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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc 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 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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SWINE FLU ; AYURVEDA SUCCESSFUL TREATMENT ; स्वाइन प्लू का सुरक्षित आयुर्वेदिक इलाज


****आयुर्वेद : आयुष**** ई०टी०जी० आयुर्वेदास्कैन ****AYURVEDA : E.T.G. AyurvedaScan **** ****आयुष आविष्कार**** ई० एच० जी० ****होम्योपैथीस्कैन **** E.H.G. Homoeopathy Scan

स्वाइन प्लू के लक्षणो पर आधारित सभी रोगियो का आयुर्वेदिक इलाज करने के बाद यह अनुभव मे आया है कि  महामारी की तरह फैल रही बीमारी का बहुत सटीक और अचूक इलाज आयुर्वेद मे है /
वायरल / अथवा स्वाइन फ्लू के रोगियो के इलाज मे मैने निम्न दवाये दी है उन्हे मै  सार्वजनिक तौर पर  देश के सभी नागरिको के लिये यहा बता रहा हू /

स्वाइन फ्लू या इस जैसी बीमारी के इलाज के लिये मेरा नुस्खा इस तरह है /

  • महामृत्युन्जय रस  दो गोली

  • कफ कुठार रस   चार गोली

  • सुदर्शन घन वटी  दो गोली

  • सप्त पर्ण घन वटी दो गोली

वयस्क व्यक्ति के लिये यह एक खुराक है /

सभी ऊपर लिखी गयी  दवओ की गोलियो को गुन्गुने पानी से तीन तीन घन्टे के अन्तर से खिलाना चाहिये three hourly a with lukwarm water

कम उम्र के  किशोरो को  ऊपर लिखी दवाओ की एक एक गोली…

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Detailed Requirements concerning the DOE in the Regulatory Submission Dossier: EMA’s and FDA’s Recommendations


DRUG REGULATORY AFFAIRS INTERNATIONAL

The EMA has published together with the FDA a new question & answer (Q&A) paper at the end of 2014. This document answers questions on detailed requirements in connection with the documents concerning regulatory submissions. Among others it contains the answer to the question “What level of detail should be considered for design of experiments (DOEs) in a regulatory submission?

GMP News
25/02/2015

http://www.gmp-compliance.org/enews_4652_Detailed-Requirements-concerning-the-DOE-in-the-Regulatory-Submission-Dossier-EMA-s-and-FDA-s-Recommendations_9184,7307P,9059,Z-VM_n.html

In our News dated 18 February we reported on a question & answer (Q&A) paper which was published by EMA and FDA together at the end of 2014. This document answers questions on detailed requirements in connection with the documents concerning regulatory submissions. It also answers a question on the topic design of experiments (DOE).

The document answers the question “What level of detail should be considered for design of experiments (DOEs) in a regulatory submission?” as follows:

The level of detail should be commensurate…

View original post 165 more words

FDA Approves Farydak (panobinostat) for Multiple Myeloma


Panobinostat

syn……….https://newdrugapprovals.org/2014/01/23/panobinostat/

HDAC inhibitors, orphan drug

cas 404950-80-7 

2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide

N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (alternatively, N-hydroxy-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-acrylamide)

Molecular Formula: C21H23N3O2   Molecular Weight: 349.42622

  • Faridak
  • LBH 589
  • LBH589
  • Panobinostat
  • UNII-9647FM7Y3Z

A hydroxamic acid analog histone deacetylase inhibitor from Novartis.

NOVARTIS, innovator

Histone deacetylase inhibitors

syn……….https://newdrugapprovals.org/2014/01/23/panobinostat/

FDA Approves Farydak (panobinostat) for Multiple Myeloma

February 23, 2015 — The U.S. Food and Drug Administration today approved Farydak (panobinostat) for the treatment of patients with multiple myeloma.

Multiple myeloma is a form of blood cancer that arises from plasma cells, a type of white blood cell, found in bone marrow. According to the National Cancer Institute, approximately 21,700 Americans are diagnosed with multiple myeloma and 10,710 die from the disease annually

read at

http://www.drugs.com/newdrugs/fda-approves-farydak-panobinostat-multiple-myeloma-4170.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+February+23%2C+2015&utm_content=FDA+Approves+Farydak+%28panobinostat%29+for+Multiple+Myeloma

AND

FDA approves Farydak for treatment of multiple myeloma [press release].http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm435296.htmPublished February 23, 2015. Accessed february 23, 2015

syn……….https://newdrugapprovals.org/2014/01/23/panobinostat/

syn……….https://newdrugapprovals.org/2014/01/23/panobinostat/

syn……….https://newdrugapprovals.org/2014/01/23/panobinostat/

syn……….https://newdrugapprovals.org/2014/01/23/panobinostat/

 

FDA approves Farydak for treatment of multiple myeloma [press release].http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm435296.htmPublished February 23, 2015. Accessed february 23, 2015

ANTHONY CRASTO VENTURES INTO CHINA…..MY KAIXIN BLOG 开心网 ON MEDICINAL CHEMISTRY


KAIXIN



MY EASTERN VENTURE TO PROPAGATE CHEMISTRY……………http://www.kaixin001.com/home/?_profileuid=159073878

CHINA

MY EASTERN VENTURE TO PROPAGATE CHEMISTRY……………http://www.kaixin001.com/home/?_profileuid=159073878

MY EASTERN VENTURE TO PROPAGATE CHEMISTRY……………http://www.kaixin001.com/home/?_profileuid=159073878

MY EASTERN VENTURE TO PROPAGATE CHEMISTRY……………http://www.kaixin001.com/home/?_profileuid=159073878\

 

 
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KHAJURAHO INDIA

Khajuraho Group of Monuments is located in India

Khajuraho Group of Monuments
Location of Khajuraho Group of Monuments in India.

Location in Madhya PradeshLocation in Madhya Pradesh

  1. Khajuraho Group of Monuments – Wikipedia, the free …

    en.wikipedia.org/wiki/Khajuraho_Group_of_Monuments

    The Khajuraho Group of Monuments are a group of Hindu and Jain temples in Madhya Pradesh, India. About 620 kilometres (385 mi) southeast of New Delhi, …

Hotel Chandela – A Taj Leisure Hotel

New TB Drug Enters Trials Neglected Diseases: Milestone comes despite waning pharma interest


TBA-354

New TB Drug Enters Trials

Neglected Diseases: Milestone comes despite waning pharma interest
chemical and eng news
Volume 93 Issue 8 | p. 5 | News of The Week
Issue Date: February 23, 2015 | Web Date: February 19, 2015

For the first time in six years, a new tuberculosis drug candidate has entered human clinical trials. Supported by the nonprofit Global Alliance for TB Drug Development, Phase I testing of TBA-354 began on Feb. 19.

TBA-354 is a nitroimidazole, a class of drugs effective against drug-resistant TB. The compound arose from a collaboration among the TB Alliance and researchers at New Zealand’s University of Auckland and the University of Illinois, Chicago, to find a next-generation nitroimidazole with more potent bactericidal activity and more favorable pharmacokinetic properties

TBA 354

CAS No: 1257426-19-9, 1403987-02-9

436.34, C19 H15 F3 N4 O5

2-Nitro-6(S)-[6-[4-(trifluoromethoxy)phenyl]pyridin-3-ylmethoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]

5H-​Imidazo[2,​1-​b]​[1,​3]​oxazine, 6,​7-​dihydro-​2-​nitro-​6-​[[6-​[4-​(trifluoromethoxy)​phenyl]​-​3-​pyridinyl]​methoxy]​-​, (6S)​-

6S)-2-Nitro-6-({6-[4-(trifluoromethoxy)phenyl]-3-pyridinyl}methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

TBA-354 is a potent anti-tuberculosis compound; maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates.

TBA-354

Nitroimidazoles represent a promising new class of anti-tubercular agents with potential for the treatment of drug sensitive and drug resistant disease. Two first generation compounds (PA-824 and OPC67683) are currently in clinical development. To maximize the potential of this class for tuberculosis (TB), we conducted a medicinal chemistry program to identify a next generation nitroimidazole. Ultimately, we selected TBA-354 [(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine] for in-depth profiling and preclinical development.
TBA-354 is more potent than PA-824 against M. tuberculosis in vitro, and against acute and established murine TB. This potency advantage is maintained on dosing as monotherapy in the initial and continuation phases of treatment, and when administered in combination with moxifloxacin and pyrazinamide. TBA-354 possesses a favorable pharmacokinetic (PK) profile with good oral bioavailability and excellent exposures in preclinical species. Due to these combined advantages, predicted clinically therapeutic doses are once daily and low, differentiating TBA-354 as a next generation anti-tubercular nitroimidazole.

TBA-354 was discovered by the TB Alliance in partnership with the University of Auckland and the University of Illinois at Chicago. The TB Alliance is a not-for-profit product development partnership (PDP) that operates like a biopharmaceutical company. The medicinal chemistry that led to discovery of TBA-354 was conducted at the Auckland Society for Cancer Research Center at University of Auckland and the biology was conducted at the University of Illinois at Chicago. Further in-depth profiling of the compound was led by the TB Alliance in collaboration with Johns Hopkins University, University of Illinois at Chicago and RTI International. Financial support for this project was provided by the Bill & Melinda Gates Foundation and UK Aid. The work was presented at ICAAC 2012 in San Francisco on Sept 10th 2012.

TBA-354’s excellent efficacy and pharmacokinetic profile make it a promising candidate to deliver superior bactericidal results from a small daily pill. The evidence of TBA-354’s effectiveness was found in animal models of TB, which, while often predictive, have their limitations. Clinical trials are needed to evaluate TBA-354’s effectiveness against TB in patients. Before proceeding to clinical trials, the safety and tolerability of TBA-354 must be evaluated; these toxicology and safety pharmacology studies are underway and will provide more information concerning the potential of this compound.

One of the major challenges of TB treatment, as well as drivers of drug-resistance remains the length and complexity of current treatment. Defeating the TB pandemic will require new drugs that shorten and simplify treatment. Given the disproportionate skew of the TB burden in the developing world, all new TB treatments must also be inexpensive enough to facilitate scale-up. As the most potent anti-tubercular nitroimidazole under development to date, TBA-354 offers great promise in many ways. Its potency may enable the reduction of length, cost, and side-effects of TB treatment. It is compatible with commonly used AIDS medications in ways that some currently used TB treatments are not. Further, nitroimadzoles have already proven combinable with other experimental TB drugs to form novel treatments regimens with the potential to cure both drug-sensitive and MDR-TB.

TBA-354 belongs to the nitroimadazole class. Other drugs from this class have exhibited promising activity against TB bacteria in the lab and in clinical trials — two of the most advanced new TB drug candidates (PA-824and delamanid) belong to this class. Having shown greater potency compared to PA-824 and an improved pharmacokinetic profile compared to delamanid, along with other promising properties, TBA-354 offers the potential to shorten and simplify TB treatment further than therapies currently under clinical development. Its increased potency against TB could also reduce the cost, pill size, frequency and/or side effects of treatment with a nitroimidazole by achieving comparable efficacy with less drug amount. Importantly, because it belongs to a novel class of drugs, TBA-354 projects to be effective in treating both drug-sensitive and drug-resistant TB.

TBA-354 emerged from studies designed to identify a next generation nitroimidazole for TB

• It is the first new TB drug candidate to begin a Phase 1 clinical trial since 2009

• 1.5 million people die each year from TB, and more than nine million were diagnosed with the disease

FEB 2015 NEW YORK — The Global Alliance for TB Drug Development (TB Alliance) has commenced the first human trial of a new tuberculosis (TB) drug candidate, designated TBA-354, the not for profit organization announced Wednesday..

It is the first new TB drug candidate to begin a Phase 1 clinical trial since 2009.

The World Health Organization reported that 1.5 million people die each year from TB, and more than nine million were diagnosed with the disease. The lack of short, simple, and effective treatments is a significant obstacle to TB control.

Owing to lack of economic incentive to develop new tools, there are not enough promising drugs in the pipeline, which could hinder efforts to develop the appropriate treatments needed to combat the TB epidemic.

“There is a critical gap of new compounds for TB,” said Mel Spigelman, MD, President and CEO of TB Alliance.

“The advancement of TBA-354 into clinical testing is a major milestone, not only because of the potential it shows for improving TB treatment, but because it is the first new TB drug candidate to begin a Phase 1 clinical trial in six years.”

TBA-354 emerged from studies designed to identify a next generation nitroimidazole for TB. It comes from the nitroimidazole class of chemicals, known for being effective against drug-sensitive and drug-resistant tuberculosis.

The class also includes the experimental TB drug pretomanid (formerly PA-824), which is being tested as a component of other novel regimens in multiple clinical trials.

TB Alliance conducted the studies in collaboration with the University of Auckland and University of Illinois-Chicago. Once identified, TB Alliance further advanced TBA-354 through pre-clinical development and is now the sponsor of the Phase 1 study

“Our chemistry team has worked on this since 2006 when the TB Alliance approached us to help with this project,” said Professor Bill Denny, director of the Auckland Cancer Society Research Centre and a Principal Investigator of the Maurice Wilkins Centre at the University of Auckland. “We made several hundred compounds, from which TBA-354 was selected for clinical development in 2011.”

“It’s very pleasing for us to see this drug go all the way through to Phase one clinical trial. It’s a validation of our work designing this compound to create a new and improved drug for the treatment of tuberculosis,” stated Denny in a statement.

In preclinical studies, TBA-354 demonstrated more potent anti-bactericidal and sterilizing activity compared to pretomanid. Recruitment is under way to enroll nearly 50 U.S. volunteers for the randomized, double-blind Phase 1 trial, which will evaluate the safety, tolerability, pharmacokinetics, and dosing of TBA-354.

In late 2012 a promising New Zealand compound targeting treatment-resistant tuberculosis (TB) was selected as a drug candidate by international non-profit drug developer the Global Alliance for TB Drug Development (TB Alliance).

NZ TB drug selected

Image: Micrograph of Mycobacterium tuberculosis, the bacterium that causes tuberculosis. Image courtesy of Dr Ray Butler and Janice Carr (Centres for Disease Control).

New drug candidate TBA-354 was designed by scientists from the Auckland Cancer Society Research Centre (ACSRC) and Maurice Wilkins Centre in partnership with the TB Alliance and University of Illinois at Chicago. The TB Alliance expects to complete preclinical studies by early 2013, and then seek permission from the US Food and Drug Administration to begin human trials.

