DIPINE SERIES


 



1 CILNIDIPINE
2 ISRADIPINE
3
4
5
6


1 CILNIDIPINE




Cilnidipine
西尼地平
CAS 132203-70-4
  • (E) – (±) 1 ,4 a dihydro-2 ,6 – dimethyl-4 – (3 – nitrophenyl) -3,5 – pyridinedicarboxylic acid, 2 – methoxy- ethyl butylester 3 – phenyl – 2 – propenyl ester FRC-8653 Cinalong
  • More FRC 8653 1,4-Dihydro-2 ,6-dimethyl-4-(3-nitrophenyl) 3 ,5-pyridinedicarboxylic acid 2-methoxyethyl (2E)-3-phenyl-2-propenyl ester
  • Molecular formula:C 27 H 28 N 2 O 7
  • Molecular Weight:492.52
CAS Name: 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-methoxyethyl (2E)-3-phenyl-2-propenyl ester
Additional Names: (±)-(E)-cinnamyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate
Cinnamyl 2-methoxyethyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
Manufacturers' Codes: FRC-8653
Trademarks: Atelec (Morishita); Cinalong (Fujirebio); Siscard (Boehringer, Ing.)
Percent Composition: C 65.84%, H 5.73%, N 5.69%, O 22.74%
Properties: Crystals from methanol, mp 115.5-116.6°. LD50 in male, female mice, rats (mg/kg): ³5000, ³5000, ³5000, 4412 orally;³5000 all species s.c.; 1845, 2353, 441, 426 i.p. (Wada).
Melting point: mp 115.5-116.6°
Toxicity data: LD50 in male, female mice, rats (mg/kg): ³5000, ³5000, ³5000, 4412 orally; ³5000 all species s.c.; 1845, 2353, 441, 426 i.p. (Wada)
Ajinomoto (INNOVATOR)
 Antihypertensive; Dihydropyridine Derivatives; Calcium Channel Blocker; Dihydropyridine Derivatives.


Cilnidipine (INN) is a calcium channel blocker. It is sold as Atelec in Japan, asCilaheart, Cilacar in India, and under various other trade names in East Asian countries.
Cilnidipine is a dual blocker of L-type voltage-gated calcium channels in vascular smooth muscle and N-type calcium channels in sympathetic nerve terminals that supply blood vessels. However, the clinical benefits of cilnidipine and underlying mechanisms are incompletely understood.
Clinidipine is the novel calcium antagonist accompanied with L-type and N-type calcium channel blocking function. It was jointly developed by Fuji Viscera Pharmaceutical Company, Japan and Ajinomoto, Japan and approved to come into market for the first time and used for high blood pressure treatment in 1995. in india j b chemicals & pharmaceuticals ltd and ncube pharmaceutical develope a market of cilnidipine.
Hypertension is one of the most common cardiovascular disease states, which is defined as a blood pressure greater than or equal to 140/90 mm Hg. Recently, patients with adult disease such as hypertension have rapidly increased. Particularly, since damages due to hypertension may cause acute heart disease or myocardial infarction, etc., there is continued demand for the development of more effective antihypertensive agent.
Meanwhile, antihypertensive agents developed so far can be classified into Angiotensin II Receptor Blocker (ARB), Angiotensin-Converting Enzyme Inhibitor (ACEI) or Calcium Chanel Blocker (CCB) according to the mechanism of actions. Particularly, ARB or CCB drugs manifest more excellent blood pressure lowering effect, and thus they are more frequently used.
However, these drugs have a limit in blood pressure lowering effects, and if each of these drugs is administered in an amount greater than or equal to a specific amount, various side-effects may be caused. Therefore, there have been many attempts in recent years to obtain more excellent blood pressure lowering effect by combination therapy or combined preparation which combines or mixes two or more drugs.
Particularly, since side-effect due to each drug is directly related to the amount or dose of a single drug, there have been active attempts to combine or mix two or more drugs thereby obtaining more excellent blood pressure lowering effect through synergism of the two or more drugs while reducing the amount or dose of each single drug.
For example, US 20040198789 discloses a pharmaceutical composition for lowering blood pressure combining lercanidipine, one of CCB, and valsartan, irbesartan or olmesartan, one of ARB, etc. In addition, a combined preparation composition which combines or mixes various blood pressure lowering drugs or combination therapy thereof has been disclosed.
cilnidipine Compared with other calcium antagonists, clinidipine can act on the N-type calcium-channel that existing sympathetic nerve end besides acting on L-type calcium-channel that similar to most of the calcium antagonists. Due to its N-type calcium-channel blocking properties, it has more advantages compared to conventional calcium-channel blockers. It has lower incidence of Pedal edema, one of the major adverse effects of other calcium channel blockers. Cilnidipine has similar blood pressure lowering efficacy as compared to amlodipine. One of the distinct property of cilnidipine from amlodipine is that it does not cause reflex tachycardia.
In recent years, cardiovascular disease has become common, the incidence increased year by year, about a patient of hypertension in China. 3-1. 500 million, complications caused by hypertension gradually increased, and more and more young patients with hypertension technology. In recent years, antihypertensive drugs also have great development, the main first-line diuretic drug decompression 3 – blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, ar blockers and vascular angiotensin II (Ang II) receptor antagonist.
In the anti-hypertensive drugs, calcium antagonists are following a – blockers after another rapidly developing cardiovascular drugs, has been widely used in clinical hypertension, angina and other diseases, in cardiovascular drugs in the world, ranked first.
Cilnidipine for the long duration of the calcium channel blockers, direct relaxation of vascular smooth muscle, dilation of peripheral arteries, the peripheral resistance decreased, with lower blood pressure, heart rate without causing a reflex effect.
Cilnidipine is a dihydropyridine CCB as well as an antihypertensive. Cilnidipinehas L- and N-calcium channel blocking actions. Though many of the dihydropyridine CCBs may cause an increase in heart rate while being effective for lowering blood pressure, it has been confirmed that cilnidipine does not increase the heart rate and has a stable hypotensive effect. (Takahiro Shiokoshi, “Medical Consultation & New Remedies” vol. 41, No. 6, p. 475-481)

