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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India, in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK- GENERICS LTD, Research centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now sSanofi, Searle India ltd, now Rpg lifesciences, etc. he is now helping millions, has million hits on google on all organic chemistry websites. His New Drug Approvals, Green Chemistry International, Eurekamoments in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 25 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide . He gas good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, polymorphism etc He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, amcrasto@gmail.com

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Bristol-Myers Squibb to Market Japanese Hypertension Drug in China


Bristol-Myers Squibb licensed exclusive China rights to market Coniel, a calcium channel blocker treatment for hypertension and angina pectoris, from Kyowa Hakko Kirin Co. BMS said the transaction, its first China-specific in-licensing deal, demonstrated the company’s long-term commitment to China. Previously, Kyowa Hakko Kirin handled China marketing of the product itself. 

O5-methyl O3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

Benidipine (INN), also known as Benidipinum or benidipine hydrochloride, is a dihydropyridine calcium channel blocker for the treatment of high blood pressure (hypertension).

Molecular Structure of 105979-17-7 (3,5-Pyridinedicarboxylicacid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester, (4R)-rel-)

Dosing

Benidipine is dosed as 2–4 mg once daily.[1]

Benidipine is sold as Coniel by Kyowa Hakko Kogyo.

Benidipine is only licensed for use in Japan and selected Southeast Asian countries, where it is sold as 4 mg tablets.

Also known as: 105979-17-7, NCGC00185768-01, Benidipene, AC1LCVDP, SureCN24516, CTK8E8626, AKOS015895389, H007

Molecular Formula: C28H31N3O6   Molecular Weight: 505.56224

  1.  Hi-Eisai Pharmaceutical, Inc. “Coniel (benidipine) package insert (Philippines)”.MIMS Philippines. CMPMedica. Retrieved 2008-03-31.
  2. Hirayama, N. and Shimizu, E.: Acta Cryst., C47, 458 (1991)

Benidipine hydrochloride, A calcium channel protein inhibitor

Benidipine hydrochloride C28H31N3O6.HCl [91599-74-5]

Alternative Name: KW 3049

Chemical Name: (4R)-rel-1,4-Dihydro-2,6-dimethyl-4​-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methyl 5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride

Biological Activity

Orally active antihypertensive agent which displays a wide range of activities in vitro and in vivo. Inhibits L-, N- and T-type Ca2+ channels. Also inhibits aldosterone-induced mineralocorticoid receptor activation. Exhibits cardioprotective and antiartherosclerotic effects.

Technical Data

M.Wt:

542.02

Formula:

C28H31N3O6.HCl

Solubility:

Soluble to 75 mM in DMSO and to 10 mM in ethanol

Storage:

Desiccate at RT

CAS No:

91599-74-5

References

Yao et al (2006) Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel long-acting calcium channel blocker. J.Pharmacol.Sci. 100 243. PMID: 16565579.

Kosaka et al (2010) The L-, N-, T-type triple calcium channel blocker benidipine acts as an antagonist of mineralocorticoid receptor, a member of nuclear receptor family. Eur.J.Pharmacol. 635 49. PMID: 20307534.

Benidipine hydrochloride, whose chemical name is (±)-(R*)- 1 ,4-dihydro-2,6-dimethyl-4-(meta-nitrophenyl)-3 ,5-pyridinedica rbolate methyl ester [(R*)-l-benzyl-3-piperidine alcohol ester], belongs to dihydropyridine receptor antagonist. It can bind to dihydropyridine receptors at the binding site with high affinity and high specificity, and shows a strong inhibitory effect on Ca channel. Benidipine not only has an inhibitory effect on muscular (L-type) Ca channel, but also has an inhibitory effect on voltage-dependent N- and T-type Ca channels. It is, up to now, the only calcium antagonist that can inhibit all the three Ca channels mentioned above. Furthermore, benidipine has highly affinity with cell membrane, has vascular selectivity and renal protection effect. Therefore, it is an ideal, safe and effective agent for the treatment of hypertension and renal parenchymal hypertension and angina.