TB is second only to HIV/AIDS as the greatest infectious killer worldwide. While most cases and deaths occur in low and middle income countries, it is a major health concern in the Asia-Pacific region. Treatment regimens are complex, lengthy and challenging to follow and the disease is developing resistance to current antibiotics. If a new drug proves more effective than current treatments it may reduce the duration, cost and side effects of treatment.

Laboratory studies to date have been very promising, with TBA-354 proving much more potent and broad-spectrum than PA-824, the first-generation compound it was designed to improve upon. TBA-354 and PA-824 are members of the first new class of drugs developed for TB in nearly fifty years and the first designed to attack the persistent form.

the TB Alliance contracted the New Zealand scientists to develop second-generation compounds to overcome some of its known limitations. The New Zealanders optimised each part of the drug, and in the process developed a new method of synthesis that will simplify and reduce the cost of producing drugs of this class.

“TBA-354 is an improved, second-generation version of PA-824,” says Professor Bill Denny,
ACSRC Co-Director and a Maurice Wilkins Centre principal investigator. “It is much more
potent than PA-824, longer lasting, and has greater activity against resistant strains. Recent
trials show that PA-824 can dramatically shorten the treatment period for TB, and it’s
encouraging that in TBA-354 we have a compound that is clearly superior to it.”

“This has been an excellent and productive international collaboration, across groups with
different skills, where we have learned much that we can apply in future,” says Associate
Professor Brian Palmer of the ACSRC and Maurice Wilkins Centre, who led the project’s
chemistry team of Drs Adrian Blaser, Iveta Kmentova, Hamish Sutherland and Andrew
Thompson.

“New Zealand has an outstanding reputation in drug discovery and it’s exciting to see the
ACSRC’s expertise in cancer drug development being applied to the fight against one of
the most devastating infectious diseases in the world,” says Centre Director Professor
Rod Dunbar.

 http://www.google.co.in/patents/EP2459571A1?cl=en

[0093] E. Synthesis of (6S)-2-nitro-6-({6-[4-(trifluoromethoxy)phenyI]-3- pyridinyI}methoxy)-6,7-dihydro-5H-imidazo[2,l-A][l53]oxazine (6) by the method of Scheme 4.

Figure imgf000025_0001

NaH (60% w/w, 0.584 g, 14.6 mmol) was added to a solution of oxazine alcohol 41 (2.073 g, 1 1.2 mmol) and 2-chloro-5-(chloromethyl)pyridine (48) (2.0 g, 12.3 mmol) in anhydrous DMF (40 mL) at 5 0C. The resulting mixture was stirred at room temperature for 16 h and then quenched with water (150 mL). The precipitate was filtered off, washed with water and dried to give (65)-6-[(6-chloro-3-pyridinyl)methoxy]-2-nitro-6,7-dihydro-5//-imidazo[2,l- ft][l,3]oxazine (49) (3.39 g, 97%) as a light yellow solid: mp 191-193 0C; 1H NMR [(CD3)2SO] δ 8.37 (d, J- 2.3 Hz, 1 H), 8.02 (s, 1 H), 7.79 (dd, J = 8.3, 2.4 Hz, 1 H), 7.51 (br d, J = 8.2 Hz, 1 H), 4.74 (d, J= 12.4 Hz, 1 H), 4.69-4.64 (m, 2 H), 4.47 (d, J= 1 1.8 Hz, 1 H), 4.29-4.21 (m, 3 H). HRESIMS calcd for C12Hi2ClN4O4 mlz [M + H]+ 313.0513, 311.0542, found 313.0518, 311.0545.

Chloride 49 (1.0 g, 3.22 mmol) and 4-(trifluoromethoxy)phenylboronic acid (44) (0.788 g, 3.82 mmol) were suspended in DME (50 mL) and an aqueous solution Of K2CO3 (2M, 10 mL) was added. The mixture was purged with N2 and then treated with Pd(dppf)Cl2 (50 mg, 0.068 mmol) and stirred at 85 0C in an N2 atmosphere for 1 day, monitoring by MS. Further 44 (0.150 g, 0.728 mmol) was added and the mixture was stirred at 85 0C in an N2 atmosphere for 1 day. The resulting mixture was diluted with water (50 mL), and extracted with EtOAc (3 x 100 mL). The dried (MgSO4) organic layers were adsorbed onto silica gel and chromatographed on silica gel, eluting with EtOAc. Trituration of the product in Et2O gave 6 (0.942 g, 67%) as a white powder: mp 217-219 0C; 1H NMR [(CD3)2SO] δ 8.63 (d, J = 1.7 Hz, 1 H), 8.20 (dt, J = 8.9, 2.1 Hz, 2 H), 8.03 (s, 1 H), 7.99 (dd, J = 8.2, 0.5 Hz, 1 H), 7.84 (dd, J = 8.2, 2.2 Hz, 1 H), 7.47 (dd, J = 8.8, 0.8 Hz, 2 H), 4.77 (d, J = 12.3 Hz, 1 H), 4.71-4.68 (m, 2 H), 4.49 (d, J= 11.7 Hz, 1 H), 4.31-4.26 (m, 3 H). Anal. (Ci9Hi5F3N4O5) C, H, N. HPLC purity: 98.9%.

…………………

PATENT

http://www.google.com/patents/US20120028973

 

…………………

PAPER

Journal of Medicinal Chemistry (2010), 53(23), 8421-8439

http://pubs.acs.org/doi/full/10.1021/jm101288t

217 – 219 °C MP

http://pubs.acs.org/doi/suppl/10.1021/jm101288t/suppl_file/jm101288t_si_001.pdf

(6S)-2-Nitro-6-({6-[4-(trifluoromethoxy)phenyl]-3-pyridinyl}methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (93).
1)via bromide 160 :
Reaction of bromide160and 4-(trifluoromethoxy)phenylboronic acidunder the Suzuki coupling conditions described in Procedure A, followed by chromatographyof the product on silica gel, eluting with EtOAc, gave93(70%) as a cream solid: mp 217-219°C;
1H NMR [(CD3)2SO]
δ8.63 (d,J =1.7 Hz, 1 H),
8.20 (dt,J =8.9, 2.5 Hz, 2 H),
8.03 (s,1 H),
7.99 (dd,J =8.2, 0.5 Hz, 1 H),
7.84 (dd,J =8.2, 2.2 Hz, 1 H),
7.47 (br d,J =8.8 Hz, 2H),
4.77 (d,J =12.3 Hz, 1 H),
4.74-4.67 (m, 2 H),
4.49 (br d,J =11.7 Hz, 1 H),
4.33-4.22(m, 3 H).
Anal. (C19H15F3N4O5) C, H, N.F

 

Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
§ Global Alliance for TB Drug Development, 40 Wall Street, New York, New York 10005, United States
J. Med. Chem., 2010, 53 (23), pp 8421–8439
DOI: 10.1021/jm101288t

Andrew M. Thompson

*Corresponding author. Phone: (+649) 923 6145. Fax: (+649) 373 7502. E-mail: am.thompson@auckland.ac.nz.

+64 9 373 7599

Map of University of Auckland-Grafton Campus 85 Park Rd, Grafton, Auckland 1023, New Zealand
Street View
University of Auckland-Grafton Campus 85 Park Rd Grafton, Auckland 1023, New Zealand

Address details

M&HS BUILDING 504

Level 1, Room 504-117

85 PARK RD

Auckland 1023

GRAFTON

New Zealand

REF

International Journal of Computational Biology and Drug Design (2014), 7(1), 1-30.

http://www.inderscience.com/info/inarticle.php?artid=58583

 

 

University of Auckland – Faculty of Medical & Health Science

 

Auckland Food Tasting and Market Tour

 

Newmarket is a shopper’s paradise just minutes away from central Auckland. Offering a great mix of high street fashion, a large mall and designer boutiques, ..

SILODOSIN………For treatment of benign prostatic hypertophy


 

Silodosin.png

SILODOSIN

Urief, 160970-54-7, Rapaflo, KMD 3213, Silodyx, KAD 3213, KMD-3213
Molecular Formula: C25H32F3N3O4
Molecular Weight: 495.53449 g/mol

Alpha 1A adrenoceptor antagonist

Prostate hyperplasia

Kissei Pharmaceutical Co Ltd  INOVATOR

CAS 160970-54-7

2,3-Dihydro-1-(3-hydroxypropyl)-5-[(2R)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carboxamide

160970-64-9 (racemate)
169107-04-4 (diHBr)

Properties: [a]D25 -14.0° (c = 1.01 in methanol).
Optical Rotation: [a]D25 -14.0° (c = 1.01 in methanol)
Therap-Cat: In treatment of benign prostatic hypertophy.
a-Adrenergic Blocker.

In February 2008, the FDA accepted for review an NDA for silodosin for the treatment of dysuria associated with BPH . In October 2008, the FDA approved the drug . In April 2009, Actavis launched silodosin for the treatment of the signs and symptoms of BPH .

Silodosin.pngSILODOSIN

1-(3-hydroxypropyl)-5-[(2R)-2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-2,3-dihydroindole-7-carboxamide

 

Kissei Pharmaceutical, Daiichi Sankyo (formerly Daiichi Seiyaku), Actavis (formerly Watson) and Recordati have developed and launched silodosin (Urief; Trupass; Rapaflo; Thrupas; Silodyx; Urorec; KMD-3213; Youlifu), an oral alpha 1A adrenoceptor antagonist selective for prostatic receptors . The product is comarketed in Europe by several licensees. The drug is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).

Silodosin, a highly selective alpha1A-adrenoceptor antagonist, was launched in May 2006 in Japan for the oral treatment of urinary disturbance associated with benign prostatic hyperplasia (BPH). The product was launched in the U.S. for the treatment of signs and symptoms of benign prostatic hyperplasia in 2009. In 2009, a positive opinion was received in the E.U. for this indication and final approval was obtained in 2010. Launch in the E.U. took place the same year.

In May 2006, silodosin was launched as a capsule formulation in Japan. Actavis launched the drug in the US in April 2009. In June 2010, EU launched began, initially with Germany ; in November 2010, the drug was launched in France; by December 2010, the drug was launched in Spain.

In 2001, Kissei established an agreement with Daiichi Pharmaceutical to codevelop and comarket silodosin. An oral, once-daily formulation of silodosin filed in the U.S. by Watson (now Actavis) was approved in 2008. Watson (now Actavis) obtained exclusive rights in 2004 to develop and market the drug in the U.S.

PRODUCT Was developed and launched byKissei Pharmaceutical, Daiichi Sankyo, Actavis and Recordati. Family members of the product case EP0600675 have SPC protection in most EU states until 2018; while its Orange Book listed equivalent, US5387603, expire in the US in 2018 with US156 extension.

Silodosin (trade names Rapaflo (USA), Silodyx (Europe and South Africa), Rapilif (India), Silodal (India), Urief (Japan), Urorec (Russia)) is a medication for the symptomatic treatment of benign prostatic hyperplasia. It acts as an α1adrenoceptor antagonist with high uroselectivity (selectivity for the prostate).

Silodosin
Silodosin.png
Systematic (IUPAC) name
1-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]indoline-7-carboxamide
Clinical data
  • US: B
  • Not approved for use in women
Legal status
  • Prescription only
Routes Oral
Pharmacokinetic data
Bioavailability 32%
Protein binding 97%
Metabolism Hepatic glucuronidation (UGT2B7-mediated); also minor CYP3A4 involvement
Half-life 13±8 hours
Excretion Renal and fecal
Identifiers
CAS number 160970-54-7 
ATC code G04CA04
PubChem CID 5312125
IUPHAR ligand 493
ChemSpider 4471557 Yes
UNII CUZ39LUY82 Yes
ChEMBL CHEMBL24778 Yes
Synonyms KAD-3213, KMD-3213
Chemical data
Formula C25H32F3N3O4 
Molecular mass 495.534 g/mol

History

Silodosin received its first marketing approval in Japan in May 2006 under the tradename Urief, which is jointly marketed by Kissei Pharmaceutical Co., Ltd. and Daiichi Sankyo Pharmaceutical Co., Ltd.

Kissei licensed the US, Canadian, and Mexican rights for silodosin to Watson Pharmaceuticals, Inc. in 2004.

On February 12, 2008, Watson announced that the New Drug Application submitted to the United States Food and Drug Administration for silodosin has been accepted for filing. FDA approved this drug on October 9, 2008.[1] Silodosin is marketed under the trade names Rapaflo in the US and Silodyx in Europe.[2] and Rapilif in India (Ipca Urosciences)

Pharmacology

Since silodosin has high affinity for the α1A adrenergic receptor, it causes practically no orthostatic hypotension (in contrast to other α1 blockers). On the other side, the high selectivity seems to cause more problems with ejaculation.[3]

As α1A adrenoceptor antagonists are being investigated as a means to male birth control due to their ability to inhibit ejaculation but not orgasm, a trial with 15 male volunteers was conducted. While silodosin was completely efficacious in preventing the release of semen in all subjects, 12 out of the 15 patients reported mild discomfort upon orgasm. The men also reported the psychosexual side effect of being strongly dissatisfied by their lack of ejaculation.[4]

 

///////////////////////////////

CN 103848772

http://www.google.com/patents/CN103848772A?cl=en

silodosin (Silodosin) is 〃 2 Japanese orange Johnson invented – receptor antagonist, for the treatment of benign prostatic hyperplasia or hypertrophy, and other related symptoms. Clinical trials showed that 25% of patients with benign prostatic hyperplasia need for drugs or surgery. Although prostatectomy is better, the mortality rate is not high, but patients bring varying degrees of damage. So look for an effective and safe non-surgical treatment, not only can control the further development of the disease, while relieving the symptoms of the patient.

  benign prostatic hyperplasia in older male patients have a higher prevalence, and clinical alternative drugs rarely, so the development of a benign prostatic hyperplasia drug treatment, not only has good social benefits, but also to bring good economic benefits. The study confirmed that silodosin is the treatment of benign prostatic hyperplasia in an important class of drugs.

Figure CN103848772AD00031

Currently, the research reported in the published literature on the preparation of compounds of silodosin, are:

Figure CN103848772AD00032
Figure CN103848772AD00041

Early 1995, Kitazawa M et al patent US5387603, the reporter silodosin total synthesis method, but the method reaction step is long, the yield is not too high, not suitable for our industrial production.

Figure CN103848772AD00042

  In 2009, 翟富民 et al patent CN102115455A, which reported a method for preparing Sailuoduoxin key intermediates. The appropriate method for improving existing methods, although shorter than the previous method step in the step, but low synthesis yield of the process, we can not meet the needs of industrial production.

