What Is Benidipine?

The chemical name of Benidipine is (±) -2,6, -dimethyl-4- (3-nitrophenyl) -1,4-dihydro-3,5-pyridinedicarboxylic acid, 3- (1- Benzyl-3-piperidinyl) ester-5-methyl ester, with a density of 1.29 g / cm3, is clinically used to treat hypertension and angina pectoris.

Chinese name: Benidipine
Foreign name: Benidipine

CAS number: 105979-17-7
Molecular formula: C28H31N3O6

Introduction to Benidipine Compounds

Benedipine Basic Information

Chinese name: Benidipine

Chinese alias: (R ^^, R ^^)-(±) -2,6-dimethyl-4- (3-nitrobenzene) -1,4-dihydro-3,5-pyridinedicarboxylic acid Methyl ester (R ^^)-1-benzyl-3-piperidinyl ester; (+/-)-(R *)-3-((R *)-1-benzyl-3-piperidinyl) -5-methyl-1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridine dicarboxylate; (R *, R *)- (1-Benzyl-3-piperidinyl) -5-methyl-1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedi Formate hydrochloride;

English name: Benidipine;

English alias: 5-O-[(3R) -1-benzylpiperidin-3-yl] 3-O-methyl (4R) -2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3 , 5-dicarboxylate; (+/-)-(R *)-3-[(R *)-1-benzyl-3-piperidyl] methyl-1,4-dihydro-2,6-dimethyl-4- (m -nitrophenyl) -3,5-pyridinedicarboxylate hydrochloride; H007; Benidipene;

CAS number: 105979-17-7

Molecular formula: C ₂₈ H ₃₁ N ₃ O ₆

Structural formula:

Molecular weight: 505.56200

Exact mass: 505.22100

PSA: 113.69000

LogP: 5.00030

Physical and Chemical Properties of Benidipine

Density: 1.29 g / cm ³

Boiling point: 625.2ºC at 760 mmHg

Flash point: 331.9ºC

Refractive index: 1.621

Vapor pressure: 1.5E-15mmHg at 25 ° C ^[1]

Benedipine Toxicology Data

1. Acute toxicity: oral LD50 in mice: 218mg / kg;

Benedipine molecular structure data

1. Molar refractive index: 137.61

2. Molar volume (cm / mol): 390.7

3. Isometric Zhang Rong (90.2K): 1078.4

4. Surface tension (dyne / cm): 58

5. Dielectric Constant: None available

6. Polarizability (10cm): 54.55

7. Mass of single isotope: 505.2221286 Da

8. Nominal mass: 505 Da

9. Average quality: 505.5622 Da

Benedipine Computational Chemistry Data

1. Hydrophobic parameter calculation reference value (XlogP): None

2.Number of hydrogen-bonded donors: 1

3.Number of hydrogen bond acceptors: 8

4.Number of rotatable chemical bonds: 8

5.Number of tautomers: 5

6. Topological molecular polar surface area 114

7.Number of heavy atoms: 37

8.Surface charge: 0

9.Complexity: 933

10.Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 2

12. Uncertain number of atomic stereocenters: 0

13. Determine the number of chemical bond stereocenters: 0

14. Uncertain number of chemical bond stereocenters: 0

15.Number of covalent bond units: 1

Benidipine synthesis method

Method 1: Acid chloride method. 2.5 g (-)-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (I) and 0.57 ml of chlorine The sulfoxide is reacted in dichloromethane-dimethylformamide to obtain the acid chloride (II). (II) reacted with 1.51 g of (+)-1-benzyl-3-hydroxypiperidine for 2 h. After acidification, 2.72 g of (+)-benidipine hydrochloride was obtained. (-)-Benidipine hydrochloride is also available.

Method 2: Common method ring. The side chain was made into the corresponding acetoacetate (III). Then () and 3-nitrobenzaldehyde and methyl 3-aminobutenoate are heated in isopropanol to cyclize to form benidipine.

Benedipine uses

1. Dihydropyridine calcium antagonist, used for hypertension and angina pectoris.

2. Dihydropyridine calcium antagonists. For hypertension and angina. It can relax blood vessels, reduce blood pressure and increase coronary flow, and has a stronger effect than nifedipine, but its bioavailability is low. ^[2]

Benedipine pharmacological action

Combining this product with the DHP-binding site of the membrane-membrane-potential-dependent calcium channel inhibits the influx of calcium ions, thereby expanding the coronary arteries and peripheral blood vessels. It is speculated that this product mainly enters the cell membrane and combines with DHP binding sites. In addition, by studying the inhibitory effect of this product on constriction of retreating blood vessels and its affinity with DHP binding sites, it has been proved that this product has strong affinity with DHP binding sites and has a very slow dissociation rate, so it shows a continuous pharmacological effect and has a blood concentration No correlation.