  • http://www.mcyy.com.cn/e-product2.asp
  • Löhn M, Muzzulini U, Essin K, et al. (May 2002). “Cilnidipine is a novel slow-acting blocker of vascular L-type calcium channels that does not target protein kinase C”. J. Hypertens. 20 (5): 885–93. PMID 12011649.


Cilnidipine (CAS NO.: 132203-70-4), with its systematic name of (+-)-(E)-Cinnamyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate, could be produced through many synthetic methods.
Following is one of the synthesis routes: By cyclization of 2-(3-nitrobenzylidene)acetocetic acid cinnamyl ester (I) with 2-aminocrotonic acid 2-methoxyethyl ester (II) by heating at 120 °C.
....................
http://www.google.com/patents/EP0161877A2?cl=en
AN EXAMPLE
Example 1
  • 3.51 g (10 mM) of 2-(3-nitrobenzylidene) acetoacetic acid cinnamyl ester were mixed with 1.38 g (12 mM) of 3-aminocrotonic acid methyl ester, and heated at 120°C for 3 hours. The reaction mixture was separated by silica gel column chromatography, and 3.00 g of cinnamyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (trans) were obtained (yield 67%). This derivative was recrystallized once from methanol.
  • Elemental Analysis; C 25 H 24 N 2 0 6
    • Calcd. (%) C: 66.95, H: 5.39, N: 6.25
    • Found (%) C: 67.03, H: 5.31, N: 6.20
(trans)
    • m.p.; 143.5-144.5°C
    • IR (cm-1); vNH 3370, νCO 1700, νNO2 1530, 1350
    • NMR δCDCl3; 2.34(s,6H), 3.60(s,3H), 4.69(d,2H), 5.13(s,lH), 6.14(tt,lH), 6.55(d,lH), 7.1-8.1(m,9H)
(cis)
    • m.p.; 136-137°C
    • IR (cm-1); vNH 3360, νCO 1700, 1650, νNO2 1530, 1350
    • NMR δCDCl3; 2.30(s,6H), 3,60(s,3H), 4.80(d,lH), 5.10(s,1H), 5.77(tt,lH), 6.56(d,1H), 6.64(bs,1H), 7.1-8.1(m,9H)
 EXAMPLE 13

  • Example 13 Cinnamyl 2-methoxyethyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
  • Elemental Analysis; C27H28N2O7
    • Calcd. (%) C: 65.84, H: 5.73, N: 5.69
    • Found (%) C: 65.88, H: 5.70, N: 5.66
    • m.p.; 115.5-116.5°C
    • IR (cm-1); vNH 3380, νCO 1710, 1680, νNO2 1530, 1350
    • NMR δCDCl3; 2.34(s,6H), 3.25(s,3H), 3.50(t,2H), 4.15(t,2H), 4.68(d,2H), 5.15(s,lH), 5.9-6.9(m,3H), 7.1-8.2(m,9H)

<br /><br /> Cilnidipine<br /><br /> pk_prod_list.xml_prod_list_card_pr?p_tsearch=A&p_id=131335<br /><br />
cyclization of 2-(3-nitrobenzylidene)acetocetic acid cinnamyl ester (I) with 2-aminocrotonic acid 2-methoxyethyl ester (II) by heating at 120 C.