  In summary, the compounds prepared silodosin more synthetic methods are constantly improved, but there are still a lot of flaws. Therefore, there is need for further research on the preparation of compounds of silodosin to get simple process, product yield, product easy separation of the new preparation. SUMMARY

  The present invention is to overcome the above problems of the prior art, there is provided a method for preparing important intermediates silodosin, the present invention is simple process, high yield, easy separation of the product, the method suitable for industrial production .

To achieve the above technical object, to achieve the above technical result, the present invention is realized by the following technical scheme:

One kind of silodosin preparation of important intermediate, comprising the steps of:

Step I) in a flask, 282g of raw materials 1-acetyl-5- (2-bromo-propyl) indoline, 222g phthalimide potassium salt and 700mL DMF, was heated at 110 ° C for 2h; After completion of the reaction, to which was added the right amount of water to wash away the excess solvent DMF and salt extraction desolventizing after EA, was 296g crude;

Step 2) In a flask was added 296g crude product obtained in step I, dissolved 800mL ethanol, was added 165mL of hydrazine hydrate, 50 ° C is heated to precipitate a white solid; After completion of the reaction, cooling suction filtered, the filter cake washed with ethanol, and then the mother liquor removing solvent under reduced pressure; After dissolving EA, washed with water to wash away the excess hydrazine, and finally the organic phase the solvent was removed to give 165g intermediate, i.e. 1-acetyl-5- (2-aminopropyl) indoline;

Step 3) In the three-necked flask, 165g of Intermediate 1-acetyl-5- (2-aminopropyl) indoline, dissolved 600mL methanol, stirred at room temperature, and thereto was slowly added dropwise bromine; the addition was complete After stirring at room temperature 5-6h; After completion of the reaction, slowly poured into saturated NaHSO3, and wash away excess bromine; extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate; After filtration, the solvent was removed in vacuo to give the crude product recrystallized from toluene to give 177g pure product;

Step 4) In a flask was added 177g of pure product obtained in Step 3 and 65g CuCN, after use 700mL DMF, was heated at 110 ° C for 3 to 5h; After completion of the reaction, the amount of water was added thereto, washing off excess solvent DMF and salt, EA desolventizing crude extract, after recrystallization 121g pure 1-acetyl-5- (2-bromo-propyl) -7-cyano-indoline that silodosin important intermediates;

Step (1), (2), (3), (4) synthesis reaction is:

Figure CN103848772AD00051

Further, the step I) to step 4) by TLC plate tracking point detection reaction.

The beneficial effects of the present invention are:

Preparation silodosin important intermediate of the present invention, mention of the method is simple, high reaction yield, product easily separated, suitable for industrial production and so on.

 

Preparation Method  A silodosin important intermediate, comprising the following steps: Step I) in a flask, 282g of raw materials 1-acetyl-5- (2-bromo-propyl) indoline, 222g o phthalimide potassium and 700mL DMF, heated at 110 ° C for 2h; After completion of the reaction, to which was added the right amount of water to wash away the excess solvent DMF and salt extraction desolventizing after EA, was 296g crude;

Step 2) In a flask was added 296g crude product obtained in step I, dissolved 800mL ethanol, was added 165mL of hydrazine hydrate, 50 ° C is heated to precipitate a white solid; After completion of the reaction, cooling suction filtered, the filter cake washed with ethanol, and then the mother liquor removing solvent under reduced pressure; After dissolving EA, washed with water to wash away the excess hydrazine, and finally the organic phase the solvent was removed to give 165g intermediate, i.e. 1-acetyl-5- (2-aminopropyl) indoline;

Step 3) In the three-necked flask, 165g of Intermediate 1-acetyl-5- (2-aminopropyl) indoline, dissolved 600mL methanol, stirred at room temperature, and thereto was slowly added dropwise bromine; the addition was complete After stirring at room temperature 5-6h; After completion of the reaction, slowly poured into saturated NaHSO3, and wash away excess bromine; extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate; After filtration, the solvent was removed in vacuo to give the crude product recrystallized from toluene to give 177g pure product;

Step 4) In a flask was added 177g of pure product obtained in Step 3 and 65g CuCN, after use 700mL DMF, was heated at 110 ° C for 3 to 5h; After completion of the reaction, the amount of water was added thereto, washing off excess solvent DMF and salt, EA desolventizing crude extract, after recrystallization 121g pure 1-acetyl-5- (2-bromo-propyl) -7-cyano-indoline that silodosin important intermediates;

Step (1), (2), (3), (4) synthesis reaction is:

Figure CN103848772AD00061

Further, the step I) to step 4) by TLC plate tracking point detection reaction.

…………………………………………………

WO2013056842

http://www.google.com/patents/WO2013056842A1?cl=en

Silodosin is commercially available under the tradenames RAPAFLO® or

UROPvEC as a capsule formulation for oral use containing 4 mg or 8 mg of the drug. The capsules are to be taken orally once daily for the treatment of the signs and symptoms of benign prostatic hyperplasia. US 5,387,603 and EP 0 600 675 disclose silodosin as a therapeutic agent for the treatment for dysurea associated with benign prostatic hyperplasia. The molecular structure of silodosin (XXV) is shown below.

(XXV)

The synthesis of silodosin is relatively complex and requires a sequence of multiple steps. A key intermediate compound in the synthesis of silodosin is the optically active amine compound represented by the general formula R-Y:

1

wherein, R represents a protecting group and R represents a cyano (CN) or carbamoyl (CONH2) group. The intermediate compound R-Y bears the asymmetric carbon atom that imparts the optical activity to silodosin. Therefore, it is important to obtain the compound R-Y with high optical purity, because according to the methods reported in the state of the art the optical purity of the compound R-Y determines the optical purity of the final product silodosin.

JP 2001-199956 discloses a process for the preparation of a compound of formula R-Y, wherein l-(3-benzoyloxypropyl)-7-cyano-5-(2-oxopropyl)-2,3- dihydroindole or the corresponding 7-carbamoyl derivative is reacted with an optically active amine, namely L-2-phenylglycinol or L-l-phenylethanamine, to afford an imine compound of formula III as depicted in the below scheme 1. Scheme l . JP 2001-199956

R1 = COPh; R2 = CN or CONH2; R3 = H or OH a = 1. cat. deprotection

2. frational crystallization with L-tartaric acid

b = 1. chromatographic separation

2. cat. deprotection

The optically active imine III is subjected to catalytic hydrogenation using platinum(IV) oxide as a catalyst affording the diastereomers IV in a ratio of 3.8:1. The chiral auxiliary II is subsequently removed by catalytic hydrogenation using 10% palladium on carbon, i. e. under the typical conditions which lead to the cleavage and removal of benzylic protecting groups from nitrogen or oxygen atoms. The catalytic deprotection reaction affords the desired intermediate compound R-Y with an optical purity corresponding to the ratio of the diasteromers obtained in the previous step, i. e. the ratio of compound R-Y to S-Y is approximately 3.8: 1, which corresponds to an optical purity of approximately 58.3% enantiomeric excess (e.e.).

In order to increase the optical purity of the intermediate R-Y JP 2001-199956 suggests to conduct a fractional crystallization of the desired enantiomer with L-tartaric acid. After a series of fractional crystallizations the compound R-Y is obtained with an optical purity of 97.6% enantiomeric excess. Alternatively, the diastereomers of the compound of formula IV are separated using chromatographic techniques as column chromatography on silicagel. The pure diastereomer R-TV affords the desired enantiomer R-Y with an optical purity of 100% e.e. after removal of the chiral auxiliary II with hydrogen using 10% palladium on carbon as catalyst.

Another approach for the synthesis of the key intermediate compound R-Y is reported in JP 2002-265444. The route of synthesis disclosed in said document is depicted in the below scheme 2.

Scheme 2. JP 2002-265444

R1 = CH2Ph (Bn); R2 = CN The process involves the reaction of an enantiomeric mixture of the compound of formula VI with (I S, 2R)-2-benzylaminocyclohexane methanol (VII) to obtain a diastereomeric mixture containing the salt VIII. After a series of crystallizations the diastereomer VIII was obtained with an optical purity of 92.8% diastereomeric excess (d.e.). Subsequently, the salt VIII was treated with an acidic aqueous solution to release the acid R-Vl from the salt. After extraction from the aqueous solution with ethyl acetate the acid R-Vl is converted into its amide IX. The compound IX is finally subjected to a Hofmann type rearrangement reaction to obtain the desired intermediate compound R-V.

WO 201 1/030356 discloses a process for the preparation of the intermediate compound R-V, which avoids the resolution of the enantiomers of specific intermediate compounds using chiral auxiliaries or optically active bases. The route of synthesis described in WO 201 1/030356 starts from L-alanine (X), which is a naturally occurring optically active amino acid. The process described in

WO 2011/030356 is depicted in the below scheme 3.

R1 = trimethylsilyl (TMS), tert-butyl dimethylsilyl (TBDMS), allyl, benzyl, propargyl R2 = CN or CONH2 The amino acid is protected by the addition of ethyl chloroformate and subsequently activated by the addition of oxalyl chloride to afford i?-(N-ethoxycarbonyl)alanine as an acyl chloride (XI). Said acyl chloride is reacted with hydroxy protected l-(3- hydroxypropyl)-7-cyano-2,3-dihydroindole of formula XII in a Friedel-Crafts acylation reaction, which gives a compound of formula XIII. The oxo group in compound XIII is reduced to afford a compound of formula XIV that is subsequently subjected to a hydrolysis reaction to yield the key intermediate compound R-Y. It is an object of the present invention to provide a process for preparing silodosin or a pharmaceutically acceptable salt thereof, which process affords the drug with high optical purity and with better yield compared to the prior art processes. This object is solved by the subject matter as defined in the claims.

Scheme 5. Conversion of com ound V to silodosin

R = protecting group

R2 = CN or CONH2

X = leaving group

Example 11. Silodosin (XXV)

A. The compound XXIV (18.0 g) was dissolved in methanol (150 ml) and 5% aqueous sodium hydroxide solution (50 ml). The reaction mixture was stirred at room temperature for 2 h. The deprotected compound XXIV, i. e. a compound of formula XXIV with R = hydrogen and R = cyano, was extracted with toluene. Subsequently, a 10% lactic acid solution (25 ml) was added to the toluene phase in order to extract the product in the aqueous phase. The aqueous solution was separated and then basified. The deprotected product was finally extracted with ethyl acetate. Removal of the solvent gives the deprotected compound to XXIV (R1 = H and R2 = CN; 1 1.0 g) as an oily mass.

B. A mixture of compound XXIV (R1 = H and R2 – CN; 10.0 g), DMSO (80 ml) and 5N NaOH solution (9.0 ml) was stirred for 15 min. at room temperature. An aqueous H202 (30%) solution (1 1.0 ml) was added to the reaction mixture, which was stirred at room temperature for additional 2 h after completion of the addition. Water was added to the reaction mixture, the product was extracted with ethyl acetate, and the solvent was subsequently evaporated to afford 9.0 g crude silodosin.

Example 12. Silodosin (XXV)

10.0 g of crude silodosin (optical purity = 85.0% e.e.) was dissolved in ethyl acetate (120 ml) at 55°C. The resulting clear solution was gradually cooled to 25°C under stirring. The suspension was further cooled to 15°C and stirred for 2 hours. The precipitated solid was filtered and dried at 50°C under vacuum to obtain 7.2 g of XXV with an optical purity of 97.5% e.e.

Example 13. Silodosin (XXV)

10.0 g of crude silodosin (optical purity = 98.5% e.e.) was dissolved in ethyl acetate (120 ml) at 55°C. The resulting clear solution was gradually cooled to 25 °C under stirring. The suspension was further cooled to 15°C and stirred for 2 hours. The precipitated solid was filtered and dried at 50°C under vacuum to obtain 7.2 g of XXV with an optical purity of 99.9% e.e.

Example 14. Silodosin (XXV)

10.0 g of crude silodosin (optical purity = 90.0 %e.e.) was dissolved in ethyl acetate (120 ml) at 55°C. The resulting clear solution was gradually cooled to 25°C under stirring. The suspension was further cooled to 15°C and stirred for 2 hours. The precipitated solid was filtered and dried at 50°C under vacuum to obtain 7.2 g of XXV with an optical purity of 97.0% e.e.

Example 15. Silodosin (XXV)

10.0 g of crude silodosin (optical purity = 92.0% e.e.) was dissolved in isopropyl acetate (160 ml) at 55°C. The resulting clear solution was gradually cooled to 25°C under stirring. The suspension was further cooled to 15°C and stirred for 2 hours. The precipitated solid was filtered and dried at 50°C under vacuum to obtain 8.2 g of XXV with an optical purity of 98.0% e.e. Example 16. Silodosin (XXV)

10.0 g of crude silodosin (optical purity = 98.0% e.e.) was dissolved in isopropyl acetate (160 ml) at 55°C. The resulting clear solution was gradually cooled to 25°C under stirring. The suspension was further cooled to 15°C and stirred for 2 hours. The precipitated solid was filtered and dried at 50°C under vacuum to obtain 8.0 g of XXV with an optical purity of 99.5% e.e.

………………………………

EP2475634

http://www.google.com/patents/EP2475634A2?cl=en

Scheme- 1.

Scheme-2.

Scheme-3.

Scheme-4.

Scheme-5.

