66085-59-4 Usage
Uses
Used in Pharmaceutical Industry:
Nimodipine is used as a calcium channel blocker for treating ischemic cerebrovascular disease, mild to moderate hypertension, migraine, cerebral vasospasm, and sudden deafness. Its anti-ischemic and anti-vasoconstriction effects contribute to improved cerebral vasodilation and brain function.
Used in Neuroprotection Research:
Nimodipine is used as an L-type calcium channel (LTCC) inhibitor to evaluate its neuroprotective activity in various experimental models, potentially offering insights into its therapeutic potential in neurological conditions.
Used in Analytical Chemistry:
Nimodipine serves as a standard in the enantioseparation of chiral drugs by high-performance liquid chromatography (HPLC), aiding in the development and optimization of chiral separation methods.
Used in Pharmacological Studies:
Nimodipine is utilized in pharmacological studies for the measurement of spine voltage escape, providing valuable data for understanding the mechanisms of action and potential applications in treating neurological disorders.
Calcium channel blockers
Nimodipine, molecular formula C21H26N2O7, was first developed by Germany Bayer pharmaceutical industry. It is the latest generation of 1,4-dihydropyridine calcium channel blocker that is calcium blockers. It can inhibit the influx of calcium into vascular smooth muscle cells. It has bronchodilation effects isolated or intracorporal cerebral artery or ischemia cerebral artery. It can significantly improve cerebral blood flow, and effectively prevent and treat cerebral ischemic damage, migraines, sudden deafness that caused by cerebral vascular spasm which is induced by subarachnoid hemorrhage. Nimodipine can also be used for mild and moderate hypertension. It can effectively regulate the body's calcium in order to maintain the normal physiological function. It has particularly prominent effects on cerebral vascular, and it can combine with specific receptors of central nervous system. Cerebral vessels can be selectively expanded at a suitable dose, and it can hardly affect peripheral vascular. It also has a good effect on high blood pressure when its dose is increased.
The above information is edited by the lookchem of Ge Qian.
Pharmacological action
Nimodipine is calcium channel blockers. It can relieve vasospasm by effectively preventing Ca2+ into the cell and inhibiting contraction of smooth muscle. It is highly lipophilic, and easily permeates the blood-brain barrier. It has a strong effect on cerebral artery. In addition, it also has positive effect on protecting memory and recovering intelligence. Nimodipine has selective effects on cerebrovascular smooth muscle. It can expand cerebral blood vessels, increase cerebral blood flow and significantly reduce ischemic brain damage caused by vasospasm.
Pharmacokinetics
1. When taken orally, nimodipine can be rapidly absorbed after oral administration, and the concentration will reach a peak within about 1 hour. T1/2 is 1 to 2 hours, and the elimination time is 8 to 9 hours. After taken orally four times a day, the blood has no obvious accumulation of nimodipine for seven days. When its concentration is between 10ng/L and 10μg/mL, more than 95% of drugs combine with plasma protein. Most of nimodipine will be excreted in the form of metabolites after oral, and about 1% of the ingredients exit the body unchanged in the urine. Due to the rapid metabolism of nimodipine in a first phase, the bioavailability after taken orally is 13%. The biological activity of nimodipine in patients with chronic liver damage increases. And the maximum concentration can be up to twice as high as normal people.
2. Intravenous injection: The dosage for intravenous injection is 0.03mg/kg. The half-life (t1/2) is (1.1±0.2) h. According to the study, 15 patients with subarachnoid space bleeding (grade 1-3) have been injected with this product for 48mg a day, lasting 14 days. The average plasma concentration is 36~ 72μg/L. The protein binding rate is 96% to 99%. The steady state distribution of apparent volume is 1.6~3.1L/kg. The concentration of plasma drug decline quickly, and the metabolites almost has no activity. It is mainly eliminated through bile. 80% can be excreted by the intestine with faeces and 20% by the kidneys with the urine.
Synthesis route
The first step: using hydrogen chloride, concentrated sulfuric acid or acetic acid-piperidine as a catalyst, m-nitrobenzaldehyde (2) and 2-methoxy-ethyl acetoacetate (3) generate 2-(3-nitrobenzylidene) ethyl 2-methoxyethyl acetoacetate (4) by condensation.
The second step: concentrated hydrochloric acid and absolute ethanol are heated to the reflux reaction conditions under nitrogen. (4) and 3-amino butyric acid isopropyl ester (5) are heated to obtain crude product of (1). After cooling crystallization, pumping filtered, the filter cake is washed with cold ethanol. Then it is dried to get pale yellow crystals nimodipine (1).