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NMR
CARBOHYDRATE POLYMERS 90 PG 1719-1724 , YR2012
Numerous peaks were found in the spectrum of cilnidipine: 2.3555 (3H, s, CH3), 2.3886(3H, s, CH3), 3.2843(CD3OD), 3.3292(3H, s, OCH3), 3.5255–3.5623(2H, m, CH3OCH2CH2 ), 4.1224–4.1597(2H, m, CH3OCH2CH2 ), 4.6695–4.7293(2H, m, CH2 CH CH ), 4.8844(D2O), 5.1576(1H, s, CH), 6.2609(1H, dt, CH2 CH CH ), 6.5518(1H, d, CH2 CH CH ), 7.2488–7.3657(6H, m, ArH), 7.7002(1H, dd, ArH), 7.9805(1H, dd, ArH), 8.1548(1H, s, ArH)
CILNIDIPINE FT IR

CILNIDIPINE NMR

References: 
Dihydropyridine calcium channel blocker. Prepn: T. Kutsuma et al., EP 161877; eidem, US 4672068(1985, 1987 both to Fujirebio).
Pharmacology: K. Ikeda et al., Oyo Yakuri 44, 433 (1992).

Mechanism of action study: M. Hosonoet al., J. Pharmacobio-Dyn. 15, 547 (1992).
LC-MS determn in plasma: K. Hatada et al., J. Chromatogr. 583, 116 (1992). Clinical study: M. Ishii, Jpn. Pharmacol. Ther. 21, 59 (1993).
Acute toxicity study: S. Wada et al., Yakuri to Chiryo 20, Suppl. 7, S1683 (1992), C.A. 118, 32711 (1992).