(1) Antihypertensive effect

Spontaneously hypertensive rats, DOCA-salt-hypertensive rats, and renal hypertensive dogs can all show slow-acting and long-lasting antihypertensive effect when administered orally.

No drug resistance was seen after long-term administration.

Patients with essential hypertension orally take this product once a day can produce a 24-hour stable antihypertensive effect without affecting the diurnal changes of blood pressure.

(2) Anti-angina pectoris effect

This product significantly improves cardiac dysfunction and ischemic electrocardiogram changes caused by experimental angina pectoris and canine coronary ischemia-reperfusion in rats.

Oral administration of this product in patients with exertional angina pectoris can significantly improve ischemic changes caused by exercise load (reduction of ECG ST).

(3) Maintaining renal function

Renal insufficiency (nephrectomy 5/6) in spontaneously hypertensive rats, when continuously administered orally, can show a hypotensive effect and improve renal function.

This product can significantly increase renal blood flow in patients with essential hypertension. Patients with chronic renal insufficiency accompanied by hypertension can significantly increase creatinine clearance and urea nitrogen clearance to maintain renal function. ^[3]

(4) Inhibition of vascular remodeling and protection of vascular endothelium This product increases NO production by activating endothelial NO synthase (eNOS) and enhancing eNOS gene expression, and inhibits NO inactivation through its antioxidant effect, eventually expanding NO organisms Activity, thereby inhibiting vascular remodeling and protecting the vascular endothelium. ^[4]

Benidipine Toxicity Study

Acute toxicity of Benidipine

Humans and mice continuously orally administered this product for 0.38, 1.5, 3, 6, 25, 50, and 100 mg / kg for 3 months. Fatty deposits in the liver were observed in the group above 6 mg / kg (the marginal zone of the hepatic lobules to the middle zone). Can be recovered or has a tendency to recover. The non-toxic dose is 1.5 mg / kg.

Dogs were given orally to this product 0.17, 0.5, 1.5, 3, 6, 12 mg / kg for 3 months. Heart rate and heart weight increased in the group above 1.5 mg / kg, and atrioventricular block was seen at 6 mg / kg. The non-toxic dose is 0.5 mg / kg.

Benedipine chronic toxicity

Rats were orally given this product continuously for 0.38, 0.75, 1.5, 6 mg / kg for 12 months. In the group above 0.75 mg / kg, the weight of thymus was reduced and the edge of the liver was dulled. The weight of heart, lung and spleen was increased in the above 1.5mg / kg group. 6mg / kg inhibited weight gain and increased liver and kidney weight.

Dogs were given orally to this product continuously for 0.004, 0.02, 0.1, 0.38, 1.5, 6 mg / kg for 12 months, and the heart rate increased and gingival hyperplasia was seen in the above 1.5 mg / kg group. Atrioventricular block was seen at 6 mg / kg, but no pathological changes were found in the heart by histopathological examination.

Benidipine reproductive toxicity

The rats were given 3-50 mg / kg orally before pregnancy and early pregnancy, and the amount of corpus luteum was slightly reduced at 50 mg / kg. However, the number of implants and fetuses in all administration groups were not different from the control group, and The fetuses developed well.

Oral administration of 6-35mg / kg of this product in rats during organ formation, 6-100mg / kg of this product in rabbits orally. Rats showed a slight increase in the number of fetal deaths at 35mg / kg, and rabbits at 100mg / kg. An increase in the rate of dead embryos was observed, but no teratogenicity was seen.

Oral administration of 6-35mg / kg to rats during perinatal and lactation periods. Prolonged pregnancy can be seen above 25mg / kg, prolonged delivery time and increased number of dead pigs can be seen at 35mg / kg, and lactation period can be seen above 12mg / kg. Inhibition of weight gain in pups. ^[3]

Pharmacokinetics of Benidipine

1. Absorption

This product is absorbed quickly after oral administration, and the blood drug concentration reaches a peak about 1 hour after oral administration (2, 4, 8 mg) in healthy adults, and the half-life is 1 to 2 hours. The pharmacokinetic results are shown in the table below:

Dosage	Cmax (ng / mL)	Tmax (hr)	T1 / 2	AUC0- (ng · hr / mL)
2mg	0.55 ± 0.41	1.1 ± 0.5	-	1.04 ± 1.26
4mg	2.25 ± 0.84	0.8 ± 0.3	1.70 ± 0.70	3.94 ± 0.96
8mg	3.89 ± 1.65	0.8 ± 0.3	0.97 ± 0.34	6.70 ± 2.73

Distribution

1) Distribution of tissues in the body (reference: data from rats)

After oral administration of 14C-benidipine hydrochloride to rats at 1 mg / kg, benidipine is mainly distributed in the liver, kidney, adrenal gland, submandibular gland, lung, pituitary, and pancreas, but less in the brain, spinal cord, and testis.