There are two chiral atoms in the molecule of benidipine hydrochloride, which locate on site 4 of the dihydropyridine ring and site 3′ of the side chain piperidine ring. Accordingly, benidipine hydrochloride has 4 optical isomers: (S)-(S)-(+)-a, (R)-(R)-(-)-a, (R)-(S)-(+)^ and (S)-(R)-(-)^, and the active ingredients for drug are the mixture of (S)-(S)-(+)-a and (R)-(R)-(-)-0L Therefore, it is necessary to separate a and β isomers during the post- treatment stage of benidipine hydrochloride preparation.

Based on the order of synthesis of dihydropyridine main ring, there mainly are two groups of total 5 synthesis routes of benidipine hydrochloride. Among them, there are two routes which involve synthesis of the main ring first: 1) acylchloridizing the main ring of dihydropyridine and then linking the side chain to synthesize directlybenidipine hydrochloride; 2) After acylchloridizing the main ring of dihydropyridine, 3-piperidinol and then benzyl is added. The routes involve the synthesis of the main ring later includes the following; 1) synthesizing the main ring via β-aminocrotonate; 2) synthesizing the main ring via acetylacetate ester; 3) the One-pot’ method involving 3-nitrobenzaldehyde, β-aminocrotonate and acetylaceate ester.

Several synthetic routes of benidipine hydrochloride and its analogues have been disclosed in EP0063365A1, EP0161877A2, JP57-171968A, EP0106275 A2, etc. Among them, EP0106275 A2 gave a summary of the synthetic pathways ofbenidipine hydrochloride. In all of the above references, it was mentioned to separate the benidipine hydrochloride prepared through column chromatography and spit it into its a and β isomers, thus obtain the therapeutically active (±)-a-benidipine hydrochloride.

In order to obtain a highly purified benidipine hydrochloride meeting pharmaceutical use, it is necessary to perform multiple recrystallization with acetone and/or ethanol. Moreover, the crystallization condition is relatively strict since it should be performed below freezing point or even below -20 °C . Furthermore, the crystallization process usually need a relatively long time (more than 24 hours).

JP2007-8819A thus disclosed a method for preparing highly purified benidipine hydrochloride meeting pharmaceutical use by first preparing the monohydrate of benidipine hydrochloride.

Because benidipine hydrochloride has a very low solubility, for dissolving in a solvent quickly, benidipine hydrochloride is often grounded into nanoparticles. CN 1794993 A provided a method to grind benidipine hydrochloride into particles of 1.0^50.0 μπι. The mechanical grinding method is performed by grinding larger particles of crystals into desired smaller size of crystals. This method consumes large amount of energy and time, and results in a widely distribution of the crystal particle size.

PEOPLE found the desired sizes of benidipinehydrochloride nanoparticles could be obtained by ultrasonic crystallization technology. Unlike the method of CN 1794993 A, the method according to the present invention obtains crystals from smaller to larger sizes. The distribution of particle sizes in the method of the present invention is relatively narrower since the solvent crystalizes rapidly and steadily in the solution. Overall, the present invention can save time and energy, and is readily for preparation. Summary of the invention

benidipine preparation are disclosed in EP0106275, after JP 2007008819 discloses the industrial preparation methods, Kyowa Hakko Kogyo Co., Japan Institute of Pharmacology at Arzneimittelforschung magazine published a hydrochloric Benidipine physical and chemical properties and stability studies Japanese Pharmacopoeia 15th edition reproduces the drug. Benidipine given above literature its infrared spectrum (IR) in 3170cm “\ 3066 cm-1, 2950cm-1, 2523cm-1, 1694cm-1, 1666cm-1, 1642cm_ \ l533cm_ \ l491cm_ \ l432cm_ \ l348cm_ \ l299cm_ \ l218cm_ \ lll6cm_ \ l088cm_ \

 

 

HPLC

Purity test of benidipine hydrochloride (area normalization method): Chromatography conditions

Detector: ultraviolet absorption detector (detection wavelength: 237nm)

Chromatography column: stainless steel column: 4.6 mm x 10 cm, with octadecylsilyl (ODS) silica as filler.

