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DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

CILNIDIPINE 西尼地平

 GENERIC, Uncategorized  Comments Off on CILNIDIPINE 西尼地平
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.

 

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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).

 

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.

    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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Process for synthesis of chiral 3-substituted tetrahydroquinoline derivatives……..WO 2013140419…CSIR INDIA PATENT

 drugs, Uncategorized  Comments Off on Process for synthesis of chiral 3-substituted tetrahydroquinoline derivatives……..WO 2013140419…CSIR INDIA PATENT
Oct 012013
 

sumanirole

179386-43-7
179386-44-8 (maleate)

 

Sumanirole maleate, U-95666 (free base), U-95666E, PNU-95666E

Process for synthesis of chiral 3-substituted tetrahydroquinoline derivatives
Council Of Scientific & Industrial Research
The present invention relates to novel and concise process for the construction of chiral 3-substituted tetrahydroquinoline derivatives based on proline catalyzed asymmetric α-functionalization of aldehyde, followed by in situ reductive cyclization of nitro group under catalytic hydrogenation condition with high optical purities. Further the invention relates to conversion of derived chiral 3-substituted tetrahydroquinoline derivatives into therapeutic agents namely (-)-sumanirole (96% ee) and 1-[(S)-3-(dimethylamino)-3,4-dihydro-6,7-dimethoxy-quinolin-1(2H)-yl]propanone[(S)-903] (92% ee).
Process,sumanirole
Indications Restless legs syndrome; Parkinsons disease
Target-based Actions Dopamine D2 receptor agonist
Other Actions Anxiolytic; Antiparkinsonian
Inventors Boopathi, Senthil, Kumar; Arumugam, Sudalai; Rawat, Varun
IPC Codes C07D 215/20; C07D 471/06; C07D 215/38
DRUG      sumanirole
Publication Date 26-Sep-2013         WO-2013140419-A1

Sumanirole (PNU-95,666) is a highly selective D2 receptor full agonist, the first of its kind to be discovered. It was developed for the treatment of Parkinson’s disease andrestless leg syndrome. While it has never been approved for medical use  it is a highly valuable tool compound for basic research to identify neurobiological mechanisms that are based on a dopamine D2-linked (vs. D1, D3, D4, and D5-linked) mechanism of action

sumanirole

 

OTHER INFO

D-Phenylalanine (I) was protected as the methyl carbamate (II) by acylation with methyl chloroformate under Schotten-Baumann conditions. The N-methoxy amide (III) was then prepared by coupling of (II) with O-methyl hydroxylamine in the presence of EDC. Cyclization of (III) to the N-methoxy quinolinone (IV) was accomplished by treatment with bis(trifluoroacetoxy)iodobenzene in the presence of trifluoroacetic acid. Simultaneous reduction of the N-methoxy lactam and carbamate functions of (IV) by means of borane-methyl sulfide complex provided diamine (V). The aliphatic amino group of (V) was then selectively protected as the benzyl carbamate (VI) by using N-(benzyloxycarbonyloxy)succinimide at -40 C. Reaction of (VI) with phosgene, followed by treatment of the intermediate carbamoyl chloride with O-methyl hydroxylamine gave rise to the N-methoxy urea derivative (VII). This was cyclized with bis(trifluoroacetoxy)iodobenzene to the imidazoquinolinone (VIII). The N-methoxy and N-benzyloxycarbonyl groups of (VIII) were then removed by hydrogenolysis in the presence of Pearlman’s catalyst, and the title compound was finally converted to the corresponding maleate salt.

JOC 1997,62,(19):6582

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Roche Gets Breakthrough Status for Lung Cancer Drug

 breakthrough designation, Uncategorized  Comments Off on Roche Gets Breakthrough Status for Lung Cancer Drug
Sep 242013
 

 

ALECTINIB

http://www.who.int/medicines/publications/druginformation/issues/PL_108.pdf

9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-
6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
tyrosine kinase inhibitor, antineoplastic

C30H34N4O2, CAS 1256580-46-7

The U.S. Food and Drug Administration (FDA) has granted breakthrough therapy designation for Roche’s alectinib – a promising investigational 2nd generation ALK inhibitor – based on data that will be presented at European Cancer Congress (ECC). Read more…http://www.dddmag.com/news/2013/09/roche-gets-breakthrough-status-lung-cancer-drug?et_cid=3497158&et_rid=523035093&type=cta

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The strategy of enantiomer patents of drugs

 Uncategorized  Comments Off on The strategy of enantiomer patents of drugs
Sep 152013
 

The strategy of enantiomer patents of drugs

Drug Discovery Today, Volume 15, Issues 5–6, March 2010, Pages 163-170

http://www.sciencedirect.com/science/article/pii/S1359644610000310

  • Organic Chemistry, Institute of Chemistry, The Hebrew University of Jerusalem, Philadelphia Building 201/205, Edmond J. Safra Campus, Jerusalem 91904, Israel

