anthony crasto – Page 5 – All About Drugs

AltheRx obtains US patent for solabegron combination therapy for OAB treatment

phase 2, Uncategorized Comments Off

Oct 212013

solabegron

AltheRx Pharmaceuticals has received a notice of allowance for its patent application from the US Patent and Trademark Office (USPTO) for the use of solabegron, a beta 3-adrenergic receptor agonist, in combination with antimuscarinics at both therapeutic and sub-therapeutic doses, for the treatment of overactive bladder (OAB).

AltheRx obtains US patent for solabegron combination therapy for OAB treatment

http://www.pharmaceutical-technology.com/news/newsaltherx-obtains-us-patent-for-solabegron-combination-therapy-for-oab-treatment?WT.mc_id=DN_News

Solabegron (GW-427,353) is a drug which acts as a selective agonist for the β3 adrenergic receptor. It is being developed for the treatment of overactive bladder andirritable bowel syndrome.^[1]^[2]^[3] It has been shown to produce visceral analgesia by releasing somatostatin from adipocytes.,^[4]^[5]

Solabegron was discovered by GlaxoSmithKline and acquired by AltheRx in March 2011. Solabegron relaxes the bladder smooth muscle by stimulating beta-3 adrenoceptors, a novel mechanism compared to older established drug treatments for overactive bladder syndrome such as the anticholinergic agents. Astellas Pharma have developed the first commercially available β3 adrenergic receptor, mirabegron, which is now licensed in Japan^[6] and the US^[7] for overactive bladder. Mirabegron is not licensed for irritable bowel syndrome.

A Phase II study of Solabegron for overactive bladder (OAB) looked at 258 patients with moderate to severe incontinence experiencing an average of 4.5 wet episodes per day. Results demonstrated a statistically significant improvement with Solabegron as compared to placebo, as measured by the percent reduction of the number of wet episodes and the absolute number of daily voids.

A Phase II study for irritable bowel syndrome (IBS) evaluated 102 patients with IBS. Solabegron demonstrated significant reduction in pain associated with the disorder and a trend for greater improvement in the quality of life, compared to placebo.

Both Phase II studies indicated a tolerability profile for Solabegron that was similar to placebo. The OAB patients did not suffer from dry mouth, constipation, increase in heart rate or cognitive issues.

AltheRx is currently preparing to advance Solabegron into a large clinical study in OAB.

Synthesis

Hicks A, McCafferty GP, Riedel E, Aiyar N, Pullen M, Evans C, Luce TD, Coatney RW, Rivera GC, Westfall TD, Hieble JP. GW427353 (solabegron), a novel, selective beta3-adrenergic receptor agonist, evokes bladder relaxation and increases micturition reflex threshold in the dog. Journal of Pharmacology and Experimental Therapeutics. 2007 Oct;323(1):202-9.doi:10.1124/jpet.107.125757 PMID 17626794
Grudell AB, Camilleri M, Jensen KL, Foxx-Orenstein AE, Burton DD, Ryks MD, Baxter KL, Cox DS, Dukes GE, Kelleher DL, Zinsmeister AR. Dose-response effect of a beta3-adrenergic receptor agonist, solabegron, on gastrointestinal transit, bowel function, and somatostatin levels in health.American Journal of Physiology. Gastrointestinal and Liver Physiology. 2008 May;294(5):G1114-9. PMID 18372395
Kelleher DL, Hicks KJ, Cox DS, et al. Randomized, double-blind, placebo (PLA)-controlled, crossover study to evaluate efficacy and safety of the beta 3-adrenergic receptor agonist solabegron (SOL) in patients with irritable bowel syndrome (IBS). Neurogastroenterol Motil 2008;20 (Suppl 2):131.
Cellek S, Thangiah R, Bassil AK, Campbell CA, Gray KM, Stretton JL, Lalude O, Vivekanandan S, Wheeldon A, Winchester WJ, Sanger GJ, Schemann M, Lee K. Demonstration of functional neuronal beta3-adrenoceptors within the enteric nervous system. Gastroenterology. 2007 Jul;133(1):175-83.
Schemann M, Hafsi N, Michel K, Kober OI, Wollmann J, Li Q, Zeller F, Langer R, Lee K, Cellek S. The beta3-adrenoceptor agonist GW427353 (solabegron) decreases excitability of human enteric neurons via release of somatostatin.Gastroenterology 2009 Sep 25. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/22384458
http://chembl.blogspot.co.uk/2012/07/new-drug-approvals-2012-pt-xiv.html

MONOCLONAL ANTIBODIES

MONOCLONAL ANTIBODIES Comments Off

Oct 172013

PPT from many87

Production of MAb

Fig.1 Production of MAb

Large Scale Production Of MAbs:

Commercially, on large scale, MAbs are produced by two methods.