 2


ISRADIPINE
1 Vote

Isradipine.png
Isradipine
CAS Registry Number: 75695-93-1
CAS Name: 4-(4-Benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester
Additional Names: isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylate; 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydro-3-isopropyloxycarbonylpyridine-5-carboxylic acid methyl ester; isrodipine
Manufacturers’ Codes: PN-200-110
Trademarks: Clivoten (Lifepharma); DynaCirc (Novartis); Esradin (Sigma-Tau); Lomir (Novartis); Prescal (Novartis)
Molecular Formula: C19H21N3O5
Molecular Weight: 371.39
Percent Composition: C 61.45%, H 5.70%, N 11.31%, O 21.54%
Properties: mp 168-170°.
Melting point: mp 168-170°
Derivative Type: S(+)-Form
Manufacturers’ Codes: PN-205-033
Properties: Crystals from ether + hexane, mp 142°. [a]D20 +6.7° (c = 1.5 in ethanol).
Melting point: mp 142°
Optical Rotation: [a]D20 +6.7° (c = 1.5 in ethanol)
Derivative Type: R(-)-Form
Manufacturers’ Codes: PN-205-034
Properties: Crystals from ether + hexane, mp 140°. [a]D20 -6.7° (c = 1.67 in ethanol).
Melting point: mp 140°
Optical Rotation: [a]D20 -6.7° (c = 1.67 in ethanol)
Keywords: Antianginal; Antihypertensive; Dihydropyridine Derivatives; Calcium Channel Blocker; Dihydropyridine Derivatives.
Isradipine (tradenames DynaCirc, Prescal) is a calcium channel blocker of the dihydropyridine class. It is usually prescribed for the treatment of high blood pressure in order to reduce the risk of stroke and heart attack. More recent research in animal models suggests that isradipine may have potential uses for treating Parkinson’s disease Chan et al. 2007.
Isradipine is given as either a 2.5mg or 5mg capsule. [1]
 Isradipine is a drug used to lower blood pressure but recently it was found by a team from Nortwestern University, that this molecule can also slow the progression of Parkinson’s disease, and restore the dopamine neurons (In animals tests). Isradipine is a calcium channel blocker of the 1,4-dihydropyridine class with a benzoxadiazole moiety in position 4.
The synthesis of the 1,4-dihydropyridine ring is quite classic, the first step consists in a Knoevenagel reaction of methyl acetoacetate on the benzoxadiazole 4-carboxaldehyde using piperidine and acetic acid as catalyst and diisopropylether as solvent in a 61% yield (this is the first time I see a Knoevenagel reaction in an ether!!!???? DCM, Toluene OK, but maybe I am wrong). The second step of this synthesis is the condensation of the acrylate obtained with the isopropyl aminocrotonate in ethanol to give the desire 1,4-dihydropyridine Isradipine in 67% yield after recrystallisation.
(WO/2005/005437) An improved Process for the Manufacture of Isradipine (Shasun Chemical & Drugs Limited)
http://www.google.com.ar/patents/WO2005005437A1?cl=en
Isradipine is 4-(4-Benzofi–razanyl)-l,4-d–hydro-2,6-dimethyl-3,5- pyiicϊ-nedicarboxylic acid med yl 1-methylethyl ester having die chemical structure of formula (I).
Figure imgf000002_0001
( I ) Isradipine is therapeutically indicated for treating cardiovascular diseases.
The cardiovascular diseases include angina, pectoris, hypertension and congestive heart failure. It is also used to treat high blood pressure. Isradipine was disclosed in the German specification DE 2949491 and US patent Nos. 4466972 and 4567271. DE 2949491 describes the general procedure to prepare 1,4-dihydropyridine derivatives. US 4466972, GBQ2103203A, LU 0088342A9, EP 0000150A1, EP 0000150B1, AU 0538515B2 and od er related patents describe the general mediod for d e preparation of Benzoxadiazoles and dieir derivatives of general formula (EL). These references in its entirety is hereby incorporated by reference into this application.
Figure imgf000003_0001
( II ) Where in Ri is -CH3 and -R2 is — CH(CH3)2 it refers to Isradipine of formula ( I ). When Ri and R2 are not identical the general procedures described in diese patent specifications produces a mixture of isomers of formula ( II ). These procedures for the preparation of Isradipine is characteristic of formation of the ‘ isomeric impurities, 1) 4-(4-Benzoi-urazanyl)-l,4-α^ydro-2,6-climedιyl-3,5- pyridinedicarboxylic acid di-methyl ester of formula ( III ) and 2) 4-(4- Benzofurazanyl)-l,4-α^ydro-2,6-d–methyl-3,5-pyrid–nedicarboxylic acid di-1- med ylethyl ester of formula ( IV) along with Isradipine. The US patent 4466972 describes the preparation of compounds of general formula (II) by refluxing 2, 1, 3-benzoxadiazole-4-carboxaldehyde, keto ester and concentrated ammonia or a β-amino ester in presence of ethanol, followed by evaporation and purification by chromatography.
H
Figure imgf000004_0001
( HI )H
Figure imgf000004_0002
( I V ) Tl ese symmetrical ester isomers ( III ) and ( IN ) are difficult to separate from the Isradipine and the separation is effected only by a chromatographic purifications. The drawback witii the procedures described in these patents is that it is very difficult to produce die product in commercial quantities as it involves d e purification of the product by chromatographic separations. A single step process for the preparation of Isradipine was described in CH 661270. This procedure involves first reacting 2,l,3-benzoxadiazole-4- carboxaldehyde with isopropyl acetoacetate in the presence of catalytic quantities of acetic acid and piperidine in refluxing toluene, and further reacting it widi mediyl-β-aminocrotonate. The Isradipine formed in d e reaction mixture was dien- separated by toluene distillation followed by cyclohexane treatment. The crude product obtained was dien crystallised from etiianol to get Isradipine. When we have repeated this process in our laboratory we got the Isradipine with substantially higher amount of symmetrical ester isomers ( III ) and ( IV ) are present in d e product. Removal of these symmetrical ester isomers is very difficult even after several repurifications from ethanol.
Figure imgf000006_0001
Stap 2
Figure imgf000006_0002
Example 4
Preparation of Isradipine using crude 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester Dissolved the crude 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester ‘ obtained in example – 1 (25 g, 0.10 mol) in absolute edianol (375 ml) and added in to the solution isopropyl-β-aminocrotonate (13.15 ml, 0.09 mol). Stirred the reaction mixture under nitrogen atmosphere at 25-28 °C for 7 hr. Removed sample from d e reaction mixture and analysed die sample by qualitative HPLC. Distilled ethanol from the reaction mixture- under vacuum at 50°C. Dissolved d e residue in ethyl acetate (235 ml) and washed twice widi water (90 ml). Dried the organic layer over sodium sulphate and distillation under vacuum at 50 °C. Dissolved the concentrate in ethanol (65 ml) at 70°C and slowly cooled to 5°C to get die product crystallised. Filtered the product and washed with pre cooled ethanol (25 ml). Recrystauised the product from ethanol (60 ml) and dried at 70°C under vacuum to obtain Isradipine (yield = 20 g, purity = 98.2% and Impurity III = 0.64%, Impurity IV = 0.51% by HPLQ
Example 5 Preparation of Isradipine using purified 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester Dissolved 2-acetyl-3-benzo–urazan-4-yl-acrylic acid methyl ester (25 g, 0.10 mol) in absolute ethanol (375 ml) and added in to the solution isopropyl-β- aminocrotonate (13.15 ml, 0.09 mol). Stirred the reaction mixture under nitrogen atmosphere at 25-28 °C for 5 hr. Removed sample from the reaction mixture and analysed the sample by qualitative HPLC. Distilled ethanol from the reaction mixture under vacuum at 50°C. Dissolved the residue in ethyl acetate (235 ml) and washed twice wid w?ater (90 ml). Dried die organic layer over sodium sulphate and distillation under vacuum at 50 °C. Dissolved the concentrate in ethanol (65 ml) at 70°C and slowly cooled to 5°C to get the product crystallised. Filtered the product. and washed with pre cooled ethanol (25 ml). Recrystallised the product from edianol (60 ml) and dried at 70°C under vacuum to obtain 25 g Isradipine (yield = 67%, purity 99.5%, Impurity III = 0.20%, and Impurity IV = 0.12% by HPLC)
Example 6 Preparation of Isradipine using purified 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester Dissolved the purified 2-acetyl-3-benzofurazan-4-yl-acrylic acid mediyl ester, obtained in example — 3 (25 g, 0.10 mol) in absolute ethanol (375 ml) and added in to the solution isopropyl-β-aminocrotonate (13.15 ml, 0.09 mol). Stirred the reaction mixture under nitrogen atmosphere at 25-28 °C for 5 hr. Removed sample from the reaction mixture and analysed the sample by qualitative HPLC. Distilled ethanol from die reaction mixture under vacuum at 50°C. Dissolved die residue in ethyl acetate (235 ml) and washed twice with water (90 ml). Dried the organic layer over sodium sulphate and distillation under vacuum at 50 °C. Dissolved the concentrate in ethanol (65 ml) at 70°C and slowly cooled to 5°C to get the product crystallised. Filtered the product and washed with pre cooled ethanol (25 ml) and dried at 70°C under vacuum to obtain 30g Isradipine (purity = 99.4%, Impurity III = 0.22%, and Impurity IV = 0.11% by HPLC). Throughout this application, various publications are referenced.