2) Distribution (reference: data from rats)

Distribution in the fetus	C-Benidipine hydrochloride was orally administered to pregnant rats at 1 mg / kg. The distribution of the drug was seen in the fetuses, and the total amount was less than 1/3 of the maternal plasma.
Distribution in breast milk	C-Benidipine hydrochloride was orally administered to the lactating rats at a concentration of 1 mg / kg, and the drug concentration in the milk was basically consistent with the drug concentration in the plasma.

3) protein binding rate

In vitro (human serum)	98.46 98.93 (1 100,000ng / ml 3H-benidipine hydrochloride)
In vivo (human plasma: results of tests in the UK)	75.0% (oral C-benedipine hydrochloride 8mg, blood collected after 1 hour) 76.0% (oral C-benedipine hydrochloride 8mg, blood collected 2 hours later)

3. Metabolism

According to the metabolites detected in human plasma and urine, and metabolism studies in animals, it is believed that the human metabolic reaction is mainly to remove the benzyl group at the 3-position side (N-dealkylation), and to hydrolyze the 1-position at the 3-position. Benzyl-3-piperidine ester and methyl ester at 5-position, oxidizing dihydropyridine ring, and oxidizing methyl group at 2-position.

4, excretion (refer to the test results in the UK)

Five adult males in Western Europe, with a single oral dose of 14C-benidipine hydrochloride 8mg, accumulated radioactive excretion rate, the urine excretion amount within about 48 hours after administration was about 35% of the total dose, and excretion in feces was about It was 36%, and the urine excretion was 36% and the fecal excretion was about 59% within 120 hours after the administration. ^[4]

Benedipine indications

This product is used to treat hypertension and angina. ^[3]

Benidipine buck mechanism

Benedipine achieves antihypertensive and antianginal effects by blocking L-shaped channels. In the "membrane pathway" mode, it shows its characteristics of gentle onset and continuous reduction of blood pressure. Benidipine binds to the DHP-binding site of the cell membrane potential-dependent calcium channel, inhibits calcium influx, and thereby dilates coronary arteries and peripheral blood vessels.

Protect the kidneys by blocking T-channels. It is known that only the renal arterioles are present in the L-shaped channel and there is no efferent arterioles, but there are T-type calcium channels in the efferent arterioles. Benedipine can partially block T-channels.

The heart rate does not increase after the medication is because the block of the N-type channel is reached to reduce the reflex sympathetic nerve excitation.

Benedipine Taboo:

1. Patients with cardiogenic shock [may worsen symptoms].

2. Pregnant women or women who may be pregnant ^[3]

Benedipine dosage and dosage

Taken orally after breakfast. Adult dosage is usually 2mg-4mg once daily. The dose should be adjusted according to age and symptoms. If the effect is not satisfactory, it can be increased to 8mg each time, once a day. Patients with severe hypertension should take 4 to 8 mg each time, once a day. ^[4]

Essential hypertension: In the case of benidipine hydrochloride, the dosage for adults is usually once a day, 2-4 mg once, taken orally after breakfast, and should be increased or decreased according to age and symptoms. When the effect is not good, it can be increased to once a day, 8mg once. Patients with severe hypertension, once a day, 4-8mg once a day, orally after breakfast.

Angina Pectoris: Calculated by benidipine hydrochloride, the dosage for adults is usually 2 times a day, 1 mg once a day, morning and evening, orally after meals, and should be increased or decreased according to age and symptoms. ^[3]

Benedipine adverse reactions

The use of this drug from the registered clinical trial to October 1997 was investigated, and the total sample size was 4679 cases. Among them, 219 cases (4.7%) and 361 cases had side effects and abnormal clinical test values. The main side effects included palpitations in 24 cases (0.5%), facial flushing in 22 cases (0.5%), and headache in 20 cases (0.4%). ^[3]

The common adverse reactions are as follows and should be observed carefully. If abnormalities occur, the dosage should be reduced or discontinued and appropriate treatment should be performed.