(a) Ascites production in mice

(b) In-vitro fermentation

The production method is summarized in Fig.no.2a & 2b.

a) Ascites Production In Mice:

The first monoclonal antibodies approved by FDA for therapeutic use OKTS, is produced by ascitic technology¹⁹.

In this method hybridoma cells are injected into peritoneal cavity of histocompatible mice. The mice are pretreated by i.p. injection of Pristane to irritate the peritoneal cavity which facilitates the growth of ascitic tumor. The fluid produced may contain the high concentration of secreted MAbs, 2 to 20 μg / ml and 2 to 6 ml or more can be harvested per mouse. Comparison of different MAb production^22,23 methods is shown inTable 1.

Drawbacks of this method are:

1. It is very costly, very difficult and not reliable.

2. Product may get contaminated with mouse immunoglobulins and also with other mouse proteins.

3. Viruses can be introduced as contaminants.

4. Antibody yield is often less as compared to other methods.

b) In-Vitro Fermentation:

In this method, the cells are grown and gradually moved to larger and larger culture ensuring exponential growth. Typical antibody levels in the culture supernatant ranges from 5-50 μg/ml depending on the individual clone and on cell density. When more production of antibody is required 1-litre cultures in roller bottles are used. Required cells are removed from rest of media by centrifugation or filtration, generally followed by ultra filtration step for concentrating the filtrate by up to 20 folds.

Advantages of this method are:

(1) As serum required in culture media is reduced, it is cost effective.

(2) There will not be any contamination with mouse immunoglobulin.

But the major drawback is that of contamination of final product with serum or protein based growth factors.

Table 1: Comparison of different MAb production methods.

Production system	Scale	Volume (ml)	Concentration (mg/ml)	Production time (weeks)	Quality
Ascites (in vivo)	20-250 mg	5-10	< 20	2-3	Low
Stir growth	—	100-2500	0.01-0.1	2-3	High
Dialysis membrane	< 50 mg	10-25	0.1-1.5	2-5	High
Roller bottles	< 2 gm	100-2000	0.01-0.2	2-6	High
Hollow fiber	0.15-30 gm	25-1000	0.2-0.3	3-12	High
Fermentor	2-100 gm	< 2000 lit	0.05-0.5	2-12	High

MAb Production

Fig. 2a: MAb Production (Flowchart)

Freeze Dried MAb Production

Fig. 2b: Freeze Dried MAb Production (Flowchart)

i) Purification:

Contamination, during production process, such as protein, nucleic acid, endotoxins, immunoglobulin and adventitious agent can be removed by purification method. The purification methods such as precipitation with ammonium sulphate, zone electrophoresis, ion exchange chromatography, hydrophobic interaction chromatography, gel filtration and affinity chromatography are used¹⁹.

· Affinity chromatography is often used for initial purification.

· Ion exchange chromatography is used for removing endotoxins and DNA.

· Gel filtration chromatography can remove both high and low molecular form of monoclonal antibodies and it is usually used as the final polishing step.

j) Characterization:

The final determination of monoclonality requires biochemical and biophysical characterization of the immunoglobulin. It is also characterized immunochemically to define its affinity for antigen, its immunoglobulin subclass, the epitopes for which it is specific and the effective number of binding site that it possesses¹⁹.

k) Final Processing:

Depending upon the intended application, the antibody may be conjugated to specific radionuclide or toxin. Then the stabilizing agent is added, and the product is filled into final container under inert gas or other specialized conditions. Lyophillization is frequently applied to get freeze dried product.

Antigenicity Of Murine MAb:

The main problem for mouse MAb is that, human body recognizes it as a foreign agent and produces antibodies against such mouse MAb. The induced human anti-mouse antibodies (HAMA) quickly reduce the effectiveness of mouse MAb and also their interaction may lead to allergic reactions.