Side effects

Common side effects include: [2]
  • Dizziness
  • Warmth, redness, or tingly feeling under your skin
  • Headache
  • Weakness, tired feeling
  • Nausea, vomiting, diarrhea, upset stomach
  • Skin rash or itching
Serious side effects include: [2]
  • Lightheadedness or fainting
  • Shortness of breath, especially from minimal physical activity
  • Swelling in the hands and feet
  • Rapid and/or heavy heartbeat
  • Chest pain
If you experience one or more of these serious side effects, contact your health care provider immediately.

Significant drug interactions

There are other interactions beyond those listed below. Make sure to speak with a Pharmacist or Doctor if you have any concerns.
Three major interactions are listed below.
1. It is advised that those using Isradipine not take Anzemet (Dolasetron), as both agents can cause a dose-dependent PR intervaland QRS complexprolongation. [3]
2. Onmel/Sporanox (Itraconazole) exhibits a negative inotropic effect on theheart and thus could spur an additive effect when used concomitantly with Isradipine. Onmel/Sporanox also inhibits an important cytochrome liver enzyme (CYP 450 3A4) which is needed to metabolize Isradipine and otherCalcium Channel Blockers. This will increase plasma levels of Isradipine and could cause an unintentional overdose of the medication. Caution is advised when administering both agents together. [4]
3. Zanaflex (Tizanidine) demonstrates anti-hypertensive effects and should be avoided in patients taking Isradipine due to the possibility of synergism between both medications. [5]
4. The anti-biotic Rifadin (Rifampin) lowered plasma concentrations of Isradipine to below detectable limits. [1]
5. Tagamet (Cimetidine) increased Isradipine mean peak plasma levels. A downward dose adjustment may be necessary with this particular instance ofpolypharmacy. [1]
6. Severe hypotension was reported with Duragesic (Fentanyl) anesthesiawhen it was combined with other Calcium Channel Blockers. Even though Isradipine, another Calcium Channel Blocker, has not been used in conjunction with Fentanyl anesthesia in any studies, caution is advised. [1]
Note: There was no significant interaction between Isradipine and Warfarin (Coumadin), Isradipine and Microzide Hydrochlorothiazide, Isradipine and Lanoxin (Digoxin), and Isradipine and Nitrostat (Nitroglycerin).