Figure 1: Synthesis route of nimodipine
Indications
Nimodipine is a calcium antagonist of selective expansion of cerebral blood vessels. It can increase cerebral blood flow, improve cerebral blood circulation, prevent ischemic cerebral vasospasm, reduce calcium influx, protect ischemic brain cell function, prevent the occurrence and development of brain vascular disease and delay and prevent the occurrence of stroke. Nimodipine is mainly used for cerebral insufficiency, cerebral vasospasm, subarachnoid hemorrhage, stroke and migraine. It has a certain effect on sudden deafness.
Attentions
1.Nimodipine should be used for patients with cerebral edema and intracranial hypertension with caution. Nimodipine metabolites has toxicity. So patients with liver dysfunction should be used with caution. Nimodipine can cause a lowering of blood pressure. For patients with hypertensive subarachnoid hemorrhage or stroke patients, the dosage of antihypertensive drugs should be paid attention to be reduced or temporarily stopped, or the dosage of nimodipine should be reduced. That can produce intestinal pseudo-obstruction, manifested as abdominal distension, decreased bowel sounds. When the above symptoms appears, the dosage should be reduced and observation should be hold.
2.Nimodipine can be secreted by milk. Breast-feeding women should not use. Animal experiments suggest that this product has teratogenicity.
Untoward reaction
There are about 11.2% of patients with subarachnoid hemorrhage that have adverse reactions. The most common symptoms are blood pressure dropping (the extent of decline is related to drug dose), hepatitis, skin irritation, gastrointestinal bleeding, thrombocytopenia, occasionally transient dizziness, headache, facial flushing, vomit, gastrointestinal discomfort and the like. In addition, after taken nimodipine orally, individual patients may appear alkaline phosphatase (ALP), lactate dehydrogenase (LDH), blood sugar elevating and platelet count increasing for individual human.
Usage and dosage
The usage and dosage of this product is very different for different symptom and severity.
1. Nimodipine can be taken orally when symptoms are mild:
Ischemic cerebrovascular disease: 20~40mg, 3 times/d, continuous use for a month.
Migraine: 40mg, 3 times/d; 12 weeks for a course of treatment.
Hypertension: 40~80mg, 3 times/d.
Sudden deafness: 10~20mg, 3 times/d; 5 days as a course of treatment, usually for 3 to 4 courses.
Cerebral vasospasm caused by subarachnoid hemorrhage: 10~20mg, 3~4 times/d; 3 to 4 weeks for a course of treatment.
2. Severe patients with the above-mentioned diseases may be considered to use ntravenous injection: the beginning of 0.5mg/h, gradually increase after 2h to 1~2mg/h; 5~10d later change to oral.
Chemical property
Light yellow crystalline powder, odorless and tasteless. Soluble in ethanol or acetone, insoluble in water. Melting point 124~128℃. Acute toxicity LD50 in mice and rats (mg/kg): 3562, 6599. Oral: 33. Intravenous injection: 16.
(+)-Configuration: [α] D20+7.9° (C=0.439, dioxane).
(-)-Configuration: [α] D20-7.93° (C=0.374, dioxane).
Production method
Method 1: Nimodipine can be synthesized from nitrobenzaldehyde first by condensation with methoxyethyl acetoacetate catalyzed by hydrochloric acid or concentrated sulfuric acid, and then heated with 3-amino butyric acid isopropyl ester in ethanol by cyclization.
Method 2: Nitrobenzaldehyde and isopropyl acetoacetate also can be dissolved with stirring at room temperature firstly. Then add glacial acetic acid and piperidine and stir at 40-50℃ to solidify (about 6~7h). After processing for 4h at 40-50℃, 95% ethanol is added, and then heated under reflux until the solid dissolved. Cooled to 0~5℃, precipitated crystals can be filtered and dried to give 2-(3-nitrophenyl methylene) acetyl isopropyl acetate. The yield is 90.6%. Then it reacts with 3-amino butyric acid and 2-methoxy-ethyl ester to obtain the crude product. The crude product can be recrystallized from ethanol to get nimodipine. The yield is 84%, and the melting point is 125~126℃.
The second step can also be carried out as follows: 3.8g 2-(3-nitrophenyl methylene) acetyl isopropyl acetate, 8g 2-methoxy-ethyl acetoacetate and 6ml of concentrated ammonia are heated at reflux for 8h in 80ml of ethanol. The product is recrystallized with petroleum ether-ethyl acetate to obtain nimodipine. The yield is 49%, and the melting point is 125℃.