Example-14

Preparation of Preparation of l-(3-Hydroxy-propyl)-5-(2(R)-{2-[2-(2, 2, 2-trifluoro- ethoxy)-phenoxy]-ethyIamino}-propyl)-2,3-dihydro-lH-indol-7-carboxylic acid amide (I)(Silodosin)

To a solution of Benzoic acid 3-[5(R)-(2-amino-propyl)-7-cyano-2, 3-dihydro-indol-l- yl]-propyl ester (XV) (3.5 g, 10 mmole) in Dimethyl sulphoxide (60 ml), charged Hydrogen peroxide (10% w/w) (11 ml). Then added 5 N sodium hydroxide solution (12.3 ml) and reaction mass was stirred for 2 hours. After completion of reaction water was added and extracted the product in ethyl acetate. Organic layer was washed with brine and dried over sodium sulphate. The solvent was evaporated below 40°C under reduced pressure and added methanol (25 ml). To this solution charged glacial acetic acid (0.25 g, 4mmole) and [2-(2, 2, 2-Trifluoro-ethoxy)-phenoxy]-acetaldehyde (VIII) (3 g, 0.0125 mole). Reaction mixture was stirred at 25-30°C for 1 hour. Then reacted with sodium cyanoborohydride (0.15 g, 2.8 mmoles) and heated at 40-45°C for 2 hours. After the completion of reaction solvent was distilled off below 40°C under reduced pressure and added water to the residue. Reaction mass was then acidified with aqueous mineral acid. The aqueous layer was then basified and product was extracted in ethyl acetate. Organic layer was washed with water and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (5/95) as eluent to give 0.8g of (I) as yellow solid. Purity (by HPLC) = 98%

 

Example 15

Preparation of l-(3-hydroxypropyl)-5-[(2R)-({2-[2-(2, 2, 2-trifIuoroethoxy) phenoxy]-ethyl} amino) propyl]-2, 3-dihydro-lH-indole-7-carbonitriIe (XVII) A mixture of 3-[7-Cyano-5 (R)-[-2-{2-[2-(2,2,2-trifluoroethoxy)-phenoxy] ethyl} amino) propyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate (XVI) (6.0 g , 0.010 mole), methanol (30 ml) and aqueous solution of Sodium hydroxide ( 1.6 g in 8 ml of water) was stirred at ambient temperature for 6 hours. To the reaction mixture water (90ml) was added and product was extracted with ethyl acetate (90 ml). The organic layer was washed with saturated sodium bicarbonate solution followed by brine wash and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 3.85 g of (XVII). Example 16

Preparation of l-(3-Hydroxy-propyl)-5(R)-(2-{2-[2-(2, 2, 2-trifluoro-ethoxy)- phenoxy]-ethylamino}-propyl)-2, 3-dihydro-lH-indol-7-carboxylic acid amide (I) (Silodosin)

To a solution of l-(3-hydroxypropyl)-5(R)-[2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]- ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile (XVII) (6.0 g , 0.013 mole) in dimethylsulfoxide (75 ml) was added 5 N sodium hydroxide solution (4.5 ml). To this reaction mixture, 30 % hydrogen peroxide (2.63 ml) was added slowly below 25°C. Reaction mixture was stirred at ambient temperature for 6 hours. Aqueous solution of sodium sulfite (2.1 in 150 ml water) was added to the reaction mixture. The reaction mixture was extracted with ethyl acetate. The combined ethyl acetate layer was extracted 2N hydrochloric acid. The aqueous layer was neutralized with sodium bicarbonate and extracted the product in ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution followed by brine wash and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was cooled to 5°C and filtered to get 4.51 g of (I) as solid.

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WO2012147019

http://www.google.com/patents/WO2012147019A1?cl=en

The present invention provides a process for the preparation of Silodosin of formula (I). More particularly, the present invention provides the process for preparation of tartrate salt of 3-[7-cyano-5[(2R)-2-({2-[2-(2,2,2- trifluoroethoxy)phenoxy ] ethyl } amino)propyl] -2, 3 -dihydro- 1 H-indol- 1 -y 1 } propyl benzoate of formula (IV), which is a precursor in the preparation of Silodosin.

Background of the Invention:

A compound of 3-[7-cyano-5[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy] ethyl}amino)propyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate (IV) is a key intermediate for preparation of Silodosin. The chemical name of Silodosin is l-(3- hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino) propyl]-2,3-dihydro-lH-indole-7-carboxamide and structurally represented as

(IV)

(I)

U.S.Pat. No. 5,387,603 discloses Silodosin as therapeutic agents for the treatment of dysuria, urinary disturbance associated with benign prostatic hyperplasia.

U.S.Pat. No. 6,310,086 discloses a process for preparing a Silodosin analogue compound from reaction of (R)-3-{5-(2-aminopropyl)-7-cyano-2,3- dihydro- 1 H-indol- 1 -yl jpropylbenzoate with 2-(2-Ethoxyphenoxy)ethyl methane sulfonate and finally isolated as residue and purified by column chromatography on silicagel. The said literature process has certain drawbacks like use of column chromatography.

U.S.Pat. No. 7,834,193 (IN 3178/DELNP/2007) discloses the process for preparation of monooxalate salt of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2- trifluoroethoxy)phenoxy ] ethyl } amino)propyl] -2, 3 -dihydro- 1 H-indol- 1 -y 1 } propyl benzoate (IV). This patent specifically discloses the preparation of monooxalate salt of formula (IV) helps to remove N,N-dialkyl impurity to certain extend. CN 101993405 A discloses the reaction of (R)-5-(2-aminopropyl)-l-(3-(4- fluorobenzoyloxy)propyl)-7-cyanoindoline with 2-(2-(2,2,2-trifluoroethoxy) phenoxy)ethyl methane sulfonate followed by oxalic acid salt preparation.

The main drawback in the prior art process, the formation of N,N-dialkyl impurity compound of formula (VI), as disclosed in detailed description, in the preparation of Silodosin, during condensation of compound of formula (II) with compound of formula (III), the impurity which is not removable by crystallization method or precipitation technique and column chromatography purification is not suitable for commercial purpose. So considering the commercial importance of Silodosin, the present invention focus on the preparation of pure Silodosin, and surprisingly found that the isolation of formula (IV) as tartrate salt helps to prepare Silodosin having less than 0.2 % of N,N dialkyl impurity and with good yield. None of the prior arts teaches or motivates isolation of tartaric acid addition salt of formula (IV). The preparation of Silodosin from tartrate salt of 3-{7-cyano-5-[(2R)- 2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl}amino)propyl]-2,3-dihydro-lH- indol-l-yl} propyl benzoate (IV) or its freebase of the present invention has purity of greater than 99.6 %.

 

Example 3

Preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy] ethyl-} amino) propyl]-2,3-dihydro-lH-indole-7-carboxamide (Silodosin)

Method A: The compound of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2- trifluoroethoxy)phenoxy] ethyl- } amino)propyl] -2,3 -dihydro- 1 H-indole-7- carbonitrile of formula (V) in dimethylsulfoxide was treated with 48% hydrogen peroxide and 20% sodium hydroxide solution and stirred at room temperature till completion of reaction. After completion of reaction, reaction mass quenched with 5% sodium bisulphite solution and ethylacetate was added over it. The ethylacetate layer was separated and treated with 20 % aqueous hydrochloric acid. The aqueous layer separated, neutralized with sodium bicarbonate solution and extracted with ethylacetate. The separated organic layer was washed with 10% sodium bicarbonate solution, brine solution and dried under vacuum. The organic layer distilled upto residue under vacuum at 50-55°C. The obtained residue was crystallized in ethylacetate.

Method B: To the tartrate salt of 3-[7-cyano-5[(2R)-2-({2-[2-(2,2,2- trifluoroethoxy) phenoxy] ethyl}amino)propyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate (IV) (100 grams) in methanol, aqueous potassium hydroxide solution (38.38 grams) was added and stirred at room temperature till reaction completion. After completion of reaction, DM water and dichloromethane was added over it under stirring. Organic layer separated, washed with brine solution distilled under vacuum upto less than 1 volume. To the solution, dimethyl sulphoxide, 20% sodium hydroxide and hydrogen peroxide was added and stirred till completion of reaction. After completion of reaction, water containing sodium bisulfite was added to the reaction mass. The pH of the reaction mixture adjusted to about 8.5 using 10% sodium hydroxide and extracted in dichloromethane twice, washed with water, dried and concentrated upto 1-2 volume under vacuum. To the obtained solution, toluene was added over it at room temperature under stirring. The reaction mixture maintained for complete solid formation, filtered and dried under vacuum. Yield 58 grams. Example 4

Purification of Silodosin:

Method A: To the mixture of toluene and acetonitrile solvent, Silodosin was added over it and heated to 50° – 55 °C for complete dissolution. The reaction mass gradually cooled to room temperature and maintained for completion of solid formation. The obtained solid is filtered, washed with toluene and dried under vacuum. Method B: To the mixture of ethyl acetate and toluene solvent, Silodosin was added over it and heated to 60° – 65 °C for complete dissolution. The reaction mass gradually cooled to room temperature and maintained for completion of solid formation. The obtained solid is filtered, washed with toluene and dried under vacuum.

 

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CN101993407

http://www.google.com/patents/CN101993407B?cl=en

silodosin for selective inhibition of urethral smooth muscle contraction and reduce the pressure within the urethra, but no significant impact on blood pressure, for the treatment of benign prostatic hyperplasia. At present, the method of synthesis Silodosin many reports, but the lack of high yield method for industrial production.

  JP200199956 reported that benzoic acid as a starting material, 1_ (3_ benzoyloxy-propyl) indoline hydrochloride (structural formula (1), R is a hydrogen atom) in 60% yield, then through the multi-step reaction was further prepared silodosin intermediate 1- (3-benzoyloxy-propyl) -5- (2-nitro-propyl) -7-cyano-indoline (structural formula VIII ), the total yield is low, and only 20 percent. Compound (VIII) with potassium carbonate, the reaction of hydrogen peroxide to yield compound (IX), impurities, and purified by column chromatography to be not suitable for industrial production. Compound (IX) under catalysis of molybdenum oxide, and L- (S) – benzyl glycyl alcohol asymmetric reactions, protecting groups may be due to steric hindrance is small, low chiral induction, is 3.8: I.

 

Figure CN101993407BD00061

 

Figure CN101993407BD00071

Silodosin Preparation: 12  Example

  Example 11 to give 8 g solid, dissolved in DMSO 100ml, was added 5mol / L NaOH 12ml, 18 ~ 20 ° C was added dropwise slowly with 30% H2027 grams, then 30 ° C, the reaction ended 4h. Extracted with ethyl acetate, the combined organic layer was washed 2N HCl and then the organic layer, the aqueous layer was neutralized with sodium hydroxide, and then extracted with ethyl acetate, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and evaporated concentrated and then dissolved in ethyl acetate, natural cooling crystallization, filtration, drying 5 g (87%), purity> 99%.

  Mp 105 ~ 108 ° C

  [a] 20d = -16.2 C = I, MeOH

  1NMR spectrum (DMS0-d6): δ ppm 0.9-1.0 (3H, d), 1.5-1.6 (1H, s), 1.6-1.7 (2H, m),

2.3-2.4 (1H, dd), 2.6-2.7 (1H, dd), 2.8-3.0 (5H, m), 3.1-3.2 (2H, m), 3.3-3.4 (2H, m),

3.4-3.5 (2H, t), 4.0-4.1 (2H, t), 4.2-4.3 (1H, s), 4.6-4.8 (2H, t), 6.9-7.15 (6H, m),

7.2-7.3 (1H, s), 7.5-7.6 (1H, s)

…………………………………………………..

WO 2015015512

see

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=E9E91192EB93FE4A861ABF346BF6AD06.wapp1nB?docId=WO2015015512&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Silodosin is (I) (formula 1, claim 1, page 31).

Process for the prepartion of pure polymorphic gamma form of silodosin – comprising dissolving any polymorphic form of silodosin in a solvent and seeding gamma form of silodosin.

Crude (I) (50 g) was dissolved in methanol, filtered and solvent was distilled under vacuum. The residue was dissolved in isopropanol at 50 degreeC, cooled and seed of (I) gamma form was added and further cooled and cyclohexane (500 mL) was added, solid was filtered, washed and dried to obtain pure polymorphic form gamma of (I) having a toluene content of 12 ppm (example 10, pages 29-30).

A process for the preparation of silodosin and/or its salt is claimed, comprising the reaction of 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-yl]propyl benzoate(2R,3R)-monotartrate with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate to form a cyano benzyloxy intermediate, followed by hydrolysis to form a cyano hydroxy intermediate, which is then reacted with tartaric acid and hydrolyzed in the presence of an oxidizing agent to obtain the product. An alternate method of preparation of silodosin comprising the hydrolyses of tartrate salt of cyano hydroxy intermediate in the presence of an oxidizing agent, pure polymorphic form gamma of silodosin, and the cyano hydroxy intermediate are also claimed. Further processes for the prepartion of the pure polymorphic form gamma of silodosin are claimed, wherein the process involves the dissolution of of any polymorphic form of silodosin in a solvent by heating at 30-100 degree C, cooling before and after seeding with gamma form of silodosin, adding an antisolven, isolating the polymorph and optionally micronizing.

 

 

The present invention provides an improved and efficient process for the preparation of

It acts as an selective ai -adrenoceptor antagonist and is useful in the symptomatic treatment of benign prostatic hyperplasia (BPH). Chemically it is known as l-(3-hydroxypropyl)-5-[(2R)- ( { 2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino) propyl] indoline-7-carboxamide.

Silodosin and its pharmaceutically acceptable salts are first disclosed in US patent 5,387,603. Synthetic approach for the production of silodosin, is described in patent ‘603 can be represented as shown below in scheme 1.

l

Scheme 1

As represented in scheme 1, silodosin is prepared by the reaction of l-acetyl-5-(2r aminopropyl)indoline-7-carbonitrile with 2-[2-(2,2,2-trifiuoroethoxy)phenoxy] ethyl methanesulfonate in the presence of sodium bicarbonate in ethanol to give l-acetyl-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carbonitrile, which upon reaction with di-tert-butyldicarbonate in methylene chloride produces protected acetyl indoline carbonitrile compound. Further deacetylation with sodium hydroxide in ethanol followed by treatment with acetic acid provides protected indoline carbonitrile compound, which upon hydrolysis using dimethyl sulfoxide, 30% hydrogen peroxide, sodium hydroxide and acetic acid gives protected indoline carboxamide, which upon further reaction with 2-tert-butyldimethylsiloxy)ethyl-4-nitrobenzene sulfonate in the presence of cis-dicyclohexano-18 crown-6 and potassium carbonate in dioxane gives protected (tert-butyl-dimethylsiloxy) ethyl indoline carbonitrile. Further treatment with tetrabutylammonium fluoride in tetrahydrofuran produces N-boc protected hydroxy deprotected propyl indoline carbonitrile, which under goes facile deprotection of boc group upon treatment with trifluoroacetic acid, in methylene chloride to yield silodosin. The complete process is very complex, make use of pyrophoric reagents

which are very difficult to handle in large scale and have many extra steps involving protection and depfotection. Further in US patent ‘603, concrete detail of preparation and purification of silodosin have not been reported. Furthermore, isolated silodosin is characterized using IR, NMR and specific rotation but the patent is silent on product appearance and crystalline nature. There are several processes known for the preparation of silodosin and its intermediates viz; in JP 4634560; JP 4921646; JP-2006- 188470; WO2011/124704 and WO2011/101864. In most of the inventions, silodosin is prepared by following reaction as shown in scheme 2. Major disadvantages of these processes are the formation of N,N dialkyl impurity, and other impurities which forms during the condensation of 3-[5-((2/?)-2-aminopropyl)-7-cyano-2,3-dihydro-lH-indol-l-yl]propyl benzoate or its salts like monotartrate with 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methanesulfonate. N,N dialkyl impurity forms in about 12-15% and may form due to reaction of one molecule of benzoate compound with two molecules of methanesulfonate compound. Removal of this impurity is not possible by simple purification

wherein R is benzoyl, benzyl, tetrahydropyranyl, 2-trimethylsilylethyl, dinitrophenyl, diphenyl methyl and the like

Scheme 2

US patent 7,834,193 discloses a process for preparation of silodosin with similar condensation of 3-[5-((2R)-2-arriinopropyl)-7-cyano-2,3-dihydro-lH-indol-l-yl]pfopyl benzoate or its salts like monotartrate with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate, but 3-{7-cyano-5-[(2R)-2-({2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl)-2,3-dihydro-lH-indol-l-yl)-propylbenzoate is purified by preparing monooxalate salt as shown below in

scheme 3. This patent specifically prepares monooxalate salt of 3- {7-cyano-5-[(2R)-2-({ 2- (2,2,2-trifluoroethoxy)-phenoxy]ethyl }amino)propyl)-2,3-dihydro-lH-indol-l-yl)-propyl benzoate to remove N,N÷dialkyl impurity, but impurity has not been removed completely, only a certain % of it, has been removed.