Overdose

Symptoms of an Isradipine overdose include: [1]

…………………
US 4466972

………………………………….
isradipine is a class Benzofurazan dihydropyridine class of compounds, the synthesis is more complex, especially in the purified material is particularly difficult.
US Patent US4466972 and PCT application W02005 / 00437 respectively disclose two synthetic isradipine
Methods. However, the product prepared by conventional methods contain a certain amount of a formula homologues impurity, the impurity is structured as follows:

Figure CN101768153BD00041
 wherein, R1, R2 simultaneously or separately as methyl, ethyl and isopropyl.The homologue of the impurities with isradipine extremely difficult to separate, resulting in ineffective purification isradipine.
 In addition, conventional processes for preparing key intermediates involved in 4-methyl benzofurazan. However, the preparation method of the key intermediates is still unsatisfactory. For example, the Chinese Patent 200 510 125 267 (Publication No. CN1847233A) in
Discloses an intermediate 4-methyl benzofurazan preparation methods, the preparation process is as follows:

Figure CN101768153BD00051
 It is clear that the above method steps long, dangerous operation, poor control, and cause a lot of pollution.
 Accordingly, there is an urgent need to develop new, efficient and simple isradipine important intermediates for preparing 4-methyl benzofurazan method.

[0019]
Figure CN101768153BD00052
[0020] (b) in an inert solvent, such that 4-methyl benzofurazan oxide reduction to form 4-methyl benzofurazan, i.e. a compound of formula 3;
[0021]
Figure CN101768153BD00053
[0028]
Figure CN101768153BD00061
[0029] to form isradipine.
Figure CN101768153BD00081

Example 7 β – amino crotonic acid isopropyl ester (Compound 8)
 The isopropyl acetoacetate (72.0g, 0 5mol.), Ammonium acetate (57. 8g, 0 75mol.) And tert-butanol / ethanol (1: 1,600ml) were mixed in IOOOml flask, 300 mesh sieve (50g), heated to reflux, TLC plate monitor. After the reaction is substantially completed, cooled to room temperature, filtered and the filtrate was concentrated until no liquid was distilled off, the residual liquid was distilled under reduced pressure, to collect 110-120 ° C fraction (degree of vacuum of 0. IMPa) to give compound 8 (66. Og). Y = 92. 4%.
 1H-WR (CDCl3):…… 5 02-4 95 (1H, m), 4 48 (1H, s), 1 88 (3H, d), 1 23-1 21 (6H , d)
 Example 8 isradipine (Isradipine)
 In the protection teams, three-necked flask Compound 6 (3.0g, 20mmol), i3- amino crotonic acid isopropyl ester (Compound 8) (2. 7g, 16. 6mmol), methyl acetoacetate (3. 50g, 30mol), Ac2O (2. 05g, 20mmol), conc. H2SO4 (0. 4g, 4mmol) and tert-butanol / ethanol (1: 1,65ml) mixing the liquid phase monitoring, when the remainder is less than 3 Compound 6 When the 7% to terminate the reaction. The reaction was concentrated, the residue was dissolved CH2Cl2 (55ml), washed with water (45ml X Magic, dried, concentrated, drain pump, to give 6. 7g end yellow foam-like solid. Ethanol QOml) dissolved by heating, stirring crystallization (overnight) to give a pale yellow powder isradipine (4. 3g) (HPLC purity> 99.8%, impurity content homologues thereof are less than 0.1), yield 66.8%.
 1H-WR (CDCl3):…… 7 62-7 60 (lH, m), 7 31-7 26 (2H, m), 5 46 (lH, s), 4 92-4 . 86 (1H, m), 3. 57 (3H, s), 2. 32-2. 30 (6H, m), 1. 21-1. 19 (3H, d), 0. 95-0. 94 (3H, d)
 Comparative Example 1
isradipine (Isradipine) prepared by the United States Patent US4466972:
 In the protection teams, three-necked flask Compound 6 (3.0g, 20mmol), i3- amino crotonic acid isopropyl ester (Compound 8) (2. 7g, 16. 6mmol), methyl acetoacetate (3. 50g, 30mol), Ac2O (2. 05g, 20mmol), conc. H2SO4 (0. 4g, 4mmol) and ethanol (65ml) were mixed and stirred, the liquid phase monitoring, when the compound 6 is less than 3.7% remaining, the reaction is stopped. The reaction was concentrated, the residue was dissolved CH2Cl2 (55ml), washed with water (45ml X Magic, dried, concentrated, drain pump, to give 6. 3g end yellow foam-like solid. Ethanol OOml) was dissolved by heating, stirring crystallization (overnight) to give a pale yellow powder isradipine (4. Ig) (HPLC purity: 99.0%, impurity content was homologues greater than 0.3%), a yield of 63.7%.
 Compared with Comparative Example 1 (homolog impurity content was greater than 0.3%), was the content of impurities isradipine homologs prepared in Example 1-8 is less than 0.1% by the embodiment of the present invention.
 The 10 cases of isradipine
 Example 8 was repeated, except that, with t-butanol / ethanol (1: 2,70ml) or t-butanol / ethanol O: 1, 70ml) replaces t-butanol / ethanol (1: 1,65ml) 0
The results showed that isradipine yield of about 62%, the test substance impurity content of less than 0.1% homologous.