To overcome the problem, Human MAbs can be used. Though difficult, this is possible by fusion of EBV (Epstein Barr Virus) transformed human B-lymphocyte with appropriate fusion partners²¹. EBV is a lymphotrophic DNA herpes virus which is capable of converting normal B-lymphocytes of human and/or mouse into cancer cell having proliferating capacity in vitro. But the presence of EBV as contaminant can pose a problem of producing cancer²⁴.

Even the human-human hybridomas producing MAbs have been produced ^25,26. Olsson and Kaplan in the year 1980 produced first human-human myeloma (SKO-007), against the hapten 2, 4-dinitrophenyl (DNP)¹⁹.

The routine production of human MAbs is prevented due to following reason:-

Sources of antibody producing cells²⁷.
Reliable methods for lymphocytes immortalization.
Stability²⁸ and antibody producing capacity.
Administration of some antigens to humans could endanger their health²⁹.
Recovery of B-lymphocytes from the spleen of human is impracticable.
The fusion of human lymphocytes with human lymphoblastoid cell lines is a very inefficient process.
Low production yield of human monoclonal antibody.

Hence, other alternatives methods come forth.

Advantages Of MAbs:

Pure one molecular species with high specificity for a particular antigenic target.
Anti-serum titer values are high.
Antibodies with high avaidity can be produced.
In vitro and in vivo production is possible.
Radiolabelling and fluorescent conjugation of monoclonal antibody are easy.

Disadvantages Of MAbs:

Initial cost involved in the technique is high. However, continuous production is somewhat economical.
Methods are time consuming.
Antigenicity of Murine MAb.
MAbs have comparatively less complement fixing ability than that of convectional antiserum.
MAbs are highly selective for a particular single antigenic determinant. This renders them incapable of distinguish between different molecules, cells bearing the chemical structure or determinants except one against which it is targeted.
The high antibody avidity (energy of binding to an antigen) of MAbs is advantageous for immunoassay but some property is undesirable for purification process.

Formulation Development of Insoluble Drugs

drugs, GENERIC, MANUFACTURING, nanotechnology Comments Off

Oct 152013

Formulation development of insoluble drugs has always been a challenge in pharmaceutical development. This presentation reviews some current options to old problem.

by PharmaDirections, Inc., Working at PharmaDirections, Inc

Formulation Development of Insoluble Drugs formulation from PharmaDirections, Inc.

…

Theories of solubulisation from venkatesh thota

Pilot plant scale up for tablets from Robin Gulati

Advances in tableitng technology from Sameera Sam

MannKind Resubmits New Drug Application to U.S. FDA for AFREZZA for the Treatment of Adults with Diabetes

NDA Comments Off

Oct 152013

VALENCIA, Calif., October 14, 2013 –(BUSINESS WIRE)–MannKind Corporation (Nasdaq: MNKD) today announced the resubmission on October 13, 2013 of a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval for the marketing and sale of AFREZZA® (insulin human [rDNA origin]) Inhalation Powder with an indication to improve glycemic control in adults with type 1 or type 2 diabetes. The resubmission is based on the entire data set from the extensive AFREZZA clinical development program and particularly the positive results from two recent Phase 3 trials, one in patients with type 1 diabetes (study 171) and one in patients with type 2 diabetes (study 175).

Psoriasis

Uncategorized Comments Off

Oct 112013

Psoriasis from Harshad Deshpande

Statins and Memory

drugs Comments Off

Oct 112013

Pravastatin, one of the most common cholesterol-lowering drugs, causes cognitive side effects when administered for a long period of time

Keryx’s NDA for kidney drug accepted for filing by US FDA

NDA Comments Off

Oct 102013

Keryx Biopharmaceuticals has announced that its new drug application (NDA) for Zerenex (ferric citrate coordination complex) has been accepted for filing by the US FDA.

Keryx’s NDA for kidney drug accepted for filing by US FDA

http://www.pharmaceutical-technology.com/news/newskeryxs-nda-kidney-drug-accepted-filing-us-fda?WT.mc_id=DN_News

Zerenex aims to lower blood levels of phosphorous in patients undergoing kidney dialysis.

X-ray Powder Diffraction in Solid Form Screening and Selection

drugs Comments Off

Oct 082013

Ann Newman, Ph.D.