Enantiomer patents (ENPTs), constituents of chiral switches, claim single enantiomers of chiral drugs previously claimed as racemates. In this article, the strategy of ENPTs and recent court decisions and trends in case law worldwide are highlighted. ENPTs are challenged frequently (e.g. anticipation, obviousness, double patenting and insufficient disclosure), even though the novelty of enantiomers is not destroyed by the description of racemates. For establishing inventiveness (nonobviousness), the description in ENPTs should include superior pharmacological and/or pharmaceutical properties of enantiomer vis-á-visracemate, above the expected 2:1 ratio. ENPTs were ‘obvious-to-try’ (unless taught away) since the mid-1980s. General concern about evergreening by ENPTs is not justified. ENPTs should be evaluated on a case-by-case basis. ENPT litigations are especially susceptible to settlements.

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ESCITALOPRAM

 GENERIC, Uncategorized  Comments Off on ESCITALOPRAM
Sep 152013
 

File:Escitalopram structure.svg

128196-01-0 ESCITALOPRAM

Escitalopram (also known under various trade names) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults and children over 12 years of age with major depressive disorder and generalized anxiety disorder. Escitalopram is the (S)-stereoisomer (enantiomer) of the earlier Lundbeck drug citalopram, hence the name escitalopram. Escitalopram is noted for its high selectivity with serotonin reuptake inhibition. The similarity between escitalopram and citalopram has led to accusations of “evergreening“, an accusation that Lundbeck has rejected.[1]

Escitalopram has FDA approval for the treatment of major depressive disorder and generalized anxiety disorder in adults.[2]

Off-label uses

Escitalopram is sometimes prescribed off-label for the treatment of other conditions: social anxiety disorder,[3] panic disorder[4]and obsessive-compulsive disorder.[5] There is some evidence favouring escitalopram over the antidepressants citalopram andfluoxetine in the first two weeks of major depression.[6] Concerns of sponsorship bias with the studies are however noted.[6] In another review escitalopram and sertraline had the highest rate of efficacy and acceptability among adults receiving treatment for major depression with second-generation antidepressants.[7]

Efficacy

There is some controversy over selective publishing of SSRI clinical trials.[8] A meta-analysis analyzing published as well as unpublished trials found placebos to be similarly effective to SSRIs in treating mild depression, although SSRIs were more effective than placebo in more severe cases, with the magnitude of SSRI superiority increasing with increasing depression severity.[9]

A series of randomized, double-blind trials have found Escitalopram to be more efficacious and have fewer adverse effects than Citalopram.[10][11][12][13] Meta-analysis show a “small” but statistically significant improvement in effect strength [14][15] and some dispute these findings.[16]

Pharmacology

Cipralex brand escitalopram 10mg package and tablet sheet

Escitalopram increases intrasynaptic levels of the neurotransmitter serotonin by blocking the reuptake of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently on the market, escitalopram has the highest affinity for the human serotonin transporter (SERT). The enantiomer of escitalopram ((R)-citalopram) counteracts to a certain degree the serotonin-enhancing action of escitalopram. As a result, escitalopram has been claimed to be a more potent antidepressant than citalopram, which is a mixture of escitalopram and (R)-citalopram. In order to explain this phenomenon, researchers from Lundbeck proposed that escitalopram enhances its own binding via an additional interaction with another allosteric site on the transporter.[42] Further research by the same group showed that (R)-citalopram also enhances binding of escitalopram,[43] and therefore the allosteric interaction cannot explain the observed counteracting effect. In the most recent paper, however, the same authors again reversed their findings and reported that R-citalopram decreases binding of escitalopram to the transporter.[44] Although allosteric binding of escitalopram to the serotonin transporter is of unquestionable research interest, its clinical relevance is unclear since the binding of escitalopram to the allosteric site is at least 1000 times weaker than to the primary binding site.

In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram. The resulting metabolites, desmethylescitalopram and didesmethylescitalopram, are significantly less active and their contribution to the overall action of escitalopram is negligible.

History

Escitalopram was developed in close cooperation between Lundbeck and Forest Laboratories. Its development was initiated in the summer of 1997, and the resulting new drug application was submitted to the U.S. FDA in March 2001. The short time (3.5 years) it took to develop escitalopram can be attributed to the previous extensive experience of Lundbeck and Forest with citalopram, which has similar pharmacology.[45] The FDA issued the approval of escitalopram for major depression in August 2002 and for generalized anxiety disorder in December 2003. Escitalopram can be considered an example of “evergreening“[46] (also called “lifecycle management”[47])– the long-term strategy pharmaceutical companies use in order to extend the lifetime of a drug, in this case of the citalopram franchise. Escitalopram is an enantiopure compound of theracemic mixture citalopram, used for the same indication, and for that reason it required less investment and less time to develop. Two years after escitalopram’s launch, when the patent on citalopram expired, the escitalopram sales successfully made up for the loss. On May 23, 2006, the FDA approved a generic version of escitalopram by Teva.[48]On July 14 of that year, however, the U.S. District Court of Delaware decided in favor of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.[49]

In 2006 Forest Laboratories was granted an 828 day (2 years and 3 months) extension on its US patent for escitalopram.[50] This pushed the patent expiration date from December 7, 2009 to September 14, 2011. Together with the 6-month pediatric exclusivity, the final expiration date was March 14, 2012.