Scheme 3

In PCT publication WO2012/131710, preparation of silodosin is described wherein improved processes for preparation of 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-lH-indol-l- yl]propyl benzoate have been disclosed which is then converted to silodosin by condensation with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate. In exemplified process, 3-[5- ((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-lH-indol-l-yl]propyl benzoate is condensed with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate and the resulting benzoate compound is hydrolyzed to give l-(3-hydroxy propyl)-5-[(2R)-2-({ 2-[2,2,2-trifluoroethoxy) phenoxy] ethyl }amino)propyr]-2,3-dihydro-lH-indol-7-carbonitrile.The carbonitrile compound is treated with oxalic acid to prepare its oxalate salt having purity greater than 99%, which is then hydrolyzed using a base to prepare free carbonitrile compound having purity greater than 99%, but this patent is silent about N, N- dialkyl impurity or its removal.

In PCT publication WO2012/147019, preparation of silodosin using 3-{ 7-cyano-5-[(2R)-2-({2- (2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl)-2,3-dihydro-lH-indol-l-yl)-propyl benzoate tartrate salt has been described as shown below in scheme 4.

Scheme 4

One other PCT publication WO2012/147107 describes preparation of silodosin by preparing hydrochloride and acetic acid salts of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy) phenoxy] ethyl }amino)propyl]-2,3-dihydro-lH-indol-7-carbonitrile to remove N,N dialkyl impurity. It has been observed that in exemplified process, wherein hydroxy compound namely l-(3-hydroxy propyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy) phenoxy] ethyl }amino)propyl]-2,3-dihydro-lH-indol-7-carbonitrile is purified by preparing its acetate salt to, remove the impurities but still N, N-dialkyl impurity remains in an amount of 0.6%, which is difficult to remove in next stage or require extra purifications.

Beside to use highly pure silodosin, use of a pure polymorphic form of API is an essential requirement of drug formulation, these both aspects when address jointly, and obtained silodosin can be converted to pure polymorph then only a complete solution of prior art problems can be achieved. Apart from above mentioned process patents/publications which aimed to prepare the pure silodosin, there are exist some polymorph patents/publications which also aims to prepare pure polymorphic form of silodosin.

Polymorphism is considered as one of the- most important solid-state property of drug substance, since different polymorph have different physiochemical and biological properties and in pharmaceutical chemistry it is often desired to obtain one particular form that is biologically active and also offers ease of handling during formulation. The available literature references related to polymorph of silodosin are incorporated herein.

Japanese patent 3331048 (publication No.H07-330726), discloses a process for purification of silodosin wherein silodosin is dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, solvent is distilled off and again dissolved in ethyl acetate at 70°C and crystallizes below room temperature. The resulting product is characterized by melting point, IR, NMR and specific rotation. Here also disclosure is silent about polymorphic form of product.

US patent publication US2006/0142374A1 (equivalent European patent EP1541554B 1) discloses polymorphic forms of silodosin including three crystalline polymorphic form of silodosin which are named as alpha (a), beta (β) and gamma (γ) and one amorphous form. These polymorphic forms have been characterized by X-ray powder diffraction pattern. In the patent publication, processes for the preparation of all these three crystalline forms have been disclosed. In. a given process, form alpha is prepared by dissolving crude silodosin in appropriate amount of ethyl acetate, ethyl formate, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran or mixture of acetone and acetonitrile (1: 1), preferably ethyl acetate under heating, allowing to stand at room temperature to precipitate the crystal gradually. Similarly, form beta is prepared by dissolving crude silodosin in appropriate amount of methanol under heating, adding petroleum ether as a anti-solvent, crystal precipitation is ensured using vigorous stirring.

In a second process, to prepare the form beta, crude silodosin is dissolved in ethanol or 1-propanol and the reaction mass is cooled quickly. The crystalline form gamma is prepared by dissolving crude silodosin in appropriate amount of toluene or a mixture of acetonitrile and toluene (1:4) or ethyl acetate and toluene (1: 19), preferably in toluene, under heating, cooling to room temperature and allowing to precipitate gradually upon standing. In a second process to prepare form gamma, crude silodosin is dissolved in 2-propanol and the crystals are precipitated by adding an appropriate amount of toluene. In spite of disclosing three crystalline polymorphic forms, the patent publication prefers preparation and use of form alpha by highlighting the problems faced for preparation and use of other forms. It is disclosed that crystal form beta has manufacturing difficulties at industrial scale since precipitation occurs only when the nonpolar antisolvent is added to warm solution which leads to inconsistency in quality of crystals.

With the second process for preparation of form beta, desired level of yield and purity has not been achieved. Further, according to this publication, preparation of gamma form involves use of toluene which can not be removed completely from final product, because of its high boiling point and raises the problem of residual solvent. In the case of toluene, a class 2 solvent, its limits should not be more than 890 ppm. In the exemplified process, toluene content has not been disclosed, which clearly reflects that product was not suitable for pharmaceutical composition having problem of high residual content of toluene. Furthermore patent publication also states that all the three crystal forms donot have any difference in hygroscopicity and stabilities.

Thereafter, several patents/publications disclose preparation of polymorphic forms alpha and beta. For example a PCT publication WO2012/147107 discloses a process for preparation of beta form using isopropyl acetate and methyl isobutylketone. In another PCT publication WO2012/077138, preparation of alpha and beta forms are disclosed using various solvent , system. Similarly, in a Chinese patent CN102010359, crystalline form beta is prepared by dissolving the crude silodosin in alcoholic solvent by heating and the product is crystallized by cooling or by adding an antisolvent such as ketone or ether.

European patent EP2474529 discloses new polymorphic forms delta (δ) and eta (ε) of silodosin by using a solvent (tetrahydrofuran) and antisolvent (n-heptane, n-hexane, cyclohexane, tert butylmethyl ether).Further it discloses conversion of delta form to beta form by just heating the delta form at a particular temperature. The form delta can also be transformed into form eta by. slurrying in aqueous methanol. One new crystalline form designated as delta has also been disclosed in a Chinese patent publication CN102229558. An Indian patent application 478/MUM/2010, also discloses a new polymorphic form Zy-S which is prepared by using solvent such as esters, aromatic hydrocarbons, ketones, and alcohols.

All the above disclosures are silent about the preparation of gamma form of silodosin and only available disclosure reports that gamma form have problem of residual solvent, as impurity and is not suitable for pharmaceutical compositions.

 

Method C: l-(3-HydroxypropyI)-5-[(2R)-2-({2-[2,2,2-trifIuoroethoxy)phenoxy] ethyl} amino) propyl]-2,3-dihydro-lH-indol-7-carbonitrile tartrate (lOg) dissolved in dimethylsulfoxide (120 ml) and to this solution, was added 5 mol/L aqueous sodium hydroxide solution (15ml). To the reaction mixture, 30% hydrogen peroxide (5ml) was added and keeping the temperature below 25°C. The reaction mixture was stirred at 20-25°C, for 5 hours. To the reaction mixture, sodium sulfite (5g) dissolved in water (100ml) was added slowly. The reaction mixture was extracted with ethyl acetate (1x200ml) and ethyl acetate layer was concentrated under reduced pressure. The resulting product was dissolved in methanol and clear solution was filtered through micron filter paper of size 0.22 micron two times and filtrate was concentrated.The resulting compound was dissolved in toliiene (70ml) and isopropyl alcohol (7ml) at 50-55°C and the solution was cooled to 20-25°C, cyclohexane was added and stirred for further 4 hours, filtered and dried to give title compound having purity 99.86% and N,N-dialkyl impurity not detected by HPLC. Example 5: Preparation of pure Polymorphic Form Gamma (γ) of Silodosin

Silodosin (15g) having toluene content 1872 ppm, was micronized under air pressure. The micronized product was dried under vacuum at 55°C-60°C for 23.0 hours to afford pure polymorphic form gamma of silodosin having toluene content 460 ppm.

Example 6: Preparation of pure Polymorphic Form Gamma (γ) of Silodosin

Silodosin [having toluene content 1327 ppm] was micronized under air pressure. The micronized product was dried under vacuum at 55°C-60°C for 16 hours to afford pure polymorphic form gamma of silodosin having toluene content 350 ppm.

Example 7: Preparation of pure Polymorphic Form Gamma (γ) of Silodosin

Silodosin crude (3.0g) was dissolved in isopropanol (12ml) at 50°C and reaction mass was cooled to 35°C and seed of silodosin gamma form (O.lg) was added. Thereafter reaction mass was again cooled to 15-20°C and cyclohexane (30ml) was added to the reaction mass and stirred for further 0.5 hour. The resulting solid, thus obtained, was filtered, washed with cyclohexane and dried to afford pure polymorphic form gamma of silodosin having toluene content 34 ppm.

 

References

External links

a1a-Adrenoceptor antagonist. Prepn: M. Kitazawa et al., EP 600675; eidem, US 5387603 (1994, 1995 both to Kissei).PRODUCT PATENT

Adrenoceptor binding study: K. Shibata et al., Mol. Pharmacol. 48, 250 (1995); and tissue selectivity: S. Murata et al., J. Urol. 164, 578 (2000).

Pharmacology: K. Akiyama et al., Pharmacology 64, 140 (2002).

Series of articles on pharmacology, pharmacokinetcs and toxicology: Yakugaku Zasshi 126, 187-263 (2006).

Review of development and therapeutic potential: F. Kamali, Curr. Opin. Cent. Peripher. Nerv. Syst. Invest. Drugs 1, 248-252 (1999)

CN101993405A * Aug 27, 2009 Mar 30, 2011 浙江华海药业股份有限公司;上海医药工业研究院 Indoline derivative as well as preparation method and application thereof
JP2006188470A * Title not available
US7834193 * Apr 16, 2007 Nov 16, 2010 Kissei Pharmaceutical Co., Ltd. industrial production of silodosin (for treating dysuria associated with benign prostatic hyperplasia) via mixing 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino]propyl]-2,3-dihydro-1H-indol-1-yl}-propyl benzoate and oxalic acid, nitrilizing, hydrolyzing
WO2011030356A2 * Sep 13, 2010 Mar 17, 2011 Sandoz Ag Process for the preparation of indoline derivatives and their intermediates thereof
WO2011124704A1 * Apr 8, 2011 Oct 13, 2011 Ratiopharm Gmbh Process for preparing an intermediate for silodosin
WO2012131710A2 * Mar 27, 2012 Oct 4, 2012 Panacea Biotec Ltd Novel process for the synthesis of indoline derivatives
JP2006188470A * Title not available
Patent Submitted Granted
Solid drug for oral use [US2006018959] 2006-01-26
Crystal for oral solid drug and oral solid drug for dysuria treatment containing the same [US2006142374] 2006-06-29
Device for transdermal administration for the treatment of urinary tract disorders [US2005226919] 2005-10-13
Methods for identifying novel multimeric agents that modulate receptors [US2003087306] 2003-05-08

 

Patent Submitted Granted
Combination therapy for the treatment of benign prostatic hyperplasia [US6410554] 2002-06-25
Indoline compound and process for producing the same [US7834193] 2007-08-23 2010-11-16
Agents and crystals for improving excretory potency of urinary bladder [US8252814] 2009-10-22 2012-08-28
METHODS FOR TREATING BENIGN PROSTATIC HYPERPLASIA [US2011319464] 2011-12-29
PREVENTIVE AND/OR THERAPEUTIC AGENT FOR URINE COLLECTION DISORDER ACCOMPANYING LOWER URINARY TRACT OBSTRUCTION [US2009227651] 2009-09-10
PREVENTIVE AND/OR THERAPEUTIC AGENT FOR URINE COLLECTION DISORDER ACCOMPANYING LOWER URINARY TRACT OBSTRUCTION [US2010137399] 2010-06-03
Agents for improving excretory potency of urinary bladder [US2004116457] 2004-06-17
Medicinal Composition for Prevention of Transition to Operative Treatment for Prostatic Hypertrophy [US2008090893] 2008-04-17
METHODS FOR TREATING BENIGN PROSTATIC HYPERPLASIA [US2008242717] 2008-10-02
Agents and crystals for improving excretory potency of urinary bladder [US2006281725] 2006-12-14

Lupin and Celon Pharma partner for generic version of GSK’s Advair Diskus


 

Vinita Gupta, 43, Group President and CEO, Lupin Pharmaceuticals and Director, Lupin

India-based drugmaker Lupin has signed an agreement with Polish biopharmaceutical firm Celon Pharma to develop a fluticasone / salmeterol dry powder inhaler (DPI).

Under the deal, Lupin will take the responsibility for commercialisation of the product, which is a generic version of GlaxoSmithKline’s (GSK) Advair Diskus.

Lupin CEO Vinita Gupta said: “We are very pleased to partner with Celon given their experience in the development and manufacturing of fluticasone/salmeterol DPI in Europe…………..http://www.pharmaceutical-technology.com/news/newslupin-celon-pharma-partner-generic-version-gsks-advair-diskus-4514718?WT.mc_id=DN_News

Vinita Gupta, 43, Group President and CEO, Lupin Pharmaceuticals and Director, Lupin, is based in the United States, but has been in India a lot in the past one year.