Originator
Bayer (W. Germany)
Manufacturing Process
After 8 hours boiling of solution of 3.8 g of 3'-nitro-benzylideneacetoacetic
acid isopropylester, 8 grams of acetoacetic acid β-metoxyethyl ester and 6 ml
conc ammonia in 80 ml ethanol under reflux, 2,6-dimethyl-4-(3'-nitrophenyl)-
1,4-dihydropyridine 3-β-methoxyethyl ester 5-isopropyl ester of melting point
125°C (petroleum ether/ acetic ester) was obtained. Yield 49% of theory.
Therapeutic Function
Vasodilator
Biological Activity
L-type Ca 2+ channel blocker.
Biochem/physiol Actions
Nimodipine enhances the survival of dopaminergic substantia nigra neurons.
Clinical Use
Calcium-channel blocker:
Prevention and treatment of ischaemic neurological
deficits following subarachnoid haemorrhage
Drug interactions
Potentially hazardous interactions with other drugs
Aminophylline: possibly increases aminophylline
concentration.
Anaesthetics: enhanced hypotensive effect.
Antibacterials: metabolism accelerated by rifampicin;
metabolism possibly inhibited by clarithromycin,
erythromycin and telithromycin.
Antidepressants: enhanced hypotensive effect with
MAOIs .
Antiepileptics: effect reduced by carbamazepine,
barbiturates, phenytoin and primidone.
Antifungals: metabolism possibly inhibited by
itraconazole and ketoconazole; negative inotropic
effect possibly increased with itraconazole.
Antihypertensives: enhanced hypotensive effect,
increased risk of first dose hypotensive effect of post synaptic alpha-blockers.
Antivirals: concentration possibly increased by
ritonavir; use telaprevir with caution.
Grapefruit juice: concentration increased - avoid.
Theophylline: possibly increased theophylline
concentration.
Metabolism
Nimodipine is extensively metabolised in the liver via the
cytochrome P450 isoenzyme CYP3A4. It is eliminated
as metabolites, mainly by dehydrogenation of the
dihydropyridine ring and oxidative O-demethylation.
Oxidative ester cleavage, hydroxylation of the 2- and
6-methyl groups, and glucuronidation as a conjugation
reaction are other important metabolic steps. The three
primary metabolites occurring in plasma show no or only
therapeutically negligible residual activity.
The metabolites are excreted about 50% renally and 30%
in faeces via the bile.
References
1) Cohen and McCarthy (1987),?Nimodipine block of calcium channels in rat anterior pituitary cells; J. Physiol.,?387?195
2) Batuecas?et al.?(1998),?Effects of chronic nimodipine on working memory of old rats in relation to defects in synaptosomal calcium homeostasis; Eur. J. Pharmacol.,?350?141
3) LeVere?et al.?(1989),?Recovery of function after brain damage: facilitation by the calcium entry blocker nimodipine; Behav. Neurosci.,?103?561
4) Herzfeld?et al.?(2014),?Investigation of the neuroprotective impact of nimodipine on Neuro2a cells by means of a surgery-like stress model; Int. J. Mol. Sci.,?15?18453
5) Schampel?et al.?(2017),?Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis; Proc. Natl. Acad. Sci. USA,?114?E3295
6) Allen?et al.?(1983),?Cerebral arterial spasm – a controlled trial of nimodipine in patients with subarachnoid hemorrhage; N. England J. Med.,?308?619
Check Digit Verification of cas no
The CAS Registry Mumber 66085-59-4 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 6,6,0,8 and 5 respectively; the second part has 2 digits, 5 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 66085-59:
(7*6)+(6*6)+(5*0)+(4*8)+(3*5)+(2*5)+(1*9)=144
144 % 10 = 4
So 66085-59-4 is a valid CAS Registry Number.