Brand names

Escitalopram is sold under the following brand names:

  • Animaxen (Colombia)
  • Anxiset-E (India)
  • Cipralex
  • Escital (Nigeria)
  • Citalin
  • Citram (Croatia)
  • Ecytara (Slovenia)
  • Elicea
  • Entact (Greece)
  • Escitalopram Actavis (Finland)
  • Escitil (Czech Republic)
  • Esitalo (Australia)
  • Esopram, by Actavis (Iceland)
  • Esto (Israel)
  • Escitalopram Teva (Israel)
  • Exodus (Brazil)
  • Lexam
  • Lexamil (South Africa)
  • Lexapro
  • Losita (Bangladesh)
  • Nexito
  • Reposil (Chile)
  • Selectra (Russia)
  • Selpram (Pakistan)
  • Seroplex
  • Sipralexa (Belgium)

References

  1. ^ a b c NHS pays millions of pounds more than it needs to for drugs, The Independent. Retrieved 05/10/2011.
  2. ^ “Escitalopram Oxalate”. The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
  3. ^ Kasper, S; Stein, DJ; Loft, H; Nil, R (2005). “Escitalopram in the treatment of social anxiety disorder: Randomised, placebo-controlled, flexible-dosage study”. The British journal of psychiatry : the journal of mental science 186 (3): 222–6.doi:10.1192/bjp.186.3.222. PMID 15738503.
  4. ^ Stahl, SM; Gergel, I; Li, D (2003). “Escitalopram in the treatment of panic disorder: A randomized, double-blind, placebo-controlled trial”. The Journal of clinical psychiatry 64(11): 1322–7. PMID 14658946.
  5. ^ Stein, DJ; Andersen, EW; Tonnoir, B; Fineberg, N (2007). “Escitalopram in obsessive-compulsive disorder: A randomized, placebo-controlled, paroxetine-referenced, fixed-dose, 24-week study”. Current medical research and opinion 23 (4): 701–11. doi:10.1185/030079907X178838. PMID 17407626.
  6. ^ a b Cipriani, A; Santilli C; Furukawa TA; Signoretti A; Nakagawa A; McGuire H; Churchill R; Barbui C (2009 April 15). “Escitalopram versus other antidepressant agents for depression”. In Cipriani, Andrea. Cochrane database of systematic reviews(2): CD006532. doi:10.1002/14651858.CD006532.pub2. PMID 19370639. CD006532.
  7. ^ Cipriani, A; Furukawa TA; Salanti G; Geddes JR; Higgins JP; Churchill R; Watanabe N; Nakagawa A; Omori IM; McGuire H; Tansella M; Barbui C (2009 February 28). “Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis”. Lancet 373 (9665): 746–58. doi:10.1016/S0140-6736(09)60046-5. PMID 19185342.
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  26. ^ Davidson JR, Bose A, Wang Q (2005). “Safety and efficacy of escitalopram in the long-term treatment of generalized anxiety disorder”. J Clin Psychiatry 66 (11): 1441–6.doi:10.4088/JCP.v66n1115. PMID 16420082.
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  28. ^ Guerdjikova, AI; McElroy SL, Kotwal R, et al. (January 2008). “High-dose escitalopram in the treatment of binge-eating disorder with obesity: a placebo-controlled monotherapy trial”. Human Psychopharmacology: Clinical and Experimental23 (1): 1–11. doi:10.1002/hup.899. PMID 18058852.
  29. ^ Levenson M, Holland C. “Antidepressants and Suicidality in Adults: Statistical Evaluation. (Presentation at Psychopharmacologic Drugs Advisory Committee; December 13, 2006)”. Retrieved 2007-05-13.
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AstraZeneca pays $50 million upfront for Merck & Co cancer drug

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Sep 122013
 

AstraZeneca has licensed a drug which is in mid-stage studies for ovarian cancer from Merck & Co.