Vinita Gupta, 43, Group President and CEO, Lupin Pharmaceuticals and Director, Lupin,
Vinita Gupta

With an expanding role in Lupin’s universe, Vinita has been spending more time outside the US, at times taking her six-year-old son, Krish with her. “He is getting exposure at a much younger age,” she says. Gupta herself was exposed to business at the age of 11 by her father Desh Bandhu Gupta, Lupin’s founder and Chairman.

“We almost had a family board at home, discussing work,” she says. Currently work goes well indeed, with Gupta taking new initiatives in India and also making the business more global. “I am focusing on drivers for growth in our business for the next five years,” she says.

Gupta is married to US-based businessman Brij Sharma.

 

 

 

 

DB Gupta (centre) Chairman, Vinita Gupta (right) CEO and Nilesh Gupta

 

Sex has another benefit: It makes humans less prone to disease over time


ClinicalNews.Org

Public Release: 16-Feb-2015

Mixing our genes through sex helps purge us of disease mutations

University of Montreal

For decades, theories on the genetic advantage of sexual reproduction had been put forward, but none had ever been proven in humans, until now. Researchers at the University of Montreal and the Sainte-Justine University Hospital Research Centre in Montreal, Canada have just shown how humanity’s predispositions to disease gradually decrease the more we mix our genetic material together. This discovery was finally made possible by the availability in recent years of repositories of biological samples and genetic data from different populations around the globe.

What we already knew

As humans procreate, generation after generation, the exchange of genetic material between man and woman causes our species to evolve little by little. Chromosomes from the mother and the father recombine to create the chromosomes of their child (chromosomes are the larger building blocks of…

View original post 600 more words

Palatin’s Bremelanotide Under Clinical Trials, Female Libido Enhancer


Bremelanotide chemical structure.png

Female Libido Enhancer  – Bremelanotide

Bremelanotide is a compound that is currently under investigation for its potential uses in managing reperfusion injury, female sexual dysfunction or hemorrhagic shock. The chemical may also see success in managing modulate inflammation or limiting the effects of ischemia.

N-Acetyl-L-norleucyl-L-alpha-aspartyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-lysine (2-7)-lactam

Bremelanotide,  PT 141, CAS NO.: 189691-06-3

Synonym…..N-Acetyl-L-norleucyl-L-alpha-aspartyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-lysine (2-7)-lactam, Bremelanotide PT 141
Molecular FormulaC50H68N14O10
Molecular Weight1025.16
Gedeon Richter….licensee
In May 2014, the company planned to file an NDA in the first half of 2016, and at that time, approval was expected in the first half of 2017

Bremelanotide Listeni/ˌbrɛmɨˈlænətd/ (formerly PT-141) is a compound under drug development by Palatin Technologies as a treatment for female sexual dysfunction, hemorrhagic shock and reperfusion injury. It functions by activating the melanocortin receptors MC1R and MC4R, to modulate inflammation and limiting ischemia.[2] It was originally tested for intranasal administration in treating female sexual dysfunction but this application was temporarily discontinued in 2008 after concerns were raised over adverse side effects of increased blood pressure. As of December 2014, Palatin is conducting a human Phase 3 study[3] using a subcutaneous drug delivery system that appears to have little effect on blood pressure.

Palatin, in collaboration with European licensee Gedeon Richter, is developing an sc formulation of the synthetic peptide bremelanotide (PT-141; BMT), a melanocortin MCR-4 agonist and a synthetically modified analog of PT-14, also analogous to alpha-melanocyte-stimulating hormone (alpha-MSH), for the potential treatment of female sexual dysfunction (FSD) including hypoactive sexual desire disorder (HSDD)

The Bremelanotide or PT-141 is a mean that explains the revolution caused by the medical world in a silent but attractive manner in the human health related study. Bremelanotide is the latest arrival from the company called Palatin Technologies which forms the basic treatment for the hemorrhagic shock and reperfusion injury.( In short about the company, the Palatin Technologies is the owner of this research and is located in New Jersey. Hence this medicine is a Jersey based Product. And regarding the product under research, is waiting for the approval from the Food and Drug Association. Once this is done, the company has targeted to reach those customers, whom the Viagra has approached. This has the effect of helping the male patients suffering with an erectile dysfunction syndrome. Also if it gets the approval as a treatment measure for the female sexual dysfunction, then this medicine is expected to bring a relief to the post-menopausal and also supports or provides their sexual happiness and also they are checking regarding thehyposexual desire disorder. This is expected to be a blockbuster, if released. So this medicine is waiting for a confirmation as well as an approval.

In February 2015, a randomized, double-blind, placebo-controlled, open-label extension, phase III trial (NCT02338960; BMT-302, Reconnect Study) was initiated in the US in premenopausal women (expected n = 550) with hypoactive sexual desire disorder to evaluate the efficacy and safety of bremelanotide. At that time, the trial was expected to complete in July 2017

Study – Potential Use Erectile Dysfunction

One study has explored the potential use of bremelanotide as a replacement for natural peptide melanocyte stimulating hormones for the sake of treating erectile dysfunction.

  • The goal of this study was to determine if the effects of bremelanotide stimulating sexual desire that was shown in male rats could be replicated in the brains of female rats. To do this, hormone primed female rats in a control group and a test group that were treated with bremelanotide and known to have consummatory sexual disorders was introduced to a group of male rats and the reactions were measured.
  • Heart racing, hops and darts, pacing and customary sexual behaviors were assessed while the brain was stimulated. The stimulation of specific molecular markers within the brain was examined to determine arousal in the female subjects.
  • Results indicated that the females saw an increase in sexual behavior when bremelanotide was applied to the limbic and hypothalamic regions of their brains. It is suggested that this was because the chemical that stimulated the mPOA terminals, leading to activated dopamine in the brain.

Additional study is necessary to determine the extent of the effects bremelanotide has on the brain and natural stimulating chemicals.

Bremelanotide and Ongoing Research

This is an advanced research involved even now. This functions by activating the Melanocortin, which is a group of peptide hormones which includes the adrenocorticotropic hormone and also the different forms of the melanocyte stimulating hormones. These melanocortins are produced or prepared from the proopiomelanocortin in the pituitary glands. The melanocortin releases or exert their effects by making a bind with the melanocortin and thereby activating it).The Bremelanotide functions by activating the melanocortin receptors and thereby makes a modulation in the inflammation. This is actually produced for making use in treating the sexual dysfunction. Due to certain reasons; the process of researching was kept under hold in recently, since it created some adverse side effects of increased blood pressure. In the chemistry of the preparation of the bremelanotide, the Peptide Melanaton II forms the basic compound. This compound is tested using a sunless tanning agent.

The actual information about the peptide melanaton has the effect of making sexual arousal and speed as well as sudden erections and some other side effects. However, there are several other measures taken to test the property of the same under several other health situations to make a detailed study about the chemical compound structure to make a change in the combination of the chemical structure. This medicine has made a revolution in the field of science of the human structure. When made a deep verification of the compound structure of the chemical study showed the following information. The structural design has an appearance of white colored powder like material, which has an accurate purity of nearly 98%. The actual molecular weight of the compound formed is around 1025.2. This compound has the collective share of Amino acids in the composition, peptide and acetate contents also.

The study of the compound structure PT-141 has an enhanced support of making a recombination that produces a different profile of the same medicine but in a different standard with different properties that may support the human requirement.

Bremelanotide PT-141 is known for its aphrodisiac properties

Development

Bremelanotide was developed from the peptide hormone Melanotan II which underwent testing as a sunless tanningagent. In initial testing, Melanotan II did induce tanning but additionally caused sexual arousal and spontaneous erections as unexpected side effects in nine out of the ten original male volunteer test subjects.[4]

In studies, bremelanotide was shown to induce lordosis in an animal model[5] and was also effective in treating sexual dysfunction in both men (erectile dysfunction or impotence) and women (sexual arousal disorder). Unlike Viagra and other related medications, it does not act upon the vascular system, but directly increases sexual desire via the nervous system.[6]

A Phase III clinical trial was scheduled to begin in the first half of 2007, but was delayed until August 2007. On August 30, Palatin announced that the U.S. Food and Drug Administration had expressed serious concerns regarding therisk/benefit ratio of bremelanotide with regards to the side effect of increased blood pressure. The FDA stated that it would consider alternate uses for bremelanotide, including as a treatment for individuals who do not respond to more established ED treatments. However, On May 13, 2008, Palatin Technologies announced it had “discontinued development of Bremelanotide for the treatment of male and female sexual dysfunction” while concurrently announcing plans to develop it as a treatment for hemorrhagic shock instead.[7] The company additionally announced intentions to focus its attention on another compound, PL-6983, that causes lower blood pressure in animal models.[8]Palatin has since re-initiated Bremelanotide studies for ED and FSD using a subcutaneous delivery method. On August 12, 2009, the company announced that in a double-blind study of 54 volunteers bremelanotide failed to evoke the hypertensive side effects seen with the nasal delivery system used in prior studies, concluding that “variability of uptake” inherent in intranasal administration of the drug resulted in “increases in blood pressure and gastrointestinal events…primarily related to high plasma levels in [only] a subset of patients” and that subcutaneous administration of the drug circumvented the potential for this side effect.[8] Palatin has completed a human Phase 2B study utilizing subcutaneous administration and reported positive results.[9]

Structure

Bremelanotide is a cyclic hepta-peptide lactam analog of alpha-melanocyte-stimulating hormone (alpha-MSH) that activates the melanocortin receptors MC3-R and MC4-R in thecentral nervous system. It has the amino acid sequence Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH or cyclo-[Nle4, Asp5, D-Phe7, Lys10]alpha-MSH-(4-10). It is a metabolite of Melanotan II that lacks the C-terminal amide function.

Bremelanotide
Bremelanotide chemical structure.png
Systematic (IUPAC) name
(3S,6S,9R,12S,15S,23S)-15-[(N-acetyl-L-norleucyl)amino]-9-benzyl-6-{3-[(diaminomethylidene)amino]propyl}-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexaa zacyclotricosane-23-carboxylic acid
Clinical data
Legal status
  • US: Unscheduled
Pharmacokinetic data
Half-life 120 minutes[1]
Identifiers
CAS number 189691-06-3 Yes
ATC code None
PubChem CID 9941379
ChemSpider 8116997 Yes
UNII 6Y24O4F92S Yes
KEGG D06569 
ChEMBL CHEMBL2070241 
Chemical data
Formula C50H68N14O10 
Molecular mass 1025.2 g/mol

Sexual dysfunction, including both penile erectile dysfunction or impotence and female sexual dysfunction, are common medical problems. Significant effort has been devoted over the last twenty or more years to develop methods, devices and compounds for treatment of sexual dysfunction. While more effort has been undertaken for treatment of penile erectile dysfunction, female sexual dysfunction is also an area to which significant research and effort has been devoted.

At present, one commonly used orally administered drug for treatment of sexual dysfunction in the male is Viagra®, a brand of sildenafil, which is a phosphodiesterase 5 inhibitor, increasing the persistence of cyclic guanosine monophosphate and thereby enhancing erectile response. There are several other medical treatment alternatives currently available depending on the nature and cause of the impotence problem. Some men have abnormally low levels of the male hormone testosterone, and treatment with testosterone injections or pills may be beneficial. However, comparatively few impotent men have low testosterone levels. For many forms of erectile dysfunction, treatment may be undertaken with drugs injected directly into the penis, including drugs such as papaverin, prostaglandin E1, phenoxybenzamine or phentolamine. These all work primarily by dilating the arterial blood vessels and decreasing the venous drainage. Urethral inserts, such as with suppositories containing prostaglandin, may also be employed. In addition, a variety of mechanical aids are employed, including constriction devices and penile implants.

A variety of treatments have also been explored for female sexual dysfunction, including use of sildenafil, although the Food and Drug Administration has not specifically approved such use. Testosterone propionate has also been employed to increase or augment female libido.

Melanocortin receptor-specific compounds have been explored for use of treatment of sexual dysfunction. In one report, a cyclic α-melanocyte-stimulating hormone (“α-MSH”) analog, called Melanotan-II, was evaluated for erectogenic properties for treatment of men with psychogenic erectile dysfunction. Wessells H. et al., J Urology 160:389-393 (1998); see also U.S. Pat. No. 5,576,290, issued Nov. 19, 1996 to M. E. Hadley, entitled Compositions and Methods for the Diagnosis and Treatment of Psychogenic Erectile Dysfunction and U.S. Pat. No. 6,051,555, issued Apr. 18, 2000, also to M. E. Hadley, entitled Stimulating Sexual Response in Females. The peptides used in U.S. Pat. Nos. 5,576,290 and 6,051,555 are also described in U.S. Pat. No. 5,674,839, issued Oct. 7, 1997, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Cyclic Analogs of AlphaMSH Fragments, and in U.S. Pat. No. 5,714,576, issued Feb. 3, 1998, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Linear Analogs of AlphaMSH Fragments. Melanotan-II is a peptide of the following formula:

Figure US06794489-20040921-C00001

Additional related peptides are disclosed in U.S. Pat. Nos. 5,576,290, 5,674,839, 5,714,576 and 6,051,555. These peptides are described as being useful for both the diagnosis and treatment of psychogenic sexual dysfunction in males and females. These peptides are related to the structure of melanocortins.

In use of Melanotan-II, significant erectile responses were observed, with 8 of 10 treated men developing clinically apparent erections, and with a mean duration of tip rigidity greater than 80% for 38 minutes with Melanotan-II compared to 3.0 minutes with a placebo (p=0.0045). The drug was administered by subcutaneous abdominal wall injection, at doses ranging from 0.025 to 0.157 mg/kg body weight. Transient side effects were observed, including nausea, stretching and yawning, and decreased appetite.

The minimum peptide fragment of native α-MSH needed for erectile response is the central tetrapeptide sequence, His6-Phe7-Arg8-Trp9 (SEQ ID NO:1). In general, all melanocortin peptides share the same active core sequence, His-Phe-Arg-Trp (SEQ ID NO:1), including melanotropin neuropeptides and adrenocorticotropin. Five distinct melanocortin receptor subtypes have been identified, called MC1-R through MC5-R, and of these MC3-R and MC4-R are believed to be expressed in the human brain. MC3-R has the highest expression in the arcuate nucleus of the hypothalamus, while MC4-R is more widely expressed in the thalamus, hypothalamus and hippocampus. A central nervous system mechanism for melanocortins in the induction of penile erection has been suggested by experiments demonstrating penile erection resulting from central intracerebroventricular administration of melanocortins in rats. While the mechanism of His-Phe-Arg-Trp (SEQ ID NO:1) induction of erectile response has not been fully elucidated, it has been hypothesized that it involves the central nervous system, and probably binding to MC3-R and/or MC4-R.