Column temperature: constant, about 25 °C

Mobile phase: mixed solution of 0.05 mol/L potassium dihydrophosphate solution (pH 3.0): methanol : tetrahydrofuran (65:27:8) Flow rate: adjusted to render the retention time of benidipine hydrochloride to be about 20 min.

Chromatogram record time: about 2 times of the peak time of benidipine hydrochloride

 

CLINICAL TRIALS

http://clinicaltrials.gov/show/NCT00135551

Benidipine-based Comparison of Angiotensin Receptors, β-blockers, or Thiazide Diuretics in Hypertensive Patients Completed Cardiovascular Disease February 19, 2012

 

 

 

Title: Benidipine
CAS Registry Number: 105979-17-7
CAS Name: (4R)-rel-1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl (3R)-1-(phenylmethyl)-3-piperidinyl ester
Additional Names: (±)-(R*)-3-[(R*)-1-benzyl-3-piperidyl] methyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate; (±)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-(1-benzyl-3-piperidyl) ester-5-methyl ester
Molecular Formula: C28H31N3O6
Molecular Weight: 505.56
Percent Composition: C 66.52%, H 6.18%, N 8.31%, O 18.99%
Literature References: Dihydropyridine calcium channel blocker. Prepn (stereochemistry unspecified): K. Muto et al., EP 63365;eidem, US 4448964 (1982, 1984 both to Kyowa). Prepn: eidem, EP 106275 (1984 to Kyowa); and toxicity data: eidem, Arzneim.-Forsch. 38, 1662 (1988). Structural studies: N. Hirayama, E. Shimizu, Acta Crystallogr. C47, 458 (1991). Series of articles on properties, pharmacology, determn and clinical evaluation: Arzneim.-Forsch. 38, 1666-1763 (1988). Review: H. Suzuki, T. Saruta,Cardiovasc. Drug Rev. 7, 25-38 (1989).
Derivative Type: Hydrochloride
CAS Registry Number: 91599-74-5
Manufacturers’ Codes: KW-3049
Trademarks: Coniel (Kyowa)
Molecular Formula: C28H31N3O6.HCl
Molecular Weight: 542.02
Percent Composition: C 62.05%, H 5.95%, N 7.75%, O 17.71%, Cl 6.54%
Properties: Yellow crystalline powder, mp 199.4-200.4°. uv max (ethanol): 238, 359 nm (e 2.80 ´ 104, 6.68 ´ 103). Soly at 25° (%): methanol 6.9; ethanol 2.2; water 0.19; chloroform 0.16; acetone 0.13; ethyl acetate 0.0056; toluene 0.0019; n-heptane 0.00009. pKa 7.34. Partition coefficient (n-octanol/water): 1230 (pH 6.4, 22°). LD50 orally in male mice: 218 mg/kg (Muto, 1988).
Melting point: mp 199.4-200.4°
pKa: pKa 7.34
Log P: Partition coefficient (n-octanol/water): 1230 (pH 6.4, 22°)
Absorption maximum: uv max (ethanol): 238, 359 nm (e 2.80 ´ 104, 6.68 ´ 103)
Toxicity data: LD50 orally in male mice: 218 mg/kg (Muto, 1988)
Therap-Cat: Antihypertensive.
Keywords: Antihypertensive; Dihydropyridine Derivatives; Calcium Channel Blocker; Dihydropyridine Derivatives.