The pact centres around the US drug major’s MK-1775, an oral small molecule inhibitor of WEE1 kinase, a cell cycle checkpoint protein regulator. Preclinical data indicate that disruption of WEE1 may enhance the cell killing effects of some anticancer agents and the compound is in Phase IIa studies in combination with standard of care therapies for the treatment of patients with certain types of ovarian cancer………….read all at

http://www.pharmatimes.com/Article/13-09-11/AZ_pays_50_million_upfront_for_Merck_Co_cancer_drug.aspx

MK-1775

MK-1775 is a potent and selective Wee1 inhibitor with IC50 of 5.2 nM; hinders G2 DNA damage checkpoint. Phase 2. IC50 of 5.2 nM

Chemical Name: 1,2-dihydro-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-2-(2-propen-1-yl)-3H-Pyrazolo[3,4-d]pyrimidin-3-one

Elemental Analysis: C, 64.78; H, 6.44; N, 22.38; O, 6.39

CAS 955365-80-7

C27H32N8O2

MW 500.61

Biological Activity:

 

A potent and selective Wee1 kinase inhibitor in vitro and in vivo.

 

MK 1775 abolishes cyclin-dependent kinase 1 (CDC2) activity by phosphorylation of the Tyr15 residue. It abrogates a DNA damage checkpoint (G2-phase), leading to apoptosis in combination with several DNA-damaging agents selectively in p53-deficient tumor cell lines. It is under clinical trial for advanced solid tumors.

 

References:  

 

H. Hirai et al. Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol. Cancer. Ther. 2009, 8(11), 2992-3000. [online]

 

S. Schellens et al. A Phase I and pharmacological study of MK-1775, a Wee1 tyrosine kinase inhibitor, in both monotherapy and in combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors. J. Clin. Oncol. 2009, 27(15s), abstr 3510.

 

H. Hirai et al. MK-1775, a small molecule Wee1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer Biol. Ther. 2010, 9(7), 523-525. [online]

 

CC Porter et al. Integrated genomic analyses identify WEE1 as a critical mediator of cell fate and a novel therapeutic target in acute myeloid leukemia. Leukemia 2012, 26, 1266-1276.  [online]

 

MK-1775 is an inhibitor of Wee1, a kinase that phosphorylates CDC2 to inactivate the CDC2/cyclin B complex (regulating the G2 checkpoint). Since most human cancers harbor p53-dependent G1 checkpoint abnormalities, they are dependent on the G2 checkpoint. G2 checkpoint abrogation may therefore sensitize p53 deficient tumor cells to anti-cancer agents

 

MK-1775 inhibits phosphorylation of CDC2 at Tyr15 (CDC2Y15), a direct substrate of Wee1 kinase in cells. MK-1775 abrogates G2 DNA damage checkpoint, leading to apoptosis in combination with DNA-damaging chemotherapeutic agents such as gemcitabine, carboplatin, and cisplatin selectively in p53-deficient cells. In vivo, MK-1775 potentiates tumor growth inhibition by these agents, and cotreatment does not significantly increase toxicity. The enhancement of antitumor effect by MK-1775 was well correlated with inhibition of CDC2Y15 phosphorylation in tumor tissue and skin hair follicles. Our data indicate that Wee1 inhibition provides a new approach for treatment of multiple human malignancies. [Mol Cancer Ther 2009;8(11):2992-3000].

 

MK-1775 is a first in class Wee1 inhibitor that is well tolerated and shows promising anti-tumor activity in previously treated pts. for detail see: http://meeting.ascopubs.org/cgi/content/abstract/27/15S/3510.

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Melatonin: It’s Not Just for Bedtime Anymore – Part 1

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Sep 102013
 

melatonin 300x200

Melatonin is a neurohormone that is produced in the brain, primarily by the pineal gland, from the amino acid tryptophan. Its most well known functions include helping to regulate sleep and the body’s circadian rhythm.

The amount of melatonin we produce is determined by how dark or light our surroundings are. Our eyes have specialized light-sensitive receptors that relay this message to a cluster of nerves in the brain called the suprachiasmatic nucleus, or SCN. The SCN sets our internal biological clock (circadian rhythm) while also regulating sleep. When our surroundings are dark, the SCN tells the pineal gland to produce melatonin, which is thought to trigger sleep. Some melatonin is also made in the stomach and intestines.

Melatonin: It’s Not Just for Bedtime Anymore – Part 1 read all at

http://blog.designsforhealth.com/blog/bid/186477/Melatonin-It-s-Not-Just-for-Bedtime-Anymore-Part-1#!

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This Biotech Has So Many Reasons to Be Liked

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Sep 062013
 

This Biotech Has So Many Reasons to Be Liked
Motley Fool
With promising mid-stage results, the drug is expected to do well in phase 3 evaluation for pancreatic cancer.

Positive phase 3 results will open the door to the lucrative pancreatic cancer market, on top of the myelofibrosis market that is expected to …

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http://www.fool.com/investing/general/2013/09/05/this-biotech-has-so-many-reasons-to-be-liked.aspx

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