InChI:InChI=1/C21H26N2O7/c1-12(2)30-21(25)18-14(4)22-13(3)17(20(24)29-10-9-28-5)19(18)15-7-6-8-16(11-15)23(26)27/h6-8,11-12,17,19H,9-10H2,1-5H3/t17?,19-/m0/s1
66085-59-4Relevant articles and documents
METHODS FOR TREATING CHRONIC FATIGUE SYNDROME AND MYALGIC ENCEPHALOMYELITIS
-
, (2021/03/13)
In one aspect the invention relates to a method of treatment selected from the group consisting of: (a) treating a symptom such as pain in a subject identified or diagnosed as having Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); (b) treating a symptom such as pain in a subject having dysfunctional TRPM3 ion channel activity; (c) restoring NK cell function in a subject having dysfunctional TRPM3 ion channel activity; and (d) restoring calcium homeostasis in a subject having dysfunctional TRPM3 ion channel activity. The method comprises the step of administering to the subject a therapeutically effective amount of at least one therapeutic compound selected from the group consisting of: (i) an opioid receptor antagonist; (ii) an opioid antagonist; and (iii) a therapeutic compound that restores TRPM3 ion channel activity. In some embodiments the therapeutic compound is naltrexone hydrochloride.
Nimodipine impurity IV reference substance as well as preparation method and application thereof
-
Paragraph 0057-0059, (2020/11/22)
The invention discloses a nimodipine impurity IV reference substance and a preparation method thereof. The method includes the steps that diketene, ethyl alcohol and triethylamine are taken and addedinto a container to be heated and cooled, reaction liquid is washed with water, washing liquid is discarded, anhydrous sodium sulfate is added and placed overnight, filtrate is obtained after filtration, ammonia gas is introduced into the filtrate until the filtrate is saturated, and the nimodipine impurity IV reference substance is obtained; and after the reaction is finished, m-nitrobenzaldehyde, methoxyethyl acetoacetate and ethanol are added, heating refulx is performed, the mixture is cooled and filtered, the solvent is removed through volatilization in a water bath to obtain a yellow viscous liquid, and recrystallization is carried out to obtain a yellow acicular crystal, namely the nimodipine impurity IV reference substance. The invention also discloses an application of the nimodipine impurity IV reference substance in nimodipine tablet consistency evaluation. According to the preparation method, the impurity IV can be prepared in a general analysis laboratory, special preparation equipment is not needed, the operation is simple, the purity of the obtained impurity reference substance can reach 98.4%, the purity requirement of the reference substance is met, and the preparation method can be used for consistency evaluation of the variety.
Metal-free-mediated oxidation aromatization of 1,4-dihydropyridines to pyridines using visible light and air
Wei, Xiaojing,Wang, Lin,Jia, Wenliang,Du, Shaofu,Wu, Lizhu,Liu, Qiang
supporting information, p. 1245 - 1250 (2015/02/05)
A metal-free and environmentally friendly aerobic aromatization photosensitized by organic dye eosin Y bis(tetrabutyl ammonium salt) (TBA-eosinY) has been developed. With the aid of K2CO3, the aerobic catalytic system converts 1,4-dihydropyridines to their corresponding pyridine derivatives efficiently under visible light irradiation (λ=450 nm) at room temperature.
Polymorph Compositions, Methods of Making, and Uses Thereof
-
Paragraph 0290; 0291; 0292, (2013/11/19)
The described invention provides a biodegradable, biocompatible delivery system of flowable sustained release microparticulate composition of a substantially pure crystalline form of a bioactive agent such as, for example, nimodipine, a process of preparing a therapeutic form of a substantially pure crystalline form of the bioactive agent and a method for treating an interruption of a cerebral artery in a subarachnoid space at risk of interruption caused by brain injury in a mammal, which reduces signs or symptoms of at least one delayed complication associated with brain injury.
THERAPY FOR COMPLICATIONS OF DIABETES
-
, (2009/07/02)
A method for enhancing glycemic control and/or insulin sensitivity in a human subject having diabetic nephropathy and/or metabolic syndrome comprises administering to the subject a selective endothelin A (ETA) receptor antagonist in a glycemic control and/or insulin sensitivity enhancing effective amount. A method for treating a complex of comorbidities in an elderly diabetic human subject comprises administering to the subject a selective ETA receptor antagonist in combination or as adjunctive therapy with at least one additional agent that is (i) other than a selective ETA receptor antagonist and (ii) effective in treatment of diabetes and/or at least one of said comorbidities other than hypertension. A therapeutic combination useful in such a method comprises a selective ETA receptor antagonist and at least one antidiabetic, anti-obesity or antidyslipidemic agent other than a selective ETA receptor antagonist.
ANTIHYPERTENSIVE THERAPY
-
, (2009/09/08)
A new use of darusentan is provided in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy with one or more drugs. The composition comprises darusentan in an amount providing a therapeutically effective daily dose; wherein (a) the composition is orally deliverable and/or (b) the daily dose of darusentan is effective to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures. Further provided is a new use of darusentan in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy, wherein the composition is administered adjunctively with at least one diuretic and at least one antihypertensive drug selected from ACE inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers and calcium channel blockers.