Further reading and references

  1.  “”Isradipine: Brands, Medical Use, Clinical Data””.
  2.  “Isradipine Side Effects”.
  3. “”Isradipine and Anzemet Drug Interactions””.
  4. “”Isradipine and Onmel Drug Interactions””.
  5.  “”Isradipine and Zanaflex Drug Interactions””.
  • Hattori T, Wang P (2006). “Calcium antagonist isradipine-induced calcium influx through nonselective cation channels in human gingival fibroblasts.”. Eur J Med Res 11 (3): 93–6. PMID 16751108.
  • Ganz M, Mokabberi R, Sica D (2005). “Comparison of blood pressure control with amlodipine and controlled-release isradipine: an open-label, drug substitution study.”. J Clin Hypertens (Greenwich) 7 (4 Suppl 1): 27–31. doi:10.1111/j.1524-6175.2005.04450.x. PMID 15858400.
  • Johnson B, Roache J, Ait-Daoud N, Wallace C, Wells L, Dawes M, Wang Y (2005). “Effects of isradipine, a dihydropyridine-class calcium-channel antagonist, on d-methamphetamine’s subjective and reinforcing effects.”.Int J Neuropsychopharmacol 8 (2): 203–13.doi:10.1017/S1461145704005036. PMID 15850499.
  • Fletcher H, Roberts G, Mullings A, Forrester T (1999). “An open trial comparing isradipine with hydralazine and methyl dopa in the treatment of patients with severe pre-eclampsia.”. J Obstet Gynaecol 19 (3): 235–8.doi:10.1080/01443619964977. PMID 15512286.
  • Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C, Tkatch T, Meredith GE, Surmeier DJ (2007). “‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease.”.Nature 447 (3): 1081–1086.doi:10.1038/nature05865. PMID 17558391.
synthesis………..will be updated

External links

…………
CN1847233A21 Nov 200518 Oct 2006圣玛精细化工有限责任公司Method for preparing 4-formoxylbenzofuran
US446697219 Mar 198221 Aug 1984Sandoz Ltd.Hypotensive, antiischemic, antispasmodic agents
WO2005005437A115 Jul 200420 Jan 2005Radhakrishnan Selvar MullaiyurAn improved process for the manufacture of isradipine.
References: Dihydropyridine calcium channel blocker. Prepn: P. Neumann,DE 2949491; idem, US 4466972 (1980, 1984 both to Sandoz). Prepn of enantiomers: A. Vogel, DE 3320616 (1983 to Sandoz), C.A. 101, 7162s (1984). Comparative study of in vitro effects on human and canine cerebral arteries: E. Müller-Schweinitzer, P. Neumann, J. Cereb. Blood Flow Metab.3,354 (1983). Effect on a-adrenoceptor mediated vasoconstriction in rats: K. Jieet al., Arch. Int. Pharmacodyn. 278, 72 (1985). Pharmacokinetics: F. L. S. Tee, J. M. Jaffe, Eur. J. Clin. Pharmacol. 32, 361 (1987). Clinical evaluation in angina and coronary artery disease: C. E. Handler, E. Sowton, ibid. 27, 415 (1984); in hypertension: E. B. Nelson et al., Clin. Pharmacol. Ther. 40, 694 (1986). Comparison of hemodynamic effects of enantiomers: R. P. Hof et al., J. Cardiovasc. Pharmacol. 8, 221 (1986). Series of articles on pharmacology and clinical use: Am. J. Med. 86, 1-146 (1989).
ISRADIPINE
Isradipine.png
SYSTEMATIC (IUPAC) NAME
3-methyl 5-propan-2-yl 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
CLINICAL DATA
TRADE NAMESDynaCirc
AHFS/DRUGS.COMmonograph
MEDLINEPLUSa693048
  • C
LEGAL STATUS
ROUTESOral
PHARMACOKINETIC DATA
BIOAVAILABILITY15-24%
PROTEIN BINDING95%
METABOLISM100% Hepatic
HALF-LIFE8 hours
EXCRETION70% Renal, 30% Fecal
IDENTIFIERS
CAS NUMBER75695-93-1 Yes
ATC CODEC08CA03
PUBCHEMCID 3784
DRUGBANKDB00270
CHEMSPIDER3652 Yes
UNIIYO1UK1S598 Yes
KEGGD00349 Yes
CHEMBLCHEMBL1648 Yes
CHEMICAL DATA
FORMULAC19H21N3O5 
MOLECULAR MASS371.387 g/mol






 3



 4

 



5










6




EXTRAS

U.S Patent No. 4,572,909 discloses amlodipine;
U.S Patent No. 4,446,325 discloses aranidipine;
U.S Patent No. 4,772,596 discloses azelnidipine;
U.S Patent No. 4,220,649 discloses barnidipine;
U.S Patent No. 4,448,964 discloses benidipine;
U.S Patent No. 5,856,346 discloses clevidipine;
U.S Patent No. 4,466,972 discloses isradipine;
U.S Patent No. 4,885,284 discloses efonidipine; and
U.S Patent No. 4,264,61 1 discloses felodipine.