Liver: A small number of patients (0.1 to 5%) show signs of liver damage such as elevated GOT, GPT, -GTP, AI-P, bilirubin, and LDH. Therefore, it is necessary to pay attention to observation and discontinue treatment if abnormal.
Kidney: A few patients (0.1 to 5%) developed BUN and creatinine.
Blood: A few patients (0.1 to 5%) showed a decrease in white blood cell count and an increase in eosinophils.
Circulatory system: A small number of patients (0.1 to 5%) have palpitations, facial flushing, hot flashes, and lowering blood pressure, and a very small number of patients (<0.1%) have chest pressure, bradycardia, tachycardia, and extrasystoles. By.
Nervous system: A few patients (0.1 to 5%) have headache, head weight, dizziness, gait instability, orthostatic hypotension, and very few patients (<0.1%) have drowsiness and numbness.
Digestive system: A small number of patients (0.1 to 5%) have constipation, and a very small number of patients (<0.1%) have abdominal discomfort, nausea, heartburn, thirst, and diarrhea and vomiting.
Allergies: A few patients (0.1 to 5%) have a rash, a very small number of patients (<0.1%) have an itching sensation, and some have photosensitivity. If rash, pruritus, photosensitivity occur, the drug should be discontinued.
Others: A few patients (0.1 to 5%) have edema (face, legs, hands), GPK rise, and a very small number of patients (<0.1%) have tinnitus, redness or heat in the fingers, shoulder condensation, cough, frequent urination, fatigue sense. ^[4]

Benidipine precautions

1.The following patients should not take medication:

1) Patients with cardiogenic shock [taking this product may worsen symptoms].

2) Pregnant women, women who may become pregnant, and lactating women are prohibited.

2.Prudent use of drugs (the following patients should be used with caution)

1) Patients with low blood pressure.

2) This product may aggravate liver damage, and be used with caution in patients with severe liver damage.

3) The reference for elderly patients (medicine for elderly patients).

3. Important basic considerations

1) Sudden discontinuation of calcium antagonists. Cases with worsening symptoms are reported. Therefore, when discontinuing this product, it should be gradually reduced and observed carefully. In addition, patients should not be told to stop taking their own medicine.

2) Taking this product may cause excessive lowering of blood pressure and transient loss of consciousness. If such symptoms occur, the drug should be discontinued and treated appropriately.

3) Dizziness caused by blood pressure reduction may occur. Therefore, attention should be paid to dangerous mechanical operations such as working at heights and driving cars.

4. Other matters needing attention

According to reports, in patients undergoing continuous outpatient peritoneal dialysis, sometimes the dialysis discharge is cloudy, so attention should be paid to the identification of peritonitis.

Benedipine for pregnant and lactating women:

Pregnant women or women who may become pregnant should avoid medication [It has been reported that fetal toxicity is seen in animal experiments (rats, rabbits), and administration in the third trimester will prolong the pregnancy and delivery time].

Breastfeeding women should not take medication, and should stop breastfeeding as a last resort [It is reported that the distribution of the drug in breast milk can be seen in animal experiments (rats)].

Benedipine medication for children:

Safety has not been established for preterm infants, newborns, infants, young children or children (no experience with use).

Benedipine for elderly:

In general, elderly patients should not be excessively hypotensive. Therefore, elderly patients suffering from hypertension should start with a small dose (2mg / day), and pay attention to observe the medication, and it is advisable to administer it carefully. ^[3]

Benidipine drug interactions

1 Other antihypertensive drugs: The antihypertensive effect is enhanced, which may cause excessive reduction in blood pressure.

2 Digoxin: Inhibit the secretion of digoxin in the renal tubules, and increase the concentration of digoxin in the blood. May cause digitalis poisoning.

3 Cimetidine: Cimetidine inhibits the calcium antagonist metabolic enzymes of liver microsomes, while reducing gastric acid and increasing drug absorption. It may cause excessive lowering of blood pressure.

4 Rifampicin: Rifampicin induces drug metabolizing enzymes in the liver, and promotes the metabolism of calcium antagonists, which can reduce the blood concentration of benidipine and weaken the hypotensive effect.

5 Grapefruit juice: Grapefruit juice inhibits the metabolism of this product in the liver and increases the blood concentration of this product. It may cause excessive lowering of blood pressure. ^[4]

Benidipine overdose

Overdose may cause excessive reduction in blood pressure. If severe blood pressure reduction occurs, lower limbs should be raised, and appropriate treatment such as infusion or booster medication should be performed. In addition, due to the high protein binding rate of this product, the method of dialysis removal is not effective. ^[3]