Other peptides and constructs have been proposed which are ligands that alter or regulate the activity of one or more melanocortin receptors. For example, International Patent Application No. PCT/US99/09216, entitled Isoquinoline Compound Melanocortin Receptor Ligands and Methods of Using Same, discloses two compounds that induce penile erections in rats. However, these compounds were administered by injection at doses of 1.8 mg/kg and 3.6 mg/kg, respectively, and at least one compound resulted in observable side effects, including yawning and stretching. Other melanocortin receptor-specific compounds with claimed application for treatment of sexual dysfunction are disclosed in International Patent Application No. PCT/US99/13252, entitled Spiropiperidine Derivatives as Melanocortin Receptor Agonists.

Both cyclic and linear α-MSH peptides have been studied; however, the peptides heretofore evaluated have had an amide or —NH2 group at the carboxyl terminus. See, for example, Wessells H. et al., J Urology, cited above; Haskell-Luevano C. et al., J Med Chem 40:2133-39 (1997); Schiöth H. B. et al., Brit J Pharmacol 124:75-82 (1998); Schiöth H. B. et al., Eur J Pharmacol 349:359-66 (1998); Hadley M. E. et al., Pigment Cell Res 9:213-34 (1996); Bednarek M. A. et al., Peptides20:401-09 (1999); U.S. Pat. Nos. 6,054,556, 6,051,555 and 5,576,290; and, International Patent Applications PCT/US99/04111 and PCT/US98/03298. While significant research has been conducted in an effort to determine the optimal structure of α-MSH peptides, including a variety of structure-function, agonist-antagonist, molecular modeling and pharmacophore studies, such studies have relied upon peptides with an art conventional —NH2 group at the carboxyl terminus. Further, it has long been believed that biologically active neuropeptides, including α-MSH peptides, are amidated, with an —NH2 group at the carboxyl terminus, and that such amidation is required both for biological activity and stability. See, for example, Metabolism of Brain Peptides, Ed. G. O’Cuinn, CRC Press, New York, 1995, pp. 1-9 and 99-101.

…………………………………………….

Bioorganic and Medicinal Chemistry Letters, 2005 ,  vol. 15,  4  pg. 1065 – 1068

http://www.sciencedirect.com/science/article/pii/S0960894X04014842

Full-size image (23 K)

Figure 2.

NMR structural analysis on compound 3.

Full-size image (24 K)

Figure 4.

NMR structural analysis of compound 1.

……………………………………………….

US6794489

In a preferred embodiment, the invention provides the peptide

Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH  Compound 1

The peptide of Compound 1 has a formula of C50H68N14O10, and a net molecular weight of 1025.18. This peptide may be synthesized by solid-phase means and purified to greater than 96% purity by HPLC, yielding a white powder that is a clear, colorless solution in water. The structure of Compound 1 is:

Figure US06794489-20040921-C00002

In general, the peptide compounds of this invention may be synthesized by solid-phase synthesis and purified according to methods known in the art. Any of a number of well-known procedures utilizing a variety of resins and reagents may be used to prepare the compounds of this invention.

The peptides of this invention may be in the form of any pharmaceutically acceptable salt. Acid addition salts of the compounds of this invention are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. The acetate salt form is especially useful. Where the compounds of this invention include an acidic moiety, suitable pharmaceutically acceptable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts.

The invention provides a pharmaceutical composition that includes a peptide of this invention and a pharmaceutically acceptable carrier. The carrier may be a liquid formulation, and is preferably a buffered, isotonic, aqueous solution. Pharmaceutically acceptable carriers also include excipients, such as diluents, carriers and the like, and additives, such as stabilizing agents, preservatives, solubilizing agents, buffers and the like, as hereafter described.

EXAMPLE 1

Peptide Synthesis

The peptide Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH was synthesized by standard solid phase peptide synthesis methods, and is a cyclic heptapeptide melanocortin peptide analog with a free acid at the carboxyl terminus and an acetylated amino group at the amino terminus, with the structure:

Figure US06794489-20040921-C00003

The peptide has a net molecular weight of 1025.18, and is supplied in an acetate salt form. The peptide is a white, odorless amorphous hygroscopic powder, soluble in 0.9% saline, composed of C50H68N14O10. For synthesis, an Fmoc-Lys(R3)-p-alkoxybenzyl alcohol resin was transferred to a solid phase peptide synthesizer reactor with a mechanical stirrer. The R3group, such as 1-(1′-adamantyl)-1-methyl-ethoxycarbonyl (Adpoc), allyloxycarbonyl (Aloc) or 4-methyltrityl (Mtt), was removed and the next Fmoc-protected amino acid (Fmoc-Trp(Boc)-OH) was added to the resin through standard coupling procedures. The Fmoc protective group was removed and the remaining amino acids added individually in the correct sequence, by repeating coupling and deprotection procedures until the amino acid sequence was completed. After completion of coupling with the last Fmoc-amino acid derivative, Fmoc-Nle-OH, and cleavage of the Fmoc protective group, the exposed terminal amino group was acetylated with acetic anhydride and pyridine in N,N-dimethylformamide (DMF). The peptide-resin was dried and the Lys and Asp protective groups cleaved. The Lys and Asp deprotected peptide resin was suspended in a suitable solvent, such as DMF, dichloromethane (DCM) or 1-methyl-2-pyrrolidone (NMP), a suitable cyclic coupling reagent, such as 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(2-oxo-1(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) or N,N′-dicyclohexylcarbodiimide/1-hydroxybenzotriazole (DCCl/HOBt) was added, and coupling initiated by use of a suitable base, such as N,N-diispropylethylamine (DIPEA), sym-collidine or N-methylmorpholine (NMM). After cyclization, the peptide-resin was washed and the peptide cleaved from the resin and any remaining protective groups using trifluoroacetic acid (TFA) in the presence of water and 1,2-ethanedithiol (EDT). The final product was precipitated by adding cold ether and collected by filtration. Final purification was by reversed phase HPLC using a C18 column. The purified peptide was converted to acetate salt by passage through an ion-exchange column.

…………………………………………..

WO2014071339

Compounds of the Invention.

in a preferred embodiment of the present invention, fie rneianocortin receptor agonist is;

Ac-Nie”Cyc/o{-Asp-His–D–Phe-Arg–Trp»Lys)–OH (bremeianotide)

The peptide of bremeianotide has a formula of CsaHesN< C½, and a net mofecufar weight of 1025.18, This peptide may be synthesized by conventional means, including either solid-phase or Squid-phase techniques, and purified to greater than 99% purity by HPLC, yielding a white powder that is a clear, colorless solution in water. The structure of bremeianotide is:

Figure imgf000017_0001

in one embodiment of the invention, bremeianotide is synthesized by solid-phase synthesis and purified according to methods known in the art. Any of a number of well-known procedures utilizing a variety of resins and reagents may be used to prepare bremeianotide.

Bremeianotide may be in the form of any pharmaceutically acceptable salt. Acid addition salts of the compounds of this invention are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacefie, maieic, citric, tartaric, oxalic, succinic or methanesu!fonic acid. The acetate salt form is especially useful.

in a preferred embodiment, bremelanotide is an acetate salt form, and is formulated in a buffered aqueous solution including giycerin, and prepackaged in a syringe and auto-injector device. In alternative embodiments, bremelanotide is any pharmaceutically acceptable salt form, and is formulated in any pharmaceutically acceptable aqueous solution, the aqueous solution optionally including one or more salts, such as sodium chloride, one or more acids, such as citric acid, and one or more additional ingredients, including cellulose or derivatives thereof, saccharides o

polysaccharides such as dextrose, and any of a wide variety of surfactants, chelating agents and preservatives.

………………………………………….

US20050222014

In yet another embodiment of the present invention, the melanocortin receptor agonist is:
AcNle-cyclo(-AspHisDPheArgTrpLys)-OH PT-141

The peptide of PT-141 has a formula of C50H68N14O10, and a net molecular weight of 1025.18. This peptide may be synthesized by conventional means, including either solid-phase or liquid-phase techniques, and purified to greater than 99% purity by HPLC, yielding a white powder that is a clear, colorless solution in water. The structure of PT-141 is:

Figure US20050222014A1-20051006-C00001

In one embodiment of the invention, PT-141 is synthesized by solid-phase synthesis and purified according to methods known in the art. Any of a number of well-known procedures utilizing a variety of resins and reagents may be used to prepare PT-141.

PT-141 may be in the form of any pharmaceutically acceptable salt. Acid addition salts of the compounds of this invention are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, citric, tartaric, oxalic, succinic or methanesulfonic acid. The acetate salt form is especially useful. Where the compounds of this invention include an acidic moiety, suitable pharmaceutically acceptable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts.

In a preferred embodiment, PT-141 is an acetate salt form, and is formulated in a buffered aqueous solution including glycerin, prepackaged in a metered unit dose intranasal delivery device. In alternative embodiments, PT-141 is any pharmaceutically acceptable salt form, and is formulated in any pharmaceutically acceptable aqueous solution, the aqueous solution optionally including one or more salts, such as sodium chloride, one or more acids, such as citric acid, and one or more additional ingredients, including cellulose or derivatives thereof, saccharides or polysaccharides such as dextrose, and any of a wide variety of surfactants, chelating agents and preservatives. In one preferred embodiment, PT-141 is administered to patients in volumes of 100 μL, with the quantity of PT-141 delivered determined by the concentration thereof. As described hereafter, in one preferred embodiment a metered unit dose contains 7.5 mg of PT-141.

While certain embodiments of the present invention are described primarily in the context of PT-141, it is to be understood that other melanocortin receptor agonists may be employed. For example, the metallopeptide melanocortin receptor agonists disclosed in WO 02/064091, filed on Feb. 13, 2001, and U.S. Ser. No. 10/640,755, filed on Aug. 13, 2003, both entitled Melanocortin Metallopeptides for Treatment of Sexual Dysfunction; and WO 01/13112, filed on Jun. 14, 2000, entitled Melanocortin Metallopeptide Constructs, Combinatorial Libraries and Applications, may be employed. In addition, the peptidomimetic melanocortin receptor agonists disclosed in U.S. Ser. No. 10/776,419, filed on Feb. 10, 2004, entitled Peptidomimetics of Biologically Active Metallopeptides; the pyrrolidine melanocortin receptor agonists disclosed in U.S. Ser. No. 10/766,657, filed on Feb. 10, 2004, entitled Pyrrolidine Melanocortin-Specific Compounds; and the bicyclic melanocortin receptor agonists disclosed in PCT/US04/01505, filed on Jan. 20, 2004, entitled Bicyclic Melanocortin-Specific Compounds, may also be employed. Also particular preferred are the piperazine melanocortin agonists disclosed in PCT/US04/01462, filed on Jan. 20, 2004 and U.S. Ser. No. 10/762,079, filed on Jan. 20, 2004, both entitled piperazine Melanocortin-Specific Compounds; the melanocortin agonists disclosed in WO 03/006620, filed on Jul. 11, 2002, entitled Linear and Cyclic Melanocortin Receptor-Specific Peptides; WO 04/005324, filed on Jul. 9, 2003, entitled Peptide Compositions for Treatment of Sexual Dysfunction; PCT/US00/18217, filed on Jun. 29, 2000 and U.S. Ser. No. 10/040,547, filed on Jan. 4, 2002, entitled Compositions and Methods for Treatment of Sexual Dysfunction; and U.S. Ser. No. 10/638,071, filed on Aug. 8, 2003, entitled Cyclic Peptide Compositions and Methods for Treatment of Sexual Dysfunction. The entire disclosure of each of the foregoing are incorporated here by reference. It is to be understood that the foregoing listing of patent applications disclosing melanocortin receptor agonists is intended to only be exemplary, and that other melanocortin receptor agonists, whether heretofore known or hereafter developed, may similarly be used in the practice of this invention.

…………………….

NMR prediction

H-NMR spectral analysis
bremelanotide NMR spectra analysis, Chemical CAS NO. 189691-06-3 NMR spectral analysis, bremelanotide H-NMR spectrum
13 C NMR PREDICTION
bremelanotide NMR spectra analysis, Chemical CAS NO. 189691-06-3 NMR spectral analysis, bremelanotide C-NMR spectrum
References
  1.  King SH, Mayorov AV, Balse-Srinivasan P, Hruby VJ, Vanderah TW, Wessells H (2007).“Melanocortin receptors, melanotropic peptides and penile erection”. Current Topics in Medicinal Chemistry 7 (11): 1098–1106. doi:10.2174/1568026610707011111.PMC 2694735. PMID 17584130.
  2.  Bremelanotide for Organ Protection and Related Indications, Palatin Technologies fact sheet. Retrieved on 2009-01-18.
  3.  “Palatin Announces Start of Bremelanotide Phase 3 Program For Female Sexual Dysfunction”. PR Newswire. Retrieved 2015-02-17.
  4.  “Tanning drug may find new life as Viagra alternative”. CNN. 1999. Retrieved2007-09-16.
  5. Pfaus JG, Shadiack A, Van Soest T, Tse M, Molinoff P (July 2004). “Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist”. Proc. Natl. Acad. Sci. U.S.A. 101 (27): 10201–4. doi:10.1073/pnas.0400491101. PMC 454387.PMID 15226502.
  6. Vicki Mabrey (2006). “ABC News “The Business of Desire – Love Potion””. ABC News. Retrieved 2009-01-24.
  7.  “Palatin Technologies announces new strategic objectives and reports third quarter 2008 financial results”. Palatin Technologies press release. 2008. Retrieved 2008-08-21.
  8.  “Palatin Technologies Announces New Strategic Objectives”. Retrieved 2008-05-13.
  9.  http://www.palatin.com/news/news.asp?ud=306