  • Planar chemical structures of these calcium blockers of formula (I) are shown below.
    Figure 00070001
    Figure 00070002
    Figure 00070003
    Figure 00070004
    Figure 00070005
    Figure 00080001
    Figure 00080002
    Figure 00080003
    Figure 00080004
  • Amlodipine is 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine disclosed in USP 4,572,909, Japanese patent publication No. Sho 58-167569 and the like.
  • Aranidipine is 3-(2-oxopropoxycarbonyl)-2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,446,325 and the like.
  • Azelnidipine is 2-amino-3-(1-diphenylmethyl-3-azetidinyloxycarbonyl)-5-isopropoxycarbonyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,772,596, Japanese patent publication No. Sho 63-253082 and the like.
  • Barnidipine is 3-(1-benzyl-3-pyrrolidinyloxycarbonyl)-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,220,649, Japanese patent publication No. Sho 55-301 and the like.
  • Benidipine is 3-(1-benzyl-3-piperidinyloxycarbonyl)-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine and is described in the specifications of U.S. Patent No. 4,501,748, Japanese patent publication No. Sho 59-70667 and the like.
  • Cilnidipine is 2,6-dimethyl-5-(2-methoxyethoxycarbonyl)-4-(3-nitrophenyl)-3-(3-phenyl-2-propenyloxycarbonyl)-1,4-dihydropyridine disclosed in USP 4,672,068, Japanese patent publication No. Sho 60-233058 and the like.
  • Efonidipine is 3-[2-(N-benzyl-N-phenylamino)ethoxycarbonyl]-2,6-dimethyl-5-(5,5-dimethyl-1,3,2-dioxa-2-phosphonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,885,284, Japanese patent publication No. Sho 60-69089 and the like.
  • Elgodipine is 2,6-dimethyl-5-isopropoxycarbonyl-4-(2,3-methylenedioxyphenyl)-3-[2-[N-methyl-N-(4-fluorophenylmethyl)amino]ethoxycarbonyl]-1,4-dihydropyridine disclosed in USP 4,952,592, Japanese patent publication No. Hei 1-294675 and the like.
  • Felodipine is 3-ethoxycarbonyl-4-(2,3-dichlorophenyl)-2,6-dimethyl-5-methoxycarbonyl-1,4-dihydropyridine disclosed in USP 4,264,611, Japanese patent publication No. Sho 55-9083 and the like.
  • Falnidipine is 2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)-3-(2-tetrahydrofurylmethoxycarbonyl)-1,4-dihydropyridine disclosed in USP 4,656,181, Japanese patent publication (kohyo) No. Sho 60-500255 and the like.
  • Lemildipine is 2-carbamoyloxymethyl-4-(2,3-dichlorophenyl)-3-isopropoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine disclosed in Japanese patent publication No. Sho 59-152373 and the like.
  • Manidipine is 2,6-dimethyl-3-[2-(4-diphenylmethyl-1-piperazinyl)ethoxycarbonyl]-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,892,875, Japanese patent publication No. Sho 58-201765 and the like.
  • Nicardipine is 2,6-dimethyl-3-[2-(N-benzyl-N-methylamino)ethoxycarbonyl]-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 3,985,758, Japanese patent publication No. Sho 49-108082 and the like.
  • Nifedipine is 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridine disclosed in USP 3,485,847 and the like.
  • Nilvadipine is 2-cyano-5-isopropoxycarbonyl-3-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,338,322, Japanese patent publication No. Sho 52-5777 and the like.
  • Nisoldipine is 2,6-dimethyl-3-isobutoxycarbonyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,154,839, Japanese patent publication No. Sho 52-59161 and the like.
  • Nitrendipine is 3-ethoxycarbonyl-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 3,799,934, Japanese patent publication (after examination) No. Sho 55-27054 and the like.
  • Pranidipine is 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-3-(3-phenyl-2-propen-1 -yloxycarbonyl)-1,4-dihydropyridine disclosed in USP 5,034,395, Japanese patent publication No. Sho 60-120861 and the like.

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