Method for treating resistant hypertension
-
, (2008/06/13)
A method is provided for lowering blood pressure in a patient having clinically diagnosed resistant hypertension. The method comprises administering darusentan to the patient adjunctively with a baseline antihypertensive regimen that comprises administration of at least one diuretic and at least two antihypertensive drugs selected from at least two of (a) ACE inhibitors and angiotensin II receptor blockers, (b) beta-adrenergic receptor blockers and (c) calcium channel blockers. The darusentan is orally administered at a dose and frequency effective, in combination with the baseline regimen, to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures.
Syntheses, calcium channel antagonist and anticonvulsant activities of substituted 1,4-dihydro-3,5-pyridinedicarboxylates containing various 3-alkyl ester substituents
Yiu, Sai-Hay,Knaus, Edward E.
, p. 35 - 43 (2007/10/03)
A group of 3-alkyl-5-isopropyl 4-aryl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylates 10-20 containing an amine, quaternary ammonium, aryl(heteroaryl)alkenyl, 4-(4-fluorophenyl)-piperazin-1-yl or methoxy moiety in the C-3 alkyl ester R-substituent in combination with a C-4 phenyl ring bearing a 2,3-Cl2, 3-NO2, 3-NMe2, 4-NMe2 or 3,4,5-(OMe)3 X-substituent were prepared using the Hantzsch 1,4-dihydropyridine reaction. In vitro calcium channel antagonist activity (CCA) was determined using a guinea pig ileum longitudinal smooth muscle assay. In the C-4 3-nitrophenyl series of compounds, the C-3 ester R substituent was a determinant CCA activity where the relative potency order was -CH2CH2CH=C-(2-methylphenyl)2 ≤ -CH2CH2NMe2.HCl > -CH2CH2CH=C (3-methyl-2-thienyl)2 > -CH2CH2+NMe3I-. The position and nature of the C-4 phenyl X-substituent, were also determinants of CCA activity where the relative activity order was 3-NMe2>4-NMe2>3,4,5-(OMe)3. Anticonvulsant activities were determined in mice using the subcutaneous metrazol (scMet) and maximal electroshock (MES) screens. The compounds investigated were generally not effective for protecting against scMet induced seizures, except for 10 {X = 2,3-Cl2, R = 2-[4-(4-fluorophenyl)piperazin-1-yl]ethyl} and 14a (X = 3-NMe2.HCl, R = CH2CH2OMe), which exhibited modest activity. Compound 11a (X = 3-NO2, R = -CH2CH2NMe2.HCl) was the most effective agent in the MES screen. All of the compounds investigated, except for 11b (X = 3-NO2, R = -CH2CH2+NMe3 I-, Kp = 0.15) are lipophilic with n-octanol/aqueous phosphate buffer (pH = 7.4) partition coefficients (Kp) in the 121-424 range relative to the reference drug nimodipine (Kp = 187). The structure-activity relationship acquired reinforce the concept that calcium is only one of several factors that are involved in seizure generation.
Approaches to combinatorial synthesis of heterocycles: A solid-phase synthesis of 1,4-dihydropyridines
Gordeev, Mikhail F.,Patel, Dinesh V.,Gordon, Eric M.
, p. 924 - 928 (2007/10/03)
N-Immobilized enamino esters 2 derived from amine-functionalized PAL or Rink polystyrene resins react with preformed 2-arylidene β-keto esters or directly with β-keto esters and aldehydes to afford, upon trifluoroacetic acid cleavage, 1,4-dihydropyridine (DHP) derivatives in good yields. The mechanism of this transformation on solid support has been studied using 13C NMR and IR spectroscopies. This new solid-phase synthesis has been applied to the preparation of several bioactive DHPs and is designed to be amenable to the 'split and pool' protocol for combinatorial library synthesis.
1,4-Dihydro-2,6-dimethyl-4-(2'-chlorophenyl)-3,5-dicarboxylic acid,methyl or ethyl,trifluoroethyl ester
-
, (2008/06/13)
The invention relates to optically active 1,4-dihydropyridine compounds of Formulas Ia and Ib as defined hereinabove which are effective for influencing circulation. Also included in the invention are compositions containing said optically active compounds and methods for the use of said compounds and compositions.