External links

PALATIN TECHNOLOGIES, INC.: ‘Bremelanotide in Premenopausal Women With Female Sexual Arousal Disorder and/or Hypoactive Sexual Desire Disorder‘ CLINICALTRIALS.GOV (NCT01382719, [Online] 20 March 2012, page 1 Retrieved from the Internet: <URL:http://clinicaltrials.gov/archive/NCT0 1382719/ 2012-03 20> [retrieved on 2014-02-10]
2 * PALATIN TECHNOLOGIES, INC.: ‘Reports Positive Bremelanotide Study; Improved Safety Profile with Subcutaneous Administration‘ PR NEWSWIRE., [Online] 12 August 2009, Retrieved from the Internet: <URL:http://www.thefreelibrary.com/Palatin +Technolo9ies,+Inc.+Reports+Positive+Bremel anotide+Study%38…-a020561 3302> [retrieved on 2014-02-10]
3 * SAFARINEJAD, MR.: ‘Evaluation of the Safety and Efficacy of Bremelanotide, a Melanocortin Receptor Agonist, in Female Subjects with Arousal Disorder: A Double-Blind Placebo-Controlled, Fixed Dose, Randomized Study”.‘ INTERNATIONAL SOCIETY FOR SEXUAL MEDICINE. vol. 5, 2008, pages 887 – 897
US8455617 Jun 7, 2010 Jun 4, 2013 Astrazeneca Ab Melanocortin receptor-specific peptides
US8455618 Oct 26, 2011 Jun 4, 2013 Astrazeneca Ab Melanocortin receptor-specific peptides
US8487073 Nov 23, 2010 Jul 16, 2013 Palatin Technologies, Inc. Melanocortin receptor-specific peptides for treatment of sexual dysfunction
US8729224 Jun 5, 2013 May 20, 2014 Palatin Technologies, Inc. Melanocortin receptor-specific peptides for treatment of female sexual dysfunction
EP2266567A1 May 26, 2009 Dec 29, 2010 Æterna Zentaris GmbH Use of cetrorelix in combination with PDE V inhibitors for the treatment of sex hormone dependent disorders
EP2266568A1 May 26, 2009 Dec 29, 2010 Æterna Zentaris GmbH Use of LHRH antagonists in combination with PDE V inhibitors for the treatment of sex hormone dependent disorders
WO2013067309A1 Nov 2, 2012 May 10, 2013 Xion Pharmaceutical Corporation Methods and compositions for oral administration of melanocortin receptor agonist compounds
WO2014071339A2 * Nov 5, 2013 May 8, 2014 Palatin Technologies, Inc. Uses of bremelanotide in therapy for female sexual dysfunction
WO2009151714A2 * Mar 24, 2009 Dec 17, 2009 Palatin Technologies, Inc. Therapeutic for treatment of circulatory shock, ischemia, inflammatory disease and related conditions
US6794489 * Jan 4, 2002 Sep 21, 2004 Palatin Technologies, Inc. Peptide sequence ac-nle-cyclo(-asp-his-d-phe-arg-trp-lys)-oh derived from a melanocyte-stimulating hormone (? alpha -msh?) analog, called melanotan-ii
US20050222014 * May 26, 2005 Oct 6, 2005 Palatin Technologies, Inc. Administering phosphodiestarase inhibitors and melanocortin receptor antagonist: synergistic mixture
US20110065652 * Nov 23, 2010 Mar 17, 2011 Palatin Technologies, Inc. Melanocortin Receptor-Specific Peptides for Treatment of Sexual Dysfunction

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KHAJURAHO INDIA

Khajuraho Group of Monuments is located in India

Khajuraho Group of Monuments
Location of Khajuraho Group of Monuments in India.

Location in Madhya PradeshLocation in Madhya Pradesh

  1. Khajuraho Group of Monuments – Wikipedia, the free …

    en.wikipedia.org/wiki/Khajuraho_Group_of_Monuments

    The Khajuraho Group of Monuments are a group of Hindu and Jain temples in Madhya Pradesh, India. About 620 kilometres (385 mi) southeast of New Delhi, …

Hotel Chandela – A Taj Leisure Hotel

LATUR, MAHARASHTRA, INDIA

http://en.wikipedia.org/wiki/Latur

Latur
लातूर
Lattalur, Ratnapur
City
Latur is located in Maharashtra

Latur
Latur

Location in Maharashtra, India

Coordinates: 18.40°N 76.56°ECoordinates18.40°N 76.56°E
Country  India
State Maharashtra
Region Aurangabad Division
District Latur
Settled Possibly 7th century AD
Government
 • Body Latur Municipal Corporation
 • Mayor Akhtar Shaikh
Area[1]
 • Total 117.78 km2(45.48 sq mi)
Area rank 89
Elevation 515 m (1,690 ft)
Population (2011)
 • Total 382,754
 • Rank 89th
 • Density 3,200/km2(8,400/sq mi)
Demonym Laturkar
Languages
 • Official Marathi
Time zone IST (UTC+5:30)
PIN
  • 413 512
  • 413 531
Telephone code 91-2382
Vehicle registration MH-24
Sex ratio 923.54 /1000 
Literacy 89.67
Distance from Mumbai 497 kilometres (309 mi) E (land)
Distance fromHyderabad 337 kilometres (209 mi) NW (land)
Distance fromAurangabad, Maharashtra 294 kilometres (183 mi) SE (land)
Climate BSh (Köppen)
Precipitation 666 millimetres (26.2 in)
Avg. summer temperature 41 °C (106 °F)
Avg. winter temperature 13 °C (55 °F)
http://www.citypopulation.de/world/Agglomerations.html

Map of latur city

his Is The Famous ‘Ganj-Golai’ As The Central Place Of The Latur City. There Are 16 Roads Connecting To This Place And Seperate Markets i.e. Jewellers …

लातूर जिल्हयातील चित्र संग्रह


LATUR AIRPORT

LATUR AIRPORT

2012 Navratri Mahotsav in Latur

SOS Children’s Village Latur

Latur, India: Carnival Resort

Ausa Near Latur

Chakur near Latur


Vilasrao Deshmukh’s ancestral home at Babhalgaon village in Latur. Machindra Amle

UDGIR: Udgir is one of the most important towns of Latur district. Udgir has a great historical significance. It has witnessed the war between the Marathas …

The city of Latur is located in India’s welathiest state, Maharashtra. Together with many of the surrounding villages, Latur was all but destroyed in the

US Orphan status for Bexion’s brain tumour drug BXQ-350


SDVYCEVCEFLVKEVTKLIDNNKTEKEILDAFDKMCSKLPKSLSEECQEVVDTYGSSILSILLEEV SPELVCSMLHLCSG [SEQ ID NO: 2].

BXQ-350

Cincinnati Children’s Hospital  ……..innovator

Bexion Pharmaceuticals……….under license

In February 2015, the US FDA granted saposin C Orphan designation for the treatment of glioblastoma multiforme

File:Saposin C 2qyp.png

SAPOCIN C

 

Recombinant human Saposin C (SapC) bound to a liposomal formulation of the dioleoylphosphatidylserine

Bexion’s Saposin C – the active ingredient in the brain tumour therapy BXQ-350 – has been awarded Orphan Drug status by US regulators.

Read more at: http://www.pharmatimes.com/Article/15-02-17/US_Orphan_status_for_Bexion_s_brain_tumour_drug.aspx#ixzz3S3zXdHlO

Bexion Pharmaceuticals, under license from the Cincinnati Children’s Hospital, is investigating a human saposin C (SapC)/liposomal dioleoylphosphatidylserine (DOPS) conjugate, SapC-DOPS (BXQ-350), a nanovesicle-formulated pro-apoptotic sphingomyelinase activating molecular imaging agent and anticancer agent, for the potential diagnosis and treatment of cancer , . In October 2013, Bexion was planning a phase I first-in-human trial for the therapy of glioblastoma multiforme

 

Bexion Pharmaceuticals LLC announced today that the U.S. Food and Drug Administration (FDA) has granted the company Orphan Drug designation for Saposin C, active ingredient in its proprietary drug BXQ-350 for the potential treatment of glioblastoma multiforme.

The FDA’s Office of Orphan Drug Products Development reviews applications for Orphan Drug status to support development of medicines for underserved patient populations, or rare disorders that affect fewer than 200,000 people in the United States. The successful application submitted by Bexion and the FDA granting of Orphan Drug status entitles the company to a seven-year period of marketing exclusivity in the United States for BXQ-350, if it is approved by the FDA for the treatment of glioblastoma multiforme. Orphan Drug status also enables the company to apply for research grant funding for Phase I and II Clinical Trials, tax credits for certain research expenses, and a waiver from the FDA’s application user fee, as well as additional support from FDA and a potentially faster regulatory process.

Bexion was previously awarded a prestigious Phase II Bridge Award (Small Business Innovation Research Grant; SBIR) from the National Cancer Institute (NCI) to support the manufacture and clinical testing of BXQ-350.

“Orphan Drug status for BXQ-350 is an important milestone in the development of this new treatment modality,” stated Dr. Ray Takigiku, founder and CEO of Bexion. “Few treatment options are available for patients suffering from glioblastoma multiforme and this designation recognizes the unmet need that exists with this disease, as well as the unique attributes of BXQ-350. In addition, orphan designation allows Bexion to benefit from important financial, regulatory and commercial considerations and we have seen recently that products with orphan designation have become sought after assets.”

 

About Orphan Drug Designation
Orphan Drug designation is a status assigned to a medicine intended for use in rare diseases. In the U.S., the Orphan Drug Designation program confers Orphan Drug status to successful applicants for medicines intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the U.S. or that are not expected to recover the costs of developing and marketing a treatment.1

The approval of an orphan designation request does not alter the standard regulatory requirements and process for obtaining marketing approval for investigational use. Sponsors must establish safety and efficacy of a compound in the treatment of a disease through adequate and well-controlled studies. However, the FDA review process may be speedier for Orphan Drugs than those which do not receive Orphan Drug designation.

About BXQ-350
In pre-clinical studies, Bexion’s first-in-class biologic, BXQ-350 has shown promising results in selectively inducing cell death in the laboratory. BXQ-350 is a proprietary nanovesicle formulation of Saposin C (sphingolipid activator protein C, or SapC) and the phospholipid dioleoylphosphatidylserine (DOPS).

About Bexion Pharmaceuticals
Bexion Pharmaceuticals is a privately held biotech company focused on the development and commercialization of innovative cures for cancer.  Initial products are based on a proprietary platform technology licensed from Cincinnati Children’s Hospital Medical Center.  The technology has demonstrated potential for development as a therapeutic, diagnostic and surgical imaging reagent, and as a carrier for other pharmaceutical agents, such as oligonucleotides.  For more information, visit www.bexionpharma.com or contact Margaret van Gilse atmvangilse@bexionpharma.com.

U.S. Food and Drug Administration web site. “Regulatory Information: Orphan Drug Act.”http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/significantamendmentstothefdcact/orphandrugact/default.htm.

Margaret van Gilse859-757-1652mvangilse@bexionpharma.com

SOURCE Bexion Pharmaceuticals LLC

 

Glioblastoma is the most common primary CNS malignant neoplasm in adults, and accounts for nearly 75% of the cases. Although there has been steady progress in their treatment due to improvements in neuro-imaging, microsurgery, and radiation, glioblastomas remain incurable. The average life expectancy is less than one year from diagnosis, and the five-year survival rate following aggressive therapy, including gross tumor resection, is less than 10%. Glioblastomas cause death due to rapid, aggressive, and infiltrative growth in the brain. The infiltrative growth pattern is responsible for the un-resectable nature of these tumors. Glioblastomas are also relatively resistant to radiation and chemotherapy, and therefore post-treatment recurrence rates are high. In addition, the immune response to the neoplastic cells is mainly ineffective in completely eradicating residual neoplastic cells following resection and radiation therapy.

One problem in treating glioblastoma is the tumor’s protection behind the blood-brain tumor barrier (BBTB). A significant obstacle in the development of therapeutics for glioblastoma is the inability of systemic therapies to efficiently cross the BBTB. Saposin C (SapC) is a sphingolipid- activating protein that functions to catabolize glycosphingolipids. SapC-DOPS forms stable nanovesicles which can efficiently cross the blood-brain tumor barrier and fuse with GBM cells inducing cell death.

Rapamycin is a macrolide antibiotic produced by Streptomyces hygroscopicus, which was discovered first for its properties as an antifungal agent. Streptomyces hygroscopicus has also been implicated as a cancer agent.

There remains a need in the art for new therapeutics for the treatment of glioblastoma.

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https://www.google.com/patents/US20040229799?cl=en22

Example 1Purification of Recombinant Saposin C

[0106] Recombinant saposin C was overexpressed in E. coli cells by using the isopropyl-1-thio-β-D-galactopyranoside inducing pET system (Qi et al. (1994) J. Biol. Chem. 269:16746-16753, herein incorporated by reference in its entirety). Expressed polypeptides with a His-tag were eluted from nickel columns. After dialysis, the polypeptides were further purified by HPLC chromatography as follows. A C4 reverse phase column was equilibrated with 0.1% trifluoroacetic acid (TFA) for 10 minutes. The proteins were eluted in a linear (0-100%) gradient of 0.1% TFA in acetonitrile over 60 minutes. The major protein peak was collected and lyophilized. Protein concentration was determined as previously described (Qi et al. (1994) J. Biol. Chem. 269:16746-16753).

Example 2Bath Sonication of Sanosin C and Dioleoylphosphatidylserine

[0107] Dioleoylphosphatidylserine (DOPS) was obtained from Avanti Polar Lipids (Alabaster AL). Twenty to thirty imoles of DOPS in chloroform were dried under N2 and vacuum to lipid films. Five to ten μmoles saposin C polypeptide was added to the dried films and suspended in 50 μl McIlvanine buffer (pH 4.7). The suspension was then brought to a 1 ml volume with either cell culture medium or phosphate buffered saline (PBS) (Ausubel et al. (2002) Current Protocols in Molecular Biology. John Wiley & Sons, New York, New York, herein incorporated by reference). The mixture was sonicated in a bath sonicator for approximately 20 minutes. Ice was added as needed to prevent overheating the samples.

 

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http://www.google.com/patents/WO2014078522A1?cl=en

The SapC-DOPS composition comprises a phospholipid, an isolated saposin C-related polypeptide, wherein the polypeptide comprises an amino acid sequence at least 75% identical to the entire length of SEQ ID NO: 2, and a pharmaceutically acceptable carrier, wherein the phospholipid forms a nano vesicle incorporating the polypeptide. In certain embodiments, the polypeptide comprises an amino acid sequence at least 85% identical to the entire length of SEQ ID NO: 2. In certain embodiments, the polypeptide comprises an amino acid sequence at least 95% identical to the entire length of SEQ ID NO: 2. In certain embodiments, the polypeptide comprises an amino acid sequence at least 99% identical to the entire length of SEQ ID NO: 2.

The Sequence Listing, filed electronically and identified as SEQ_LIST_OSIF-2013- 102.txt, was created on November 12, 2013, is 5,548 in size, and is hereby incorporated by reference.

[0004] SEQ ID NO: 1

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SEQ ID NO: 2

 

BEXION PHARMA

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