Kyowa Hakko Kirin seeks MHLW Approval for Additional Indication for ATL, PTCL and CTCL of Mogamulizumab


Kyowa Hakko Kirin Co., Ltd. has been filed an application to Japan’s Ministry of Health, Labour and Welfare (“MHLW”) seeking approval for additional indication for untreated CCR4-positive adult T-cell leukemia-lymphoma (ATL), relapsed CCR4-positive peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) of Mogamulizumab (brand name: POTELIGEO® Injection 20 mg).

read at…………

http://japan.pharmaintellect.com/2013/07/kyowa-hakko-kirin-seeks-mhlw-approval.html?utm_source=feedburner&utm_medium=email&utm_campaign=Feed%3A+Pharmainvest+%28PharmaInvest%29

Mogamulizumab (USAN; trade name Poteligeo) is a humanized monoclonal antibodytargeting CC chemokine receptor 4 (CCR4). It has been approved in Japan for the treatment of relapsed or refractory adult T-cell leukemia/lymphoma.[1]

Mogamulizumab was developed by Kyowa Hakko Kirin Co., Ltd.[2] It has also been licensed to Amgen for development as a therapy for Asthma.[3]

 

  1.  Subramaniam, J; Whiteside G, McKeage K, Croxtall J (18). “Mogamulizumab: First Global Approval”Drugs 72 (9): 1293–1298. doi:10.2165/11631090-000000000-00000. Retrieved 10 September 2012.
  2.  “Statement On A Nonproprietary Name Adopted By The USAN Council: Mogamulizumab”American Medical Association.
  3.  “Kyowa Hakko Kirin R&D Pipeline”. Kyowa Hakko Kirin. Retrieved 10 September 2012.

Poteligeo(mogamulizumab)-单克隆抗体

 
简介: 单克隆抗体Poteligeo(mogamulizumab)获得日本厚生劳动省批准治疗白血病-淋巴瘤日本厚生劳动省批准Kyowa Hakko Kirin公司的Poteligeo治疗复发或难治性CC趋化因子受体4(CCR4,CD194)阳性的T细胞性白 …
 单克隆抗体Poteligeo(mogamulizumab)获得日本厚生劳动省批准治疗白血病-淋巴瘤
日本厚生劳动省批准Kyowa Hakko Kirin公司的Poteligeo治疗复发或难治性CC趋化因子受体4(CCR4,CD194)阳性的T细胞性白血病-淋巴瘤。厚生劳动省还批准了Kyowa公司这一抗体的两个诊断方法,用于测试IHC和FCM,从而确定最有可能对治疗有应答的患者亚群。Amgen公司拥有Poteligeo在除日本、韩国、中国大陆和台湾以外地区的所有非癌症适应症的开发和商业化独占权。Amgen公司正在进行本品用于治疗哮喘的Ⅰ期临床研究。

 

 

 

Kyowa Hakko Kirin, has received approval for NOURIAST tablets 20 mg (istradefylline), a novel antiparkinsonian agent, has been approved for manufacturing and marketing in Japan


Istradefylline (KW-6002) is a selective antagonist at the A2A receptor. It has been found to be useful in the treatment of Parkinson’s disease.[1] Istradefylline reduces dyskinesia resulting from long-term treatment with classical antiparkinson drugs such as levodopa. Istradefylline is an analog of caffeine.

 

References

Peter A. LeWitt, MD, M. Guttman, James W. Tetrud, MD, Paul J. Tuite, MD, Akihisa Mori, PhD, Philip Chaikin, PharmD, MD, Neil M. Sussman, MD (2008). “Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces off time in Parkinson’s disease: A double-blind, randomized, multicenter clinical trial (6002-US-005)”. Annals of Neurology 63 (3): 295–302. doi:10.1002/ana.21315. PMID 18306243.

 

TUE 26 MAR 2013

Kyowa Hakko Kirin, has received approval for NOURIAST tablets 20 mg (istradefylline), a novel antiparkinsonian agent, has been approved for manufacturing and marketing in Japan.
NOURIAST is a selective adenosine A2A receptor antagonist for Parkinson’s disease of which action site is clearly distinct from the existing agents acting on dopamine receptors or dopamine metabolism.
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