Seventh Street Development Group

Abstract

Solid form screening is commonly performed to find a candidate with optimal properties for early development or to find a form with different properties to improve a formulation in later development. A variety of screens can be performed including polymorph, salt, co-crystal, amorphous, and amorphous dispersion. X-ray powder diffraction (XRPD) is commonly used at various stages of screening to identify and characterize new forms. It is also used to help evaluate other properties, such as physical stability and manufacturability, in order to choose the best form for development. This paper discusses the use of XRPD during screening and form selection of pharmaceutical materials.

read at

http://www.americanpharmaceuticalreview.com/Featured-Articles/36946-X-ray-Powder-Diffraction-in-Solid-Form-Screening-and-Selection/

Canada Approves Valeant’s Jublia for Fungi Infections

CANADA Comments Off

Oct 042013

efinaconazole

str credit kegg

http://www.ama-assn.org/resources/doc/usan/efinaconazole.pdf

1-Piperidineethanol, α-(2,4-difluorophenyl)-β-methyl-4-methylene-α-(1H-1,2,4-triazol-1- ylmethyl)-, (αR,βR)-
(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1- yl)butan-2-ol

MOLECULAR FORMULA C18H22F2N4O
MOLECULAR WEIGHT 348.39

SPONSOR Dow Pharmaceutical Sciences, Inc.
CODE DESIGNATION KP-103
CAS REGISTRY NUMBER 164650-44-6

Company: Valeant Pharmaceuticals International, Inc.

Treatment for: Onychomycosis, Toenail, Onychomycosis, Fingernail

Efinaconazole is a topical triazole antifungal in development for the treatment of onychomycosis.

Valeant Pharmaceuticals International Inc. announced that the New Drug Submission for Jublia has been approved from the Canadian regulatory authority, Health Canada, for the treatment of mild to moderate onychomycosis, a common and destructive nail infection caused predominantly by dermatophyte fungi.

read all at

http://www.dddmag.com/news/2013/10/canada-approves-valeants-jublia-fungi-infections?et_cid=3516952&et_rid=523035093&type=cta

US FDA STATUS

NOT APPROVED

May 28, 2013 Valeant Pharmaceuticals International, Inc. today announced that it has received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) regarding its New Drug Application (NDA) for efinaconazole for the treatment of onychomycosis. A CRL is issued by the FDA’s Center for Drug Evaluation and Research when the review of a file is completed and questions remain that preclude the approval of the NDA in its current form. The questions raised by the FDA pertain only to Chemistry, Manufacturing and Controls (CMC) related areas of the container closure apparatus. As no efficacy or safety issues were raised by the FDA, Valeant believes that these items can be addressed and is working for a timely response to the FDA as soon as possible. Valeant remains committed to bringing efinaconazole to market as a potential new treatment for onychomycosis.

About Valeant Pharmaceuticals International, Inc.

Valeant Pharmaceuticals International, Inc. is a multinational specialty pharmaceutical company that develops, manufactures and markets a broad range of pharmaceutical products primarily in the areas of dermatology, neurology and branded generics. More information about Valeant Pharmaceuticals International, Inc. can be found at www.valeant.com.

(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (nonproprietary name (INN): Efinaconazole, hereinafter sometimes abbreviated as KP-103) which is the compound represented by formula 1 and known to be effective against mycotic diseases in humans and animals (the compound described in Example 1 in Patent Document 1) or salts of this compound.

