.

3 metabolism.

After oral administration, trandolapril mainly forms its diacid compound through non-specific hydrolysis. A small number of two compounds with -lactam structure in the aromatization pathway, the diketopiperazine derivative of trandolapril and the diketopiperazine derivative of quandopril diacid. But these metabolites did not inhibit ACE activity. Another metabolic pathway is the generation of gadouride and gadouronic acid conjugated derivatives of randodopril.

4 eliminate.

Trendopril can be eliminated after 7 days in the body (99. 2 ± 0.3%): about 1/3 is excreted from the urine, and 2/3 is excreted from the feces. Eliminate 88.5% of the drug within 48 hours. The elimination rate is very fast: its elimination half-life averages 0.7 hours. After a single 2 mg oral administration of Quandopril, the cumulative renal clearance in 24 hours is 3.81 L / h.

Contraindications

1. In patients with renal failure, if the creatinine clearance rate is <30ml / min, the dose should be reduced accordingly.

2. The blood concentration of patients with liver dysfunction will increase, so the drug should be started from 0.5mg, and the dose should be adjusted according to the treatment response.

3. Banned during pregnancy and lactation.

4. Patients with drug-induced hypertension or patients with vascular neurotic water caused by taking ACE inhibitors are contraindicated.

Adverse reactions

Incidence is low, and drug withdrawal is rarely required.

A few patients have had adverse reactions for a long time: dry cough, headache, dizziness, weakness, palpitations (> 1% of patients); hypotension, nausea, gastrointestinal disorders, pruritus, rash (<1% of patients), and edema. Children taking trandolapril have not reported efficacy and adverse reactions.

medicine interactions

Combination with diuretics can improve the efficacy, but it should be noted that the blood pressure is too low.

references

[1] Trendopril · Mobe Chemical Search · http: //baike.molbase.cn/cidian/37834

[2] Trendopril · Medical Encyclopedia · http: //www.wiki8.com/qunduopuli_32554/

[3] Pharmacology of ACE inhibitor Trandolapril [J]. Foreign Medicine. Synthetic Medicine. Biochemical Medicine. Preparations Volume, 1994, (No. 2).