Methods for obtaining aminoalcohols by the ring-opening addition reaction of epoxides with amines are generally performed at high temperature for a prolonged time using a large excess of amines. Since a large excess of amines are used, the conventional methods give rise to a lot of by-products and require the step of recovering amines; hence, if the amines are expensive, the conventional methods are not desirable not only from the viewpoint of production cost but also as an industrial production process. In order to realize an enhanced reactivity, it has been proposed that the above-described reaction be performed using Lewis acids but the Lewis acids that can be used are either expensive or labile and are not suitable for industrial use; perchlorates or the like are highly toxic and dangerous and because of this low level of safety, they have posed various problems such as the need to take utmost care in use (Non-Patent Documents 1 and 2). It was also reported that by using lithium bromide, the reactivity at room temperature under a solventless condition could be enhanced (Non-Patent Document 3). The method reported in that document uses amines and epoxides that are liquid at ordinary temperature, so its success is probably due to the reaction of the starting materials at high concentrations under a solvnetless condition. It then follows that this method is not applicable to amines and epoxides that are solid at ordinary temperature, especially those with high melting points.
Returning now to the compound of formula 1, it is produced by the ring-opening addition reaction of an epoxide with an amine as described in Patent Document 1. In this production method, (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (hereunder sometimes abbreviated as “epoxytriazole”) is used as the epoxide and 4-methylenepiperidine (hereunder sometimes abbreviated as “4-MP”) is used as the amine. In this method, the ring-opening addition reaction uses a large excess of 4-MP in water and involves prolonged heating under reflux, so it has the disadvantage that a lot of by-products are generated during reaction and need be removed. As a further problem, 4-methylenepiperidine which is produced by the method described in Patent Document 2 is obtained as dissolved in water, so its purity is low enough to affect the reactivity and impurities are unavoidably generated by the heat applied to the step of isolation by distillation.

- Patent Document 1: pamphlet of WO94/26734
- Patent Document 2: pamphlet of WO97/11939

NON-PATENT DOCUMENTS

- Non-Patent Document 1: Synthesis, 2004, No.10, pp 1563-1565
- Non-Patent Document 2: J. Org. Chem., 2007, vol. 72, pp 3713-3722
- Non-Patent Document 2: Eur. J. Org. Chem., 2004, No.17, pp 3597-3600
- The process BELOW for producing the compound of formula (1) which, as formulated below, comprises reacting (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane with an acid addition salt of 4-methylenepiperidine in a reaction solvent in the presence of a hydroxide of an alkali metal or an alkaline earth metal selected from the group consisting of lithium, sodium, calcium, and strontium or a hydrate of the hydroxide:
- (where HX signifies the acid in the acid addition salt)
- ¹H-NMR (500 MHz, CDCl₃)
  δ: 0.96 (3H, dd, J = 2.68, 7.08 Hz), 2.13-2.26 (4H, m), 2.35 (2H, br), 2.70 (2H, br), 2.90-2.94 (1H, q, J = 7.08 Hz), 4.64 (2H, s), 4.82 (1H, dd, J = 0.73, 14.39 Hz), 4.87 (1H, dd, J = 0.73, 14.39 Hz), 5.45 (1H, s), 6.72-6.81 (2H, m), 7.51 (1H, dt, J = 6.59, 9.03 Hz), 7.78 (1H, s), 8.02 (1H, s).
  FAB-MS m/z: 349 [M+H]⁺
  melting point: 86-89 °C
  optical rotation: [α]_D ²⁵ -87 to -91 ° (C = 1.0, methanol)

CILNIDIPINE 西尼地平

GENERIC, Uncategorized Comments Off

Oct 032013

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

Manufacturers’ Codes: FRC-8653

Trademarks: Atelec (Morishita); Cinalong (Fujirebio); Siscard (Boehringer, Ing.)

Molecular Formula: C27H28N2O7

Molecular Weight: 492.52

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)

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.

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)

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).

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.

U.S Patent No. 5,399,578 discloses Valsartan; European Patent No. 0 502 314 discloses Telmisartan; U.S Patent No. 5,138,069 discloses Losartan; U.S Patent No. 5,270,317 discloses Irbesartan; U.S Patent No. 5,583,141 and 5,736,555 discloses Azilsartan; U.S Patent No. 5,196,444 discloses Candesartan; U.S Patent No. 5,616,599 discloses Olmesartan; and U.S Patent No. 5,185,351 discloses Eprosartan.

U.S Patent No. 4,374,829 discloses enalapril; U.S Patent No. 4,587,258 discloses ramipril; U.S Patent No. 4,344,949 discloses quinapril; U.S Patent No. 4,508,729 discloses perindopril; U.S Patent No. 4,374,829 discloses lisinopril; U.S Patent No. 4,410,520 discloses benazepril; U.S Patent No. 4,508,727 discloses imidapril; U.S Patent No. 4,316,906 discloses zofenopril; U.S Patent Nos. 4,046,889 and 4,105,776 discloses captopril; and U.S Patent No. 4,337,201 discloses fosinopril.

Planar chemical structures of these calcium blockers of formula (I) are shown below.
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.